Genetic predisposition to endocrine tumors: Diagnosis, surveillance and challenges in care

Genetic predisposition to endocrine tumors: Diagnosis, surveillance and challenges in care

Author’s Accepted Manuscript Genetic Predisposition to Endocrine Tumors: Diagnosis, Surveillance and Challenges in Care Elisabeth Joye Petr, Tobias El...

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Author’s Accepted Manuscript Genetic Predisposition to Endocrine Tumors: Diagnosis, Surveillance and Challenges in Care Elisabeth Joye Petr, Tobias Else

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S0093-7754(16)30042-2 YSONC51956

To appear in: Seminars in Oncology Received date: 18 June 2016 Accepted date: 10 August 2016 Cite this article as: Elisabeth Joye Petr and Tobias Else, Genetic Predisposition to Endocrine Tumors: Diagnosis, Surveillance and Challenges in Care, Seminars in Oncology, This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Genetic Predisposition to Endocrine Tumors: Diagnosis, Surveillance and Challenges in Care Elisabeth Joye Petr, MD and Tobias Else, MD Elisabeth Joye Petr, MD Fellow Physician Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes University of Michigan Health System Ann Arbor, MI

Tobias Else, MD Assistant Professor Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes University of Michigan Health System Ann Arbor, MI

Corresponding Author: Tobias Else, MD MSRB2, Office #2560E Ann Arbor, MI 48109 Phone: (734) 936-1319 Fax: (734) 647-2145 email: [email protected]

Financial Disclosures, Conflicts of interest: None


Endocrine tumor syndromes, e.g. Multiple Endocrine Neoplasia type 1 & 2, were among the first recognized hereditary predisposition syndromes to tumor development. Over time, the number of endocrine tumor syndromes has significantly expanded, e,g, with the recent inclusion of Hereditary Paraganglioma Syndromes. Associations of nonendocrine tumors with hereditary endocrine tumor syndromes and endocrine tumors with non-classical endocrine tumor syndromes have emerged. These findings have certainly expanded the scope of care, necessitating a multidisciplinary approach by a team of medical professionals and researchers, integrating shared patient decisionmaking at every step of surveillance, diagnosis and treatment. In the absence of evidence-based guidelines, multiple aspects of patient care remain individualized, based on a patient’s clinical presentation and family pedigree. This is particularly important when determining a surveillance plan for unaffected or disease-free mutation carriers. In this review, we describe the main endocrine tumor manifestations found in familial cancer syndromes in an organ-based approach, focusing on adrenocortical carcinoma,






differentiated thyroid cancer, and medullary thyroid cancer. We highlight the challenges in diagnosis, surveillance and therapy unique to the patient population with hereditary syndromes. Furthermore, we underscore the importance of evaluating for genetic predisposition to tumor development, provide features that can identify index patients, and discuss the approach to screening surveillance for mutation carriers.

Introduction to Endocrine Tumor Syndromes

Endocrine tumors are a diverse group of neoplasms with unique aspects to consider when approaching diagnosis and therapy. In contrast to other fields of oncology, endocrine tumors often produce hormones, which can aid in diagnosis, but also pose challenges for treatment due to the resultant hormone excess syndromes. Therefore, specialized Endocrine Oncology Clinics depend on multidisciplinary collaboration between the diagnostic specialties, such as radiology, pathology and nuclear medicine, and the core disciplines of endocrinology, endocrine surgery, genetic counseling and oncology to provide optimal care for patients with benign and malignant endocrine tumors. Although several endocrine tumors are rare entities (e.g. pheochromocytomas (PCC), paragangliomas (PGL), adrenocortical carcinomas (ACC), and medullary thyroid cancer (MTC)), others are much more common than generally perceived. For example, differentiated thyroid cancer (DTC) is amongst the ten most commonly diagnosed cancers in the United States; and neuroendocrine tumors are one of the most prevalent tumors of the gastrointestinal tract [1, 2]. Endocrine tumor syndromes are classic illustrations of hereditary cancer syndromes, including core diseases such as the Multiple Endocrine Neoplasia syndromes type 1 & 2 (MEN1, MEN2) and the more recently described Hereditary Paraganglioma Syndromes (HPGL)[3]. Despite this, the evaluation for genetic predisposition syndromes in patients presenting with endocrine tumors is often overlooked. Almost all endocrine tumors are known to potentially be part of inherited syndromes, and all patients with rare tumors such as PCC/PGL, adrenocortical carcinoma, or medullary thyroid carcinoma should be referred for genetic counseling, evaluation and testing [4-6].

In general, one can subdivide the syndromes with endocrine tumor manifestations into three subgroups: 1) Core endocrine tumor syndromes that mainly manifest in endocrine organs, such as MEN1, MEN2 and HPGL; 2) Genetic syndromes with main manifestations in endocrine organs, such as von Hippel-Lindau disease (VHL) and PTEN Hamartoma Tumor syndrome (Cowden Disease, PHTS); and 3) Genetic tumor predisposition syndromes, that are mainly characterized by other tumor entities, but also significantly raise the lifetime risk for certain rare endocrine tumors, such as Li-Fraumeni syndrome (LFS) and Lynch syndrome (LS).

In this review, we will focus on several aspects of patient care, in which both Cancer Genetics and Endocrine Oncology are important. In an organ based approach, we will discuss how the diagnosis of an endocrine tumor can serve to identify index patients with a tumor predisposition syndrome and which surveillance should be recommended for mutation carriers (Figure 1, Table 1).

Pheochromocytoma (PCC) and Paraganglioma (PGL)

PCC and PGL are rare endocrine tumor entities with an estimated incidence of clinically relevant PCC of 0.8 per 100,000 [7]. Although most of these tumors are benign, episodic as well as chronic catecholamine release can cause significant morbidity and mortality, manifesting as hypertensive crisis (especially with trigger situations, such as pregnancy or surgery), myocardial infarction, cardiomyopathy, or stroke [7, 8]. PCCs

occur in the adrenal medulla and PGL can occur anywhere from the skull base to the pelvic area, originating from the paraganglia of the autonomic nervous system. While adrenal








parasympathetic head and neck PGL (HNPGL) are often biochemically silent, with the exception of some carotid body tumors and tumors of the sympathetic chain. PCC/PGL are paradigm tumors with regards to genetic predisposition syndromes with ~25% of PCC and likely >30% of HNPGL arising in patients with germline mutations [4, 8-10].

A germline mutation should be considered in all patients with PCC/PGL [7]. The most common germline genetic mutations that predispose to PCC/PGL are in RET (MEN2), VHL (VHL), NF1 (Neurofibromatosis type 1), SDHx (HPGL), TMEM127, and MAX [4, 11]. Most recently, PCC/PGL have also been recognized as part of Hereditary Leiomyomatosis and Renal Cell Cancer syndrome (HLRCC) due to fumarate hydratase (FH) mutations [12]. Certain clinical characteristics increase the suspicion for an inherited genetic mutation, such as age of onset less than 45 years, family history of PCC/PGL, bilateral, multifocal, or extra-adrenal PCC/PGL’s or the presence of other syndrome-associated tumors [8]. Traditionally, prioritization of individual gene testing was based on phenotypic features. Currently, next-generation sequencing (NGS) panels have become the preferred alternative, instead of sequential gene testing, making the process more efficient and likely less costly.

The goal of screening surveillance for patients at risk for PCC/PGL is to prevent three main complications: 1) cardiovascular morbidity and mortality, 2) progression and

metastasis of malignant tumors, and 3) sequelae of local tumor invasion and surgical treatment-related complications, which are particularly devastating in HNPGL. Therefore, it is prudent to diagnose these tumors early. The modalities of surveillance are two-fold: laboratory evaluation for elevated metanephrine levels, which is likely able to identify PCC/PGL posing the greatest cardiovascular risk, and imaging, which can identify tumor extent and biochemically silent tumors. When deciding on imaging frequency, it is important to keep in mind that PCC/PGLs, are generally slow growing neoplasms [13].

Multiple Endocrine Neoplasia type 2 (MEN2)

MEN2 has a prevalence of ~1:35,000. The core clinical features of MEN2 are medullary thyroid carcinoma (MTC) (MEN2A and B), primary hyperparathyroidism (pHPT) (MEN2A), and mucosal and gastrointestinal ganglioneuromas and marfanoid habitus (MEN2B). RET genetic testing should be discussed with patients presenting with these unusual tumors. A substantial proportion of apparently sporadic MTC are associated with RET germline mutations [6, 14, 15]. The morbidity associated with MEN2 is primarily caused by either MTC or PCC. About 50% of patients with MEN2 develop PCC [16].

Screening for PCC in MEN2 carriers should begin at the age of thyroidectomy or by the age of 5 years, whichever comes first, and should be repeated annually. PCCs in MEN2 are almost always located in the adrenal gland, initially emerging as adrenomedullary

hyperplasia, and are epinephrine/metanephrine secreting. Therefore, screening should be conducted by measuring annual plasma free metanephrine levels. Imaging procedures are only necessary in patients with increased metanephrine levels [16].

Von Hippel-Lindau disease (VHL)

VHL has an estimated prevalence of 1:36,000. The core VHL-associated neoplasms are PCC, renal cell carcinoma (RCC), hemangioblastomas of the retina and CNS, endolymphatic sac tumors (ELST), and pancreatic neuroendocrine tumors (pNET). PCCs occur in up to 20% of VHL patients and often occur before the age of 30 [4]. VHLassociated PCC/PGL are almost invariably norepinephrine/normetanephrine producing and are most often found in the adrenal gland (often bilateral), but can occur in extraadrenal localizations [7].

Traditionally, VHL has been classified in subgroups according to the predominant tumor phenotype in an individual patient or a family pedigree. Patients of the subgroup VHL type 2c often only present with PCC, and lack other features of the syndrome [7]. However, even a presumed VHL type 2c does not exclude the occurrence of other syndrome-associated tumors and screening of mutation carriers should always follow general screening recommendations. The VHL Alliance has put forward PCC screening recommendations which include yearly plasma free metanephrine levels, starting at age 5, and visualization of the adrenal glands on annual imaging which is primarily performed as screening for pancreatic neuroendocrine tumors (pNETs) and renal cell

carcinoma (RCC) [17].

Neurofibromatosis type 1 (NF1)

Neurofibromatosis 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. PCCs occur in about 5-7% of those with NF1 mutations, although higher rates have been found on autopsy [4]. Age of onset of PCC in NF1 is the same as in sporadic cases, often occurring in the third or fourth decade of life [4, 7]. A diagnosis of NF1 in patients with PCC can generally be made on clinical grounds and genetic testing is rarely necessary.

Although there are no general screening recommendations for PCC in NF1 carriers, patients should be monitored with annual blood pressure checks starting at the age of 1 year [18]. In the workup of elevated blood pressure, it is important to consider PCC as well as other causes of NF1-associated hypertension, such as vascular fibromuscular dysplasia resulting in renal artery stenosis, and aortic stenosis or coarctation [18] . Plasma free metanephrines should definitely be checked in any NF1 patient with hypertension and can be considered as a yearly baseline screening [4].

Succinate dehydrogenase mutations (SDHx) in Hereditary Paraganglioma Syndromes (HPGLs)

The most prevalent cause for hereditary predisposition to PCC/PGLs are mutations in the genes encoding the succinate dehydrogenase complex (SDHx), with mutations most commonly in SDHB (PGL4) and SDHD (PGL1), followed by SDHC (PGL3), and rarely in SDHA (PGL5) or SHAF2 (PGL2). Phenotypes vary significantly, with SDHBassociated PGLs mainly occurring in extra-adrenal locations, predominantly the abdomen, but also in the head and neck area. SDHB-associated sympathetic PGLs often secrete norepinephrine/normetanephrine and appear to have an increased risk for malignancy [19]. SDHD-associated HPGL is characterized by paternal inheritance due to gene imprinting. Only individuals inheriting the mutation from the father are at risk for tumor development. SDHD-associated tumors can occur in any location, but most are HNPGLs, and are often biochemically silent. SDHC-associated PGLs are usually HNPGL, but can also occur in the mediastinum [20]. The phenotype of SDHA- and SDHAF2-associated tumors is not yet well established due to the small number of individuals with proven germline mutations in these genes [19].

The penetrance of SDHB- and SDHD-associated tumors is currently believed to be as high as ~70-80% over a patient’s lifetime. However, this is likely influenced by ascertainment bias and future studies are needed to define the true penetrance. SDHC is likely associated with a low penetrance; in our own experience, only index patients in families have been found to have PCC/PGL tumors [20]. SDHA mutations, which account only for a small number of HPGL, are likely associated with low penetrance given the fact that some of the suspected pathogenic mutations, such as the stopgain

mutations SDHA p.R31X and p.R75X, are fairly common in the general population (~1/3500) [21].

Despite the fact that SDHx germline mutation carriers are the fastest growing population in most specialized Endocrine Genetics clinics, there are no published guidelines regarding surveillance of these patients. The general expert consensus is to perform annual physical exams with blood pressure measurements and plasma or urine free metanephrine levels. Due to the fact that a significant proportion of SDHx-associated tumors are biochemically silent, imaging is necessary and best achieved by whole body MRIs every 2 years. In one study, MRI surveillance detected tumors in 15.6% of scans [22]. Over the last decade, it has become clear that there is also an increased risk for other associated tumors, including RCC, gastrointestinal stromal tumors (GIST) and pituitary adenomas [23, 24]. GIST are sometimes found in families carrying SDHx mutations, particularly SDHA and SDHC, with very little other manifestations, sometimes even completely lacking any family history of PCC/PGL [25]. 18% of patients with pituitary tumors and PCC/PGL carry an SDHx mutation [23]. It is likely that the tumor spectrum associated with SDHx mutations will further expand. None of these tumor risk increases currently warrants any additional screening, and fortunately most of these tumor entities should be detectable on the surveillance whole body MRI scans [26].

TMEM127 and MAX

Little is known about the phenotype and associated tumors with MAX and TMEM127 mutations. TMEM127 has been associated with bilateral adrenal PCC and extra-adrenal PGLs, with an average onset at age 45 and low risk of malignancy. Most recently an increased risk of RCC has also been described [11, 27]. MAX mutations have been linked to bilateral adrenal PGLs and an increased risk of malignancy [4, 7].

Adrenocortical Carcinoma (ACC)

While benign adrenal adenomas are relatively common, occurring in 5-10% of the population, adrenocortical carcinomas (ACC) are rare, affecting only about 1 to 2 per million persons per year [28]. Approximately 10% of ACCs are associated with germline mutations. The most common associated genetic syndromes are LFS (2-4% of ACC cases, 50-80% in children), Lynch syndrome (LS) (3% of ACC cases), MEN1 (1-2% of ACC cases), and rarely, Familial Adenomatous Polyposis (FAP) and BeckwithWiedemann syndrome (BWS). 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 [5].

Li-Fraumeni Syndrome (LFS)

LFS has an estimated prevalence of 1:20,000 to 1:1,000,000, and ACC is a core malignancy. According to the Chompret testing criteria, every patient with a diagnosis of ACC should be offered testing for TP53 mutations or deletion/duplications [29]. Carriers of TP53 mutations are at risk for multiple cancers including breast and brain cancer, sarcoma, leukemia and ACC [30]. Half of all children with ACC have a TP53 mutation, but only 3-10% of those with LFS will develop ACC [31]. Particularly in ACC patients, TP53 germline mutations are diverse, and a significant number are de novo mutations (up to 20%) [31]. Therefore, ACC patients should consider genetic testing regardless of family history, in order to initiate appropriate screening for other syndrome-related tumors. Villani et al have recently shown the feasibility of childhood screening for ACC in TP53 carriers with abdominal ultrasound and biochemical testing for hormone production (17-OH-progesterone, androstenedione, DHEA-S) at a frequency of every 34 months [32]. It is important to note that even with intensive screening many children with ACC manifest symptoms and signs of hormone excess at the time of screening detection [33]. Therefore, in addition to offering screening protocols, it is imperative that physicians discuss signs and symptoms of precocious puberty and Cushing syndrome with parents of children with LFS. The incidence of ACC in adults with LFS is much lower than in children and annual total body MRI screening and a physical exam should evaluate for signs and symptoms of hormone excess.

Lynch Syndrome (LS)

LS is characterized by an increased risk for colorectal, endometrial, ovarian and pancreatic cancer and sebaceous neoplasms, associated with germline mutations in EPCAM, PMS2, MSH2, MSH6, and MLH1, and an overall prevalence of 1:440. LS confers a dramatically increased relative risk for ACC, and 3% of patients diagnosed with ACC are found to have LS [28, 34]. Because ACC can be the presenting malignancy











immunohistochemistry (IHC) and possibly microsatellite instability analysis (MSI), as is the usual practice for other LS-associated cancers, such as colorectal and endometrial cancers.

Multiple Endocrine Neoplasia type 1 (MEN1)

About 1-2% of all patients with ACC are found to have MEN1 mutation, and patients usually have other syndrome manifestation at the time of diagnosis. Adrenal enlargement is common and ~10% of MEN1 patients have distinct adrenal tumors of which 14% are ACCs (1-2% of all patients) [35]. The adrenal glands should be reviewed in yearly imaging conducted to detect pancreatic neuroendocrine tumors (pNETs). Special attention should be given to those patients with a known prior adrenal lesion as several of the reported ACCs have arisen in patients with pre-existing adrenal adenomas. Any adrenal lesion in a patient with MEN1 should undergo an endocrine evaluation.

Beckwith-Wiedemann Syndrome (BWS) and Familial Adenomatous Polyposis (FAP)

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. About 1% of children with BWS develop ACC, and benign adrenal cysts and adenomas are common [36]. Interestingly, the ACC risk (like other cancer risks in this syndrome) tapers off by adulthood.

Rarely, ACC has been diagnosed in those with Familial Adenomatous Polyposis (FAP). Patients with FAP often have adrenocortical adenomas (~15%) [37, 38], which should be evaluated in accordance with guidelines for the evaluation of all adrenal masses.

Neuroendocrine tumors (NETs)

Neuroendocrine tumors (NETs) originate from neuroendocrine cells found in different organs, such as the gut, the lung, and the pancreas, where they form the islets of Langerhans, the source of pancreatic hormone production (insulin, glucagon, etc.). NETs are best categorized by their area of origin, (foregut, midgut, or hindgut), their endocrine hormonal phenotype, their grade and differentiation (e.g. well differentiated [low and intermediate grade] vs. poorly differentiated [high grade tumors]). The grading

is particularly important when making decisions on therapy. Poorly differentiated, high grade tumors are closely related to entities such as small cell lung cancer and do not commonly occur with hereditary syndromes [39]. NETs can be silent or secrete a variety of hormones.

The classical marker for midgut tumors, particularly with carcinoid syndrome, is serotonin (blood) and its metabolite 5-HIAA (urine). This marker can also be positive in pancreatic NETs (pNETs), but is virtually absent in most other foregut or hindgut tumors. Another useful marker is chromogranin A (CgA). Unfortunately, the widespread use of PPI, which leads to an increase of CgA level, often makes initial interpretation difficult, however this can be followed for disease progression or response to therapy [40]. An alternative is measurement of pancreastatin, which is less influenced by PPI, but is often negative in MEN1-associated NETs. Also, some non-functional tumors can secrete pancreatic polypeptide as a marker. The clinical presentation should prompt endocrine biochemical work-up (insulin, C-peptide, proinsulin, VIP, gastrin etc.) for NETassociated hormone access syndromes.

NETs can occur with VHL, MEN1 and NF1 [40]. NETs are almost never the first manifestation in VHL and only rarely in MEN1, where they are usually preceded by pHPT. Genetic testing for patients with NETs should generally be entertained in young onset NETs (<20-30 years), those with insulinomas or gastrinomas (MEN1), and individuals with a suggestive personal or family history (e.g. VHL).

Multiple Endocrine Neoplasia type 1-associated neuroendocrine tumors

NETs occurring in MEN1 carriers are always localized in the foregut, e.g. lung, stomach, duodenum, pancreas, and thymus. Up to 80% of MEN1 carriers develop pancreatic NET [41]. MEN1-associated NETs can either be silent or hormone-producing. NETs located in the duodenum or pancreas can produce gastrin, leading to Zollinger-Ellison Syndrome. Small, multiple gastrinomas located in the duodenum are often found in patients with MEN1. Their anatomy makes them a difficult target for surgical intervention, so these are often managed medically with proton pump inhibitors [16, 41, 42]. NETs located in the pancreas can be insulinomas or, rarely, glucagonomas (diabetes, rash) or VIPomas (Verner-Morrison Syndrome = hypokalemia, watery diarrhea and achlorhydria). Insulinomas are often detected early due to hypoglycemic symptoms, and can be treated with surgical resection [16, 41]. In contrast, glucagonomas have often metastasized by the time of diagnosis and are primarily treated with medical management (somatostatin analogs). Non-functioning pancreatic NET are associated with a worse prognosis (in patients not undergoing surveillance), likely due to delay in detection because of lack of symptoms [41]. Thymic and bronchial NETs can produce adrenocorticotropic hormone (ACTH), leading to ectopic Cushing syndrome.

MEN1-associated NETs, particularly insulinomas, can occur in early childhood. Although such early onset is rare, some experts recommend starting annual screening with fasting serum glucose and insulin levels as early as age 5. At least by the late

teenage years, providers should discuss screening protocols with patients and their families, and initiate annual imaging (preferably MRI or EUS) as well as biochemical evaluation (gastrin, proinsulin, chromogranin A, pancreatic polypeptide, glucagon and VIP) [16, 41]. Still, it is rare that tumors would be evident by biochemical abnormalities but without evidence on imaging. Surgical treatment is usually indicated in tumors >2cm or fast growing tumors.

Additionally, lung and thymic tumors, although rare in MEN1, can be quite aggressive. At least baseline or infrequent evaluation (e.g. chest CT) of these areas is recommended. MEN1 carriers should also be screened for pHPT with annual serum calcium levels and for pituitary adenomas with annual prolactin and IGF1 levels and pituitary MRI every 3-5 years [16, 41].

Von Hippel-Lindau disease-associated neuroendocrine tumors

VHL-associated NETs are exclusively found in the pancreas and are never hormoneproducing [39]. The usual age of onset is 35 years [43, 44]. Because of their lack of hormone production, surveillance is best conducted by annual imaging. Pancreatic NETs should be assessed for tumor size and doubling time. Tumors larger than 3cm, with a doubling time < 500 days, or exon 3 mutations are at highest risk for malignancy and should be evaluated for surgical removal [17, 45]. Of note, cystic lesions of the pancreas are commonly found in patients with VHL, but no increased risk for pancreatic adenocarcinoma has been identified in these lesions and therefore there is usually no

need for invasive diagnostic procedures.

Neuroendocrine tumors associated with other syndromes

Rarely, somatostatinomas, which cause diarrhea, diabetes and cholelithiasis, can occur as part of NF1. These are usually located in the periampullary region [46]. Pancreatic NETs have also recently been described in patients with SDHx mutations, and showed loss of heterozygosity, suggesting a rare but true association with the germline mutation [26].

Thyroid cancer

The average lifetime risk for thyroid cancer in the U.S. is less than 1% [47]. The incidence of thyroid cancer diagnosis is increasing, and it is one of the top 10 cancers diagnosed in the U.S [1]. This is likely due, in part, to increased discovery of small thyroid cancers found incidentally on neck and chest imaging studies. Over 90% of thyroid cancers are differentiated thyroid cancers (DTC), including papillary and follicular thyroid carcinomas. It is estimated that about 5-10% of those diagnosed with DTC have an inherited genetic syndrome [14]. Familial cancer syndromes that predispose to DTC are FAP and Cowden/PHTS. A risk increase has also been reported for Carney complex, Werner syndrome and DICER1 syndrome.

Less than 5% of thyroid cancers are medullary thyroid carcinomas (MTCs), of which up to 7% harbor a germline RET mutation [14, 15]. Therefore, all patients with a diagnosis of MTC should be considered for germline RET mutation testing [6, 15]. An estimated 90% of those carrying the RET mutation will develop MTC, and MTC is often the first clinical manifestation of MEN2. Some families will present with MTC only, a syndrome termed familial MTC (FMTC). However, families diagnosed with FMTC should still be screened for PCC and pHPT. Given the high penetrance and early age onset of MTC, it is important to perform a prophylactic thyroidectomy to decrease risk for progression to metastasis and associated morbidity and mortality. Timing of thyroidectomy should be based on the risk level of the specific RET mutation and assessment of the family pedigree. Depending on RET mutation risk level, the recommended age for prophylactic thyroidectomy varies from 6 months with the highest risk (MEN2B), to early adulthood with moderate risk [6, 16].

Familial Adenomatous Polyposis (FAP)

The frequency of FAP is estimated between 1 in 5,000 to 1 in 25,000 [48]. Those affected by FAP develop hundreds of colon polyps and early onset colon cancer. With increased survival due to prophylactic colectomies, the extra-colonic manifestations of FAP have become increasingly clinically relevant.

DTCs in patients with APC mutations are often bilateral [49], have earlier mean age onset at less than 30 years of age, and are more common in women [50]. The

cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC) is much more common in FAP than in the general population (25-33% of FAP-associated PTC vs. 0.16% non-FAP associated PTC) [49]. The isolated diagnosis of CMV-PTC should always raise suspicion for FAP as indeed CMV-PTC can be the index tumor, preceding the diagnosis of FAP [14, 51].

For surveillance of DTC in FAP, thyroid gland palpation should begin at the age of annual screening colonoscopies [47, 48, 52]. The timing and frequency of proposed thyroid ultrasound screening varies in different expert opinions. It has been suggested that most DTCs are evident at time of FAP diagnosis and therefore a thyroid ultrasound should be part of an initial evaluation and repeated every 2-5 years in order to identify most cases [49]. Thyroid nodules in FAP should be evaluated according to ATA guidelines for features of increased cancer risk (size, microcalcifications, increased vascularity, hypoechogenicity, etc), but due to increased pretest probability for malignancy, a lower threshold for detailed endocrine and imaging work-up should be considered [14, 47, 49].

PTEN Hamartoma Tumor Syndrome (PHTS)

PHTS is caused by mutations in PTEN and is characterized by trichilemmomas of the skin, mucosal cobble stoning, macrocephaly and cancers of the breast, thyroid, endometrium, kidney and GI tract. The prevalence in the U.S. is estimated at 1:200,000 with a female predominance, likely due to an ascertainment bias with uterine and breast

cancer being key features of the syndrome [53]. Despite its high penetrance (>80%) [54], PHTS diagnosis is often missed since phenotypic expression varies and because the associated malignancies are also common in the general population.

DTC is the second most common malignancy in carriers of the PTEN mutation after breast cancer. The lifetime risk for DTC in PTEN mutation carriers is up to 17% [55]. Most PHTS-associated DTCs show a follicular histology, but a papillary morphology can be observed. Onset is often by age 30’s or even in childhood [56-58]. Benign thyroid disease including nodules, goiter, and hypothyroidism is even more common in PHTS, affecting up to 70% of carriers [57].

PHTS should be suspected in anyone with DTC and additional suggestive features, such as follicular histology, macrocephaly (>97%ile, >58cm in women and >60cm in men) [56], family history of PHTS, pathognomonic CNS or skin findings, autism spectrum disorder, or those meeting a combination of suggested diagnostic criteria [57]. Recommendations for thyroid screening include annual thyroid exam starting as early as age 10 [55]. Thyroid ultrasound at time of PHTS diagnosis and annually thereafter are a good screening modality. Due to the risk of DTC in multinodular goiters with PHTS, early thyroidectomy should be discussed in select cases [53, 59].

Several other rare diseases have been implicated to have a predisposition for DTC, including Werner syndrome, Carney Complex, and DICER1 syndrome. All patients with these syndromes will commonly have other syndrome manifestations that make their

diagnosis clear. Although DTC is rarely an index malignancy in these instances, yearly surveillance should be considered. The incidence of DTC and benign thyroid disease in Carney Complex appear to be slightly higher than in the general population, estimated at 2.5% and up to 75% respectively [60]. A Japanese study of patients with Werner syndrome has shown high risk of DTC (18%), including papillary, follicular, and anaplastic histology [61]. DICER1 syndrome predisposes carriers to pleuropulmonary blastoma (PPB), Sertoli Leydig cell tumors, and several other rare benign and malignant tumors. The main thyroid manifestation is a goiter. DTC has been found in DICER1 syndrome patients with prior childhood diagnostic radiation exposure and chemotherapy treatments, suggesting a possible additional risk increase for DTC due to environmental exposure, rather than solely due to inherited genetic mutation [62].

With regards to other genetic variants that might increase the risk for DTC, most efforts thus far have been inconclusive and are based on analyses of rare individual families with a high incidence in DTC, but have not been confirmed in larger population studies. Recent reports suggest a 2-5 fold higher risk for individuals with any of the CHEK2 founder mutations (1100delC, IVS2 + 1G>A, del5395 and I157T) [63]. Decisions for CHEK2 genetic testing and surveillance of CHEK2 mutation carriers should depend on family history and patients may qualify for enhanced breast cancer screening (annual breast MRI).


Hereditary endocrine tumor syndromes are not uncommon, are likely underdiagnosed, and physician awareness of these syndromes can lead to an increase in index case identification. Often the suspicion for an inherited tumor syndrome can be raised by the observation of easily noticeable physical exam findings, and a detailed review of personal and family history of malignancies and endocrine diagnoses. It is important to remember that the family history can be entirely negative in syndromes with a high de novo gene mutation rate (e.g. VHL, LFS, NF1, FAP). The benefit in identification of an inherited tumor syndrome lies both in the ability to screen the index patient for other associated tumors, and family cascade screening to identify other at risk family members.

Endocrine tumor syndromes are an excellent example of specific challenges in clinical cancer genetics, particularly the multidisciplinary decision-making necessary to developing effective surveillance and therapy plans. It is important to understand that the goals of patient care in this population are to reduce morbidity and mortality associated with the underlying genetic condition, while at the same time keeping surveillance and therapy associated risks and costs at a necessary minimum.

Due to the lack of large studies evaluating surveillance and defining age-related penetrance of these syndromes, most recommendations are based on expert opinions. In general it is advisable to avoid screening associated risks, and to default to low risk procedures, e.g. non-radiation containing imaging. The starting age of screening in

mutation carriers should be determined by carefully balancing risks and benefits of the screening procedure. The decision for age of screening initiation should be based on the usual age of tumor occurrence rather than the ‘youngest age ever reported.’

In order to prevent major complications associated with endocrine tumor syndromes in patients who choose not to initiate or continue screening protocols, it is important to point out circumstances where evaluation is imperative. For example, for patients with hereditary predisposition to PCC/PGL, physicians should underscore the necessity of evaluating for hormonally-active tumors prior to any surgery or pregnancy. Morbidity and mortality due to hypertensive crisis in untreated PCC/PGL in both of these situations is significant and largely preventable.

The approach to management of tumors associated with endocrine tumor syndromes can be different from the management of sporadic cases. Observation and continued surveillance play a larger role in hereditary tumors, in an effort to prevent morbidity and mortality associated with invasive diagnostic or treatment procedures, and balancing the goals of cure, prevention, and anticipation of future recurrent or additional tumors. For example, most small and slow growing pNETs and RCCs in the setting of VHL can be followed on imaging until they reach a certain size or display accelerated growth. In cases requiring surgical intervention, the goal should be to keep complications and extent of surgery at a minimum, e.g. aiming for enucleations of pNETs rather than a full Whipple procedure, and aiming for partial adrenalectomies in patients with PCC in order to avoid adrenal insufficiency. In addition to surgical care, medical endocrine expertise

is vital for the successful medical management of hormone-producing tumors, which have a high rate of morbidity and complications due to hormonal excess. Patients with hereditary endocrine tumor syndromes might benefit from different therapies than patients with sporadic tumors, such as TKIs for patients with inoperable VHL- or MEN2associated tumors, or I131MIBG therapy or cytotoxic chemotherapy for SDHB-associated malignant PCC/PGL [64-66].

In conclusion, patients with hereditary tumor syndromes should be integrated into the multidisciplinary care team and empowered to make individual decisions when forming a personalized care plan. There should be an open discussion on the rationale of screening and therapy to provide appropriate expectations. Skilled genetic counselors can provide useful liaisons between physicians, patients, and their families. Guidelines should be used for guidance, but need to be considered in light of the social, financial and individual belief aspects of each patient. The goal of shared decision-making when devising an individualized surveillance program is to achieve patient adherence and ultimately reduce morbidity and mortality.

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Adrenocortical carcinoma Beckwith-Wiedemann syndrome Congenital Hypertrophy of the Retinal Pigment Epithelium Cribiform morullar variant of thyroid cancer Differentiated thyroid cancer Endolymphatic Sac Tumor Familial Adenomatous Polyposis Familial Medullary Thyroid Cancer Gastrointestinal Stromal Tumor Hereditary Paraganglioma Syndrome Hereditary Leiomyomatosis and Renal Cell Cancer Li-Fraumeni Syndrome Multiple Endocrine Neoplasia type 1 Multiple Endocrine Neoplasia type 2 Multinodular Goiter Malignant Nervesheath Tumor Medullary Thyroid Carcinoma Neuroendocrine Tumor Neurofibromatosis type 1 Next Generation Sequencing Pheochromocytoma Paraganglioma Primary Hyperparathyroidism PTEN Hamartoma Tumor Syndrome Pleuropulmonary Blastoma Renal Cell Cancer Succinate Dehydrogenase Subunit (A,B,C,D,AF2) Sertoli Leydig Cell Tumor von Hippel-Lindau Disease

Figure 1. Association of endocrine tumors (red boxes) with hereditary syndromes (orange boxes), gene mutations (blue boxes) and other syndrome associated tumors (green boxes)

Table 1. Endocrine tumors, major associated syndromes, indications for genetic evaluations, associated features and suggested surveillance for affected individuals and gene mutation carriers. Endocrine Tumor

Pheochromocytoma/ Paraganglioma

Adrenocortical Carcinoma

Consider ations for genetic testing every patient → suggest NGS panel including SDHx genes, RET, VHL, TMEM12 7, MAX, FH (3050% patients with germline mutation)

Major Gen syndromes es /tumors

Associate features/tu mors

Surveillance/ prevention


RCC, GIST, pituitary

Imaging every 1-2 years, annual plasma or urine metanephrine & normetanephri ne levels, annual physical exam, history and blood pressure

Hereditary Parganglio ma syndrome

von Hippel Lindau disease

Multiple Endocrine Neoplasia type 2A Multiple Endocrine Neoplasia type 2B Neurofibro matosis type 1


RCC, pNET, CNS/retinal hemangiobl astomas, ELST MTC, pHPT


MTC, Neuromas


gliomas, MNST, benign neural tumors brain, lung and breast cancer, leukemia, sarcomas

every Li Fraumeni TP5 3 patient → syndrome TP53 sequenci ng,

review images obtained for other purposes, annual clinical

del/dup, screen for LS by IHC or genetic testing

Neuroendocrine Tumors

Differentiated Thyroid Cancer (DTC)

testing only with suggestiv e personal or family history

testing only for patients with CMVPTC, or DTC with features suggestiv e of PHTS (e.g. uterine cancer, breast cancer,

Lynch syndrome

Multiple Endocrine Neoplasia type 1 von Hippel Lindau disease (nonfunctional pNETs) Multiple Endocrine Neoplasia type 1 (hormone producing or silent) Neurofibro matosis type 1 (somatotrop inomas) PHTS/Cow den's disease

MSH 2, MSH 6, MLH 1, PMS 2 MEN 1









colon, uterine, pancreas, sebaceous cancer

pHPT, pituitary tumors, foregut NET RCC, pNET, CNS/retinal hemangiobl astomas, ELST pHPT, pituitary tumors, foregut NET

gliomas, MNST, benign neural tumors macrocepha ly, uterine, breast cancer, MNG, colon cancer, duodenal adenoma, desmoid, CHRPE DICER1: MNG, SLCT, PPB, pituitary blastoma

evaluation, biochemcial evaluation for new tumors and hormoneproducing tumors

yearly imaging, annual physical exam, history, annual biochemical evaluation (MEN1)

Thyroid US every 2-5 years, annual physical exam


macroce phaly, acrokerat oses, trichilem momas)

Medullary Thyroid Cancer (MTC)

every patient → RET (up to 25% of apparantl y sporadic tumors positive)

Multiple Endocrine Neoplasia type 2A Multiple Endocrine Neoplasia type 2B Familial Medullary Thyroid Cancer


CHEK2: increased risk for breast cancer WRN: Werner syndrome MTC, pHPT

prophylactic thyroidectomy (age per ATA guidelines), annual calcitonin levels & US