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Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®) 6/6 –Health Professional Version - National Cancer Institute

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version

Familial Nonmedullary Thyroid Cancer

Clinical Description

Papillary and follicular cancers, along with their various histologic subtypes, arise from the follicular cells of the thyroid and are collectively referred to as differentiated thyroid cancer or nonmedullary thyroid cancer (NMTC). Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, comprising nearly 85% of all cases, and is rapidly increasing in incidence worldwide.[1,2]
Radiation exposure, particularly during childhood, has been extensively studied as a causative factor in the development of thyroid cancer; however, it accounts for only a small minority of cases.[3,4] One of the strongest risk factors for the development of thyroid cancer is a family history of the disease, in which cases are termed familial nonmedullary thyroid cancer (FNMTC). The exact incidence of FNMTC is difficult to determine because the criteria used to qualify as a heritable condition varies among studies. Criteria that have yet to be universally defined include the number of affected relatives and their relationship (i.e., first-degree relativessecond-degree relatives, etc.), pattern of inheritance, and the presence of coexisting thyroid conditions.
Further confounding the distinction between inherited and sporadic disease is the high prevalence of incidental microcarcinomas, which may be found in 10% to 15% of surgeries or autopsies.[5] Because there are no identifiable genes transmitted in the majority of families, this high background prevalence of disease poses a challenge in assessing the risk of a thyroid malignancy in other family members. This uncertainty may be especially problematic when there are borderline cases of inherited disease; for example, two second-degree relatives with thyroid cancer.
FNMTC may be part of a larger syndrome associated with tumors involving other organs or may represent a stand-alone condition. Table 7 outlines the various hereditary syndromes associated with NMTC.

Genetics, Inheritance, and Genetic Testing

The genetics of familial medullary thyroid cancer (FMTC) in the context of multiple endocrine neoplasia type 2 are well established. Genetic factors also clearly contribute to NMTC, as it has one of the highest heritabilities of any cancer site, with a relative risk of fivefold to tenfold for relatives of patients, especially (female) siblings.[6-9] FNMTC, which includes follicular subtypes, primarily papillary, is thought to account for 5% to 10% of all NMTC cases.[6,10,11] Notably, when there are only two individuals affected in a family, there is a 40% to 60% chance that the disease is actually sporadic, whereas when three or more family members are affected there is a 96% chance the disease has an inherited component.[12] With the exception of a few rare genetic syndromes with NMTC as a minor component, the majority of FNMTC is nonsyndromic and the underlying genetic predisposition is unclear. Still, the term familial cancer is somewhat misleading as FNMTC pedigrees demonstrate a definitive mendelian pattern of inheritance which is autosomal dominant with incomplete penetrance and variable expressivity.[6,13-16] However, unlike FMTC, FNMTC is a polygenic disease with no single locus responsible for the majority of cases or easily identifiable phenotype and it is likely modified by multiple low-penetrance alleles and environmental factors.[17]

Ruling out syndromic FNMTC

As there is no clinical genetic testing for nonsyndromic FNMTC, identification of at-risk families must rely on astute clinicians obtaining a thorough clinical examination and detailed personal and family history of any patient presenting with thyroid cancer or disease. Aspects of a history that suggest FNMTC include multiple generations affected, early-onset bilateral/multifocal thyroid tumors (especially in males) with a more aggressive clinical course, and association with benign thyroid pathologies.[18] Detailed work-up is critical in FNMTC as it is ultimately a diagnosis of exclusion in the sense that other familial cancer predisposition syndromes associated with NMTC must first be ruled out, such as Cowden syndrome or familial adenomatous polyposis. These differential diagnoses for FNMTC are outlined in Table 7. Notably, the association of NMTC with McCune-Albright, Peutz-Jeghers, ataxia-telangiectasia, and multiple endocrine neoplasia type 1 syndromes is less established.
Table 7. Hereditary Syndromes Associated With Nonmedullary Thyroid Cancera
ENLARGE
SyndromeGeneInheritanceIncidence of Thyroid Cancer (%)Type of Thyroid CancerExtrathyroidal Clinical Features
FAP = familial adenomatous polyposis; FTC = follicular thyroid cancer; MNG = multinodular goiter; PTC = papillary thyroid cancer.
aAdapted from Nose,[19] Sturgeon et al.,[20] and Vriens et al.[18]
FAP/Gardner syndromeAPCAutosomal dominant2PTC (cribriform morular variant)Gastrointestinal adenomatous polyps; Gardner syndrome also includes desmoid tumors, supernumerary teeth, fibrous dysplasia of skull, osteomas, epidermoid cysts, hypertrophy of retinal epithelium.
Cowden syndrome (PTEN hamartoma syndrome)PTEN (rarely SDHxKLLNAKT1PIK3CA)Autosomal dominant10–35FTC, PTCMalignant tumors and hamartomas of breast, endometrium, thyroid, kidney, gastrointestinal tract, brain, skin.
Carney complexPRKAR1αAutosomal dominant11–15FTC, PTCMyxomas of soft tissues, skin and mucosal pigmentation (blue nevi), schwannomas, tumors of adrenal, pituitary and testicle.
Werner syndromeWRNAutosomal recessive18FTC, anaplastic PTCPremature aging (adult progeria), scleroderma-like skin changes, cataracts, subcutaneous calcifications, muscular atrophy, diabetes.
DICER1 syndromeDICER1Autosomal dominantUnknownPTC (and MNG)Familial pleuropulmonary blastoma; cystic nephroma; ovarian Sertoli-Leydig cell tumors.
McCune-Albright syndromeGNASMosaic somatic mutationsUnknownFTCPolyostotic fibrous dysplasia, café-au-lait spots, endocrine hyperfunction of pituitary, adrenal, gonadal tissues.
Peutz-Jeghers syndromeSTK11 (LKB1)Autosomal dominantUnknownPrimarily PTCHamartomas of small intestine, mucocutaneous hyperpigmentation, Sertoli cell testicular tumors.
Ataxia-telangiectasiaATMAutosomal recessiveUnknownPrimarily PTCCerebellar ataxia and nystagmus, oculocutaneous telangiectasia, immunodeficiency, lymphoreticular cancers.
Multiple endocrine neoplasia type 1 (MEN1)MEN1Autosomal dominantUnknownPrimarily PTCTumors of parathyroid glands, endocrine gastroenteropancreatic tract, anterior pituitary gland.

Identifying genes and inherited variants associated with nonsyndromic FNMTC

Various methods have been employed to uncover the landscape of genetic variation associated with FNMTC, mainly genome-wide linkage analysis using microsatellite markers evenly distributed across the genome and informative large pedigrees with multiple affected family members. More than 15 genetic loci have been linked to FNMTC, which are summarized in Table 8. The loci that are italicized represent those where the susceptibility gene has been identified; the causal genes at the other loci remain unknown. The first four loci were identified by microsatellite linkage analysis. The remaining loci have been identified by increasingly dense single nucleotide polymorphism (SNP) arrays as well as microRNA arrays and, most recently, next-generation sequencing. (Refer to the PDQ Cancer Genetics Overview summary for more information about linkage analysis and next-generation sequencing.) Most of these studies have been done on groups of families with pedigrees consistent with FNMTC; however, two of the loci were identified through large, population level SNP array analysis. It is important to note that several studies have excluded the genes that are most commonly somatically altered in association with sporadic NMTC as having a role in FNMTC, namely BRAFRETRET/PTCMETMEK1MEK2RAS, and NTRK.[21]
Table 8. Nonsyndromic Familial Nonmedullary Thyroid Cancer Susceptibility Loci
ENLARGE
LocusLocationTumor TypeSample SizeaStudy TypeOriginal Cohort Country of OriginYearReferences
FTC = follicular thyroid cancer; MNG = multinodular goiter; miRNA = microRNA; NMTC = nonmedullary thyroid cancer; PRN = papillary renal neoplasia; PTC = papillary thyroid cancer; SNP = single nucleotide polymorphism; WES = whole-exome sequencing.
aCombined across studies.
MNG114q31MNG with PTCkindredMicrosatellite linkageCanada1997[22]
18 MNG
2 PTC
TCO19p13.2PTC with oxyphilia1 kindredMicrosatellite linkageFrance1998[23-26]
20 families
6 MNG
3 PTC
49 NMTC
fPTC/PRN1q21PTC with PRN1 kindredMicrosatellite linkageUnited States2000[27]
5 PTC
2 PRN
NMTC12q21PTC (follicular variant)1 kindred, 80 pedigreesMicrosatellite linkageTasmania2001[25,26,28]
19 families
49 NMTC
FTEN8p23.1-p22PTC (classic)1 kindred10K SNP arrayPortugal2008[29]
11 benign
5 NMTC
Unknown8q24PTC with melanoma26 families50K SNP arrayUnited States2009[30]
FOXE19q22.33PTC/FTC60 families300K SNP arrayIceland/Spain/United States2009[31]
197 PTC/FTC
NKX2-1/TITF-114q13.3PTC and MNG60 families300K SNP arrayIceland/United States/Spain2009[31]
197 PTC/FTC
Unknown6q22PTC/FTC (classic)38 families50K SNP arrayUnited States/Italy2009[32]
49 PTC
miR-886-3p5q31.2PTC21 PTC3K miRNA arrayUnited States2011[33]
7 FNMTC
10 normal thyroid tissue
miR-20a13q31.3PTC21 PTC3K miRNA arrayUnited States2011[33]
7 FNMTC
10 normal thyroid tissue
Telomere-telomerase complex (TERT, TRF1, TFR2, RAP1, TIN2, TPP1, POT1)5p15.3 (TERT), etc.PTC47 PTC  2008[34]
SRGAP112q14PTC38 families250K SNP arrayUnited States/Poland2013[35]
HAPB210q25-26PTC, follicular adenoma1 kindredWESUnited States2015[36]
7 PTC
RTFC (c14orf93)14q11.2PTC15 familiesWESChina2017[37]
Susceptibility loci identified through linkage analyses
MNG1, TCO, fPTC/PRN and NMTC1 are proposed FNMTC susceptibility loci identified in families with multiple affected individuals and are summarized in Table 8. Conflicting evidence exists regarding the linkage to the loci described above. MNG1 has shown strong evidence of linkage in only one Canadian kindred with multiple multinodular goiters (MNGs) and linkage analyses in 124 additional families failed to find an association between MNG1 and FNMTC. Therefore, the locus may be important for MNG alone but not for FNMTC.[22,23,27,38-40] TCO accounts for a minority of FNMTC cases, but specifically those associated with tumor cell oxyphilia, which is a rare morphology that does not apply to the majority of FNMTC cases ascertained.[23-26] fPTC/PRN is also a rare subtype of FNMTC in which PTC is associated with papillary renal neoplasia, but other than the original family reported, no additional families sharing this phenotype have been identified.[23,27,40] NMTC1 seems to predispose to the follicular variant of PTC, another rare subtype. Classic PTC and oxyphilic tumors are also associated with this locus, though to a lesser extent.[25,25,28] In 2001, a comprehensive mutation and linkage analysis of 22 international FNMTC families revealed that only one family had significant linkage to any known susceptibility locus (TCO in this case), including the ones described above.[23] This cumulative evidence suggests that these FNMTC loci account for disease in a small subset of families, which is consistent with the concept that FNMTC exhibits genetic and locus heterogeneity.
Susceptibility loci identified through genome-wide SNP arrays
Five FNMTC loci have been identified through increasingly dense SNP arrays, also listed in Table 8. The first FNMTC study done by SNP array along with microsatellite analysis was in 2008 in a Portuguese family.[29] This family had five members with PTC (4 classic and 1 follicular variant) and 11 members with benign thyroid diseases. The susceptibility locus was identified at 8p23.1-p22 and designated FTEN (familial thyroid epithelial neoplasia). The 8q24 locus was first identified from a linkage analysis study using SNP arrays of 26 FNMTC families (with PTC). One family had three generations of PTC and melanoma (and MNG); but melanoma was not reported in the other 25 families. Sequencing of genes in the 8q24 region did not reveal any candidate pathogenic variants, but gene expression analysis indicated AK023948 (PTSCC1), a noncoding RNA gene that is downregulated in PTC, could be involved.[30]
In 2009, a population-level study was done in Iceland on 197 cases of PTC or FTC and compared with genotypes of 37,196 Icelandic controls.[31] Two loci had high statistical significance, 9q22.33 and 14q13.3, which are near the genes FOXE1 and NKX2-1, respectively. Two SNPs in particular were associated with increased risk of PTC and FTC: rs944289 (near NKX2-1) and rs965513 (near FOXE1). These results were replicated in two additional large cohorts from the United States (726 individuals tested) and Spain (1,433 individuals tested), as well as other cohorts that also found additional SNPs of interest, particularly in FOXE1.[31,41,42FOXE1 remains a gene of interest in FNMTC because it produces a thyroid transcription factor with a key role in thyroid gland formation, differentiation, and function.[43] The NKX2.1/TITF-1 gene also encodes a thyroid transcription factor. A germline variant, A339V, has been reported in two FNMTC families affected with MNG or PTC/MNG;[44] however, this association could not be replicated in subsequent studies of other families.[45] Lastly, a large United States and Italian cohort (110 individuals, 49 affected, from 28 FNMTC families) was studied using a 50K SNP array. The majority of these families had classic PTC. The pooled analysis showed linkage to previously identified 1q21 locus (PRN) and a new locus at 6q22.[32]
MicroRNA (miRNA) susceptibility loci
miRNAs are small noncoding RNAs that regulate gene expression. Whole-genome miRNA microarrays were used to evaluate 21 sporadic and seven familial NMTC cases, as well as ten normal thyroid tissue samples.[33] Two miRNAs, miR-20a (13q31.3) and miR-886-3p (5q31.2), were differentially expressed between sporadic and familial NMTC, as confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Both were also downregulated in NMTC compared with normal thyroid tissues by fourfold. Cell-line transfection studies using miR-886-3p confirmed that it plays a critical role in cell proliferation and migration and it regulates genes involved in DNA replication and focal adhesion pathways.[33] Furthermore, a polymorphism in pre-miR-146a (rs2910164) has been shown to affect miRNA expression and was identified in a significant proportion of the tumors of 608 PTC patients, suggesting it could contribute to genetic predisposition to PTC and play a role in the tumorigenesis through somatic changes.[46] The role of gene regulatory mechanisms and their effect on gene expression and FNMTC tumorigenesis warrants further exploration.
Telomere-telomerase complex
Telomeres are noncoding chromosomal ends consisting of tandem repeats that are important in maintaining chromosomal stability. Telomere length is maintained by a telomerase complex that includes telomerase reverse transcriptase (TERT), along with six other proteins: TRF1, TFR2, RAP1, TIN2, TPP1, and POT1.[47] Shortened telomere length is associated with chromosomal instability that can play a role in cancer development. The telomere-telomerase complex has become a focus of investigation as another possible genetic mechanism for predisposition to FNMTC. In 2008, a cohort of patients with FNMTC was studied using qualitative PCR and fluorescence in situ hybridization to evaluate relative telomere length.[34] They found that telomere length was significantly shorter in familial PTC patients compared with unaffected family members and sporadic PTC. The same group also found that the telomeres in FNMTC cancers were relatively fragile and had a high rate of fragment formation.[48] A second study of telomere length in FNMTC also showed shorter telomere lengths in 13 affected patients compared with 31 unaffected family members.[49] However, the same study showed that relative telomere length was not associated with altered copy number or expression of telomere complex genes hTERTTRF1TFR2RAP1TIN2TPP1, or POT1. Other studies have failed to show any significant differences in telomere length between FNMTC and sporadic PTC cases.[50] The role and mechanism of the telomere-telomerase complex in predisposition to FNMTC remains to be elucidated.
Other recently identified FNMTC susceptibility genes and variants
SRGAP1 is a gene that was identified in 2013 through genome-wide linkage analysis of 38 FNMTC families with PTC from the United States and Poland.[35] Four germline missense variants were identified but two variants, Q149H and A275T, were most notable because they segregated in two separate families but not in 800 sporadic cases. SRGAP1 regulates the small G-protein CDC42 in neurons and affects cell mobility.[51] Functional assays demonstrated that Q149H and R617C variants in SRGAP1 could lead to loss-of-function changes that impair ability to inactivate CDC42, which could lead to tumorigenesis.[35] Further studies are needed to validate the association of this gene in other FNMTC cohorts.
HAPB2 was identified in 2015 through whole-exome sequencing (WES) of seven affected members of an FNMTC kindred with PTC and follicular adenoma, using unaffected spouses as controls.[36] One specific germline variant, G534E, was found in the heterozygous state in all affected cases. The group also detected this variant, through next-generation sequencing, in 4.7% of NMTC cases from the Cancer Genome Atlas. It was associated with increased protein expression in thyroid neoplasms from affected family members compared with normal thyroid tissue or sporadic PTC. Functional studies of G534E showed that it increased colony formation and cellular migration, suggesting a loss of tumor suppression function. Notably, the authors used a criterion of general population frequency of 1% or less to filter variants identified in this kindred using the 1000 Genomes Project (phase III) and HapMap3. However, subsequent correspondences commented on higher reported frequencies of G534E variants from public databases including that of the Exome Aggregation Consortium (ExAC) (2.22% in total population, 3.29% in non-Finnish Europeans) and the National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity Exome Sequencing Project database (5.5% in total, 3.88% in Americans of European descent).[52-54] Many additional studies have been conducted to ascertain the frequency of HAPB2 G534E in FNMTC with variable results. While the variant was not identified in 12 Chinese FNMTC families with PTC (nor in 217 patients with sporadic PTC) [54] or in 11 Middle Eastern FNMTC family members,[55] it was shown to segregate in several independent FNMTC kindreds with PTC from a United States study.[56] Several other studies have shown that the G534E variant has greater or equal frequency in controls and sporadic cases than in familial cases of PTC, even if it was identified in their cohort at all, or did not segregate with disease in the family.[55,57-59] Therefore, it seems that the HAPB2 G534E variant frequency differs among ancestries and populations, being low-to-moderate in European ancestry and low or absent in Asian and Middle Eastern populations. Larger validation studies are required to determine its role and association with FNMTC.
Lastly, RTFC (c14orf93) was identified through WES of FNMTC families in China.[37] Three genes were identified as candidate genes for FNMTC (RTFCPYGL, and BMP4) but the RTFC gene was the only one shown to have oncogenic function in promoting thyroid cancer cell survival under starving conditions and promoting cell migration and colony-forming capacity. Specifically, the V205M (c.613G>C) variant in RTFC was important because it was identified in FNMTC patients but absent in unaffected controls. Two additional oncogenic mutations of RTFC were identified (R115Q and G209D) in sporadic NMTC patients. Collectively, the frequencies of these variants in ExAC in East Asian populations are higher than frequencies in the total population, which could be an indicator of this gene being most relevant in East Asian FNMTC families. Larger validation studies of this gene and these variants need to be conducted.
In summary, although multiple susceptibility loci have been identified in FNMTC families, no single locus accounts for the majority of nonsyndromic FNMTC and no gene identified shows strong enough associations to warrant clinical genetic testing. Newer sequencing techniques, including WES, will allow for new genes to be discovered and evaluated. Identifying susceptibility genes will allow for screening and early diagnosis, which in turn would lead to improved outcomes for patients and families.

Surveillance

Differentiated thyroid cancer, whether inherited or sporadic, may be associated with a high rate of recurrence, depending on the clinicopathologic features of the disease. Disease recurrence may occur as late as 40 years after initial diagnosis.[60Surveillance for recurrent disease therefore plays an important role in the long-term management of patients with these tumors. The optimal follow-up strategy is dependent upon both the initial tumor characteristics and the patient's response to therapy.[61] Fortunately, for most patients, the disease is associated with a low risk of recurrence, and surveillance is accordingly less intensive. In these cases, postoperative evaluation is centered on sonographic examination of the neck and measurement of serum thyroglobulin.[61]
Thyroglobulin, a protein produced by both benign and malignant thyroid follicular cells, is used as a tumor marker for patients with differentiated thyroid cancer. Thyroglobulin measurement is most sensitive after a total thyroidectomy, so detection of thyroglobulin—particularly an increasing trend in the serum concentration—is often an early indicator of recurrent or progressive disease.[62] However, it is important to recognize several caveats about the use of this tumor marker. It is imperative to assess serum thyroid-stimulating hormone (TSH) and thyroglobulin antibody levels concomitantly at each measurement. Thyroglobulin rises with increasing TSH values; therefore, an elevating thyroglobulin level could indicate progressive disease or simply a rising TSH level. Furthermore, the presence of thyroglobulin antibodies can interfere with the accurate measurement of thyroglobulin, with most cases resulting in a spurious lowering of the tumor marker.[63] In such cases, the antibody titer may be used as a surrogate marker of disease status.[61] The final caveat about the use of thyroglobulin as a tumor marker is that the test must be performed in the same laboratory at each measurement to accurately assess the trend in levels; each assay can render a different value of thyroglobulin on the same serum sample.[61] Measurement of serum thyroglobulin to assess for recurrent or persistent disease may be performed 3 to 6 months after therapy is completed and monitored periodically thereafter, depending on the concern for persistent or recurrent disease.[61] Stimulated thyroglobulin testing (after withdrawal of thyroid hormone reaches a minimum TSH level of 30 mIU/L or after recombinant TSH injection) may be useful in select patients, particularly in patients with follicular thyroid cancer or in whom there is high clinical suspicion of recurrent or residual disease.
Whether a patient has received radioactive iodine or only surgery, careful ultrasonography of all compartments in the anterior neck is an important tool to determine if there is recurrent or residual disease because most disease is localized in this region. The initial ultrasonography is typically performed 6 to 12 months after surgery.[61] Ultrasonography may be performed sooner if there is concern about residual disease, but it is important for the sonographer to recognize the potential for false-positive findings due to postoperative swelling. The timing and need for subsequent sonographic evaluation of the neck is dependent upon the patient’s risk for recurrence and the serum thyroglobulin status.[61]
Ultrasonography combined with a serum thyroglobulin test has a very high sensitivity for identifying nodal disease, far superior to the radioiodine diagnostic whole-body scans that were historically the mainstay of surveillance.[62]

Interventions

Once a thyroid nodule is detected, further work-up includes complete ultrasonography of the thyroid, as well as a comprehensive neck ultrasonography to evaluate the central and lateral neck lymph nodes. Fine-needle aspiration (FNA) is indicated for cytologic evaluation of suspicious nodules based on size of the nodule, imaging characteristics, and associated patient risk factors.[64,65] Most current guidelines recommend FNA biopsy of all nodules measuring 10 mm or larger. Nodules smaller than 10 mm in greatest dimension may still warrant cytologic evaluation if radiographic imaging demonstrates features concerning for malignancy. Ultrasonographic features suspicious for malignancy include hypoechogenicity, complex or solid nodules, vascularity, irregular borders, and calcifications. Comprehensive preoperative neck ultrasonography not only provides the opportunity for FNA biopsy of any suspicious nodes before surgery but also allows the surgeon to plan the appropriate surgery and counsel the patient regarding a surgical procedure and its associated risks.[66] Although positron emission tomography scanning is not recommended for thyroid nodule assessment, concentrated uptake of contrast in the thyroid gland may be detected when the scan is obtained for other reasons. Incidental increase in fluorine F 18-fludeoxyglucose avidity, and an increase in nodule size (more than 50% volume) during surveillance may also be indications for FNA biopsy of nodules.[61]

Cytologic evaluation and indeterminate thyroid nodules

The Bethesda Thyroid Cytology Classification standardizes the cytologic interpretation of thyroid biopsies. Pathologic results are classified into one of the following six categories:[67]
  • Nondiagnostic or unsatisfactory.
  • Benign.
  • Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS).
  • Follicular neoplasm or suspicious for follicular neoplasm.
  • Suspicious for malignancy.
  • Malignant.
Patients with biopsy-proven malignant nodules (or nodules suspicious for malignancy) will need surgical resection as discussed below. Nodules classified as AUS/FLUS fall into the indeterminate category because the extent of architectural or cytologic atypia excludes a benign diagnosis, but the degree of atypia is insufficient for a definitive malignant classification.[67] These lesions are generally followed with repeat FNA and surgically resected if the clinical features of the nodule change, or if biopsies repeatedly result in AUS/FLUS classification.

Surgical treatment of thyroid cancer

Patients with a diagnosis of FNMTC may have increased aggressiveness of disease in comparison with sporadic cases.[68] In instances where the tumor is within a unifocal, intrathyroidal nodule, measuring less than 1 cm in dimension, incidentally identified and having low-risk features, thyroid lobectomy may be the appropriate treatment. Patients with intermediate lesions between 1 cm and 4 cm may undergo lobectomy and isthmectomy only if there is concern for noncompliance of thyroid hormone replacement therapy. Otherwise, most experts support total thyroidectomy because of the risk of increased frequency of multicentric disease, lymph node metastases, local invasion, and recurrence of aggressive disease.[68,69] Most surgeons would agree that patients with FNMTC and radiographically, clinically, or intraoperatively suspicious or biopsy-proven metastatic lymph nodes warrant total thyroidectomy and therapeutic compartment-based removal of the lymph node basin(s). Controversy exists, however, as to the appropriate treatment of nonenlarged lymph nodes of the central neck at the time of initial thyroidectomy. Specifically, some groups advocate routine prophylactic central node dissection (PCND) for all patients with known FNMTC to decrease the risk of local recurrence, although there are no specific, prospective, randomized data to support a survival benefit.[70,71] While two retrospective studies (not specific to hereditary thyroid cancer) have reported a reduction in disease recurrence rates associated with PCND,[72,73] two meta-analyses have shown that PCND does not reduce recurrence rates in a clinically significant manner.[74,75] The current recommendations published by the American Thyroid Association (ATA) state that prophylactic or bilateral Level VI lymph node dissection is recommended in patients with T3/T4 papillary cancer (whether familial or not), clinically involved lateral neck nodes or if the information will be used to plan further therapy such as radioactive iodine ablation. The ATA also states that this recommendation should be interpreted in light of available surgical expertise, acknowledging that PCND may lead to increased perioperative morbidity.[61] Currently, selective, rather than routine PCND seems the most reasonable option to guide the decision process.[76]
After total thyroidectomy, patients will need lifelong thyroid hormone replacement therapy.[61] The levothyroxine replacement therapy dose is approximately 1.6 µg/kg/day and is then titrated to reach an appropriate level of TSH suppression.[77,78] The degree of TSH suppression is also individualized on the basis of the patient’s disease status, risk of recurrence, an individual's risk of cardiovascular and bone complications with aggressive TSH suppression,[61] and clinicopathological tumor features. Patients typically undergo a surveillance regimen for recurrence consisting of laboratory evaluation and ultrasonography. In papillary and follicular cancer, thyroxine and TSH demonstrate the level of thyroid suppression, and thyroglobulin and thyroglobulin antibody levels are important markers for possible disease recurrence or metastases.
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  21. Hou P, Xing M: Absence of germline mutations in genes within the MAP kinase pathway in familial non-medullary thyroid cancer. Cell Cycle 5 (17): 2036-9, 2006. [PUBMED Abstract]
  22. Bignell GR, Canzian F, Shayeghi M, et al.: Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet 61 (5): 1123-30, 1997. [PUBMED Abstract]
  23. Bevan S, Pal T, Greenberg CR, et al.: A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1. J Clin Endocrinol Metab 86 (8): 3701-4, 2001. [PUBMED Abstract]
  24. Canzian F, Amati P, Harach HR, et al.: A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2. Am J Hum Genet 63 (6): 1743-8, 1998. [PUBMED Abstract]
  25. McKay JD, Thompson D, Lesueur F, et al.: Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer. J Med Genet 41 (6): 407-12, 2004. [PUBMED Abstract]
  26. Prazeres HJ, Rodrigues F, Soares P, et al.: Loss of heterozygosity at 19p13.2 and 2q21 in tumours from familial clusters of non-medullary thyroid carcinoma. Fam Cancer 7 (2): 141-9, 2008. [PUBMED Abstract]
  27. Malchoff CD, Sarfarazi M, Tendler B, et al.: Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 85 (5): 1758-64, 2000. [PUBMED Abstract]
  28. McKay JD, Lesueur F, Jonard L, et al.: Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21. Am J Hum Genet 69 (2): 440-6, 2001. [PUBMED Abstract]
  29. Cavaco BM, Batista PF, Sobrinho LG, et al.: Mapping a new familial thyroid epithelial neoplasia susceptibility locus to chromosome 8p23.1-p22 by high-density single-nucleotide polymorphism genome-wide linkage analysis. J Clin Endocrinol Metab 93 (11): 4426-30, 2008. [PUBMED Abstract]
  30. He H, Nagy R, Liyanarachchi S, et al.: A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24. Cancer Res 69 (2): 625-31, 2009. [PUBMED Abstract]
  31. Gudmundsson J, Sulem P, Gudbjartsson DF, et al.: Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 41 (4): 460-4, 2009. [PUBMED Abstract]
  32. Suh I, Filetti S, Vriens MR, et al.: Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: a SNP array-based linkage analysis of 38 families. Surgery 146 (6): 1073-80, 2009. [PUBMED Abstract]
  33. Xiong Y, Zhang L, Holloway AK, et al.: MiR-886-3p regulates cell proliferation and migration, and is dysregulated in familial non-medullary thyroid cancer. PLoS One 6 (10): e24717, 2011. [PUBMED Abstract]
  34. Capezzone M, Cantara S, Marchisotta S, et al.: Short telomeres, telomerase reverse transcriptase gene amplification, and increased telomerase activity in the blood of familial papillary thyroid cancer patients. J Clin Endocrinol Metab 93 (10): 3950-7, 2008. [PUBMED Abstract]
  35. He H, Bronisz A, Liyanarachchi S, et al.: SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility. J Clin Endocrinol Metab 98 (5): E973-80, 2013. [PUBMED Abstract]
  36. Gara SK, Jia L, Merino MJ, et al.: Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer. N Engl J Med 373 (5): 448-55, 2015. [PUBMED Abstract]
  37. Liu C, Yu Y, Yin G, et al.: C14orf93 (RTFC) is identified as a novel susceptibility gene for familial nonmedullary thyroid cancer. Biochem Biophys Res Commun 482 (4): 590-596, 2017. [PUBMED Abstract]
  38. McKay JD, Williamson J, Lesueur F, et al.: At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family. Eur J Endocrinol 141 (2): 122-5, 1999. [PUBMED Abstract]
  39. Lesueur F, Stark M, Tocco T, et al.: Genetic heterogeneity in familial nonmedullary thyroid carcinoma: exclusion of linkage to RET, MNG1, and TCO in 56 families. NMTC Consortium. J Clin Endocrinol Metab 84 (6): 2157-62, 1999. [PUBMED Abstract]
  40. Cavaco BM, Batista PF, Martins C, et al.: Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations. Endocr Relat Cancer 15 (1): 207-15, 2008. [PUBMED Abstract]
  41. Bullock M, Duncan EL, O'Neill C, et al.: Association of FOXE1 polyalanine repeat region with papillary thyroid cancer. J Clin Endocrinol Metab 97 (9): E1814-9, 2012. [PUBMED Abstract]
  42. Landa I, Ruiz-Llorente S, Montero-Conde C, et al.: The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genet 5 (9): e1000637, 2009. [PUBMED Abstract]
  43. Pereira JS, da Silva JG, Tomaz RA, et al.: Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC). Endocrine 49 (1): 204-14, 2015. [PUBMED Abstract]
  44. Ngan ES, Lang BH, Liu T, et al.: A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst 101 (3): 162-75, 2009. [PUBMED Abstract]
  45. Cantara S, Capuano S, Formichi C, et al.: Lack of germline A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) gene in familial papillary thyroid cancer. Thyroid Res 3 (1): 4, 2010. [PUBMED Abstract]
  46. Jazdzewski K, Murray EL, Franssila K, et al.: Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A 105 (20): 7269-74, 2008. [PUBMED Abstract]
  47. Fu D, Collins K: Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol Cell 28 (5): 773-85, 2007. [PUBMED Abstract]
  48. Cantara S, Pisu M, Frau DV, et al.: Telomere abnormalities and chromosome fragility in patients affected by familial papillary thyroid cancer. J Clin Endocrinol Metab 97 (7): E1327-31, 2012. [PUBMED Abstract]
  49. He M, Bian B, Gesuwan K, et al.: Telomere length is shorter in affected members of families with familial nonmedullary thyroid cancer. Thyroid 23 (3): 301-7, 2013. [PUBMED Abstract]
  50. Jendrzejewski J, Tomsic J, Lozanski G, et al.: Telomere length and telomerase reverse transcriptase gene copy number in patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 96 (11): E1876-80, 2011. [PUBMED Abstract]
  51. Wong K, Ren XR, Huang YZ, et al.: Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway. Cell 107 (2): 209-21, 2001. [PUBMED Abstract]
  52. Tomsic J, He H, de la Chapelle A: HABP2 Mutation and Nonmedullary Thyroid Cancer. N Engl J Med 373 (21): 2086, 2015. [PUBMED Abstract]
  53. Sponziello M, Durante C, Filetti S: HABP2 Mutation and Nonmedullary Thyroid Cancer. N Engl J Med 373 (21): 2085-6, 2015. [PUBMED Abstract]
  54. Zhou EY, Lin Z, Yang Y: HABP2 Mutation and Nonmedullary Thyroid Cancer. N Engl J Med 373 (21): 2084-5, 2015. [PUBMED Abstract]
  55. Alzahrani AS, Murugan AK, Qasem E, et al.: HABP2 Gene Mutations Do Not Cause Familial or Sporadic Non-Medullary Thyroid Cancer in a Highly Inbred Middle Eastern Population. Thyroid 26 (5): 667-71, 2016. [PUBMED Abstract]
  56. Zhang T, Xing M: HABP2 G534E Mutation in Familial Nonmedullary Thyroid Cancer. J Natl Cancer Inst 108 (6): djv415, 2016. [PUBMED Abstract]
  57. Tomsic J, Fultz R, Liyanarachchi S, et al.: HABP2 G534E Variant in Papillary Thyroid Carcinoma. PLoS One 11 (1): e0146315, 2016. [PUBMED Abstract]
  58. Sahasrabudhe R, Stultz J, Williamson J, et al.: The HABP2 G534E variant is an unlikely cause of familial non-medullary thyroid cancer. J Clin Endocrinol Metab : jc20153928, 2015. [PUBMED Abstract]
  59. Weeks AL, Wilson SG, Ward L, et al.: HABP2 germline variants are uncommon in familial nonmedullary thyroid cancer. BMC Med Genet 17 (1): 60, 2016. [PUBMED Abstract]
  60. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994. [PUBMED Abstract]
  61. Haugen BR, Alexander EK, Bible KC, et al.: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26 (1): 1-133, 2016. [PUBMED Abstract]
  62. Pacini F, Molinaro E, Castagna MG, et al.: Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 88 (8): 3668-73, 2003. [PUBMED Abstract]
  63. Spencer CA, Takeuchi M, Kazarosyan M, et al.: Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 83 (4): 1121-7, 1998. [PUBMED Abstract]
  64. Pellegriti G, Frasca F, Regalbuto C, et al.: Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013: 965212, 2013. [PUBMED Abstract]
  65. Kwak JY: Indications for fine needle aspiration in thyroid nodules. Endocrinol Metab (Seoul) 28 (2): 81-5, 2013. [PUBMED Abstract]
  66. Marshall CL, Lee JE, Xing Y, et al.: Routine pre-operative ultrasonography for papillary thyroid cancer: effects on cervical recurrence. Surgery 146 (6): 1063-72, 2009. [PUBMED Abstract]
  67. Cibas ES, Ali SZ: The Bethesda System for Reporting Thyroid Cytopathology. Thyroid 19 (11): 1159-65, 2009. [PUBMED Abstract]
  68. Mazeh H, Benavidez J, Poehls JL, et al.: In patients with thyroid cancer of follicular cell origin, a family history of nonmedullary thyroid cancer in one first-degree relative is associated with more aggressive disease. Thyroid 22 (1): 3-8, 2012. [PUBMED Abstract]
  69. Mazeh H, Sippel RS: Familial nonmedullary thyroid carcinoma. Thyroid 23 (9): 1049-56, 2013. [PUBMED Abstract]
  70. Mazzaferri EL, Doherty GM, Steward DL: The pros and cons of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma. Thyroid 19 (7): 683-9, 2009. [PUBMED Abstract]
  71. McLeod DS, Sawka AM, Cooper DS: Controversies in primary treatment of low-risk papillary thyroid cancer. Lancet 381 (9871): 1046-57, 2013. [PUBMED Abstract]
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Changes to This Summary (10/04/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Thyroid Carcinoma as reference 23.
Added text to state that in cases of de novo RET pathogenic variants, the diagnosis of multiple endocrine neoplasia type 2B (MEN2B) is often delayed, after the development of medullary thyroid cancer (MTC). The MTC is often fatal, particularly in the presence of metastatic disease, which is common at the time of diagnosis. Also added text to state that it is important for pediatricians to recognize the endocrine and nonendocrine clinical manifestations of the syndrome as an earlier diagnosis may result in lifesaving treatment of MTC, before metastatic spread (cited Makri et al. as reference 81).
Added text to state that a retrospective review of the clinical presentation of 35 cases of MEN2B with de novo RET pathogenic variants treated at a single institution found that 22 cases were diagnosed because of endocrine manifestations of the syndrome while the remaining 13 patients presented with a nonendocrine manifestation.
Added text to state that a long-term follow-up study of 20 Danish RET Y791F carriers showed no sign of MEN2A among the cohort, with a median age of 49.5 years (cited Høxbroe Michaelsen et al. as reference 138).
Revised text to state that the presence of certain RET polymorphisms or haplotypes is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, Hirschsprung disease, and age at onset of metastatic involvement with MTC (cited Kaczmarek-Ryś et al. as reference 142).
The Treatment for MTC subsection was extensively revised.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of endocrine and neuroendocrine neoplasias. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Endocrine and Neuroendocrine Neoplasias are:
  • Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
  • Sarah Nielsen, MS, LCGC (The University of Chicago)
  • Suzanne M. O'Neill, MS, PhD, CGC
  • Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
  • Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Jennifer Sipos, MD (The Ohio State University)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Endocrine and Neuroendocrine Neoplasias. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389271]
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