Molecular Landscape of Pediatric Thyroid Cancer

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1		Prerna Guleria	--	3681	2022-12-30 02:41:11	\|
2	format correct	Catherine Yang	-1 word(s)	3680	2022-12-30 04:07:38	\|

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12123136

Thyroid carcinomas (TC) are rare in the pediatric population; however, they constitute the most common endocrine malignancy. Despite some similarities with adult carcinomas, they have distinct clinical behavior and responses to therapy due to their unique pathology and molecular characteristics. The age cut-off used for defining the pediatric age group has been variable across different studies, and the universally accepted recommendations influence accurate interpretation of the available data. Moreover, factors such as radiation exposure and germline mutations have greater impact in children than in adults.

pediatric thyroid cancer molecular somatic mutations fusions

1. Introduction

Thyroid malignancies commonly arise from follicular cells and encompass differentiated thyroid carcinoma (DTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). DTCs maintain the normal physiologic characteristics of thyroid follicular cells ^[1], and papillary thyroid carcinoma (PTC) forms the bulk (>90%), followed by follicular thyroid carcinoma (FTC) (<10%) ^[2]. Medullary thyroid carcinoma (MTC) is another subset of thyroid tumors which arises from the parafollicular cells ^[2].

Though rare, thyroid malignancy is the most common endocrine malignancy in the pediatric age group ^[3]^[4]. The World Health Organization considers 19 years the age cut-off for segregating the pediatric population from adults. Subjects younger than 9 years old are considered children, and subjects of 10–19 years are considered adolescents ^[5]. The American Thyroid Association (ATA) takes 18 years as the cut-off ^[6]^[7], whereas the American Academy of Pediatrics identified the upper age limit as 21 years ^[8]. There is, to date, no consensus on the age cut-off to be used to define the pediatric age group for thyroid malignancies; the upper limit varies from 18 years ^[9]^[10] to 22 years ^[11]^[12] in different studies. A recent Japanese study recommended 14 years as the cut-off. The researchers found better disease-free survival and distant metastasis-free survival in DTC patients aged <15 years ^[13].

In contrast to adults, thyroid nodules are rarer (1–3%) in the pediatric age group, but when present, are more likely to be malignant (19–26%) ^[14]^[15], with the peak incidence of malignancy being among 15–19 years old. Fortunately, despite an advanced stage of disease at presentation and higher recurrence rates, the mortality rate remains low (<2%) ^[4]^[6]^[15]^[16]. Pediatric patients are also more likely to respond to radioactive iodine therapy (RAI) than adults ^[17]. This has been partly ascribed to the distinct molecular landscape of pediatric tumors.

Owing to the apparent differences in the clinical behavior and pathophysiology of thyroid cancer involving the pediatric age group, the ATA has laid down separate recommendations for the management of these patients ^[6]. The molecular makeup of these tumors has been variably evaluated.

2. Epidemiology

Thyroid malignancy is rare in the pediatric age group. The recent Surveillance, Epidemiology, and End Results (SEER) database revealed an incidence of only 1.9% of all cancers in patients less than 20 years of age ^[3]. As is the case in adults, PTC is the most common histological type (80–90%), followed by FTC (5–10%) ^[18]^[19]. Other primary thyroid carcinomas, such as MTC (3–5%), PDTC and ATC are even rarer. Most patients present in the second decade, with FTC showing a predisposition for slightly older patients than PTC ^[17]. There is a female preponderance. The incidence rates in males and females are 0.2 and 0.6 per 1,000,000 in children aged 0–14 years, and 1.2 and 6 per 1,000,000 in the age group 15–19 years ^[3]. Hence, the differences in the incidence rates in males and females are more pronounced in the post-pubertal age group.

3. Molecular Profile of Differentiated Thyroid Carcinomas

The mutational landscape of DTCs involves somatic point mutations of BRAF and RAS genes, and fusions involving the RET and NTRK1 tyrosine kinases. There is consequent activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways. Point mutations are commonly seen in adults (~70%), but are less frequent in children (~30%); instead, gene fusions, which occur at a lower rate in adults (~15%), predominate (~50%) ^[1].

3.1. Papillary Thyroid Carcinoma

PTCs account for about 90% of all childhood thyroid cancers. The classic and the follicular subtypes of PTC, considered ‘low-risk’ in adults, are also the most common histological types encountered in this age group. As most of the studies on pediatric thyroid neoplasms are from the pre-noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) period, its exact proportion is unknown. Limited evidence suggests that NIFTP constitutes about 4.5% of all PTC cases ^[20]. About 15–40% of pediatric PTCs are subtypes categorized as ‘high-risk’ in adults, namely tall cell, diffuse sclerosing, and solid/trabecular subtypes ^[14]^[21]. Although there are limited follow-up data, there is a suggestion that some of these ‘high-risk’ subtypes tend not to have a worse rate of event-free survival in the pediatric population ^[22]^[23].

In contrast to those in adults, PTCs in children are more commonly multifocal and have a more aggressive presentation, with higher rates of distant and nodal metastases. Despite a higher recurrence rate and more aggressive clinical presentation, their prognosis is excellent, with a very low mortality rate ^[6]. These differences are probably related to significant differences in the underlying molecular genetics of pediatric compared with adult DTC ^[24]. In addition, a decrease in the male-to-female incidence ratio in post-puberty indicates that other factors, such as different endocrine, metabolic and immune characteristics of the pediatric age, may also be involved. Being the predominant thyroid cancer type in the pediatric population, PTC has been studied relatively more than other thyroid cancers for molecular drivers.

In adult-onset PTCs, the most frequent genetic alteration observed is the mutational activation of the BRAF oncogene. A transversion of thymidine to adenine (T1799A) results in the substitution of valine to glutamate at residue 600 (V600E). Of the 402 cases of PTC evaluated in the Cancer Genome Atlas (TCGA) study, 58.5% harbored BRAF V600E mutation. Most patients were adults, except for nine patients aged < 20 years. Only 22% of the tumors developing in the latter group showed this mutation ^[25]. Although radiation exposure has a bearing on oncogenic molecular events, overall, BRAF V600E point mutation is less common in pediatric cases. Most of the available literature is from the West, with limited data from Asian countries, to which the largest contribution is from Japan ^[26]. In their study from Japan, Oishi et al. showed a higher prevalence of BRAF V600E in adult PTCs (85%) than in pediatric patients (54%). They also documented a greater frequency in patients aged 16–20 years (62%) compared with those < 15 years (28%) ^[27]. Other studies have also documented an increased prevalence of BRAF V600E mutation in patients of an age > 15 years. Sporadic cases tend to show a higher frequency (0–63%) of BRAF V600E mutation than those developing post radiation exposure (0–8%) ^[24]^[26]. There is high variability in the reported frequency of the mutation, with one series reporting it to be as high as 63% ^[28]. The reason for this may be the higher cut-off age of 22 years used ^[29]. Recently, Mitsutake et al. evaluated the genetic profile of PTCs detected during a survey following the Fukushima Daiichi nuclear reactor accident, and, unlike post-Chernobyl PTCs, found a higher prevalence of BRAF V600E ^[30].

In adults, BRAF mutation has been suggested to be a poor prognostic factor contributing to progressive disease and poor response to therapy ^[31]. This correlation remains unconfirmed in pediatric patients, but most of the available data suggest a lack of any such association ^[27]^[32]. Recently, Chakraborty from India evaluated 98 pediatric PTC patients for BRAF V600E mutation using Sanger sequencing, and found a prevalence of 14.3%. Their study cohort included 68 patients aged ≤ 18 years and 30 patients aged 19–20 years of age. This multivariate analysis revealed RAI refractoriness to be significantly associated with BRAF V600E mutation. However, none of the 17 patients with distant metastases had BRAF V600E mutation, and there was a lack of any significant association of BRAF V600E mutation with the status of disease recurrence or progression ^[33]. Contrasting results were reported by Alzahrani, who found persistent/recurrent disease to be significantly more common in patients with BRAF V600E mutation than in those without ^[7]. However, a subsequent study by the same group on a larger cohort did not find any association of BRAF V600E with any of the aggressive clinicopathological features, including persistent/recurrent disease ^[34].

Besides point mutations, the TCGA study reported BRAF fusions in 2.7% of their PTC cases. There is enough evidence documenting a higher prevalence of BRAF fusions in the pediatric age. The most common ones include Acylglycerol kinase (AGK)/BRAF and A-kinase anchoring protein 9 (AKAP9)/BRAF. Both fusions result from paracentric inversions involving chromosome 7; inv (7)(q34), and inv(7)(q21q34), respectively. Initially identified in post-radiation-exposed individuals, the fusions have been found even in sporadic pediatric cases ^[35]. Their prevalence is especially high in younger patients < 10 years of age ^[35]^[36]. While the reported frequency of AKAP9/BRAF has ranged from 0–1%, and 0–11% in sporadic and post-Chernobyl tumors, AGK/BRAF occurs at a rate of 0–19%, and 0–4%, respectively ^[35]. Cordioli et al., in two separate studies from their institute, documented for the first time the presence of AGK/BRAF in 10% and 19% of their sporadic pediatric PTC cases, respectively ^[36]^[37]. There is limited evidence suggesting an association of AGK/BRAF fusion with younger age and distant metastasis ^[37]. Interestingly, AGK/BRAF shows geographic variation in distribution ^[38], being more common in Brazil than in the United States or the Czech Republic ^[35]. Novel BRAF fusion partners identified in some geographical regions of the world include OPTN, CUL1 (Czech Republic) and SND1, MACF, MBP, POR, and ZBTB8A (post-Chernobyl Ukrainian-American patients) ^[35]. Pekova et al. studied novel fusion genes in 93 pediatric PTC patients up to 20 years of age, of which 30 had a family history of thyroid disorder. They found 20 different types of fusion genes in 56% of patients, and 5 were novel. Fusion gene-positive cases were associated with aggressive disease, more frequent extrathyroidal extension, and lymph node and distant metastases, and also required higher doses of RAI treatment ^[39]. The Ukrainian-American population studied by Efanov et al. included 65 PTCs developing in patients < 18 years of age post exposure to radiation during the Chernobyl accident. Gene fusions were observed in 46 patients, including novel fusions, as described above ^[40].

RET (rearranged during transfection) is absent in the normal thyroid follicular cells. It has approximately 20 fusion partners, of which RET/PTC is the most commonly associated with both sporadic and radiation-induced PTC ^[1]^[41]. RET/PTC rearrangements were found in 6.3% of the PTC tumors included in the TCGA cohort, but were much more frequent (22%) in their pediatric cohort ^[25]. Interestingly, these represent the most common molecular alterations encountered in children and adolescents ^[38], both in sporadic cases (22–65%) and tumors developing after radiation exposure (33–77%) ^[24]^[35]. RET/PTC1 and RET/PTC3 are the most common rearrangements. Among these, RET/PTC3 is associated with more aggressive disease ^[1]^[35]. Classic, solid, and diffuse sclerosing PTC histotypes, and the aggressive clinicopathological parameters such as extrathyroidal extension, lymph node and distant metastases are more commonly associated with RET fusions ^[1]. The prevalence of RET/PTC and BRAF V600E mutations varies with age and ethnicity. While RET/PTC fusions are more common in Caucasian children < 15 years of age, BRAF V600E is more common in the older Hispanic population ^[29].

Point mutations in the RAS genes (HRAS, NRAS and KRAS) are found in up to 25% of PTC cases, particularly in the follicular subtype ^[42]. 12% of the PTC cases included in the TCGA cohort harbored RAS mutations ^[25]. The incidence is lesser in the pediatric age group (<10%). Codon 61 of the NRAS gene is the most commonly involved, and as in adults, there is an association with the follicular subtype ^[1]^[34]. Kumagai from Japan found RAS mutations in two of their 77 cases (2.6%) of PTC involving children, adolescents and young adults. None of the patients aged < 15 years harbored this mutation ^[43]. Alzahrani also reported a low frequency of 2.5% in 79 PTC patients < 18 years of age ^[34]. Mitsutake did not find these in any of their 67 PTC cases ^[30].

TERT C288T and C250T promoter mutations occur in 10–20% of adult DTCs ^[44]. These were present in 9.4% of the cases of the TCGA cohort. None of their pediatric patients had this alteration ^[25]. In a recent study from India, none of the 98 patients harbored TERT promoter mutations ^[33]. In another study based on 81 sporadic pediatric PTC patients from Japan, TERT promoter mutations were absent in all ^[27]. Using NGS, Franco found TERT C288T mutation in a single case of PTC (follicular subtype) out of 29 PTC cases ^[45]. Most other authors have also observed low frequencies ^[35]^[46]. A single study from China has documented a higher prevalence of TERT promoter mutations. Geng observed TERT C228T mutation in 27% of their 48 PTC patients. The molecular alterations significantly correlated with aggressive clinicopathological features. None of their cases had the C250T mutation ^[47].

Additional oncogenic mutations associated with pediatric PTCs are PAX8/PPARG and the NTRK1 and NTRK3 fusions; however, data are limited. Using ThyGeNEXT, an NGS panel for detecting mutations in ALK, BRAF, GNAS, HRAS, KRAS, NRAS, PIK3CA, PTEN, RET, or TERT, and 38 fusion transcripts involving oncogenes ALK, BRAF, NTRK, or RET, Franco documented STRN/ALK, ETV6/NTRK3, and PAX8/PPARG, each in 6.9% (2/29) of their PTC cases ^[45]. Of the nine pediatric tumors included in the TCGA cohort, ETV6/NTRK3 was found in a single patient and PAX8/PPARG in none ^[25]. The STRN/ALK rearrangement, though rare, is present in up to 7% of pediatric tumors, compared with a lower reported range of 0–3% in adults ^[35]. Half of the cases (3/6) evaluated by Franco were of the follicular subtype, the remaining being classical PTC (n = 2) and the diffuse sclerosing PTC (n = 1) ^[45]. Other studies have also shown the association of these fusions with the follicular subtype ^[1]^[39]. A solid growth pattern in PTC has also been associated with NTRK fusions ^[48].

Only a handful of studies have explored the role of PIK3CA mutations in sporadic PTCs. In one study, these were found in 2 of the 79 PTC cases assessed by direct sequencing ^[34]. In another, PIK3CA mutations co-existed with BRAF V600E or NRAS Q61R, respectively, in two PTC cases ^[34]^[45]. Similarly, there are limited data on the status of DICER1 mutations in pediatric PTCs, with a single study from Korea reporting a frequency of 7.6% in their PTC cohort ^[46].

An age-dependent variation exists for the molecular profile among pediatric thyroid carcinomas. Lee et al. ^[46] from Republic of Korea comprehensively characterized age-associated genetic alterations in a large cohort of pediatric PTCs. They divided their pediatric patients into three age groups (<10 years, 10–15 years and 15–20 years). Fusions occurred at a frequency of 92.9%, 27.5%, and 13.5%, respectively, in the different age groups. The frequency of RET fusions decreased with increasing age. Point mutations (BRAF V600E, TERT, DICER1 and RAS) were observed in 7.1%, 30.0%, and 67.3%, respectively. Of these, BRAF V600E mutation was the most frequent, seen in 0%, 27.5%, and 57.7%, respectively. Notably, none of their cases showed RAS mutations ^[46].

Research on the role of molecular alterations as prognostic biomarkers in pediatric PTC is still in its infancy. A recent study investigated predictors of cervical lymph node metastases. While 68% of patients requiring neck dissection had somatic mutations, only 38% of those without lymph node metastases revealed molecular alterations. The difference was significant on univariate statistical analysis. The authors, hence, suggested that genetic mutation status is a predictor of nodal spread, and such patients should be kept on close follow-up if neck dissection was not initially required ^[49].

3.2. Follicular Thyroid Carcinoma

FTC is rare in the pediatric age group ^[50]. It presents with a larger mean tumor size, but with a favorable clinical outcome in contrast to adults ^[51]^[52]. In a study from Japan, Ito followed up 292 minimally invasive and 79 widely invasive FTC patients for a mean duration of 127 (6–339) and 123 months (3–332 months), respectively. Patients younger than 20 years were less likely to die of disease, irrespective of recurrence status ^[52].

Studies on FTC involving adult patients demonstrated RAS mutations (10–57%) and PAX8/PPARG fusions (up to 35–50%) to be the key players ^[53]^[54]^[55]^[56]^[57]. There are limited data on the molecular profile of pediatric FTC ^[14]. Vuong from Japan investigated a substantial cohort of 41 patients aged < 21 years. NRAS mutations were present in 12% and PAX8/PPARG fusions in none ^[51]. Studies from the West have also found a lower prevalence of 20–22% for RAS mutations and 0–20% for PAX8/PPARG fusions. However, the studies had a relatively small sample size ^[29]^[58].

Franco used ThyGeNEXT to assess 6 FTC cases in patients < 18 years of age. HRAS G13R, HRAS Q61R, and KRAS G12V were detected in one case each (3/6; 50%). Of their 47 benign non-neoplastic and neoplastic lesions, five showed molecular alterations. GNAS mutations were found in a case of multinodular goiter and two cases of follicular adenoma. One of the latter two cases showed an additional PAX8/PPARG translocation. A third follicular adenoma harbored PTEN mutation, and TERT C288T was identified in a case of diffuse hyperplasia. Notably, RAS mutations, often detected in adult benign nodules, were absent among their cases ^[45]. Using NGS, Ballester found a CTNNB1 (β-catenin) p.S45P mutation in the single case of FTC assessed by them ^[59]. Among thyroid tumors, CTNNB1 mutations have been reported primarily in PTC with fibromatosis/fasciitis-like/desmoid-type stroma ^[60], and ATC as a late event involved in cancer progression ^[61]. There are limited data on the role of β-catenin in FTC. Cell culture studies have revealed β-catenin activation to be dependent on PI3K/AKT activity, a pathway involved in FTC ^[62]. Another molecule of the Wnt/β-catenin signaling pathway which has been evaluated in FTC is Wnt-5a, an activator of the non-canonical Wnt pathways. When compared with normal thyroid tissue, experimental studies have revealed overexpression of Wnt-5a in FTC. The molecule promotes mesenchymal–epithelial transition by inducing cadherin expression and re-localization of β-catenin from the nuclei to the membrane ^[61]^[63].

FTC has also been associated with mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN), a tumor suppressor gene located at chromosome 10q23.3. Heterozygous germline mutation of PTEN leads to PTEN hamartoma tumor syndrome, an autosomal dominant disorder. There is a predisposition to developing malignancies in various organ systems ^[44]. FTC occurs in about 25% of carriers of PTEN mutation ^[64] and is one of the major criteria for the diagnosis of PTEN hamartoma tumor syndrome ^[65]. It has been recommended that all children diagnosed with FTC should undergo genetic counselling and testing for germline PTEN mutation ^[6]. Alzahrani and colleagues are the only ones to have studied PTEN in sporadic pediatric PTC patients and found exon 5 (c.295G > A) mutation in a single patient (1.4%) ^[34].

DICER1 is another gene which has recently been implicated in the pathogenesis of pediatric FTC. The reported frequency has ranged from 25–53% ^[66]^[67]. Importantly, DICER1 alterations are associated with the macrofollicular subtype of FTC ^[68]; hence, there is a need to evaluate young patients with this FTC variant for DICER1 alterations.

3.3. Poorly Differentiated Thyroid Carcinoma

There are negligible data on pediatric PDTC ^[7]^[30]^[43]^[69]. Mitsutake did not find any of the assessed driver mutations, namely BRAF (exon 15), H/K/NRAS (codons 12, 13 and 61), TERT promoter (C250T and C228T), RET/PTC1, RET/PTC3, AKAP9/BRAF or ETV6 (exons 4 and 5)/NTRK3 rearrangements in the single case of PDTC evaluated by them as a part of their larger cohort containing tumors detected following the accident at the Fukushima Daiichi Nuclear Power Plant in Japan ^[30]. In another study from Japan, 31 Japanese and 48 post-Chernobyl Ukrainian thyroid carcinomas involving children, adolescents and young adults were evaluated for BRAF V600E and RAS mutations. The single case of PDTC included was found to harbor BRAF V600E mutation. This tumor was focally immunopositive for CD15 and suggestive of dedifferentiation from PTC ^[43]. In a study from Saudi Arabia, Sanger sequencing did not reveal BRAF V600E and TERT promoter mutations in the single case of pediatric PDTC evaluated as a part of a mixed cohort of pediatric thyroid cancers ^[7]. Interestingly, instead of these known driver mutations, a high prevalence (83%; 5/6) of DICER1 mutations was documented by Chernock. Additional mutations were found in ATM, CDC73, TP53, MAP2K2, RBM10, ARID1A, FLT3, and EGFR genes. None of the cases had BRAF, RAS, TERT, or RET/PTC alterations ^[69].

3.4. Medullary Thyroid Carcinoma

MTC is rare in children, having an annual incidence of 0.03 per 100,000 ^[70]. In contrast to adults, pediatric patients are more likely to have localized disease (70% vs. 52%), negative regional lymph nodes (48% vs. 31%), and a better 10-year cancer-specific survival rate (80% vs. 96%) ^[71]. While most (65–75%) of the cases in adults are sporadic, pediatric cases usually occur as a part of autosomal dominant syndromes associated with gain-of-function germline mutations in the RET proto-oncogene ^[18]^[70]. MEN type 2A syndrome (Sipple’s syndrome) is the most frequent. It is highly penetrant and usually presents before six years of age. The mutations involve the extracellular cysteine-rich region of the RET tyrosine kinase receptor, usually in exon 10 (codons 609, 611, 618 or 620) or exon 11 (codon 634). Bilateral pheochromocytomas and hyperparathyroidism are other common features of this syndrome ^[70]^[72]. Patients with MEN2B syndrome are also predisposed to developing MTC and pheochromocytoma. They may also develop gastrointestinal ganglioneuromas, oral and conjunctival mucosal neuromas and a marfanoid habitus. The mutation, usually Met918Thr in exon 16, occurs in the tyrosine kinase domain in the intracellular portion of the receptor, leading to ligand-independent catalytic activity. The mutation can be either inherited (25%) or arise de novo (75%) ^[21]^[73]^[74]. Patients with MEN2B develop MTC very early, within the first year of life, and have an average life expectancy of about 21 years ^[72]. Hence, prophylactic thyroidectomy is recommended in the first year of life ^[70]^[74].

Familial MTC (FMTC) harbors mutations similar to MEN2A, involving either the extracellular or the intracellular domain of the tyrosine kinase receptor; it is now considered an MEN2A variant. As it has less clinical penetrance; MTC is usually the sole clinical presentation. The tumor is also less aggressive and manifests in the second or third decade of life ^[70].

When familial, MTC is associated with a precursor lesion, the C-cell hyperplasia. The tumors are multifocal, bilateral and typically located at the junction of the upper one-third and the lower two-thirds of the thyroid lobes. As the risk of development and progression of MTC are related to the mutated codon, the management protocol of these patients is decided based on the variant present. MEN2B patients, having a mutation in the RET codon M918T, have the highest risk of developing MTC, and should be subjected to prophylactic thyroidectomy within the first few months up to the first year of life. The high-risk category includes patients with mutations in A883F or C634 codons. They should undergo thyroidectomy by 5 years of age; the timing and extent of the surgery are guided by serum calcitonin levels. The rest of the mutations have a moderate risk of disease. Children in the moderate risk category can undergo thyroidectomy either when serum calcitonin levels rise, or earlier if parents desire ^[74].

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