Adrenal Cancer is a rare cancer that begins in one or both of the small, triangular glands (adrenal glands) located on top of your kidneys. Adrenal glands produce hormones that give instructions to virtually every organ and tissue in your body. Adrenal cancer, also called adrenocortical cancer, can occur at any age.
Adrenal Adenomas are benign neoplasms of the adrenal cortex. Adrenal adenomas are the most common cause of incidentally found adrenal tumors known as “adrenal incidentalomas.” Adrenal adenomas can be either hormonally active or inactive. These tumors are usually detected incidentally on imaging done for unrelated reasons and only in some cases do patients present with symptoms and/or features of hormonal abnormalities, most commonly overproduction of an adrenal hormone.
Types of Adrenal Cancer
The Fourth Edition of the World Health Organization (WHO) classification of endocrine tumors published in 2017 has classified adrenal cancer in two groups. The first includes tumors of the adrenal cortex, and the second group includes tumors of the adrenal medulla and extra-adrenal paraganglia.[rx] The key feature of the WHO classification is the role of genetics that may be involved in adrenal cortical carcinoma and pheochromocytoma/ paraganglioma as well as the inclusion of a few rare malignancies of the adrenal cortex and medulla.
The following are tumors of the adrenal cortex:
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Cortical carcinoma
- Cortical adenoma
- Sex cord-stromal tumors
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Granulosa cell tumor
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Leydig cell tumor
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- Adenomatoid tumor
- Mesenchymal and stromal tumors
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Myelolipoma
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Schwannoma
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Hematological tumors
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Secondary tumors
Adrenocortical adenoma (ACA), Adrenal myelolipoma (mesenchymal and stromal tumors) and adrenal adenomatoid tumor are benign neoplasms of the adrenal cortex. The sex cord-stromal tumor of the adrenal gland is rare, and there are only six reports in the literature.[rx] Primary hematological tumors are mostly lymphomas and rarely plasmacytoma. Secondary tumors of the adrenal cortex are usually metastatic lesions due to direct infiltration by adjacent cancer or more commonly via hematogenous spread from a distant site. Adrenal metastases are common in patients with advanced cancer.[rx]
Causes of Adrenal Cancer
There are specific genetic mutations associated with hormonally active and inactive adrenal adenomas. However, the exact pathogenesis is not entirely clear.
- Mutations of CTNNB1 genes that provide instructions for making beta-catenin (Wnt/beta-catenin pathway) is associated with the larger and non-secreting adrenocortical adenomas.[rx]
- The mutations associated with cortisol-producing adrenal nodules include PRKACA (cortisol producing adenoma)[rx] GNAS1 (McCune Albright syndrome),[rx] MENIN (multiple endocrine neoplasm type 1) and ARMC5 (hereditary bilateral adrenal adenoma).[rx]
- The mutations associated with aldosterone-producing adrenal adenomas include KCNJ5 [rx], ATP1A1,[rx], ATP2B3,[rx] CACNA1D and CTNNB1.
A multistep tumor progression of tumorigenesis has been proposed from genes that are known to be associated with hereditary tumor syndromes described below.
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Li-Fraumeni syndrome is a familial cancer syndrome arising from a germline mutation of the TP53 gene located at 17p13. Patients are susceptible to breast cancer, sarcomas, brain tumors, leukemia, and adrenocortical carcinoma.[rx] Variants of this disease may appear in children with sporadic ACC and germline p53 mutations without a typical history of Li-Fraumeni síndrome. In particular, pR337H, which involves a substitution of the amino acid arginine (R) to histidine (H), is a common mutation detected in Southern Brazil. The incidence of pediatric ACC is very high in Southern Brazil (10–15 times the world-wide occurrence) because of the segregation of the TP53 hotspot mutation p.R337H. The Arginine residue at codon 337 is a critical part of an alpha-helix motif involved in the protein oligomerization. Functional data have shown that the replacement of arginine by histidine disrupts the tetramer formed in a pH-dependent manner, making it functionally impaired at physiologic pH.[rx] Beyond these mutations, the TP53 polymorphisms in adult patients seem to influence overall survival.[rx]The protein p53 has a fundamental role in the cellular response to stress, oncogene activation, and DNA damage by regulating the cell cycle and apoptosis. At the somatic DNA level, mutation of TP53 is a frequent event occurring in between 16 to 70% of ACC if the whole gene is sequenced. TP53 is considered a tumor suppressor gene, and both alleles become inactivated in tumor tissue. Loss of heterozygosity (LOH) at 17p13 presents in 85% of ACC. However, other mechanisms that may lead to TP53 inactivation because LOH and mutation do not appear in all cases. The presence of abnormal nuclear staining of TP53 correlates well with TP53 mutations and could serve as a diagnostic tool. Somatic mutations of TP53 are associated with aggressive tumors and poor outcomes.[rx] Other factors that may play a role in tumorigenesis include overexpression of pituitary tumor transforming gene 1 (PTTG1), which encodes securin, a negative regulator of p53; which researchers have identified as a marker of poor survival. Loss of retinoblastoma (Rb) protein has been found in 27% of aggressive adrenocortical carcinoma. This defect is related in most cases to mutations of the RB1 gene or its allelic loss.[rx] Another study revealed the presence of RB1 mutations in 7% of tumors. Another 11% of the tumors of this cohort harbored mutations of cyclin-dependent kinase inhibitor 2A (CDKN2A), and 2% exhibited high-level amplification of cyclin-dependent kinase inhibitor 4 (CDK4). Thus, overall, 33% of the tumors had alterations of the
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Tp53 pathway.[rx] – Patients with familial adenomatous polyposis (FAP) or Gardner syndrome, which is a mutation of the adenomatous polyposis coli gene (APC) located in 5q21 chromosomal, present with multiple colonic polyps and an increased risk of early colon carcinomas. Furthermore, FAP is associated with pigmented retinal lesions, desmoids tumors, osteomas, thyroid adenoma/carcinomas, and other different malignant tumors. Adrenocortical tumors, especially nonfunctional nodular hyperplasia, cortisol-producing adenomas (CPA), and ACC occur in 7 to 13% of patients with FAP. FAP results from a germline inactivating mutation of APC, a tumor suppressor gene that inhibits Wnt/beta-catenin signaling. According to Knudson’s model, ACC in patients with FAP exhibits somatic APC mutations as a second hit. The activation of the Wnt/b-catenin signaling pathway occurs in a third of ACC cases, and less commonly observed in adrenocortical adenoma. Activation of b-catenin is mainly related to the mutation of the Catenin beta-1 gene (CTNNB1). Consistently, transcriptome studies have shown an overexpression of Wnt/b-catenin target genes in ACC.[rx] Mutations of CTNNB1 or a histologic pattern of its activation are associated with poor outcomes.[rx][rx] Somatic mutations in APC has a prevalence of 2 to 3%, suggesting the importance of somatic alterations of other mechanisms in the Wnt/beta-catenin pathway in causing ACC. Indeed, activating somatic mutations of beta-catenin itself have been reported with a prevalence of about 16% in large cohorts of ACC.[rx] Interestingly, p53 and beta-catenin mutations are frequent in ACC with poor prognosis but are almost mutually exclusive. Constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cell hyperplasia, which lead to macroscopic adenomas development.[rx] Malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion appeared only later in this context, suggesting the necessity of other associated genetic alterations. More recently, researchers identified a new actor with the Wnt/beta-catenin pathway involved in adrenal tumorigenesis. Zinc and ring finger 3 (ZNRF3), a cell-surface transmembrane E3 ubiquitin ligase that is a negative regulator of the Wnt/b-catenin pathway. ZNRF3 leads the Wingless-related integration site-low density lipoprotein receptor-related protein 6 (Wnt-LRP6) receptor complex to degradation. ZNRF3 is regulated by the R-Spondin protein that regulates the association of ZNRF3 with the related leucine-rich repeat-containing G protein-coupled receptors LGR4. This association results in membrane clearance of ZNFR3 and activation of the Wnt/b-catenin pathway. Recently, ZNRF3 was found to be the most frequently altered gene in 2 large cohorts of ACC, with a prevalence of respectively 21% and 19%.[rx][rx] The transcriptome of tumors with alterations of ZNFR3 shows activation of b-catenin targets but milder than the level observed in CTNNB1-mutated ACC. ZNFR3 also constitutes a new tumor suppressor gene. By the sum of the CTNNB1- and ZNRF3-altered ACC, activation of the Wnt/b-catenin pathway could be present in 39% of ACC.[rx]
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Beckwith-Wiedemann syndrome (BWS) characteristically demonstrates genetic and epigenetic events at the 11p15.5 region involving the cyclin-dependent kinase inhibitor 1C (CDKN1C), insulin-growth-factor II (IGF-II), and H19 genes, which results in overgrowth disorders, visceromegaly (macroglossia, hemihyperplasia), malformations (wall defect, umbilical hernia), and predisposition to embryonal malignancies. ACC belongs to the BWS tumor spectrum, which also includes Wilms tumor, hepatoblastoma, rhabdomyosarcoma and neuroblastoma with an overall risk for tumor development in children estimated at 7.5%; most of the tumors occur in the first 8 to 10 years of life.[rx] Overexpression of IGF-II has been reported in approximately 60% to 90% of adrenocortical carcinoma cases, and only rarely in ACA.[rx] H19 is a gene for a long noncoding RNA. H19 is a negative regulator (or limiting) factor for body weight and cell proliferation. The long noncoding RNA of H19, which has been associated with several cancers and is physiologically only expressed by the maternal allele, while IGF-II only gets expressed by the paternal allele. The Center IC1 regulates the expression of both genes by imprinting and is methylated on the paternal allele and unmethylated on the maternal one. CDKN1C, a growth suppression gene that is under the control of another imprinting center IC2. BWS is etiologically heterogeneous, developing from dysregulation of either one or both imprinting centers and/or imprinted growth regulatory genes found on chromosome 11p15.5. Most BWS cases are sporadic and are the result of the loss of maternal methylation at IC2, resulting in a gain of maternal methylation at IC1 or paternal uniparental disomy. Mutations in CDKN1C cause the hereditary forms of BW.[rx] Regardless of the causative molecular defect, these alterations result in IGF-II overexpression and a decrease in H19 and/or CDKN1C expression. The gain of maternal methylation at IC1 or paternal uniparental disomy is associated with a higher risk of tumor development than the other forms suggesting a role of IGF-II overexpression or H19 downregulation in the tumorigenic process.[rx] At the somatic level, IGF-II overexpression is one of the first molecular abnormalities as described in sporadic adult ACC, with a very prevalence of about 90%. This increase in expression is associated with DNA demethylation at IGF-II locus and paternal isodisomy in most cases. Further transcriptome studies confirm that IGF-II is the most upregulated gene in ACC.[rx]
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Multiple endocrine neoplasia type 1 has an abnormal genetic locus at 11q13, where a defective MEN1 gene encodes a defective tumor suppressor protein, which is the Menin protein. The abnormal function of this protein predisposes the patient to parathyroid, pituitary, endocrine pancreatic, and adrenocortical tumors, including adrenocortical carcinoma.[rx]
These candidate genes as a cause of cancer have as their basis the hypothesis that a germline alteration of the genes causing a hereditary familial tumor syndrome also occurs as a somatic event leading to a sporadic tumor. This approach was indeed very successful in identifying TP53 mutation or insulin-like growth factor 2 (IGF2) overexpression in ACC, and APC and the Wnt/b-catenin pathway. Genomewide approaches, including transcriptome, single nucleotide polymorphism (SNP) array, methylation, and microRNAs (miRNAs) analysis, have identified new genetic and epigenetic alterations.
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DNA methylation is the most characterized epigenetic mechanism of regulation of transcription. This methylation occurs in the cytosine of CpG dinucleotides in specific regions with many CpG called CpG islands. Beyond the abnormalities described at the IGF2 locus, a global alteration of methylation patterns has been described in ACC at the genome-wide level.[rx][rx][rx] In these studies, adrenocortical carcinoma presented with hypomethylation of intergenic regions and global hypermethylation of promoter regions. The profile of methylation of ACT could discriminate adrenocortical carcinoma from adrenocortical adenoma. Additionally, the levels of methylation of CpG islands distinguished two groups of ACC: one, named non-CIMP (CpG island methylator phenotype), which is slightly hypermethylated compared with ACA and another hypermethylated named CIMP. Within the CIMP group, two further subgroups were delineated: CIMP-low and CIMP-high, referring to the levels of hypermethylation. The prognosis was worse for the CIMP carcinomas than the non-CIMP and worse for the CIMP-high than the CIMP-low.[rx] Therefore, the levels of expression are inversely correlated to the level of methylation as expected. A recent study showed that tumor methylation status was a significant prognostic factor of disease-free survival (DFS) and overall survival (OS).[rx] Researchers have also identified a reliable methylation marker, taking into account the mean methylation of 4 genes (Paired Box 5 -PAX5-, Glutathione S-Transferase Pi 1 -GSTP1-, N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD) -PYCARD- and Paired Box -PAX6-). More interestingly, they showedthat this biomarker remained a significant prognostic factor for DFS and OS in multivariate analysis including the European Network of Study of Adrenal Tumors (ENSAT) databank and a marker of proliferation Ki67. This biomarker seems particularly attractive since most of the previous reported molecular markers were only investigated in univariate analysis of survival.[rx]
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MicroRNAs (miRNAs) are small RNAs (approximately 22 nucleotides) regulating gene expression at the posttranscriptional level by targeting mRNAs for cleavage or translation repression. They play an essential role in the pathogenesis of several neoplasms; they are responsible for both oncogene activation and tumor suppressor genes silencing. Their profile of expression can serve as diagnostic and/or prognosis markers and the fact that one can measure them in blood samples.[rx] In ACC deregulation of several miRNAs are known to occur. The expression of miRNAs seems to differ significantly between adrenocortical adenomas and adrenocortical carcinomas. Several miRNAs received particular focus, the most frequently reported being the downregulation of miR-335 and miR-195 and upregulation of miR-483-5p.[rx] The level of circulating miR-483-5p allows for the distinction between ACC and benign tumors.[][rxrx] In childhood adrenocortical tumors, a set of miRNAs harbors a differential expression in comparison with normal adrenal tissue. These miRNAs are mainly downregulated (miR-99a, miR-100); however, the upregulation of miR-483 occurs in both childhood ACC and adult ACC. The profile of miRNA expression shows three clusters in ACC associated with different prognosis.[rx]. In particular, miR-483-3p correlates inversely with the expression of the pro-apoptotic protein PUMA (p53 upregulated modulator of apoptosis) suggesting a role for this miR in apoptosis regulation.[rx]The gene encoding miR-483- 5p is in the IGF2 locus, and the level of IGF2 expression directly correlates with this miRNA.[rx] The miR-99a and miR-100 participate in the regulation of mammalian target of rapamycin (mTOR) signaling, a pathway involved in cellular proliferation in adrenocortical carcinoma.[rx]
Symptoms of Adrenal Cancer
The majority (~95%) of adrenal adenomas are non-functioning, in which case they are asymptomatic. If found incidentally, please refer to the Management of incidental adrenal masses: American College of Radiology white paper.
Patients with hyperfunctioning adrenal gland adenomas present with manifestations of excess hormone secretion. The most common disease states caused by functioning adenomas are Cushing syndrome (due to excess cortisol production), Conn syndrome (due to excess aldosterone production), or sex hormone-related symptoms 4.
Some of the common symptoms associated with adrenocortical adenomas include:
Musculoskeletal
- Osteopenia
- Muscle weakness/muscle atrophy
Cardiovascular
- Hypertension
Endocrine and Metabolic
- Obesity
→More prevalent in males
- virilization
→More prevalent in females
- Hyperandrogenism
- Irregular menstrual cycles
Neuropsychological
- Sleep disorders
- Depression
Skin
- Easy bruising
- Stretch marks
- Hirsutism
- Acne
Others Symptoms
- Weight gain, usually greatest above the collar bone, in the cheek area (moon face), and around the abdomen
- Fat deposits behind the neck and shoulders (fatty hump or buffalo hump)
- Purple stretch marks on the abdomen
- Excessive hair growth on the face, chest, and back in women
- Menstrual irregularities
- Weakness and loss of muscle mass in the legs
- Easy bruising
- Depression and/or moodiness
- Weakened bones (osteoporosis), which can lead to fractures
- High blood sugar levels, often leading to diabetes
- High blood pressure
Diagnosis of Adrenal Cancer
History and Physical
- Non-secreting adrenal adenomas, or the ones that secrete low levels of hormones, are usually asymptomatic and discovered incidentally on abdominal imaging. The glucocorticoid producing adrenal tumors can present with the symptoms and signs of Cushing syndrome including obesity, hypertension, hyperglycemia, fatigue, depression, menstrual irregularities, proximal muscle weakness, acne, facial plethora, striae, fractures, and osteopenia.
- Aldosterone-secreting tumors may present with hypertension that is quite frequently resistant hypertension with uncontrolled blood pressure despite the use of three or more antihypertensive medications of different classes. Other symptoms can include muscle weakness, hypokalemia, hypomagnesemia, or hypernatremia.
Clinical Examination
- One of the first steps in the evaluation of the adrenal mass like any other case begins with a diligent history and physical examination with a focus on symptoms and signs that will be due to hyperfunctioning or malignant nature of the mass. These signs and symptoms are quite well described in the literature [rx].
Biochemical Evaluation
Cushing’s Syndrome
- Overnight low-dose dexamethasone suppression test (LDDST) is used as a screening test with a sensitivity of 73–100 and 90 %, respectively [rx]. Values >5 μg/dl (138 nmol/l) are diagnostic. False positives occur with medications that accelerate the hepatic metabolism of dexamethasone like anticonvulsants and with noncompliance to the drug regimen. To decrease this false positivity, a high-dose DST can be used in which a higher dose (2, 3, or 8 mg) is used. The confirmatory test can be done using serum corticotropin, cortisol in blood and 24-h urine specimen, and midnight salivary measurement of cortisol [rx].
Phaeochromocytoma (PHEO)
- Fractionated metanephrine and catecholamine in the 24-h urinary specimen are recommended with high sensitivity and specificity (91–96 %). Fractionated plasma-free metanephrine is useful with high sensitivity (96–100 %), albeit with reduced specificity (85–89 %) and in the elderly further reducing to 77 % [rx–rx]. This can be used for confirmatory testing. False positives are seen in patients in whom there can be an increased production of endogenous catecholamines like prolonged illness and medications like a tricyclic antidepressants.
Primary Aldosteronism
- Measurement of serum potassium is not a reasonable screening test for patient with primary aldosteronism in lieu of a normal level. Morning ambulatory plasma aldosterone concentration to plasma renin activity (PRA) is an appropriate investigation. A plasma aldosterone concentration and plasma renin activity ratio of ≥20 and a plasma aldosterone concentration of ≥15 ng/dl are considered positive results. Patients on potassium-sparing diuretics need to discontinue the drug at least 4 weeks prior to testing [rx, rx, rx].
- Confirmatory tests include aldosterone suppression testing with either a saline infusion test or 24-h urinary aldosterone excretion test while the patient maintains a high-sodium diet [13]. Adrenal venous sampling should be considered in patients with bilateral adrenal hyperplasia to confirm that the mass is the cause for hyper-aldosteronism.
Other Biochemical Evaluation
- Sex hormone evaluation is to be done in patients with clinical manifestations of virilization and hirsutism. Cosyntropin stimulation testing with the measurement of cortisol precursors (e.g., 17-hydroxyprogesterone) is reserved for patients in whom the diagnosis is suspected on the basis of clinical manifestations (e.g., hyperandrogenism) or the presence of bilateral adrenal masses [rx].
Imaging
- Various imaging modalities are being used for adrenal pathologies. Of these, CECT of the abdomen and pelvis is the most commonly performed followed by magnetic resonance imaging (MRI), and positron emission tomography CT (PET-CT) is usually reserved for patients with possible extra-adrenal malignancy. Metaiodobenzyl-guanidine (MIBG) and less commonly octreotide scintigraphy may be used to identify pheochromocytomas selectively in patient with a high probability of disease like family history, associated hereditary disorder, and extra-adrenal tumors.
CECT
- The adrenal CT imaging protocol consists of a multiphase study including an unenhanced scan followed by a 1-min delayed enhanced scan and a 15-min delayed de enhanced scan. The three phases together are used for calculating absolute percentage washout (APW) and/or relative percentage washout (RPW) in order to differentiate lipid-poor adenomas from primary carcinoma and metastases.
The APW is calculated using the formula:
An APW value of greater than 60 % is diagnostic of an adenoma. In the absence of an unenhanced phase, a RPW is calculated as follows:
- A RPW value greater than 40 % is diagnostic of an adenoma [rx]. Adenomas are one of the most common adrenal lesions characterized by intracellular lipid which help in differentiating them from malignant masses. Lipid-rich adenomas usually have a Hounsfield unit (HU) less than 10 with 71 % sensitivity and 98 % specificity [rx, rx]. Washout analyses have been found to be accurate in many studies [rx–rx].
- Pheochromocytomas have a variable appearance on CECT with small lesions being homogenous while the larger ones being heterogeneous with areas of necrosis and hemorrhage [rx].
- Adrenocortical carcinomas (ACC) are usually large (>6 cm) heterogeneously enhancing with areas of central necrosis and hemorrhage and calcifications in 30 % [rx]. They may also be invading locally with venous extension being common [rx]. Adrenocortical carcinoma generally has APW and RPW values of less than 60 and 40 %, respectively, compatible with nonadenomas [rx]. Metastases to adrenal are nonspecific with heterogeneous densities, necrosis, and irregular margins in the larger masses, while in smaller masses, they are more homogenous with smooth margin [rx]. Quite often, they are bilateral in location.
MRI
- An adenoma spears dark on out of phase images while using spleen as reference. They can be differentiated from metastasis with a sensitivity of 81–100 % and specificity of 94–100 % [rx, rx]. Of adrenal adenomas, 20–30 % are lipid-poor; thus, they cannot be diagnosed with CT or MRI.
- PHEOs on MRI classically appear as markedly hyperintense on T2 weighted (T2W) images, although some of the recent series have found them to be moderately hyperintense or even hypointense [rx, rx]. On MRI, ACC appear heterogeneously iso to slightly hypointense on T1W but hyperintense with hemorrhage. On T2W, they are heterogeneously hyperintense. The advantage of MRI over CT is for patients in whom iodinated contrast cannot be used due to allergy or renal impairment or young/pregnant patients in whom radiation is a concern.
PET-CT
- Malignant masses have increased metabolic activity and hence being avid to glucose form the basis of PET in radiotracer malignant masses. Comparison with the background liver activity and the qualitative visual assessment of uptake as well as quantitative assessment using standard uptake values (SUV) helps to establish the nature of lesion. Most of the malignant adrenal masses show increased activity while the benign ones do not, with the sensitivity for this being 93–100 % [rx–rx].
MIBG
- This nuclear medicine modality is used to localize pheochromocytoma with a sensitivity of 95–100 % and specificity of 100 % [rx]. It is of particular use in patients with in whom biochemical evaluation is positive but the imaging with CT/MRI is negative [rx]. It is also used in the detection of metastasis in patients with pheochromocytoma. In cases with biochemical evidence of pheochromocytoma but negative MIBG, octreotide scanning can be used as an alternative. Iodine-131 MIBG therapy may be used for the systemic treatment of select patients with metastatic pheochromocytoma [rx].
Percutaneous Biopsy
- Biopsy for adrenal lesions is done in an indeterminate adrenal mass with a known primary. An ultrasonography-guided biopsy is feasible but CT guided is more commonly done as it is safe with low complication rate and accurate [rx]. It is done with ipsilateral decubitus position as this compresses the lung and reduces the movements thereby decreasing the chances of pneumothorax. Acaudal to cephalad approach is used and on the right side transhepatic approach may be needed.
CT scan
- It is the imaging of choice for the evaluation of adrenal tumors. Adrenal tumor size greater than 4.0 cm has high sensitivity for adrenal cancer.[rx] Adrenal lesions that exhibit less than 10 HU (Hounsfield units) on non-contrast CT scan strongly suggest a benign adenoma.[rx] Some benign adenomas may have higher than 10 HU. Delayed contrast-enhanced CT scan may help to differentiate them from malignant lesions.[rx] MRI is an alternative to the CT scan for the evaluation of adrenal tumors, but it is more expensive than CT scan.
Fine-needle aspiration biopsy
- Adrenal tumors is rarely necessary for select patients with single adrenal lesion who have a history of non-adrenal malignancy without evidence of other metastasis. In these cases, a pheochromocytoma needs to be ruled out first before any invasive procedure takes place.[rx] All patients with adrenal adenoma should be investigated for Cushing syndrome, and pheochromocytoma and patients with hypertension should additionally get investigation for hyperaldosteronism.
Twenty-four-hour urinary
- It is fractionated metanephrines, or plasma fractionated metanephrines, are measured to assess for pheochromocytoma.
Plasma aldosterone level and plasma renin activity measurements
- That are indicated in patients with adrenal adenoma who have hypertension. In patients with plasma aldosterone concentration greater than 15ng/dL and aldosterone to plasma renin activity over 20, the diagnosis is confirmed by demonstrating a lack of aldosterone suppressibility with sodium loading. In patients over 40 years of age, a selective adrenal vein sampling is indicated for localization purposes before surgery.
- Sex-hormone producing adrenal tumors test – are rare and typically present with concomitant clinical symptoms (i.e., feminization or virilization) and therefore systematic screening may not be warranted. However, an incidentaloma suspicious for adrenocortical carcinoma may necessitate screening for sex hormone production (dehydroepiandrosterone [DHEAS], 17-hydroxyprogesterone [17- OHP] and testosterone).
- Confirmatory hormonal testing – is recommended for all positive screening tests to limit false-positive results and unnecessary surgeries.
Treatment of Adrenal Cancer
Adrenal tumors that are more than 4 cm in size, hormonally indeterminate, or suspected to be malignant receive treatment with adrenalectomy. Benign appearing on imaging, less than 4 cm in size adrenal adenomas which are hormonally active on biochemical testing (Cushing syndrome, hyperaldosteronism, and pheochromocytoma) are treated with adrenalectomy as well. There is no long-term prospective data available to choose between medical and surgical treatment for patients with subclinical Cushing syndrome.
Patients with hyperaldosteronism who are not good surgical candidates due to advanced age or comorbidities, or the patients who refuse surgery, are treated with aldosterone antagonists such as spironolactone or eplerenone.
Hormonally inactive adenomas are initially managed by reimaging in 3 to 6 months, then annually for 1 to 2 years, and they should also have repeat hormonal assessment once a year for 5 years. If the mass grows more than 1 cm or becomes hormonally active, then adrenalectomy is recommended.[rx]
Recruiting clinical trials for PPGL.
| Intervention | Study design | Setting | Recruitment target, n patients | NCT number |
|---|---|---|---|---|
| Randomized studies | ||||
| Sunitinib | Phase II, placebo controlled | Palliative | 74 | Nbib1371201 |
| Phenoxybenzamine vs doxazosin | Phase III | Curative and palliative | 60 | Nbib3176693 |
| Phenoxybenzamine vs doxazosin | Phase IV | Curative | 134 | Nbib1379898 |
| Non-randomized studies | ||||
| Cabozantinib | Phase II, single arm | Palliative | 22 | Nbib2302833 |
| SGI-110 (Guadecitabine) | Phase II, single arm | Palliative | 70 | Nbib3165721 |
| Lenvatinib | Phase II, single arm | Palliative | 25 | Nbib3008369 |
| Lu-177-DOTATATE | Phase II, single arm | Palliative | 90 | Nbib3206060 |
| Studies investigating multiple disease | ||||
| 131I-MIBG | Phase II, single arm | Palliative | 80 | Nbib107289 |
| 131I-MIBG | Phase II, single arm | Palliative | 100 | Nbib1850888 |
| Nivolumab and ipilimumab | Phase II, single arm | Palliative | 707 | Nbib2834013 |
| ONC-201 | Phase II, single arm | Palliative | 24 | Nbib3034200 |
| Pembrolizumab | Phase II, single arm | Palliative | 250 | Nbib2721732 |
| PEN-221 | Phase I/IIa, single arm | Palliative | 120 | Nbib2936323 |
NCT, ClinicalTrials.gov registry number; PPGL, pheochromocytoma and paraganglioma.
Recruiting clinical trials for adrenal cortical tumors.
| Intervention | Design | Setting | Recruitment target, n patients | NCT number |
|---|---|---|---|---|
| Randomized | ||||
| Mitotane | Phase III | Adjuvant | 200 | Nbib777244 |
| ATR-101 | Phase II, placebo controlled | Palliative (symptom reduction) | 16 | Nbib3053271 |
| Surgery + medical therapy vs medical therapy | Randomized study | Curative | 110 | Nbib2364089 |
| Non-randomized | ||||
| RF-ablation | Single-arm study | Curative | 25 | Nbib2756754 |
| Pembrolizumab | Phase II, single arm | Palliative | 39 | Nbib2673333 |
| Studies investigating multiple diseases | ||||
| ABBV-176 | Phase I, single arm, basket | Palliative | 100 | Nbib3145909 |
| Cabozantinib-S-malate | Phase II, single arm | Palliative | 110 | Nbib2867592 |
| Nivolumab and ipilimumab | Phase II, single arm | Palliative | 57 | Nbib3333616 |
| Nivolumab and ipilimumab | Phase II, single arm | Palliative | 707 | Nbib2834013 |
| Pembrolizumab | Phase II, single arm | Palliative | 250 | Nbib2721732 |
Radiation Oncology
In localized adrenocortical carcinoma, radiation therapy, in combination with surgery, has been used in only a few patients registered in the National Cancer Data Base.[rx] There are no prospective data with which to define the role of adjuvant radiation therapy in ACC since the use of mitotane has become more common. Although postoperative radiation therapy in some studies has been shown to reduce local recurrence rates, this is not a universal observation in other studies.[rx][rx][rx] Furthermore, there was no survival benefit has been shown with adjuvant radiation therapy. Based on these data, there is no recommendation for the routine use of adjuvant radiation therapy after initial surgical resection. However, some patients who display a local recurrence pattern without evidence of distant disease may benefit from adjuvant radiation therapy after surgery.
Medical Oncology
HORMONAL MANAGEMENT OF ADRENOCORTICAL CARCINOMA
The combination of cancer burden and hormonal excesses occur in almost 50% of adrenocortical carcinoma patients. Agents to treat Cushing syndrome such as ketoconazole, metyrapone, and mifepristone are often used, with the hope of reducing the morbidity of cortisol excess. Ketoconazole inhibits CYP17A1, CYP11A1, and to a lesser extent, CYP11B1.[rx] The starting dose is 200 mg twice daily and can increase to 1200 mg/day. During treatment, liver enzymes require monitoring. Because ketoconazole is an inhibitor of several hepatic metabolizing enzymes, there is a potential for serious drug interactions.
Metyrapone is an inhibitor of steroidogenesis at the level of CYP11B1,[rx] and generally is started at 250 mg twice daily and can be elevated to 2 to 3 g/d in 250-mg intervals. Due to the inhibition of CYP11B1, an increase in adrenal androgens may occur, causing or worsening hyperandrogenemia. Mifepristone is a direct glucocorticoid receptor antagonist that is highly effective in controlling clinical comorbidities, mainly glucose intolerance; thus, it is a useful treatment for Cushing syndrome when it is associated with diabetes mellitus.[rx] Treatment is initiated at 300 mg daily and titrated up to 1200 mg daily. Adrenal insufficiency is a rare adverse effect of mifepristone.[rx]
Spironolactone and eplerenone are mineral corticosteroid receptor antagonists that can be used to counteract edema and hypertension associated with cortisol or aldosterone overproduction. Spironolactone can be used to manage androgen effects in females patients with androgen-secreting tumors as well as mineralocorticoid effects in those patients with mineralocorticoid-secreting tumors. Dosing may need to be as high as 200 to 400 mg/day.[rx] In males with gynecomastia, aromatase inhibitors (e.g., anastrozole and letrozole), as well as estrogen receptor antagonists (e.g., tamoxifen and raloxifene), can be used. Because cortisol production is an adverse prognostic factor, every attempt should be made to normalize hormone levels because this not only affects survival parameters but also improve QOL.
The success of hormonal control is contingent on a synchronized approach to reducing hormonal production, counteracting the effects of hormonal overproduction, and reducing disease burden via surgery or systemic chemotherapy.[rx]
LOCALIZED DISEASE
Localized ACC encompasses stages I and II disease and most patients with stage III disease. Stage I is relatively uncommon, representing only 3% of all ACC cases, whereas stages II and III make up 37 and 34%, respectively.[77] Surgery is usually the mainstay therapy in these patients, but unfortunately, many experience disease recurrence. The outcomes after surgical resection alone have remained suboptimal.[rx][rx][rx][rx] Even with complete resections, rates of local recurrence have typically ranged from at least 19% to 34% in those patients with no residual disease after surgery.[rx] The evidence that patients with ACC remain at high risk for tumor recurrence despite complete surgical tumor excision has fueled the search for adjuvant therapies.
Mitotane has been shown to significantly improved recurrence-free survival (RFS) in some studies and not others.[rx] [rx][rx] An ongoing international prospective randomized clinical trial (ADIUVO:https://www.epiclin.it/adiuvo) is exploring the efficacy of adjuvant mitotane in ACC patients deemed to have low/intermediate risk of recurrence after radical surgical resection, which is defined by R0 resection, absence of metastases and Ki67 under 10%. This study will compare mitotane treatment with a “watch and see” strategy.
Adjuvant treatment generally starts within three months of post-surgery based on animal studies.[rx] Mitotane plasma monitoring is recommended for ACC management as it has a high volume of distribution and low clearance; the drug s lipophilic and tends to accumulate in adipose tissue. Adaptive dosing of the individual based on age, sex, body mass index, lean body mass, and renal function is recommended.[rx][rx] Side effects of mitotane include gastrointestinal and neurologic abnormalities. Cortisol supplementation is required to prevent the adverse gastrointestinal effect of mitotane. Contraception, vitamin K antagonist supplementation, and combined antitumor therapies are recommended during mitotane treatment.[rx]
ADVANCED DISEASE
More than half of ACC patients present with locally advanced or metastatic disease (Stage III or IV).[rx] The advanced stage carries a poor prognosis and only a limited response to any single treatment modality. Thus, the use of a multidisciplinary approach and different treatment methods when feasible, carry the best hope of improving the grim prognosis in these patients.
Systemic therapy for metastatic disease
In metastatic disease, different parameters merit consideration: the tumoral volume, the number of metastatic organs, and the progression rates. Debulking surgery only benefits in ACC patients with a limited number of tumoral organs (less than or equal to 2), resectable tumoral mass, with a light progression and when severe hormone excess that is not manageable medically. However, most patients require medical therapy.
Mitotane remains the only medication approved by the European Medicine Executive Agency (EMEA) and the U.S Food and Drug Administration (FDA) for the treatment of “metastatic ACC.” An overview of collecting different studies showed that the objective response rate is at best, 24%.[rx][rx][rx]
Neoadjuvant Approach
The use of neoadjuvant systemic chemotherapy as a bridge to surgery correlated with a favorable outcome in one small study with borderline resectable adrenocortical carcinoma (BRACC), defined as having oligometastases, needing multiorgan or vascular resection, or having a poor performance status preventing surgery. Twelve patients (80%) received combination therapy with mitotane and etoposide/cisplatin-based chemotherapy, two patients (13%) received mitotane alone, and one patient (7%) received chemotherapy alone. Median DFS for resected BRACC patients was 28.0 months [95% confidence interval (CI), 2.9–not attained] vs 13 months (95% CI, 5.8–46.9) (p = 0.40) for initial surgery patients. Five-year OS rates were also similar: 65 % for resected BRACC vs 50 % for initial surgery (p = 0.72).[rx]
Targeted Therapy Approach
Targeted therapy may also be an option for the management of adrenocortical carcinoma. The first trials targeted epidermal growth factor receptor (EGRF) gefitinib and a combination of erlotinib and gemcitabine. Among vascular endothelial growth factor, sunitinib exhibited a modest anti-tumor effect in the phase 2 trial. VEGF can be administered in patients without mitotane treatment.[rx][rx]
Recently, drugs targeting IGF-II seemed to be very promising, as IGF-II is the most-up regulated gene in ACC (80% as described before). Preclinical studies antagonizing this pathway with pharmacological agents resulted in inhibition of growth in vitro and in vivo. This inhibition was more potent than that observed with the use of mitotane alone in decreasing xenograft growth, and the combination of IGF inhibition with mitotane resulted in greater antiproliferative effects than those observed with the use of single-agent treatment. These data establish the role of targeted disruption of IGF-1R signaling to obtain a therapeutic advantage when used with mitotane therapy or possibly other chemotherapeutics in ACC patients.[rx] Recently, a phase 2 study used an IMCA12 (cixutumumab), a fully humanized IGF-IR antibody showed a lack of efficacy in a cohort of 19 patients.[rx] Also, results of a huge phase 3 trial “GALACTIC” with a highly specific IGF-IR inhibitor linstinib (OSI-906)in a cohort of 138 metastatic ACC have been recently published: the progression-free and overall survival did not differ between the linstinib and placebo groups.[rx] However, in another study, 26 heavily pretreated ACC patients received cixutumumab with temsirolimus, an inhibitor of mammalian targets of IGF-1R signaling (mTOR inhibitor)weekly with restaging at eight weeks. Of these 26 patients, 11 (42%) had stable disease for greater than six months.[rx] Finally, because of disease heterogeneity, it appears that using one single agent is not sufficient to induce an objective response. Trials with new targeted substances are underway.
Cytotoxic Chemotherapy
Although cisplatin-containing regimens have shown some responses most studies lack power and comparisons between different regimens. The most encouraging results originate from the combinations of etoposide, doxorubicin and cisplatin with mitotane (EDP-M) achieving an overall response of 49% of 18 months duration (FIRMA-CT study). This regimen was equally effective as first-line treatment or after failing of the combination of streptozotocin with mitotane and is currently the preferred scheme. In patients who progress under mitotane monotherapy, EDP treatment is also recommended. The combination of gemcitabine with capecitabine is used for patients failing EDP- and for not responding to patients targeted therapies with tyrosine kinase inhibitors (mainly sunitinib) could be used. Although initially promising treatment with IGF-1R antagonists did not prove to be efficacious suggesting that a combination of therapies may be the way forward.
Staging
The widely adopted staging of adrenocortical carcinoma is by the European Network of Study of Adrenal Tumors (ENSAT) due to its correlation with clinical outcome.[rx][rx] This system defines:
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Stage I with a tumor size of smaller than 5 cm.
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Stage II is a tumor with a size of over 5 cm; strictly localized both stages.
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Stage III is characterized by the positive regional lymph nodes, infiltration of the tumor in the surrounding tissue, or a tumor thrombus in the vena cava and/or renal vein.
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Stage IV is defined by distant metastasis.
Complications
The complications associated with adrenocortical carcinoma are due to excess hormone production. Hormone excess occurs in 40% to 60% of patients with ACC.[rx][rx][rx] Hypercortisolism is the most common complication (50% to 80% of hormone-secreting ACCs), causing classic symptoms including diabetes mellitus, fatigue, hypertension, central obesity, muscle weakness/atrophy, and osteoporosis.[rx]
Local or regional recurrences:
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Local or regional recurrences occur in 19% to 34% of patients with no residual (R0) disease after surgery.[rx]
Distant metastases:
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More than half of ACC patients present with locally advanced or metastatic disease.[rx]
Postoperative and Rehabilitation Care
The follow-up management is not well-standardized. However, since adrenocortical carcinomas are aggressive tumors, patients should be followed every three months after initial treatment. When the patient has a recurrence free-time of 2 to 3 years, the follow-up may increase to every six months for a total of five years. After five years of disease-free survival, the surveillance can be done every 1 to 2 years, because, although rare, some patients can have a late relapse. Patients should undergo a hormonal investigation, comprehensive imaging work-up, including chest and abdominal CT scan, and complete physical examination. An [18F]FDG-PET can be a consideration, even if it is not regarded as mandatory in the follow-up of ACC patients.[rx]
Deterrence and Patient Education
Adrenal cancer happens when healthy cells in the adrenal gland grow out of control. Some people have no symptoms, but in other cases, the lesion gets discovered while undergoing an imaging test for another reason.
When adrenal cancer causes symptoms, it does so via the production of hormones. Depending on the levels of the hormones involved, this can cause symptoms such as:
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Muscle weakness
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Weight gain
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Increased hair growth, usually on the face (in women) and deep voice
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Fatigue
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Trouble sleeping
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The purple coloration on the skin
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Hypertension
Adrenal tumors can also cause other symptoms that are not related to the level of hormones. These can include:
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Weight loss or loss of appetite
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Pain in the abdomen or lower back
All symptoms listed above can result from many other disorders, and hence a thorough workup is required. However, if a patient perceives these symptoms, they need to report it to their doctor or nurse.
Tests for adrenal cancer usually include:
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Blood analysis and urine tests to determine the levels of different hormones
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CT or MRI scan
The treatment chosen will depend on the stage of adrenal cancer. Most patients with the adrenal disease are treated with surgery to remove the tumor. After surgery, some patients may require additional treatments that can include:
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Chemotherapy
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Radiation therapy
After the initial treatment, the doctor must follow the patient regularly to determine if cancer has been cured or has come back. Follow-up tests include blood and imaging tests. Having symptoms could mean the adrenal tumor has returned. The patient should inform their doctor or nurse if they have any signs or symptoms. Long-term medicinal treatment to correct the hormone levels may be necessary.
References
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