Cáncer tiroideo en niños: una entidad poco frecuente (2024)

REVIEWARTICLE

Thyroid cancer in children: a rareentity

CÃ¡ncer tiroideo en niÃ±os: una entidad pocofrecuente

RichardMarcial GÃ¡lvez Vila ^1*, https://orcid.org/0009-0000-0829-1357

CarlosLuis Vinageras Hidalgo ¹, https://orcid.org/0009-0007-4848-1797

ÃngelFÃ©lix Almeida RodrÃguez ¹, https://orcid.org/0009-0002-7043-6697Â

Claudiade la Caridad Ramos Paret ¹, https://orcid.org/0009-0004-1353-3022

¹Medical SciencesUniversity of Matanzas. Faculty of Medical Sciences of Matanzas âDr. JuanGuiteras Generâ, Matanzas, Cuba.

* Correspondingauthor: richardgalvez163@gmail.com

Received: 13/02/2024

Accepted: 21/04/2024

How to cite this article: GÃ¡lvezVila RM, Vinageras Hidalgo CL, Almeida RodrÃguez AF, Ramos Paret C. Thyroidcancer in children: a rare entity. Med. Es. [Internet]. 2024 [citedaccess date]; 4(1). Available in:Â https://revmedest.sld.cu/index.php/medest/article/view/213

ABSTRACT

Introduction:thyroid cancer in children is considered a rare disease due to its lowincidence, representing less than 1% of pediatric tumors. However, it is themost prevalent childhood endocrinological tumor and its frequency hasexperienced a significant increase in recent years.

Objective:to highlight the differences that thyroid tumors present in children comparedto adults.

Methods:30 articles were identified, of which 23 were included, more than 75 % from thelast 3 years; coming from academic search engines such as PubMed, MedLine,Ovid, ResearchGate and Google Scholar.

Development:thyroid cancer in children is diagnosed in advanced stages, when lymph nodeinvolvement and lung metastases are more frequent than in adults. However, theprognosis is excellent, except in the most aggressive tumors, which presentprecisely.

Conclusions: thyroidcancer in pediatrics presents peculiarities that make it different from thatwhich occurs in adults. It has a greater influence of genetics, a greaterprobability of locoregional extension and metastasis at diagnosis, but on thecontrary the prognosis is usually good.

Keywords:Endocrinology; Thyroid Neoplasms; Child; Pediatrics.

RESUMEN

IntroducciÃ³n:el cÃ¡ncer de tiroides en niÃ±os se considera una enfermedad rara debido a subaja incidencia, representando menos del 1 % de los tumores pediÃ¡tricos. Sinembargo, es el tumor endocrinolÃ³gico infantil mÃ¡s prevalente y su frecuencia haexperimentado un importante aumento en los Ãºltimos aÃ±os.

Objetivo:resaltarlas diferencias que presentan los tumores de tiroides en niÃ±os con respecto alos adultos.

MÃ©todos:seidentificaron 30 artÃculos de los cuales se incluyeron 23, siendo mÃ¡s del 75 %de los Ãºltimos 3 aÃ±os; provenientes de buscadores acadÃ©micos como PubMed,MedLine, Ovid, ResearchGate y Google Scholar.

Desarrollo:elcÃ¡ncer de tiroides en niÃ±os se diagnostica en estadios avanzados, cuando laafectaciÃ³n de los ganglios linfÃ¡ticos y las metÃ¡stasis pulmonares son mÃ¡sfrecuentes que en los adultos. Sin embargo, el pronÃ³stico es excelente, salvoen los tumores mÃ¡s agresivos, que se presentan con precisiÃ³n.

Conclusiones:elcÃ¡ncer de tiroides en pediatrÃa presenta peculiaridades que le hacen distintodel que se presenta en adultos. Tiene una mayor influencia de la genÃ©tica, unamayor probabilidad de extensiÃ³n locoregional y metÃ¡stasis al diagnÃ³stico, peropor el contrario el pronÃ³stico es bueno de forma habitual.

Palabrasclave: EndocrinologÃa; Neoplasias de la Tiroides; NiÃ±o;PediatrÃa

INTRODUCTION

Thyroid cancer in children is considered a rare diseasedue to its low incidence, representing less than 1 % of tumors in children ofthis age. Its incidence in pediatric patients aged 0 to 19 years is low and isaround 5 cases per million. However, it is the most prevalent childhoodendocrinological tumor and its frequency has experienced a significant increasein recent years, especially among young people and girls. ⁽¹⁾

Because it is a tumor whose incidence increases withage and is the most common tumor among cancer survivors, many children withcancer are expected to develop a thyroid tumor in adulthood, especially if theyhave received radiation therapy. ⁽¹⁾

Since thyroid cancer occurs much more frequently inadults, it is common that an important part of the knowledge and treatment ofthis pathology in pediatrics is adapted to adults. However, it is important toknow that childhood thyroid cancer differs from adult thyroid cancer inclinical presentation, pathophysiology, treatment, and long-term outcomes. ⁽²⁾

The importance of these differences is so great that itis currently recommended to stratify thyroid cancer according to the time ofonset into prepubertal, adolescent, and postpubertal. ⁽²⁾

The purpose of this article is to highlight thedifferences that thyroid tumors present in children and adults in comparisonwith epidemiology, risk factors, clinical presentation, diagnostic evaluation,treatment and prognosis.

MATERIALS AND METHODS

A bibliographic review was carried out using the keywords: endocrinology; thyroid neoplasms; child; pediatrics. 30 articles wereidentified, of which 23 were included, more than 75 % from the last 3 years.All types of articles were selected from academic medical search engines suchas PubMed, MedLine, Ovid, ResearchGate and Google Scholar, each of themallowing different aspects related to epidemiology, risk factors, clinicalpresentation, diagnostic evaluation, treatment to be analyzed and prognosis inthis entity. The search was limited to English and Spanish.

DEVELOPMENT

Epidemiology and risk factors

Despite the rare occurrence of thyroid tumors inchildren, their incidence increases with age and occurs more frequently in thesecond decade of life and more frequently in girls. Therefore, adolescent girlsare the most affected group. Thyroid cancer is rarely diagnosed in childrenunder 10 years of age, although incidence and prevalence have increased inrecent years. The histological distribution is similar to that in adults, withdifferentiated thyroid cancers clearly outnumbering undifferentiated ones. ⁽²⁾

Among differentiated tumors, the most common ispapillary (almost 90 %), followed by follicular, which barely reaches 10 %. Othertypes of childhood thyroid cancer may be considered exceptional. In general, afollicular tumor is less aggressive than a papillary tumor because it isusually less advanced at the time of diagnosis, usually unifocal, and has alower probability of metastasis and recurrence during follow-up. ⁽³⁾

Spinal cord cancer is rare in children. Papillarythyroidectomy for medullary or high-risk thyroid cancer is one of the mostcommon reasons, especially in children aged 0 to 4 years, which is why theSpanish series support that this operation extends beyond the papillary method.This increase is due to the increased availability of molecular genetictesting, which has led to prophylactic thyroidectomy in children withpathogenic RET gene variants described in the familial cascade by a parent withMEN2A or Hirschsprung disease. ⁽³⁾

Advances in genetic engineering demonstrate theusefulness of molecular genetics in tumor characterization and therapy. Apediatric patient is generally a healthy organism that has received littleradiation and usually has few other diseases. The early onset of thyroid cancerraises questions about the underlying trigger, especially when it appearsbefore the age of 10 and even before the age of 5. It has been shown thatsometimes this predisposition is genetic. ⁽⁴⁾

An association has been found between papillary thyroidcancer and several genetic variants. This effect of genetics on thyroid cancerhas been reported more frequently in children than in adults. The geneticchanges observed are mostly copy number variations and, to a lesser extent,single nucleotide variations. ⁽⁴⁾

The most frequently altered gene in thyroid cancer witha non-syndromic phenotype is BRAF. Genetic syndromes due to monogenic causesassociated with tumor risk are increasingly diagnosed in pediatrics. The Carneycomplex, Werner syndrome or the APC, PTEN, RET, DICER1 variants stand out.Considering the rarity of these syndromes and the long latency period for tumorappearance, it is unusual for them to be diagnosed in children. Therefore, itis still necessary to plan a check-up or in some cases a preventivethyroidectomy before the first year of life. ⁽⁴⁾

In addition to traditional factors, autoimmunethyroiditis, iodine deficiency, or thyroid irradiation are classic risk factorsfor pediatric thyroid cancer. In children, the risk of thyroid cancer isusually 0,02 %, but in people with hypothyroidism it is 3 %.

Thyroid exposure to chemical radiation is awell-studied risk factor, especially in children, who are particularlysusceptible to the carcinogenic effects of radiation. These children should bemonitored periodically using ultrasound. Because nodules form 15 years afterexposure, adult endocrinologists often diagnose thyroid tumors in thesechildren.^(5,6)

Presentation and diagnostic evaluation

It is usually discovered accidentally during a wellnessstudy or during follow-up ultrasounds in children with thyroid inflammation.Thyroid nodules in children are rare, and approximately 20 % of pediatricthyroid nodules have been reported to be malignant. Once found, a diagnosticprotocol should be initiated that consists of thyroid function, ultrasound,scintigraphy, and fine needle aspiration (FNAC). Thyroid function,thyroid-stimulating hormone, and free T4 are usually normal. Ultrasoundexamination of the thyroid gland plays an even more important role in adults,so the radiologist's opinion about nodules is more cancer-specific than inadulthood. In any case, the criteria for malignancy on ultrasound are the sameas in adults. ⁽⁶⁾

These criteria are detailed in the TI-RADSclassification, where they consider composition, echogenicity, shape, bordersand foci. The scan will show whether it is a cold nodule, suspicious formalignancy requiring FNAC, or a warm nodule. Although there is no indicationfor FNA in hot nodules in adults, between 8 % and 29 % of these hot nodules inchildren are thyroid cancer and therefore require FNA. If thyroid cancer issuspected, fine-needle aspiration is performed and the risk of malignancy isdetermined based on the histopathologic findings of the Bethesda system inadults. ⁽⁷⁾

Despite very high sensitivity and specificity,pediatric FNAC has limitations. Repeatedly indeterminate results are associatedwith a higher risk of malignancy (28-58 %) than in adults (6-40 %). If the FNAis benign, ultrasound monitoring of the nodule is necessary, and if itincreases in size or shows signs of malignancy, the FNA should be repeated. Inthe event of a new indeterminate result, Bethesda III or IV, hemithyroidectomy,or thyroidectomy surgery should be considered, because there is a highprobability that it is true thyroid cancer. ⁽⁷⁾

More studies should be performed before surgery due tothe possibility of local spread (nodes or laryngeal nerve) or metastasis, mainlyto the lungs. Local involvement can be evaluated by an experienced radiologistwho performs an ultrasound examination of all areas of the cervix. Chestradiography may not be sufficient to evaluate metastases, so it is necessary toinclude other more sensitive imaging techniques. If additional treatment withradioactive iodine is prescribed, do not forget that Computed Tomography withiodinated contrast is contraindicated. Younger age, male sex, multiplecolonies, and size greater than 2 centimeters determine the possibility ofwider spread. ^(8,9)

The purpose of this evaluation is to stratify the tumorbased on symptoms, size, regional invasion, and metastasis. It is classified aslow risk (limited to thyroid disease or microscopic lymph nodes), medium orhigh risk (metastasis or significant locoregional infiltration or metastasis). ⁽⁸⁾

Compared with adults, larger tumors with multiple fociat diagnosis are common, with locoregional extension of up to 30-80 % andmetastasis in 5-25 %. They are mainly detected at the lung level (10-25 %) andless frequently at the bone level (5 %). Also, thyroid nodules are less commonin children than in adults, but have a higher risk of malignancy; in adults5-10 %, while in children 22-26 %. Furthermore, decreasing age has a greatertendency to induce aggressive cancers with higher recurrence rates. ⁽⁹⁾

Treatment

Treatment should be performed in children's hospitalsand an experienced thyroid surgeon is essential. These should include oncology,endocrinology, nuclear medicine, radiology, an intensive care unit, anesthesiaand a genetics unit is recommended. The surgical approach depends on apreoperative evaluation that differentiates low, intermediate and high risktumors. Given the recurrence rate of partial resections, as a general rule,total thyroidectomy is performed even when bilateral (30 %), multifocal (30-65 %),or metastatic (16 %) disease is not suspected. ⁽¹⁰⁾

Advantages of total thyroidectomy include lowerrecurrence, easier follow-up (thyroglobulin), and the possibility of additionalevaluation with radioactive iodine. The risk of regional recurrences has beenreported to be higher than in adults, and central lymph node drainage iscontroversial in all children, regardless of tumor extension. ⁽¹⁰⁾

Therapeutic dissection is generally recommended whenmetastases are suspected in the mid-neck or posterolateral region. Prophylacticdrainage of the lymph nodes of the central compartment can be considered in allcases, without forgetting that in children it is associated with an increase incomplications derived from surgery (recurrent paralysis, hypothyroidism). Giventhat survival in the first years is 100 %, the current trend is to beconservative and for large tumors (more than 4 cm) or extrathyroidal resectiononly in the central section. ⁽¹¹⁾

Lateral or posterolateral dissection is indicated forchildren diagnosed with metastatic disease preoperatively, but never routinely.The risks of thyroidectomy in children are the same as those described inadults: hematoma, infection, hypoparathyroidism, and temporary or permanentdamage to the recurrent nerve. Although there is no difference in recurrentnerve damage, follow-up is an important recommendation. Because the surgicalfield in children is smaller and the disease is usually more extensive,surgical complications occur more frequently. The risk of transient damage torecurrent nerves is up to 3,8 % in younger children. ⁽¹¹⁾

The probability of transient hypocalcemia is greaterthan 50 %, although it is usually controlled by early calcium supplementation.The risk of long-term hypoparathyroidism is rare (2 %), but increases with theaggressiveness of the operations. If concentrations have decreased, it isrecommended to perform a PTH measurement immediately after surgery to obtaincalcium and calcitriol. If we have histological and molecular information aboutthe tumor, it is necessary to perform a postoperative evaluation that dividesthe risk into low, medium and high. ⁽¹²⁾

The objective is to evaluate the presence of localdisease and local continuity of the disease and should be performed within thefirst 2-3 months after surgery: thyroglobulin determination is performed in allpatients and thyroid remains are searched with iodine-123. In medium and highrisk patients. ⁽¹²⁾

Thyroglobulin below 0,5 ng/ml indicates absence ofthyroid tissue and tumor remains. For small tumors without extrathyroidalextension and adequate thyroglobulin levels, an iodine-123 scan may be ruledout. A level greater than 2 ng/ml indicates residual disease. In patients withelevated thyroglobulin levels, a whole-body scan and/or other imaging studies(ultrasound, CT, MRI, or SPECT) will look for residual thyroid tissue toevaluate whether another operation is necessary to supplement with iodine-131^.(13)

As already mentioned, the prevalence of thyroid canceris usually higher in children than in adults. Despite this, the prognosis isvery good. The same does not occur in the long term, which indicates anincrease in mortality in other tumors. It is important to select patients towhom iodine-131 is administered.

As Orellana MJ et al., ⁽¹⁴⁾ childrenconstitute a population group that is particularly sensitive to the effects ofradiation. They are a growing organism with immature gonads and many yearsahead. Special protocols should be created for children, explaining thepostoperative risk and reserving the most aggressive treatments for those whoneed them.

Therefore, although the most important treatment aftersurgery is the administration of iodine-131, its administration must be decidedon an individual basis. Low-risk tumors do not require iodine-131administration, but patients with intermediate- or high-risk papillary tumorsshould. Furthermore, the administration of iodine-131 is indicated withoutdiscussion in patients with tumor remains, lymph node involvement or distantmetastases. ⁽¹⁴⁾

According to Bauer A, ⁽¹⁵⁾ theadministration of iodine-131 requires a high level of TSH, and it is sufficientto stop treatment with thyroxine 14 days before administration or treatmentwith ThyrogenÂ®, which is generally not done, because it is accepted in thetechnical specifications only in exceptional cases. Thereare medications that can be considered.

ÂThe endothelial and platelet growth factor inhibitorSORAFENIB has already been used in adults and is currently showing good resultsin clinical trials in children, although it is not currently indicated inchildren. Another investigational drug is vemurafenib, a BRAF gene inhibitor,and may be used in adults with iodine-131-resistant papillary carcinoma that ismetastatic or inoperable. ⁽¹⁵⁾

In spinal cord cancer, the RET tyrosine kinaseinhibitor vandetanib is indicated and can be used for more than five years ifthe disease is unresectable or metastatic. Considering the importance ofgenetics in childhood thyroid cancer and advances in molecular genetics andpharmacogenetics, it is expected that the pharmacological treatment of thesepatients will have a promising future with new therapies depending on the typeof cancer and its molecular changes. ⁽¹⁶⁾

Long-term monitoring and prognosis

Thyroid cancer in children is diagnosed in advancedstages, when lymph node involvement and lung metastases are more common than inadults. However, the prognosis is excellent, except in the most aggressivetumors, which present precisely. In any case, early diagnosis and adequatefollow-up are important to reduce or even prevent morbidity and relapsesrelated to treatment. ⁽¹⁶⁾

After surgery and with a rest of at least two weeksbefore the administration of iodine-131, replacement therapy with levothyroxineis started. If iodine-131 is not needed, levothyroxine treatment is startedimmediately. Treatment is adjusted according to the risk of recurrence. Alow-risk TSH level (0,5-1 μIU/ml)is sought in low-risk children, a lower level (0,1-0,5 μIU/ml)in medium-risk children, and undetectable in children high-risk. The role of apediatric endocrinologist is to adjust medications to the desired TSH level andprevent symptoms of hyperthyroidism by monitoring growth, bones, heart rate,and school performance. ^(17,18)

After changing the dose of levothyroxine, an ultrasoundis initially performed every 6 months, after which time can be distributedaccording to individual risk. The risk of recurrence in the near future is verylow. However, in the long term it will increase to 15-40 percent after 30years. Therefore, monitoring must be extended over time. Survival is morelikely in patients with earlier-onset tumors, those who required moreaggressive surgery, and those whose TSH levels are not adequately controlled. ⁽¹⁸⁾

In long-term follow-up, palpation, measurement ofthyroglobulin (anti-thyroglobulin antibodies for correct interpretation) andultrasound have proven to be useful in the diagnosis of relapse. Additionally,an iodine-123 scan should be included in patients at increased risk ofrecurrence, especially if they have received isotope therapy, to confirmnegativity or determine indications for a new dose. ^(19,20)

Peculiarities of other types ofnon-papillary tumors

A follicular tumor is usually diagnosed after surgery,which in many cases is performed after two inconclusive FNAs. In the tumorstage, locoregional spread or metastases are very rare at the time of diagnosisof this type of tumors, but in such cases a total thyroidectomy is required ifit has not been previously performed. ⁽²¹⁾ Long-term progress isgood, as is the case with papillary cancer. Spinal cord cancer is characterizedby a low incidence in pediatrics. The diagnosis of MEN2A occurs when C-cellhyperplasia, a confirmed malignancy, is detected during glandular analysisafter a preventive thyroidectomy. ⁽²²⁾

These tumors do not respond to iodine-131. However,surgery is very effective if there is no metastasis. The type of variantdescribed in the RET gene determines the timing of total thyroidectomy, whichcan be before one year of age, and this thyroidectomy is one of the most commonreasons for thyroid surgery in MEN2A, thyroid surgery in pediatrics. As inadult age groups, vandetanib therapy can be used in children older than 5 yearswith unresectable tumors. ⁽²³⁾

CONCLUSIONS

Thyroid cancer in pediatrics presents peculiaritiesthat make it different from that which occurs in adults. It has a greaterinfluence of genetics, a greater probability of locoregional extension andmetastasis at diagnosis, but on the contrary the prognosis is usually good. Wemust move towards personalized medicine by establishing diagnostic protocolsthat correctly characterize the tumor and stratify the prognosis so that treatmentswith surgery, iodine-131 and new pharmacological treatments seek maximumeffectiveness and minimize side effects.

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STATEMENT OF AUTHORSHIP

RMGV: Conceptualization,research, methodology, project administration, validation, original draft writing,review, editing.

CLVH: Conceptualization,research, methodology, project administration, validation, original draftwriting, review, editing.

AFAR: Conceptualization,research, methodology, project administration, validation, original draftwriting, review, editing.

CRP: Conceptualization,research, methodology, project administration, validation, original draftwriting, review, editing.

CONFLICT OF INTERESTS

The authors declare no conflict of interest.

FINANCING

The authors did not receive funding for the developmentof this article.