Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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1 Title:
Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults
Author:
Stephen H. LaFranchi, M.D.
Address:
Department of Pediatrics [CDRCP] Oregon Health & Science University 707 SW Gaines St. Portland, OR 97239-3098
Telephone;
503 494-1927
Fax:
503 494-1933
e-mail:
[email protected]
Key words:
Thyroid nodules Differentiated thyroid cancer Children Pediatric Guidelines
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 9
2 The American Thyroid Association (ATA) first published guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) in 2006 (1), with a subsequent update in 2009. A section with one recommendation was devoted to thyroid nodules in children, as follows: “The diagnostic and therapeutic approach to one or more thyroid nodules in a child should be the same as it would be in an adult (clinical evaluation, serum TSH, US, FNA)” (2). The guidelines essentially recommended that DTC in children also be managed in a manner similar to adults. However, it has long been recognized that significant differences exist between children and adults as it relates to thyroid nodules and DTC. Thyroid nodules and cancer in children develop against the background of dynamic changes that occur with physical growth and pubertal development. The young thyroid gland is more sensitive to ionizing radiation; witness the approximate 4-fold increase in the incidence of papillary thyroid cancer (PTC) in infants and children following the Chernobyl nuclear reactor accident (3). Thyroid nodules are less common in children, but a higher proportion appear to harbor cancer. Children with DTC have more widespread cancer at presentation, yet paradoxically they have a better prognosis and overall survival. Recognizing these differences, the ATA commissioned a task force of endocrinologists (pediatric and adult), surgeons, nuclear medicine specialists, radiologists, and a molecular geneticist to develop separate guidelines for the management of thyroid nodules and DTC in children (4). The task force first developed key questions to be addressed and then undertook an extensive literature search, focused on studies in subjects < 18 years of age. Acknowledging that there are few randomized, controlled trials in children, the task force nevertheless developed 61 graded recommendations, addressing 34 key areas of evaluation and treatment, based on the scientific evidence and expert opinion.
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 9
3 The incidence of thyroid nodules is lower in children as compared to adults. In a study of school children 11 to 18 years of age in the Southwestern United States, nodules were detected in 1.8% by palpation (5). In a study of healthy Greek school children age 5 to 18 years, nodules were present in 5.1%, as determined by an ultrasound (US) examination (6). By comparison, studies in adults report that thyroid nodules are present in approximately 10% of young adults and over 50% of adults 60 years and older, as determined by US examination (7). Conversely, the percentage of thyroid nodules harboring cancer is reported to be higher in children as compared to adults. A review of 18 published studies totaling 1134 children reported cancer ranging from 9.2% to 50%, averaging 26.4% overall (8). This compares to the commonly quoted “5% of thyroid nodules are cancer in adults” (9). Although this would appear to represent a 5-fold increased risk of cancer in nodules in children, a study employing a “standardized assessment of thyroid nodules” from Boston reported cancer in 22% of children vs. 14% in adults (10), closer to a 2-fold increased risk. Emphasizing another difference, the task force recognized that the size criterion (>1-1.5 cm) for obtaining tissue for pathologic evaluation via fine needle aspiration (FNA) may not be appropriate in a growing child whose thyroid gland may be half the size of an adult. The task force therefore recommends that “US characteristics and clinical context should be used rather than size alone to identify nodules that warrant FNA” (4). Further, the task force recommends that all FNA in children be performed under US-guidance. In the context of FNA, the task force acknowledges that, while molecular testing aids management decisions in adults with indeterminate cytology, insufficient data exists in children and so its use in “routine clinical practice” cannot be recommended “until further studies are conducted” (4).
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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4 Management of autonomously functioning (“hot”) nodules likely represents another difference in children as compared to adults. In both age groups, initial treatment may be aimed at controlling the hyperthyroidism. In adults, as the risk of cancer in “hot nodules” is quoted to be in the 3% range (11), resection or radioactive iodine (RAI) ablation may not be considered initially. By contrast, up to 30% of children may be found to have incidentally discovered DTC in autonomous nodules (12). Thus, the guidelines for children recommend surgical resection at presentation for most cases. If surgery is deferred, for example, in cases of subclinical hyperthyroidism, the task force recommends that FNA be considered if the nodule has features suspicious for papillary thyroid cancer (PTC) (4). Epidemiologic studies show that the incidence of thyroid cancer rises with age; for example, age 10-14 years = 0.35 cases/100,000, while 25-29 years = 6.08 cases/100,000 (13). Studies also appear to show that there is an increasing incidence of DTC in both children and adults in the United States, with an annual percentage change (APC) of 3-4% between 1984 and 2010 for both groups (13). There are some differences in the frequency of pathologic types of thyroid cancer in children and adults. PTC is more common in children (~95% vs. 80%), follicular thyroid carcinomas occur in approximately 5% in both, while Hürthle cell and anaplastic thyroid carcinoma are rare in children (14,15). PTC is more likely to be multifocal, and more likely to have regional lymph node and distant metastases at presentation in children. At diagnosis, lymph node metastases are present in up to 78% of cases (16), and pulmonary metastases are present in approximately 9-30% of cases (17). Despite more widespread cancer at presentation, children with DTC have an excellent prognosis. Survival out to 10 years is typically 98% (13), while another study reported a cause-specific mortality of only 2% at 40 years follow-up (16). However, while death from PTC is low, long-
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 9
5 term studies report a higher than predicted number of deaths between 30 and 50 years follow-up (16). In this analysis of all-cause mortality, two-thirds of the deaths resulted from non-thyroid second primary malignancies, and three-quarters of these patients had received some form of post-operative therapeutic irradiation (16). Recognizing these issues, a major goal of the task force was to try and define cases where aggressive therapy is indicated, and, conversely, to limit over-treatment in those children who are unlikely to benefit. Towards this end, the task force developed three risk levels of thyroid cancer (see Table 6 in reference 4). In those children deemed at low-risk, defined by cancer confined to the thyroid gland, with no or only microscopic metastases to a small number of central neck lymph nodes, and with a stimulated post-operative serum thyroglobulin
Page 1 of 9
1 Title:
Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults
Author:
Stephen H. LaFranchi, M.D.
Address:
Department of Pediatrics [CDRCP] Oregon Health & Science University 707 SW Gaines St. Portland, OR 97239-3098
Telephone;
503 494-1927
Fax:
503 494-1933
e-mail:
[email protected]
Key words:
Thyroid nodules Differentiated thyroid cancer Children Pediatric Guidelines
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 9
2 The American Thyroid Association (ATA) first published guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) in 2006 (1), with a subsequent update in 2009. A section with one recommendation was devoted to thyroid nodules in children, as follows: “The diagnostic and therapeutic approach to one or more thyroid nodules in a child should be the same as it would be in an adult (clinical evaluation, serum TSH, US, FNA)” (2). The guidelines essentially recommended that DTC in children also be managed in a manner similar to adults. However, it has long been recognized that significant differences exist between children and adults as it relates to thyroid nodules and DTC. Thyroid nodules and cancer in children develop against the background of dynamic changes that occur with physical growth and pubertal development. The young thyroid gland is more sensitive to ionizing radiation; witness the approximate 4-fold increase in the incidence of papillary thyroid cancer (PTC) in infants and children following the Chernobyl nuclear reactor accident (3). Thyroid nodules are less common in children, but a higher proportion appear to harbor cancer. Children with DTC have more widespread cancer at presentation, yet paradoxically they have a better prognosis and overall survival. Recognizing these differences, the ATA commissioned a task force of endocrinologists (pediatric and adult), surgeons, nuclear medicine specialists, radiologists, and a molecular geneticist to develop separate guidelines for the management of thyroid nodules and DTC in children (4). The task force first developed key questions to be addressed and then undertook an extensive literature search, focused on studies in subjects < 18 years of age. Acknowledging that there are few randomized, controlled trials in children, the task force nevertheless developed 61 graded recommendations, addressing 34 key areas of evaluation and treatment, based on the scientific evidence and expert opinion.
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 9
3 The incidence of thyroid nodules is lower in children as compared to adults. In a study of school children 11 to 18 years of age in the Southwestern United States, nodules were detected in 1.8% by palpation (5). In a study of healthy Greek school children age 5 to 18 years, nodules were present in 5.1%, as determined by an ultrasound (US) examination (6). By comparison, studies in adults report that thyroid nodules are present in approximately 10% of young adults and over 50% of adults 60 years and older, as determined by US examination (7). Conversely, the percentage of thyroid nodules harboring cancer is reported to be higher in children as compared to adults. A review of 18 published studies totaling 1134 children reported cancer ranging from 9.2% to 50%, averaging 26.4% overall (8). This compares to the commonly quoted “5% of thyroid nodules are cancer in adults” (9). Although this would appear to represent a 5-fold increased risk of cancer in nodules in children, a study employing a “standardized assessment of thyroid nodules” from Boston reported cancer in 22% of children vs. 14% in adults (10), closer to a 2-fold increased risk. Emphasizing another difference, the task force recognized that the size criterion (>1-1.5 cm) for obtaining tissue for pathologic evaluation via fine needle aspiration (FNA) may not be appropriate in a growing child whose thyroid gland may be half the size of an adult. The task force therefore recommends that “US characteristics and clinical context should be used rather than size alone to identify nodules that warrant FNA” (4). Further, the task force recommends that all FNA in children be performed under US-guidance. In the context of FNA, the task force acknowledges that, while molecular testing aids management decisions in adults with indeterminate cytology, insufficient data exists in children and so its use in “routine clinical practice” cannot be recommended “until further studies are conducted” (4).
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 9
4 Management of autonomously functioning (“hot”) nodules likely represents another difference in children as compared to adults. In both age groups, initial treatment may be aimed at controlling the hyperthyroidism. In adults, as the risk of cancer in “hot nodules” is quoted to be in the 3% range (11), resection or radioactive iodine (RAI) ablation may not be considered initially. By contrast, up to 30% of children may be found to have incidentally discovered DTC in autonomous nodules (12). Thus, the guidelines for children recommend surgical resection at presentation for most cases. If surgery is deferred, for example, in cases of subclinical hyperthyroidism, the task force recommends that FNA be considered if the nodule has features suspicious for papillary thyroid cancer (PTC) (4). Epidemiologic studies show that the incidence of thyroid cancer rises with age; for example, age 10-14 years = 0.35 cases/100,000, while 25-29 years = 6.08 cases/100,000 (13). Studies also appear to show that there is an increasing incidence of DTC in both children and adults in the United States, with an annual percentage change (APC) of 3-4% between 1984 and 2010 for both groups (13). There are some differences in the frequency of pathologic types of thyroid cancer in children and adults. PTC is more common in children (~95% vs. 80%), follicular thyroid carcinomas occur in approximately 5% in both, while Hürthle cell and anaplastic thyroid carcinoma are rare in children (14,15). PTC is more likely to be multifocal, and more likely to have regional lymph node and distant metastases at presentation in children. At diagnosis, lymph node metastases are present in up to 78% of cases (16), and pulmonary metastases are present in approximately 9-30% of cases (17). Despite more widespread cancer at presentation, children with DTC have an excellent prognosis. Survival out to 10 years is typically 98% (13), while another study reported a cause-specific mortality of only 2% at 40 years follow-up (16). However, while death from PTC is low, long-
Thyroid Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults (doi: 10.1089/thy.2015.0275) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 9
5 term studies report a higher than predicted number of deaths between 30 and 50 years follow-up (16). In this analysis of all-cause mortality, two-thirds of the deaths resulted from non-thyroid second primary malignancies, and three-quarters of these patients had received some form of post-operative therapeutic irradiation (16). Recognizing these issues, a major goal of the task force was to try and define cases where aggressive therapy is indicated, and, conversely, to limit over-treatment in those children who are unlikely to benefit. Towards this end, the task force developed three risk levels of thyroid cancer (see Table 6 in reference 4). In those children deemed at low-risk, defined by cancer confined to the thyroid gland, with no or only microscopic metastases to a small number of central neck lymph nodes, and with a stimulated post-operative serum thyroglobulin
