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Presse Med. 2018; 00: 000 on line on www.em-consulte.com/revue/lpm www.sciencedirect.com

Quarterly Medical Review

Adrenocortical carcinoma (ACC): When and why should we consider germline testing?

Elisabeth Joye Petr, Tobias Else

Available online:

University of Michigan, Michigan Medicine, Department of Internal Medicine, Metabolism, Endocrinology and Diabetes, 500 S State St, Ann Arbor, 48109, MI, USA

Correspondence:

Tobias Else, University of Michigan Health System, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, 1500W Med Ctr Dr-MSRB2, Office 2560E, 48109 Ann Arbor, MI, USA. telse@umich.edu

In this issue

Editorial. Pheochromocytoma: when to search a germline defect? A. Buffet et al. (France)

Adrenocortical cancer: When and why should we consider germline testing? E.J. Petr et al. (USA) Genetics of micronodular adrenal hyperplasia and Carney complex A. Tirosh et al. (Israel, Spain, USA)

Genetics of primary macronodular adrenal hyperplasia M.C. Fragoso et al. (Brazil)

Molecular genetics of Conn adenomas in the era of exome analysis R. El Zein et al. (France)

Summary

Adrenocortical carcinoma (ACC), particularly when occurring during childhood, has been a tradi- tional component of the tumor spectrum of Li-Fraumeni syndrome. Recent research has defined a significant risk increase of ACC with other familial cancer syndromes, such as Lynch syndrome and multiple endocrine neoplasia. ACC patients can serve as index patients for a new family diagnosis of a hereditary syndrome, allowing for further family cascade genetic testing, impacting the care and surveillance for patients and at risk family members. Individuals carrying pathogenic genetic variants can embark on a regular preventive screening and surveillance protocol likely reducing morbidity and mortality. Although several of these hereditary predisposition syndromes lead to a very high relative risk increase for ACC, the absolute risk most often does not reach a level to recommend general screening for ACC in carriers of pathogenic mutations. The larger value lies in the ability to screen for other commonly associated tumors in pathogenic variant carriers, such as colon cancer with Lynch syndrome. Here, we review the risk for ACC associated with hereditary syndromes and suggest an approach for genetic evaluation for ACC patients.

Introduction

It has long been estimated that about 5-10% of all cancers are due to a familial single gene predisposition disorder, and these numbers have recently been confirmed in several personalized medicine studies [1,2]. Certain cancers, including several endocrine cancers such as medullary thyroid cancer and pheochromocytoma/paraganglioma, always warrant genetic testing of the affected patients [3-5]. In general, all patients who are diagnosed with cancer should undergo a careful review of their personal medical history, family medical history including a four generation pedigree, and a physical exam in order to screen for an underlying hereditary syndrome. Identifying disease-causing germline variants provides an opportunity to recommend a surveil- lance program with the goal of early detection and treatment of other syndrome-associated

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cancers in patients cured of the index tumor. Furthermore, other at-risk family members carrying the inherited genetic mutation can be identified. Cascade screening allows both for the identi- fication of at-risk individuals while they are still in a disease-free state and for the initiation of an individualized screening and surveillance program. Before recommending genetic testing, it is important to consider how the genetic test result would affect disease management, i.e. what guidelines are in place for the screening or prophylactic therapy for the manifestations of the hereditary syndrome? For common conditions, such as Heredi- tary Breast and Ovarian Cancer Syndrome (HBOC; BRCA1, BRCA2) and Lynch Syndrome (LS; MSH2, MLH1, MSH6, PMS2, EPCAM), established screening and management guidelines are based on epidemiological evidence. For rare conditions, with lower prevalence of disease, there is less epidemiologic data to guide management decisions, and physicians often must choose to follow guidelines based on expert opinion or personal experi- ence. Despite the lack of clear epidemiological evidence, there are reasonable approaches to developing individual and family surveillance programs.

In this review, we will discuss the initial genetic work-up to consider for patients with ACC, some pitfalls of genetic testing, and the implications of genetic testing both for the index patient and for the patient’s family members. We will review the key syndromes associated with a predisposition to ACC, and discuss important aspects of genetic testing including when to refer for genetic testing, the importance of a multidisciplinary approach, and how positive genetic testing affects both ACC tumor ma- nagement and long-term follow-up decisions for carriers of genetic mutations.

Glossary

ACC	Adrenocortical carcinoma
ACMG	American College of Medical Genetics and Genomics
BWS	Beckwith-Wiedemann syndrome
CAH	Congenital adrenal hyperplasia
CDMRD	Constitutional DNA-mismatch repair deficiency
CRC	Colorectal cancer
FAP	Familial adenomatous polyposis
FLCN	Folliculin
HBOC	Hereditary Breast and Ovarian Cancer Syndrome
IHC	Immunohistochemistry
LFS	Li-Fraumeni Syndrome
LOH	Loss of heterozygosity
LS	Lynch Syndrome
MEN1	Multiple Endocrine Neoplasia Type 1
MMR	Mismatch repair
MSI	Microsatellite instability
NGS	Next generation sequencing
PPNAD	Primary pigmented nodular adrenocortical disease
TCGA	The Cancer Genome Atlas
VUS	Variant of uncertain significance

Association of ACC with familial cancer syndromes

Approximately 5-10% of ACCs are associated with germline mutations and ACC is classically associated with several familial cancer syndromes [6]. The most common associated genetic syndromes are Li-Fraumeni Syndrome (LFS) (2-4% of ACC cases, 50-80% in children), Lynch syndrome (LS) (3% of ACC cases), Multiple Endocrine Neoplasia Type 1 (MEN1) (1-2% of ACC cases), and rarely, Familial Adenomatous Polyposis (FAP), Beck- with-Wiedemann syndrome (BWS) or other syndromes [5-10]. Children diagnosed with ACC should always be screened for LFS. Adults diagnosed with ACC should be screened for LFS and for LS. For all other syndromes associated with ACC, the syndrome diagnosis is usually already established at the time of ACC diagnosis [6].

Li-Fraumeni Syndrome (LFS)

LFS has an estimated prevalence of 1:20,000 to 1:1,000,000 [7]. ACC is a core cancer of LFS [11,12]. Carriers of TP53 mutations are also at risk for multiple other cancers including breast and brain cancer, sarcoma and leukemia [13]. A majority of children diagnosed with ACC (~50-80%) have a TP53 mutations, but only 3-10% of children with LFS will develop ACC [14]. Often ACC is the presenting malignancy for LFS [14]. The frequency of TP53 germline mutations in ACC decreases with age to less than 10% in adulthood [9,14]. Particularly in ACC patients, TP53 germline mutations are diverse, either due to low penetrance alleles or due to de novo mutations, which account for up to 20% of new diagnoses of LFS [14]. The relatively high prevalence of TP53 germline mutations in patients with ACC have led to the general recommendation of genetic testing for TP53 mutations and deletion/duplication analysis for all ACC patients. This recom- mendation is part of the Chompret testing criteria [11,12]. Because of the high frequency of de novo mutations, TP53 genetic testing should be recommended even in the absence of a positive family history. Genetic population screening for individuals with the low penetrance p.R337H variant followed by offering screening for ACC has proven advantageous in Southern Brazil, where the prevalence of this founder mutation is fairly high (up to 90% of children with ACC) [15]. A recent concern regarding TP53 germline testing is that hematopoietic clones and possibly circulating tumor cells can give false positive results for DNA testing that is sequenced from peripheral blood samples. and several clinical genetic testing laboratories are now more hesitant to diagnose TP53 germline mutations from peripheral blood samples [16].

Importantly, the diagnosis of LFS impacts therapeutic decision making for ACC patients. While the general practice for patients with LFS is to treat any tumor according to usual practice (e.g. chemotherapy, surgery, radiation therapy), in settings of unclear benefit (e.g. adjuvant radiation for completely resected ACC),

To cite this article: Petr EJ., Else T. Adrenocortical carcinoma (ACC): When and why should we consider germline testing? Presse Med. (2018), https://doi.org/10.1016/j.lpm.2018.07.004

Adrenocortical carcinoma (ACC): When and why should we consider germline testing?

we recommend avoiding adjuvant radiation therapy in patients with TP53 mutations due to the risk of secondary malignancies. There are no established guidelines for the screening of ACC in LFS. Villani et al. have recently shown the feasibility of screening for cancers in TP53 carriers, including ACC screening starting at birth with abdominal ultrasounds and biochemical testing for hormone production (17-OH-progesterone, androstenedione, total testosterone, DHEA-S) every 3-4 months, in which more tumors were detected at early stages in those undergoing surveillance than in those not participating in surveillance [17,18]. However, this is a very intensive screening schedule, and many children with ACC have signs and symptoms of hormone excess at the time of screening detection [15]. And so, in addition to offering screening protocols, it is essential that

physicians educate the parents of children with LFS to recognize the signs and symptoms of precocious puberty and Cushing syndrome (table I).

Lynch Syndrome (LS)

LS, due to germline mutations in DNA-mismatch repair (MMR) proteins PMS2, MSH2, MSH6, and MLH1, has an overall preva- lence of 1:440 [7]. LS is characterized by an increased risk for colorectal, endometrial, small bowel, and transitional cell of the ureter or renal pelvis tumors (Amsterdam Criteria), in addition to ovarian, pancreatic, sebaceous neoplasms and ACC. LS signifi- cantly increases the relative risk for ACC. In a prospective study of 94 patients with ACC, 3 had family histories suggestive of LS and were subsequently found to be negative for TP53 mutations

TABLE I Syndromes associated with ACC and their characteristics

Syndrome	Gene(s)	Prevalence	Prevalence of ACC	Other adrenal phenotype	Other associated features
Common
Li-Fraumeni (LFS)	TP53	1:20,000 to 1:1,000,000	50-80% of children; 3-7% of adults	n/a	Brain cancer, breast cancer, lung cancer, sarcoma, leukemia, choroid plexus tumor
Lynch (LS)	MSH2, MLH1, PMS2, MSH6, EPCAM	1:440	3% of adults	n/a	Colorectal, endometrial, small bowel, ureteral cancer, sebaceous carcinoma, pancreas cancer, prostate cancer
Rare
MEN1	MENIN	1:30,000	1-2% of adults	Adrenal enlargement, adrenal adenomas	Pituitary adenomas, primary hyperparathyroidism, pancreatic neuroendocrine tumors, other foregut neuroendocrine tumors
FAP	APC	1:30,000	Rare, case reports	Adrenal adenomas	Colon cancer, duodenal adenomas, thyroid cancer
Beckwith-Wiedemann	IGF2 locus	1:13,000	Rare, case reports; occur in childhood only	Benign adrenal cysts and adenomas	Cancers in childhood, Wilms tumor, hepatoblastoma, rhabdomyosarcoma, neuroblastoma
Very rare/case reports
NF1	NF1	1:3,000	Rare, case reports, can occur in young children	n/a	Gliomas, malignant nerve sheath tumor, benign neural tumors
Carney Complex	PRKAR1A	Rare > 700 patients in the world	Rare, case reports	PPNAD	Pituitary and thyroid tumors, cardiac myxomas, schwannomas and other tumors
Birt-Hogg-Dube	FLCN	1:100,000	Rare, case reports	n/a	Skin hamartomas, pulmonary cysts and pneumothoraces, renal oncocytomas and chromophobe renal cell cancers

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and positive for pathogenic MMR variants, with a prevalence of 3.2%. This is comparable to the prevalence of LS in colorectal (2- 4%) and endometrial (1-5%) cancers [10]. Additionally, there are case reports, including a recent case report of a mother and daughter with both LS and ACC, that offer supporting evidence that ACC is a LS-associated malignancy [19]. Because ACC can be the presenting malignancy for patients with LS, ACC tumors should be screened by immunohistochemistry (IHC) and possibly microsatellite instability analysis (MSI), as is the usual practice per National Comprehensive Cancer Network recom- mendations for other LS-associated cancers, such as colorectal and endometrial cancers [10]. With the advent of next genera- tion sequencing (NGS) panels, direct germline testing of ACC patients might also be considered.

The diagnosis of LS is significant for the index patient and their family because at-risk family members can be tested for the germline mutation, and if positive for LS, can undergo colorectal cancer (CRC) screenings and risk-reducing surgeries for endo- metrial cancer. Screening protocols have proven to reduce the risk for CRC by more than half and have been proven cost- effective [20-25]. Although ACC might be the index tumor in some LS families, the life time risk for ACC in LS is still very low, and likely does not justify large scale targeted surveillance for ACC in those with LS. Interestingly, LS-associated tumors are often hypermutated and generate a large number of neoanti- gens. For this reason, LS-associated CRC have recently been shown to be more responsive to immunotherapy based treat- ment regimens [26,27], a strategy that might prove useful for treatment of LS-associated ACC in the future.

Multiple Endocrine Neoplasia type 1 (MEN1)

About 1-2% of all patients with ACC are found to have MEN1 mutation. These patients most often have other syndrome manifestations (primary hyperparathyroidism, pancreatic neu- roendocrine tumors, or pituitary adenomas) at the time of diagnosis. Adrenal enlargement and adenomas are common in MEN1 [28], with a high prevalence of ACC in MEN1-associated adrenal tumors (13.8%) [8]. Most MEN1-associated ACC appear to be non-secretory tumors and are discovered at an early stage. Special attention should be given to those patients with a known prior adrenal lesion as several of the reported MEN1- associated ACCs have arisen from pre-existing adrenal adeno- mas [8,29]. The adrenal glands should be reviewed in yearly MEN1 surveillance imaging conducted to detect pancreatic neu- roendocrine tumors (pNETs) [30], and any adrenal lesion in a patient with MEN1 should undergo a thorough endocrine hor- monal and imaging evaluation.

Other syndromes

Familial Adenomatous Polyposis (FAP)

ACC has been associated with Familial Adenomatous Polyposis (FAP). Patients with FAP do have adrenocortical adenomas (7.4-13%) [31,32] more often than the general population

(~ 5%) [33]. Any adrenal nodule in a patient with FAP should be evaluated in accordance with guidelines for the evaluation of all adrenal masses. However, the absolute risk for ACC is still much lower compared to colon cancer in FAP patients and no dedicated screening is recommended. The reason for the rela- tively low number of ACCs is likely that patients usually only carry a couple of adrenal adenomas, but hundreds to thousands of colorectal adenomas, all having the same chance of malig- nant progression. As the survival of patients with FAP improves now that prophylactic colectomy has become the standard of care, extracolonic manifestations such as ACC might become more prevalent.

Beckwith-Wiedemann Syndrome (BWS)

Beckwith-Wiedemann (BWS) is a syndrome of increased cancer risk in childhood due to alterations of the IGF2 locus. Children with BWS have increased risk for cancers including ACC. Up to 1% of children with BWS develop ACC, and benign adrenal cysts and adenomas are common [34]. Interestingly, the ACC risk (like other cancer risks in this syndrome) tapers off by adulthood. BWS-associated adrenal lesions can pose an exceptional chal- lenge to the pathologist. In our experience, applying the Weiss criteria to these cases, usually three out of nine criteria are positive (e.g. < 25% of clear cells, high nuclear grade and diffuse architecture) even in benign BWS-associated adrenal tumors, and therefore true ACC might be overdiagnosed in these patients.

Neurofibromatosis Type 1 (NF1)

Neurofibromatosis Type 1 (NF1) is a common genetic condition with a prevalence of 1:3000. Clinical manifestations with high penetrance include neurofibromas, café-au-lait spots, axillary freckling, Lisch nodules (which can often be observed without slit lamp exam and have a penetrance of ~95%), and skeletal malformations. There are case reports of ACC in patients with NF1, mainly affecting young children [6]. At this point it is unclear if this is a true association or merely coincidence. Interestingly, constitutional DNA-mismatch repair deficiency (CDMRD, “Biallelic Lynch Syndrome”) can mimic NF1 [35], as it presents with multiple café-au-lait spots. Therefore, the his- torically described cases of NF1 and ACC association might actually represent patients who had CDMRD with ACC, rather than NF1.

Carney Complex is a rare inherited neoplasia syndrome, cha- racterized by pituitary and thyroid tumors, primary pigmented nodular adrenocortical disease (PPNAD), cardiac myxomas, schwannomas and other tumors. There are a couple case reports of ACC in patients with Carney complex, with one appearing to arise from prior PPNAD lesion [36,37]. Birt-Hogg-Dube Syndrome (BHD) is a rare inherited mutation in the Folliculin (FLCN) gene manifesting with skin hamartomas, pulmonary cysts and pneumothoraces, and renal tumors. There is one case report of ACC, an oncocytic adrenal tumor, in a patient

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Adrenocortical carcinoma (ACC): When and why should we consider germline testing?

with Birt-Hogg-Dube [38]. Recently, there has been a first publication of a male patient with ACC and Hereditary Breast and Ovarian Cancer Syndrome (HBOC) with a germline mutation and loss of heterozygosity (LOH) of BRCA2 [39]. However, these associations remain to be verified in larger studies. Current numbers for Carney Complex and Birt-Hogg-Dube do not support an association beyond doubt. A clinically meaningful association with HBOC is also unlikely, given the lack of any other case reports of ACC despite the prevalence of HBOC. Moreover, anal- ysis for loss of heterozygosity (LOH) in ACC is only of limited value as a substantial portion of ACC undergo copy number neutral LOH which often affects the whole genome, making the event of LOH of a certain allele a 50% chance, but not necessarily a pathogenic event. There has also been at least some accounts where ACC was suspected to arise in patients with Congenital Adrenal Hyperplasia (CAH) and we recently encountered one such case [40-42]. However, CAH is also a common condition and the current small number of truly path- ologically proven cases of ACC associated with CAH are not convincing for a true association.

Discussion

ACC is a classic component of several inherited familial cancer syndromes. In particular, childhood ACC has been known for decades to be associated with LFS and BWS. More recently, studies have shown that a significant proportion of adult ACC is associated with LFS and also linked with other syndromes, particularly LS. Recent Cancer Genome Atlas (TCGA) studies with the National Cancer Institute and our own experience estimate the proportion of ACC that arise in patients with a genetic predisposition syndrome to be 5-10%.

Our current approach in a multidisciplinary specialized ACC clinic is to have a detailed focus on identifying germline mutations. As a minimal approach, we provide genetic counseling, construc- tion of a 4 generation pedigree, and screening of ACC tumor tissue for absence of DNA-mismatch repair proteins (LS). Review of personal medical history and a physical exam completes the evaluation and FAP, NF1 and MEN1 will most often be identified by clinical signs and symptoms.

In cases where a particular inherited genetic syndrome is obvi- ous, we may recommend targeted germline genetic testing for that particular syndrome. However, with the advent of custom next-generation panels and the fact that TP53, APC and MEN1 often occur as de novo mutations, we currently offer direct germline testing for MSH2, MSH6, PMS2, MLH1, EPCAM, MEN1, APC and TP53 to all ACC patients in our clinic.

The challenge of the future lies in defining and discovering new contributions to ACC predisposition, either as a low penetrance manifestation with known hereditary conditions or as novel germline mutations. Most of the unknown predisposition will likely be caused by low to moderate risk alleles that will not only pose a challenge in terms of clinical care (e.g., is ACC common

enough that screening is warranted?), but also give us additional insight into the pathogenesis and molecular pathology of ACC. In times of a personalized medicine approach, it has become evident that one of the most beneficial outcomes of molecular analysis is the identification of predisposing germline muta- tions. Identifying these mutations allows for family cascade screening and surveillance for other syndrome-associated tumors.

A general argument against genetic screening of patients is the absence of clear screening guidelines for certain genetic syn- dromes. Screening guidelines are only available for LS and FAP and expert opinion is available for MEN1. Screening for patients with LFS is still largely experimental. However, forgoing testing due to the absence of general treatment guidelines, despite knowing about a possible tumor predisposition, marginalizes our ACC patients with a rare syndrome and can impact their quality of care. Additionally, for some unusual conditions, there might never be a consensus on screening guidelines due to the rarity of these syndromes. Therefore, we believe that genetic testing and construction of an individualized surveillance plan for patient and family members even in the absence of general guidelines should be attempted following the best evidence and assumed risk. Additionally, there is emerging evidence that genetic testing directly influences care, such as immunotherapy for LS or avoiding radiation for LFS.

A recent challenge that has occurred with increased genetic testing is the classification of observed genetic variants. The American College of Medical Genetics and Genomics (ACMG) has put forward very useful recommendation for classification of genetic variants. Despite these very clear recommendations, uncertainty remains on how to follow and treat patients with a genetic variant of uncertain significance (VUS), which means it is neither classifiable as pathogenic or non-pathogenic, and the function of such variant is unknown. In these cases, it is impor- tant to attempt to obtain additional information, such as segre- gation analysis in the family or functional analysis on a research basis, to help determine the meaning of the VUS. We put the greatest weight on large available databases, such as ExAC or 1000 genomes, as most of ACC syndromes are quite rare and true pathologic variants found in patients should be absent or of a very low frequency in these databases of non-affected indi- viduals. A final important step is to not only rely on laboratory testing reports, but to consider patient and family character- istics. For example, in care for a patient with a clinical diagnosis of MEN1 and a VUS in MENIN a low threshold should be applied to treat this patient and potentially their family members as carrying a pathogenic variant of MENIN. We also discuss with all our patients with a germline VUS that they should keep in touch with our clinic or the testing laboratory to follow whether there is a reclassification of the VUS to either benign (not disease- causing), or pathogenic (disease causing), while disease-spe- cific and population databases are growing.

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E.J. Petr, T. Else

We conclude that the short answer to the title of this review is: every patient with a diagnosis of ACC should be considered for a genetic evaluation. ACC is a rare malignancy, with a significant prevalence of germline predisposition syndromes in affected individuals, which justifies genetic evaluation. The extent of evaluation, whether it should be a clinical evaluation or include targeted or broad genetic testing, is an ongoing matter of debate. In our experience, offering a multidisciplinary approach with genetic counseling, personal and family history including 4 generation pedigree, and physical exam, and then shared

decision making with the patient on the depth of genetic testing analysis to pursue is generally very well received. Despite the often unfavorable prognosis of ACC and the commonly advanced stages of ACC encountered in our clinic, our patients particularly appreciate feeling empowered to take action to prevent further cancers in their families.

Disclosure of interest: the authors declare that they have no competing interest.

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Adrenocortical carcinoma (ACC): When and why should we consider germline testing?

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