Genetic Testing for Adrenal Tumors-What the Contemporary Surgeon Should Know
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Maria F. Bates, MDa,b,c, Meredith J. Sorensen, MD, MSa,b,c, *
KEYWORDS
. Adrenal . Genetic testing . Adrenalectomy . Familial syndromes
KEY POINTS
· Familial syndromes exist in many surgical adrenal diseases.
· Genetic testing is available and referral to genetic counselor should be considered for most adrenal diseases.
· Germline mutation testing can help guide perioperative management, postoperative risk assessment, postoperative follow-up, and screening of family members.
INTRODUCTION
In the last few decades, there have been many scientific advances in genetics, including the sequencing of the entire human genome in 2003.1 Shortly afterward, next-generation sequencing (NGS), a high-throughput DNA sequencing, became commercially available, allowing for rapid and cost-efficient methods used to sequence targeted gene panels.2 These advances have led to the identification of more germline mutations in various diseases. In the field of adrenal medicine, the sur- gical diseases include pheochromocytoma (PCC), paragangliomas (PGLs), primary hyperaldosteronism, Cushing syndrome, and adrenocortical carcinoma (ACC). Famil- ial syndromes are associated with all of these conditions, and multiple germline muta- tions have been identified. As medicine advances, more and more mutations are discovered each year. Historically, for example, only 10% of PCCs were thought to be familial; now it is thought that up to 40% of patients with this disease have a
a Geisel School of Medicine at Dartmouth, Hanover, NH, USA; b Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; ” Section of General Surgery, Division of Endocrine Surgery, One Medical Center Drive, Lebanon, NH 03756, USA
* Corresponding author.
E-mail address: Meredith.J.Sorensen@hitchcock.org
Twitter: @mfbates13 (M.F.B.); @MJSorensenMD (M.J.S.)
germline mutation.3,4 With these evolving discoveries, it is even more important for the adrenal surgeon to be familiar with the associated familial syndromes in surgical ad- renal diseases. Identification of patients with familial syndromes allows for the detec- tion and screening of associated syndromic neoplasms, guides surgical planning and operative approach, influences recurrence and malignancy risk assessment, aids in the development of postoperative surveillance plans, and determines the need for screening family members. Here, we review the major familial syndromes associated with adrenal surgical diseases and discuss currently available genetic testing and treatment recommendations.
PHEOCHROMOCYTOMA AND PARAGANGLIOMA Background
PCC and PGLs are both catecholamine-secreting tumors. PCCs are located within the adrenal medulla of the adrenal gland, whereas PGLs are in extra-adrenal locations, found anywhere along the sympathetic chain from the neck to the pelvis. These 2 tu- mors have similar behaviors clinically and therefore clinical treatments are similar. However, it is important to distinguish between the 2 because there are slight differ- ences in the risk of associated neoplasms, the risk for malignancy or metastatic spread, and the genetic basis.
Originally, PCCs and PGLs were considered to be 10% familial but now up to 40% of cases are associated with known mutations.3,4 In general, patients with familial dis- ease present at an earlier age and have a higher chance of bilateral disease or multi- focal disease. More than 20 genes have been found to play a role in tumor development, either as germline or as somatic mutations.5 Consequently, recommen- dations have recently changed in the last decade and current consensus is to refer all patients with these tumor types for genetic testing.4 It is important to determine if the condition is part of a familial syndrome because the genetic basis of the disease may guide surgical decision-making, risk of other syndrome-associated tumors, risk of recurrence, help establish a surveillance plan, and decide whether family members should be screened.
Familial Syndromes Associated with Pheochromocytoma and Paraganglioma
Multiple endocrine neoplasia type 2
Patients with multiple endocrine neoplasia type 2 (MEN2) carry an autosomal domi- nant mutation in the RET proto-oncogene. There are 2 primary subtypes, MEN2A and MEN2B, with MEN2A making up 95% of MEN2 syndromes. In MEN2A, 100% of patients present with medullary thyroid carcinoma (MTC), 50% develop PCC (which are bilateral 50% of the time but rarely malignant), and ~20% also develop parathyroid hyperplasia. In MEN2B, patients also present with MTC and PCC but with mucocutaneous neuromas rather than parathyroid disease. Most of the MEN2 patients diagnosed with catecholamine-secreting tumors have a PCC rather than a PGL.
Von hippel-lindau
Von hippel-lindau (VHL) is inherited via an autosomal dominant mutation in the VHL tumor suppressor gene. This syndrome is associated with CNS hemangioblastomas, pancreatic neuroendocrine tumors, and renal cell carcinomas in addition to PCCs/ PGLs. There are various types of VHL but only type II variants are associated with PCCs/PGLs. 20% of patients with VHL develop a PCC or PGL. They are generally noradrenergic tumors and can be in the abdomen, mediastinum, or pelvis. These tu- mors are rarely malignant, often develop in the younger population (with a mean age of
diagnosis of 30 years) and may be adrenal or extra-adrenal. Recurrence in patients with VHL is more common than those with sporadic PCCs.6
Neurofibromatosis type 1
Again, this syndrome has autosomal dominant inheritance and involves a mutation in the tumor suppressor gene neurofibromatosis type 1 (NF1). It classically presents with café-au-lait spots, mucocutaneous neurofibromas, inguinal or axillary freckling, Lisch nodules, optic nerve gliomas, and long bone dysplasia. In addition, 3% of people with NF1 will develop a unilateral PCC, up to 12% of which are malignant.7 Any patient with NF1 and hypertension should undergo screening for PCC.
SDHx syndromes
SDHx syndromes, also known as the paraganglioma syndromes, are caused by mu- tations in the succinate dehydrogenase (SDH) complex. Most familial PGLs are caused by SDH complex mutations. There are 5 associated types: SDHA, SDHB, SDHC, SDHD, and SDHAF2. Most of these mutations will cause PGLs; however, PCCs are seen in all 5 subtypes as well. Most importantly, SDHB mutation has a 30% to 70% risk of these patients developing malignant PGL/PCC.8
Carney triad
Carney Triad is a familial syndrome made of gastrointestinal stromal tumors, PGLs, and pulmonary chondromas. Less commonly, these patients can also develop adre- nocortical adenomas, PCCs, and esophageal leiomyomas. The Carney triad mostly affects younger women, and the onset is usually the second decade of life or later. It is thought that the syndrome is caused by downregulation of the SDH enzyme com- plex though site-specific hypermethylation of the SDHC gene.9
Genetic Testing
Traditionally, it was recommended that patients should undergo genetic testing if they had any of the following: diagnosis of PGL, bilateral PCC, unilateral PCC with family history of PCC/PGL, unilateral PCC with age less than 45 years, or other clinical find- ings of associated syndromic disorders. Recently recommendations have changed, and the new consensus is that everyone with a PCC or PGL should be tested for germ- line mutations. 10,11 Up to 40% of PCCs/PGLs have germline mutations, and up to 20% of those occur in patients without a family history, previously thought to be sporadic. 12 NGS is now the gold standard for genetic testing and sequence analysis because it is efficient and cost-effective. NGS makes it easy to test for 10 to 20 of the most common genes associated with familial PCCs/PGLs.5
Treatment
The standard of care for PCCs and PGLs is surgical resection when feasible. The pres- ence of a germline mutation or associated syndrome can affect surgical decision- making and surgical approach to PCCs and PGLs. For example, patients identified with an SDHB mutation often will undergo open resection due to the malignancy po- tential. 13 Cortical-sparing adrenalectomy is considered in patients with MEN2 or VHL because of the risk for bilateral disease.14 This approach helps avoid adrenal insuffi- ciency in most patients but also increases the risk of recurrence. Because of this, pa- tients and providers should weigh the risks and benefits of each surgical approach and assess the patient preferences.
Clinics Care Points
. At least 40% of PCCs and PGLs are familial.
· Familial syndromes with PCC and PGL include MEN2, VHL, NF1, SDHx syn- dromes, and Carney Triad.
· All patients with PCC and PGL should undergo genetic testing.
· Diagnosis of associated familial syndromes can affect surgical approach as well as surveillance recommendations.
PRIMARY HYPERALDOSTERONISM Background
Primary hyperaldosteronism, also known as Conn syndrome, 15 is a disorder that leads to excessive and autonomous aldosterone production. This leads to a clinical syn- drome of high blood pressure, often presenting at an early age, and usually requires multiple antihypertensive agents to treat. Approximately half the patients also present with hypokalemia. The most common causes for primary hyperaldosteronism are sin- gle adrenal adenoma, unilateral adrenal hyperplasia, or bilateral adrenal hyperplasia. In less common situations, primary hyperaldosteronism is caused by an ACC or inherited conditions of familial hyperaldosteronism. 16 Although the first-line treatment of familial hyperaldosteronism is typically not adrenalectomy, it is important for sur- geons to be aware of these familial syndromes to appropriately diagnose and treat this select group of patients.
Familial Primary Hyperaldosteronism
There are 4 types of familial primary hyperaldosteronism (Table 1). All follow a pattern of autosomal dominant inheritance. Familial hyperaldosteronism type I, also known as glucocorticoid remediable aldosteronism (GRA), 16 makes up 1% of cases of primary hyperaldosteronism.17 It is caused by a mutation in 2 genes, which results in chimeric gene fusion CYP11B1/CYP11B2 complex leads to endogenous adrenocorticotropic hormone (ACTH) secretion and hypersecretion of aldosterone. The phenotypic pre- sentation can vary from mild disease to severe hypertension refractory to medical management.17 Familial hyperaldosteronism type II accounts for less than 6% of pa- tients with primary hyperaldosteronism. The exact molecular basis is unclear, and it is thought to involve multiple genetic steps.16 Recent studies demonstrate association with chromosomal region 7p22,18 as well as a CLCN2 chloride channel mutation. 19 Fa- milial hyperaldosteronism type III often presents clinically before the age of 20 and also can be mild to severe. It is caused by a mutation in the KCNJ5 gene, which encodes the potassium channel Kir 3.4.20 This mutation indirectly leads to calcium influx result- ing in aldosterone production and cell proliferation. Type IV familial hyperaldosteron- ism is also known as early onset primary hyperaldosteronism and presents with seizures and neurologic abnormalities. It is due to a mutation in the CACNA1H
| Table 1 Familial primary hyperaldosteronism | ||
|---|---|---|
| Type Familial | ||
| Primary Hyperaldosteronism | Genetic | |
| Mutations | Treatment | |
| FH - I | CYP11B1/CYP11B2 | Glucocorticoids |
| FH - II | CLCN2 | MRA |
| FH - III | KCNJ5 | MRA ± Adrenalectomy |
| FH - IV | CACNA1H | MRA ± Adrenalectomy |
Abbreviation: MRA, mineralocorticoid receptor antagonist.
gene, which encodes a subunit of a voltage-gated calcium channel.21 Although its in- heritance is autosomal dominant, it demonstrates incomplete penetrance.
Genetic Testing
Genetic testing for familial hyperaldosteronism should be considered in a subset of patients.
The following individuals should be tested:
· Diagnosis of primary hyperaldosteronism at less than 20 years of age
· Family history of primary hyperaldosteronism
· Family history of stroke at young age (less than 40 years of age)
· Children or young adults with severe or resistant hypertension and positive family history of early onset hypertension and/or premature hemorrhagic stroke
Genetic testing for familial hyperaldosteronism is done via a familial hyperaldoster- onism panel that includes Southern blot or PCR for the CYP11B1/CYP11B2 mutation (very sensitive and specific for FH-I/GRA), 16 testing for CLCN2 mutations (type-II), germline mutations in KCNJ5 (type-III), and CACNA1H mutations (type-IV).22
Treatment
Most of the familial hyperaldosteronism syndromes are treated medically; however, surgical adrenalectomy is sometimes indicated. Patients with familial hyperaldoster- onism type III and type IV can develop severe bilateral adrenal hyperplasia. Initial treat- ment is medical with mineralocorticoid receptor antagonists (MRA). Occasionally, disease refractory to MRAs can be severe enough that bilateral adrenalectomy is indicated.23
Clinics Care Points
· There are 4 types of familial hyperaldosteronism.
· All are autosomal dominant.
· Genetic testing should be considered in patients diagnosed age younger than 20 years, with family history of hyperaldosteronism or stroke at age younger than 40 years, or children with severe or resistant hypertension and positive family history of early onset hypertension or premature hemorrhagic stroke.
· Management of familial hyperaldosteronism is typically medical but the disease can be severe enough in type III/IV that bilateral adrenalectomy is indicated.
CORTISOL-PRODUCING ADRENAL SYNDROMES Background
Cushing syndrome results in cortisol excess in the body. It is caused by either an excess of pituitary or ectopic ACTH or ACTH-independent cortisol production by an adrenocortical adenoma or carcinoma or adrenal hyperplasia. Adrenal adenomas are responsible for 10% to 15% of all cases of Cushing syndrome, with ACCs making up less than 5%. Somatic mutations in the PRKACA gene, which encodes a catalytic subunit of cAMP-dependent protein kinase A (PKA), is the underlying somatic muta- tion in approximately 50% of adrenal adenomas that cause overt Cushing syn- drome.24 However, a very small subset of Cushing syndrome is caused by ACTH- independent familial syndromes that result in bilateral adrenal hyperplasia.
Familial Syndromes
Carney complex
The Carney complex is a variant of primary pigmented nodular adrenal hyperplasia (PPNAD). It is a familial syndrome with autosomal dominant inheritance. PPNAD is characterized by ACTH-independent bilateral adrenal hyperplasia with pigmented ad- renal micronodules. In addition to Cushing syndrome, Carney complex can present with mesenchymal tumors such as atrial myxoma, spotty skin pigmentation, periph- eral nerve tumors, breast lesions, testicular tumors, and GH-secreting pituitary tu- mors.25 Patients with Carney complex usually present with Cushing syndrome by age 30, and 50% of patients are aged younger than 15 years when diagnosed.26 The underlying genetic cause of Carney complex is variable, with more than 135 mu- tations identified, most of which are germline mutations. The cAMP-PKA signaling pathway is the main area involved in the molecular pathogenesis of this syndrome.27 Mutations in the PKA regulatory subunit type IA (PRKAR1A) gene lead to abnormal PKA signaling.28 This mutation has been identified in 70% of patients with Carney complex.27 The biochemical diagnosis of Carney complex confirms ACTH- independent cortisol excess from the adrenal glands. Caution must be taken when relying on cross-sectional imaging to support the diagnosis because the adrenal glands often seem normal or only slightly enlarged.
Primary macronodular adrenal hyperplasia
These patients present with ACTH-independent bilateral adrenal hyperplasia with macronodules. Functionally, they can have various levels of cortisol secretion, leading to variable clinical presentations. In primary macronodular adrenal hyperplasia (PMAH), cortisol synthesis is not stimulated by ACTH. Instead, it is regulated by aber- rant hormonal receptors in the adrenal cortex, such as MC2R gene, PRKACA, and PDE11 A.29 When these are coupled to G-proteins, they activate the cAMP-PKA pathway, leading to steroid production and adrenal hyperplasia. In contrast to PPNAD, the adrenal nodules are large and can lead to massively enlarged adrenal glands. Mul- tiple genetic mutations are hypothesized to cause this syndrome. Both germline and somatic mutations have been linked to PMAH. The most common mutation is in the ARMC5 gene, a tumor suppressor gene, believed to contribute to more than 80% of familial forms of PMAH and 30% of sporadic cases. 30,31 PMAH is also seen in other types of familial syndromes including MEN1, FAP, and HLRCC (hereditary leiomyoma- tosis and renal cell cancer).
Genetic Testing
For patients with Carney complex, genetic counseling and testing for PRKAR1A gene mutations should be considered. Patients with PMAH, especially those with severe Cushing syndrome and massively enlarged adrenal glands, should consider genetic counseling and testing for ARMC5 gene mutations. 32
Treatment
In general, treatment includes both medical and surgical approaches. Treatment should be considered for patients with mild autonomous cortisol production with associated comorbidities (ie, osteoporosis, diabetes), as well as those with overt and severe Cushing syndrome.
Medical treatment includes the steroid synthesis inhibitors ketoconazole and metyr- apone. These are used when surgery is not possible and for those with mild autono- mous cortisol production and no associated comorbidities.
For both Carney complex and PMAH, bilateral adrenalectomy is curative. However, this results in adrenal insufficiency and requires lifelong steroid replacement. There- fore, unilateral or subtotal adrenalectomy may be considered. Steroid production often correlates with adrenal size, so one can consider debulking the glands. 32 Unilat- eral adrenalectomy may be reasonable if there is one dominant gland. Total unilateral adrenalectomy of the largest gland with partial adrenalectomy of the contralateral gland is another approach. Both are reasonable surgical options in patients with mild hypercortisolism and associated cortisol-excess comorbidities or in patients likely to be noncompliant with lifelong steroid replacement.31
Clinics Care Points
· Cushing syndrome is due to familial syndromes in a small percentage of patients.
. The 2 associated syndromes are Carney complex, a variant of PPNAD, and PMAH.
· Patients with adrenal Cushing syndrome and other syndromic features should be referred for genetic testing.
· Adrenalectomy (either bilateral total or subtotal) is the recommended treatment of those with associated secondary comorbidities related to cortisol excess and those with overt or severe Cushing syndrome.
ADRENOCORTICAL CARCINOMA Background
ACC is a primary malignant tumor of the adrenal cortex. Although this disease is rare, it is often an aggressive tumor with an overall 5-year survival rate in all stages of 50%. Approximately 5% to 10% of ACCs are associated with germline mutations and are associated with many familial cancer syndromes in adults, including multiple endo- crine neoplasia type I (MEN-1), familial adenomatous polyposis (FAP), and Lynch syn- drome.33,34 In contrast, 60% to 80% of children with ACC have an associated germline mutation, often Li Fraumeni syndrome (LFS) and Beckwith Wiedemann syndrome (BWS).35
Familial Syndromes Associated with Adrenocortical Carcinoma
MEN1: Approximately, 1% to 2% of patients with ACC have MEN1 mutation.36 The patients usually also have primary hyperparathyroidism, pancreatic neuroendocrine tumors, and/or pituitary adenomas. Up to 73% of patients with MEN1 develop adrenal enlargement and/or adenomas, depending on radiological methods and criteria used to define adrenal enlargement.37 In one study of 715 patients with MEN1, 13.8% of these patients were diagnosed with ACC.36 Annual abdominal imaging should be done in this patient population for neuroendocrine tumor surveillance but should also be done because of the high rate of ACCs in this syndrome. Any adrenal lesion identified on surveillance imaging needs dedicated adrenal radiographic studies as well as formal adrenal hormonal evaluation.33
FAP (Gardner syndrome): This syndrome is due to mutations in the APC gene, a tu- mor suppressor gene. Approximately 7% to 13% of FAP patients develop adrenocor- tical adenomas, compared with less than 5% in the general population. 38 Although the colorectal and adrenal adenomas have similar malignant potential, patients with FAP develop hundreds to thousands of colorectal adenomas but only 1 or 2 adrenal ade- nomas. 33 As a result, the ACC risk in patients with FAP is very low compared with the risk of colorectal cancer. For this reason, regular screening for ACC in patients with FAP is not recommended.
Lynch Syndrome (hereditary nonpolyposis colorectal cancer HNPCC): This auto- somal dominant syndrome is caused by mutations in the mismatch repair genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. Patients with Lynch syndrome have a high risk of colon cancer (20%-80%). Other associated neoplasms include, uterine, gastric, ovarian, small bowel, pancreatic, prostate, kidney, bile duct, brain, urinary tract, and adrenal. The incidence of adrenal neoplasms in Lynch syndrome is 3.2%. In one series of 94 patients with ACC, 3 tested positive for Lynch syndrome with mismatch repair gene mutations.39 The screening test for Lynch syndrome is done on tumor tissue by performing microsatellite instability testing and immunohistochem- istry testing. For patients who have undergone resection for ACC, it is recommended to perform these 2 screening tests on the tumor, which will help determine if more spe- cific genetic testing is necessary.33 Lynch syndrome-associated colorectal carcinoma has an increased response to immunotherapy, suggesting that there may also be a role for immunotherapy in Lynch syndrome-associated ACCs.33
Li Fraumeni syndrome: About 70% of patients diagnosed with LFS have a mutation in the Tp53 gene. 35 ACCs usually are the presenting cancer and most often present in childhood. In general, any ACC diagnosed in a child should raise suspicion for a germ- line mutation and an associated cancer syndrome. Patients with LFS can also present with osteosarcoma, sarcoma, acute leukemia, breast cancer, brain cancer, mela- noma, and colon cancer. 40
Beckwith-Wiedemann syndrome: This syndrome causes increased cancer risk in childhood and is due mostly to alterations on chromosome 11 in the IGF2 gene. One percent of children with BWS will get an ACC in childhood. Interestingly, the risk of developing an ACC tapers off by adulthood.33
Table 2 lists the frequency of ACC in each of the associated syndromes.
Genetic Testing
All children who are diagnosed with ACC should undergo genetic screening, specif- ically for LFS. For adults with ACC, genetic testing should also be considered and should also include testing for LFS and LS.33 For all other syndromes, the syndrome diagnosis is often already established at the time of ACC diagnosis. Established ACC programs recommend an algorithm including genetic counseling, a 4-generation pedigree, a review of personal medical history, a physical examination, and screening of ACC tumor tissue for the absence of DNA mismatch repair proteins (Lynch syn- drome). FAP and NF1 are often diagnosed on clinical examination. Direct germline testing for MSH2, MSH6, PMS2, MLH1, EPCAM, MEN1, APC, and TP53 should be offered to all patients with ACC.33 It is important to perform genetic testing in these patients because it can help establish a surveillance plan for each patient, lead to
| Syndrome | Percentage of Patients with ACC | Time of Presentation |
|---|---|---|
| Li-Fraumeni syndrome | 2%-4% | Childhood |
| Lynch syndrome | 3% | Adulthood |
| MEN1 syndrome | 1%-2% | Adulthood |
| Familial adenomatous polyposis | <1% | Adulthood |
| Beckwith-Wiedemann | <1% | Childhood |
earlier diagnosis and earlier treatment of other syndrome-associated neoplasms, and help identify and screen family members at risk.
Treatment
Treatment of ACC with associated familial syndromes is the same as for sporadic ACC. If resectable, open adrenalectomy with en bloc resection of surrounding organs and/or lymphadenectomy is recommended. In patients with Lynch syndrome, radia- tion should be avoided due to increased risk of secondary malignancies. 41
Clinics Care Points
· Familial syndromes are associated with ACC in 5% to 10% of adults and 60% to 80% of children.
. The most common syndromes are MEN1, FAP, LS, LFS, and BWS.
· All patients with ACC should undergo targeted genetic testing.
· Syndrome diagnosis helps surveil for other associated neoplasms, aids in devel- oping a surveillance plan, and helps screen at-risk family.
SUMMARY
All surgical diseases of the adrenal gland are associated with familial syndromes to varying degrees. With the advancement of DNA sequencing and molecular analysis leading to the discovery of more germline mutations, these familial associations will likely continue to increase in prevalence. Knowledge of these syndromes is essential for the adrenal surgeon. Most patients with adrenal pathologic condition should be considered for targeted genetic testing, or at least referral for genetic counseling. Diagnosis of a familial syndrome is helpful in the perioperative period for determining surgical approach, extent of surgery, recurrence risk, and malignancy risk. It also aids in developing a long-term surveillance plan for each patient. Finally, it allows us to identify at-risk family members, potentially leading to earlier diagnosis, earlier treat- ment, and ultimately better outcomes.
DISCLOSURE
The authors have nothing to disclose.
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