REVIEW URRENT C OPINION
Inherited cancer syndromes and the thyroid: an update Rosemarie Metzger a and Mira Milas b
Purpose of review Knowledge related to hereditary thyroid cancer syndromes has expanded enormously. This review identifies contributions that have changed approaches to diagnosis and broadened treatment options for patients with hereditary medullary and nonmedullary thyroid cancers related to multiple endocrine neoplasia type 2 (MEN2), Cowden syndrome, and familial adenomatous polyposis (FAP). Recent findings A new risk-stratification scheme based on type of RET gene mutation informs the age at which prophylactic thyroidectomy and diagnostic screening for MEN-associated endocrine diseases should occur. Two new US Food and Drug Administration-approved targeted medical therapies are now available for medullary thyroid cancer. There is better understanding of more aggressive clinical features and increased lifetime cancer risks for patients with well differentiated thyroid cancers as part of families with and without Cowden syndrome or FAP. This has led to a clearer appreciation for the role and timing of thyroid ultrasound screening in these populations. It has also informed the appropriate extent of thyroid surgery and the circumstances in which prophylactic thyroidectomy is reasonable to consider as part of hereditary syndromes other than MEN2. Summary Recognition and early diagnosis of these syndromes allows for comprehensive medical care and may improve thyroid cancer-related outcomes. Ultrasound-based screening programs to detect thyroid disease are advised for patients and family members with hereditary cancer syndromes. Keywords Cowden syndrome, familial adenomatous polyposis, familial nonmedullary thyroid cancer, medullary thyroid cancer, multiple endocrine neoplasia
INTRODUCTION Thyroid cancer remains the most common endocrine malignancy and has demonstrated a steadily increasing worldwide incidence [1]. In the United States alone, based on rates from 2008 to 2010, one in 92 people will be diagnosed with thyroid cancer in their lifetime [2]. The cell line from which the cancer originates determines the subtype: parafollicular C cells for medullary thyroid cancer (MTC) and follicular cells for nonmedullary thyroid cancer (NMTC). NMTC is further subdivided into papillary and follicular thyroid cancers (PTC and FTC). Both MTC and NMTC can occur sporadically or as part of an inherited syndrome or familial predisposition. This review will focus on updating the diagnosis, management, and innovation surrounding hereditary medullary thyroid cancer (HMTC), nonsyndromic familial nonmedullary thyroid cancer (FNMTC), and NMTC associated with inherited
syndromes including Cowden syndrome and familial adenomatous polyposis (FAP).
HEREDITARY MEDULLARY THYROID CANCER HMTC is a component of multiple endocrine neoplasia type 2 (MEN2), which is further subclassified into three groups: MEN2A, familial MTC (FMTC), a Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio and bDepartment of Surgery, Oregon Health and Sciences University, Portland, Oregon, USA
Correspondence to Mira Milas, MD, Division of Surgical Oncology, Oregon Health and Sciences University (OHSU), 3181 SW Sam Jackson Park Rd #L619, Portland, OR 97239, USA. Tel: +1 503 494 2277; e-mail: [email protected] Curr Opin Oncol 2014, 26:51–61 DOI:10.1097/CCO.0000000000000030
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Endocrine tumors
KEY POINTS Consideration of the presence of hereditary thyroid cancer syndromes should be part of an initial clinical visit for patients with benign or malignant thyroid disease. Two or more first-degree relatives with papillary thyroid cancer raise question of familial and more aggressive thyroid cancer. Lifetime cancer risks, including for thyroid cancer, have been defined for individuals with PTEN gene mutations. Risk stratification by RET gene mutation and new medical therapies are available for patients with hereditary medullary thyroid cancers. Ultrasound-based screening for thyroid disease is part of evaluation of patients with FAP and Cowden syndrome.
Update on management
and MEN2B. A germline mutation in the RET oncogene is identified in 98% of individuals with MEN2A, almost 95% with FMTC, and more than 98% with MEN2B [3]. The RET oncogene encodes a tyrosine kinase receptor protein. Gain-of-function mutations in exons 10 and 11 (extracellular region) or in exons 13–16 (intracellular tyrosine kinase domain) lead to HMTC; a small percentage of HMTC families will have mutations in exons 5 and 8 [4]. Castro et al. [5] recently discovered a rare exon 8 mutation (G533C) in a family with MEN2A in the United States, which had only been previously identified in one Brazilian and four unrelated Greek families [6–9]. MEN2A patients are characterized by MTC (95%), pheochromocytoma (PHEO; 50%), and primary hyperparathyroidism (PHPT; 20–30%); MEN2B patients develop an earlier, more aggressive MTC (100%), and have marfanoid habitus (75%) and mucosal neuromas. PHEOs can develop in 50%; hyperparathyroidism is not seen. FMTC is typically classified as a phenotypic variant of MEN2A with decreased penetrance of PHEO and hyperparathyroidism [3,10]. We now know genotype–phenotype characterizations for specific RET codon mutations, and have better understanding of age-related progression from C cell hyperplasia (CCH) to node-negative disease to node-positive disease (Table 1) [11]. This knowledge continues to affect the way in which HMTC is diagnosed, managed, and treated, and is beautifully summarized by Machens and Dralle in a recent review [12 ]. &
Update on diagnosis With the advent of DNA-based screening, RET mutation carriers who have not yet developed 52
www.co-oncology.com
disease can now be identified. Recognizing this diagnostic improvement, Machens et al. [13] hypothesized that the actual incidence of RET mutations would be higher than 1: 200 000, the most recently estimated population incidence [4]. Retrospective analysis of carriers with missense germline mutations in codons 609, 611, 618, 620, 630, 634, 768, 790, 791, 804, 891, or 918 of the RET proto-oncogene was used to calculate the minimum incidence rate of RET germline mutations in Germany. The minimum annual incidence rate was calculated to be 1 : 100 000, twice that of popular knowledge. Although limited by a specific, geographically defined population, the paper reinforces the need for genetic testing of all HMTC kindreds, not only those who manifest clinical symptoms [13].
The 2009 American Thyroid Association (ATA) guidelines on the management of MTC established generally accepted strategies for diagnosing, evaluating, managing, and following MTC [10], but controversies remain [14]. These include optimal range of RET mutations to be tested (e.g., exon 8) and the role of serum calcitonin in guiding the timing of prophylactic thyroidectomy. Jarzab et al. [15] reviewed recent European efforts to integrate calcitonin measurement into prophylactic thyroidectomy decision-making, stating that ATA indications were arbitrary and timing decisions needed reinforcement with serum calcitonin levels. Elisei et al. [16] have proposed personalizing the timing of thyroidectomy by delaying surgery until stimulated calcitonin becomes positive, independent of the type of RET mutation or patient age. In their study, 84 RET gene mutation carriers with MEN2A or FMTC gave consent for surgical intervention only when pentagastrin-stimulated calcitonin was elevated, regardless of specific mutation or age. Fifty-three gene mutation carriers underwent total thyroidectomy and central neck dissection. MTC was identified in every patient with a basal calcitonin above 10 pg/ml (n ¼ 20). Values between 10 and 60 pg/ml corresponded to microMTC (less than 1.0 cm) without lymph node metastases. Basal calcitonin more than 60 pg/ml was found in those with large tumors (T2, N0; n ¼ 1), extrathyroidal extension (T3, N0; n ¼ 1), or lymph node metastases (n ¼ 8), of which two were in the lateral neck. Of those with normal basal calcitonin and elevated stimulated calcitonin (n ¼ 31), 25 had microMTC and six had CCH; no lymph node metastases or extrathyroidal extension was noted. Two gene mutation carriers with normal calcitonin underwent thyroidectomy for other reasons; CCH was found in one. In summary, of Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inherited cancer syndromes and thyroid Metzger and Milas Table 1. Genotype–phenotype characterizations for specific RET codon mutations and associated risk level MEN 2Ab Codon
FMTCa
MTC
5
321
þ
8
515
þ
533
þ
609
þ
611
þ
618 620
Exon Extracellular cystein-rich domain
10
11
13
14
15
16
PHEO
MTC
PHEO
ATA risk levelc A A
A
B
B
þ
B
þ
B
630
þ
B
631
þ
634
þ/
634 bp dup
Intracellular tyrosine kinase domain
PHPT
MEN 2Bb
d
B
þ
649
þ
666
þ
/
768
þ
777
þ
790
þ
791
C B A
A
A
/
A
þ
A
804
þ
/
A
804þ805
D
804þ806
D
804þ904
819
þ
A
833
þ
A
844
þ
866
þ
883
891
þ
912
þ
918
A
D
A A
D A
A
D
ATA, American Thyroid Association. a Inheritance (þ) of medullary thyroid cancer (MTC) without primary hyperparathyroidism (PHPT) or pheochromocytoma (PHEO) has been described. Familial MTC (FMTC) () when MTC in isolation is highly unlikely. b Phenotype penetrance: Most cases, Few cases, Rare. c A – may delay surgery beyond 5 years if criteria met§; B – consider surgery before age 5 and may delay if criteria met§; C – surgery before age 5 years; D – as soon as possible within the first year of life. Symbol § indicates criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC. d Base pair duplication. Adapted from [10].
51 gene mutation carriers who had either elevated basal calcitonin (>10 pg/ml) or elevated stimulated calcitonin (>10 pg/ml), all but six had MTC identified in their final pathology. Seven patients (all from the group with basal calcitonin >60 pg/ml) had biochemical or metastatic disease in followup [16]. Elisei et al., therefore, contend personalizing prophylactic thyroidectomy to the time when basal calcitonin remains normal, but stimulated
calcitonin rises, can be curative as the disease is intrathyroidal only. As pentagastrin is not globally available, calcium-stimulated calcitonin was contemplated as a comparable alternative. To date, no studies have compared pentagastrin to calcium-stimulated calcitonin. The study by Elisei et al. [16] provokes the larger question of whether the goal of prophylactic thyroidectomy is to prevent MTC formation or to
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
53
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
54
www.co-oncology.com
Inherited cancer syndromes and the thyroid: an update Rosemarie Metzger a and Mira Milas b
Purpose of review Knowledge related to hereditary thyroid cancer syndromes has expanded enormously. This review identifies contributions that have changed approaches to diagnosis and broadened treatment options for patients with hereditary medullary and nonmedullary thyroid cancers related to multiple endocrine neoplasia type 2 (MEN2), Cowden syndrome, and familial adenomatous polyposis (FAP). Recent findings A new risk-stratification scheme based on type of RET gene mutation informs the age at which prophylactic thyroidectomy and diagnostic screening for MEN-associated endocrine diseases should occur. Two new US Food and Drug Administration-approved targeted medical therapies are now available for medullary thyroid cancer. There is better understanding of more aggressive clinical features and increased lifetime cancer risks for patients with well differentiated thyroid cancers as part of families with and without Cowden syndrome or FAP. This has led to a clearer appreciation for the role and timing of thyroid ultrasound screening in these populations. It has also informed the appropriate extent of thyroid surgery and the circumstances in which prophylactic thyroidectomy is reasonable to consider as part of hereditary syndromes other than MEN2. Summary Recognition and early diagnosis of these syndromes allows for comprehensive medical care and may improve thyroid cancer-related outcomes. Ultrasound-based screening programs to detect thyroid disease are advised for patients and family members with hereditary cancer syndromes. Keywords Cowden syndrome, familial adenomatous polyposis, familial nonmedullary thyroid cancer, medullary thyroid cancer, multiple endocrine neoplasia
INTRODUCTION Thyroid cancer remains the most common endocrine malignancy and has demonstrated a steadily increasing worldwide incidence [1]. In the United States alone, based on rates from 2008 to 2010, one in 92 people will be diagnosed with thyroid cancer in their lifetime [2]. The cell line from which the cancer originates determines the subtype: parafollicular C cells for medullary thyroid cancer (MTC) and follicular cells for nonmedullary thyroid cancer (NMTC). NMTC is further subdivided into papillary and follicular thyroid cancers (PTC and FTC). Both MTC and NMTC can occur sporadically or as part of an inherited syndrome or familial predisposition. This review will focus on updating the diagnosis, management, and innovation surrounding hereditary medullary thyroid cancer (HMTC), nonsyndromic familial nonmedullary thyroid cancer (FNMTC), and NMTC associated with inherited
syndromes including Cowden syndrome and familial adenomatous polyposis (FAP).
HEREDITARY MEDULLARY THYROID CANCER HMTC is a component of multiple endocrine neoplasia type 2 (MEN2), which is further subclassified into three groups: MEN2A, familial MTC (FMTC), a Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio and bDepartment of Surgery, Oregon Health and Sciences University, Portland, Oregon, USA
Correspondence to Mira Milas, MD, Division of Surgical Oncology, Oregon Health and Sciences University (OHSU), 3181 SW Sam Jackson Park Rd #L619, Portland, OR 97239, USA. Tel: +1 503 494 2277; e-mail: [email protected] Curr Opin Oncol 2014, 26:51–61 DOI:10.1097/CCO.0000000000000030
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Endocrine tumors
KEY POINTS Consideration of the presence of hereditary thyroid cancer syndromes should be part of an initial clinical visit for patients with benign or malignant thyroid disease. Two or more first-degree relatives with papillary thyroid cancer raise question of familial and more aggressive thyroid cancer. Lifetime cancer risks, including for thyroid cancer, have been defined for individuals with PTEN gene mutations. Risk stratification by RET gene mutation and new medical therapies are available for patients with hereditary medullary thyroid cancers. Ultrasound-based screening for thyroid disease is part of evaluation of patients with FAP and Cowden syndrome.
Update on management
and MEN2B. A germline mutation in the RET oncogene is identified in 98% of individuals with MEN2A, almost 95% with FMTC, and more than 98% with MEN2B [3]. The RET oncogene encodes a tyrosine kinase receptor protein. Gain-of-function mutations in exons 10 and 11 (extracellular region) or in exons 13–16 (intracellular tyrosine kinase domain) lead to HMTC; a small percentage of HMTC families will have mutations in exons 5 and 8 [4]. Castro et al. [5] recently discovered a rare exon 8 mutation (G533C) in a family with MEN2A in the United States, which had only been previously identified in one Brazilian and four unrelated Greek families [6–9]. MEN2A patients are characterized by MTC (95%), pheochromocytoma (PHEO; 50%), and primary hyperparathyroidism (PHPT; 20–30%); MEN2B patients develop an earlier, more aggressive MTC (100%), and have marfanoid habitus (75%) and mucosal neuromas. PHEOs can develop in 50%; hyperparathyroidism is not seen. FMTC is typically classified as a phenotypic variant of MEN2A with decreased penetrance of PHEO and hyperparathyroidism [3,10]. We now know genotype–phenotype characterizations for specific RET codon mutations, and have better understanding of age-related progression from C cell hyperplasia (CCH) to node-negative disease to node-positive disease (Table 1) [11]. This knowledge continues to affect the way in which HMTC is diagnosed, managed, and treated, and is beautifully summarized by Machens and Dralle in a recent review [12 ]. &
Update on diagnosis With the advent of DNA-based screening, RET mutation carriers who have not yet developed 52
www.co-oncology.com
disease can now be identified. Recognizing this diagnostic improvement, Machens et al. [13] hypothesized that the actual incidence of RET mutations would be higher than 1: 200 000, the most recently estimated population incidence [4]. Retrospective analysis of carriers with missense germline mutations in codons 609, 611, 618, 620, 630, 634, 768, 790, 791, 804, 891, or 918 of the RET proto-oncogene was used to calculate the minimum incidence rate of RET germline mutations in Germany. The minimum annual incidence rate was calculated to be 1 : 100 000, twice that of popular knowledge. Although limited by a specific, geographically defined population, the paper reinforces the need for genetic testing of all HMTC kindreds, not only those who manifest clinical symptoms [13].
The 2009 American Thyroid Association (ATA) guidelines on the management of MTC established generally accepted strategies for diagnosing, evaluating, managing, and following MTC [10], but controversies remain [14]. These include optimal range of RET mutations to be tested (e.g., exon 8) and the role of serum calcitonin in guiding the timing of prophylactic thyroidectomy. Jarzab et al. [15] reviewed recent European efforts to integrate calcitonin measurement into prophylactic thyroidectomy decision-making, stating that ATA indications were arbitrary and timing decisions needed reinforcement with serum calcitonin levels. Elisei et al. [16] have proposed personalizing the timing of thyroidectomy by delaying surgery until stimulated calcitonin becomes positive, independent of the type of RET mutation or patient age. In their study, 84 RET gene mutation carriers with MEN2A or FMTC gave consent for surgical intervention only when pentagastrin-stimulated calcitonin was elevated, regardless of specific mutation or age. Fifty-three gene mutation carriers underwent total thyroidectomy and central neck dissection. MTC was identified in every patient with a basal calcitonin above 10 pg/ml (n ¼ 20). Values between 10 and 60 pg/ml corresponded to microMTC (less than 1.0 cm) without lymph node metastases. Basal calcitonin more than 60 pg/ml was found in those with large tumors (T2, N0; n ¼ 1), extrathyroidal extension (T3, N0; n ¼ 1), or lymph node metastases (n ¼ 8), of which two were in the lateral neck. Of those with normal basal calcitonin and elevated stimulated calcitonin (n ¼ 31), 25 had microMTC and six had CCH; no lymph node metastases or extrathyroidal extension was noted. Two gene mutation carriers with normal calcitonin underwent thyroidectomy for other reasons; CCH was found in one. In summary, of Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inherited cancer syndromes and thyroid Metzger and Milas Table 1. Genotype–phenotype characterizations for specific RET codon mutations and associated risk level MEN 2Ab Codon
FMTCa
MTC
5
321
þ
8
515
þ
533
þ
609
þ
611
þ
618 620
Exon Extracellular cystein-rich domain
10
11
13
14
15
16
PHEO
MTC
PHEO
ATA risk levelc A A
A
B
B
þ
B
þ
B
630
þ
B
631
þ
634
þ/
634 bp dup
Intracellular tyrosine kinase domain
PHPT
MEN 2Bb
d
B
þ
649
þ
666
þ
/
768
þ
777
þ
790
þ
791
C B A
A
A
/
A
þ
A
804
þ
/
A
804þ805
D
804þ806
D
804þ904
819
þ
A
833
þ
A
844
þ
866
þ
883
891
þ
912
þ
918
A
D
A A
D A
A
D
ATA, American Thyroid Association. a Inheritance (þ) of medullary thyroid cancer (MTC) without primary hyperparathyroidism (PHPT) or pheochromocytoma (PHEO) has been described. Familial MTC (FMTC) () when MTC in isolation is highly unlikely. b Phenotype penetrance: Most cases, Few cases, Rare. c A – may delay surgery beyond 5 years if criteria met§; B – consider surgery before age 5 and may delay if criteria met§; C – surgery before age 5 years; D – as soon as possible within the first year of life. Symbol § indicates criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC. d Base pair duplication. Adapted from [10].
51 gene mutation carriers who had either elevated basal calcitonin (>10 pg/ml) or elevated stimulated calcitonin (>10 pg/ml), all but six had MTC identified in their final pathology. Seven patients (all from the group with basal calcitonin >60 pg/ml) had biochemical or metastatic disease in followup [16]. Elisei et al., therefore, contend personalizing prophylactic thyroidectomy to the time when basal calcitonin remains normal, but stimulated
calcitonin rises, can be curative as the disease is intrathyroidal only. As pentagastrin is not globally available, calcium-stimulated calcitonin was contemplated as a comparable alternative. To date, no studies have compared pentagastrin to calcium-stimulated calcitonin. The study by Elisei et al. [16] provokes the larger question of whether the goal of prophylactic thyroidectomy is to prevent MTC formation or to
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
53
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
54
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