|Year : 2018 | Volume
| Issue : 1 | Page : 105-110
Management outcomes of pediatric and adolescent papillary thyroid cancers with a brief review of literature
Ravishankar Palaniappan1, Arvind Krishnamurthy1, S Swaminathan Rajaraman2, R Krishna Kumar1
1 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Epidemiology and Biostatistics and Nuclear Medicine, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Web Publication||23-Aug-2018|
Dr. Arvind Krishnamurthy
Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Papillary carcinoma of thyroid (PTC) is a rare disease in children and adolescents and contributes to about 1.5%–3% of all pediatric malignancies. To date, no randomized trial has ever been performed in the pediatric population and management of these patients has been extrapolated from adult practice. Materials and Methods: Retrospective analysis of the patients treated for PTC in the age <21 years, between the years 1998–2013 at a tertiary cancer center from India. Results: Sixty-seven patients were treated in the above said period with a male:female ratio of 1:1.6 and a median age of 18 years. Fifty-two (77.6%) patients clinically presented as a thyroid swelling with or without nodal swelling while 13 (19.4%) presented with isolated nodal swelling. Surgery was performed in 30 patients at a nononcological hospital and was subsequently referred to our center; more than half of them needed a completion surgery at our center. Pathologically, multifocal tumors were found in close to a quarter of the patients. Among the pathological variants, classical, follicular, and tall cell variants comprised 65.7%, 28.4%, and 5.9% of the cases, respectively. Nodal positivity was noted 71.6% of the cases of which 14.5% were N1a disease and the vast majority (85.5%) harboring N1b disease. The median follow-up period of the study cohort was 104 months during which there were 3 local, 6 nodal, and 2 systemic recurrences. The 5- and 10-year disease-free survival were found to be 85.9% and 81.4%, respectively. Univariate and multivariate analysis has shown no significant clinical and pathological feature defining the disease outcomes except for the T-stage. Logistic regression revealed extrathyroidal invasion and the age ≤ 15 years correlated with nodal positivity. Conclusion: Being a rare malignancy, pediatric and adolescent PTCs tend to behave differently from adult PTC with a seemingly aggressive clinical presentation; however, they are associated with excellent survival outcomes.
Keywords: I-131 therapy, management, papillary thyroid cancer, pediatric cancer, prognosis, survival
|How to cite this article:|
Palaniappan R, Krishnamurthy A, Rajaraman S S, Kumar R K. Management outcomes of pediatric and adolescent papillary thyroid cancers with a brief review of literature. Indian J Cancer 2018;55:105-10
|How to cite this URL:|
Palaniappan R, Krishnamurthy A, Rajaraman S S, Kumar R K. Management outcomes of pediatric and adolescent papillary thyroid cancers with a brief review of literature. Indian J Cancer [serial online] 2018 [cited 2019 May 24];55:105-10. Available from: http://www.indianjcancer.com/text.asp?2018/55/1/105/239599
| » Introduction|| |
Papillary carcinoma of thyroid (PTC) is a rare disease in children and adolescents with a reported incidence of 1.5%–3% of all pediatric malignancies. About 10% of all cases of thyroid cancer occur in patients younger than 21 years of age. Being a rare disease, much of the evidence from pediatric PTCs has been obtained from the retrospective studies. Although the vast majority of pediatric PTCs have an excellent prognosis, many aspects of the biological behavior and management of these rare cancers continue to remain unclear.,, To date, no randomized trial has ever been conducted in the pediatric population and management of these patients has been extrapolated from adult practice. We present our experience from a tertiary care cancer center in South India, of patients with pediatric and adolescent PTCs managed between the years 1998 and 2013 with emphasis on the clinical presentation, surgical management, control of local/regional disease, and the long-term disease outcomes.
| » Materials and Methods|| |
The historical records of the patients treated for PTC in the age group <21 years from 1998 to 2013 were reviewed. All the clinical details including the demographic profile, clinical presentation, extent of the surgery, pathological characteristic details of the ablative therapy if given, pattern of recurrence, and disease outcomes were captured and analyzed. Patients who were treated in non-cancer hospitals and referred to our center for further oncological management were also included in the study. There was no history of radiation exposure in any of the patients. There was no patient with family history of thyroid cancer. Most of the patients underwent total thyroidectomy except in very low-risk patients. Nodal dissection is done in the presence of clinically positive nodes. Following total thyroidectomy, Iodine-131 radioactive iodine diagnostic scans were performed inpatients with well-differentiated thyroid cancers after induced postoperative hypothyroidism with serum thyroid-stimulating hormone (TSH) levels >30 Mu/L followed by iodine-131 therapy as indicated in high-risk patients. Further, the patients were kept on thyroxine replacement.
The patients were followed up with clinical, radiological, and biochemical assessment 3 monthly for the first 3 years, 6 monthly till 5 years, and annually thereafter. Disease-free survival (DFS) and overall survival (OS) were calculated from the date of complete oncological surgery to the date of the structural recurrence and the date of death attributable to the disease at the end of follow-up period (July 31, 2017), respectively. Local recurrence was defined as the presence of the histological or radiological proven tumor in the original tumor bed or the contralateral lobe. Neck nodal recurrence was defined as the recurrence in the lymphatic drainage area. Distant metastasis was defined as the presence of the histological or radiologically proven tumor in the parenchyma of any organ. Data were analyzed using statistical software package (SPSS Inc., Released 2009. PASW Statistics for Windows, Version 18.0. Chicago, IL, USA).
| » Results|| |
The demographic profile and the clinical presentation of our cohort of 67 patients are illustrated in [Table 1]. Out of 67 patients, 30 patients had initial surgery at a nononcological hospital and were referred/presented to our tertiary cancer center, and among them, 16 patients (53.3%) needed completion surgery at our center. The treatment details for all the patients are summarized in [Table 2]. Pathologically, multifocal tumors were found in close to a quarter of the patients (25.37%). Among the pathological variants, classical, follicular, and tall cell variants of PTC comprised 65.7%, 28.4%, and 5.9% cases, respectively. Ten patients (14.9%) had Hashimoto's thyroiditis found incidentally in the thyroidectomy specimen in addition to the papillary carcinoma. Extrathyroidal extension (ETE) was found in 52.23% of patients. Nodal positivity was noted 71.6% of the cases of which 14.5% were N1a disease and the vast majority (85.5%) harboring N1b disease. About 72.91% of node-positive patients had perinodal extension in the nodes. Nearly 27.08% of patients had ≤4 positive nodes while 45.83% of patients had more than 10 positive nodes. The median number of positive nodes was 5 (range 1–40). Fifty-six (83.5%) and 11 (16.5%) patients were stage grouped as Stage I and Stage II cancers, respectively.
|Table 2: Treatment details of all the patients (including those initially treated outside)|
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The median follow-up period of the study cohort was 104 months (25–235 months). Eleven patients (16.5%) had recurrence, and the recurrence pattern and the treatment of the recurrence are illustrated in [Table 3]. All the systemic recurrences occurred after 30 months, local recurrence after 34 months, whereas the nodal recurrences had been reported as early as 6 months with median duration of recurrence was observed to be 18.5 months. The 5- and 10-year DFS were found to be 85.9% and 81.4%, respectively, whereas the 10-year OS was 100%. Univariate analysis did not show any of the factors to be predicting the DFS as illustrated in [Table 4] except that T2 tumors behave better than T4a tumors (heart rate [HR] - 0.15, P < 0.05) On further analysis, ETE (Odds ratio [OR] - 3.3, P = 0.038) and age ≤15 years (OR - 11.79, P = 0.021) correlated with nodal positivity in the univariate and age ≤15 years in multivariate analysis as well [Table 5]. No factors were found to predict the distant metastasis. There was no report of second malignancy over the years of follow-up.
|Table 4: Survival and univariate analysis of various demographical, clinical, and pathological features|
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|Table 5: Univariate and multivariate analysis of factors correlating with nodal metastases|
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| » Discussion|| |
Well-differentiated thyroid cancers are the most common endocrine tumors in children and adolescents. A significant increase in the incidence of thyroid cancers was observed in children exposed to the atomic blasts in Japan and also following the nuclear reactor meltdown at Chernobyl in 1986., Further, it has been noted that radiation-induced PTCs in children do not differ from the sporadic PTCs in terms of clinical manifestations., Screening for PTC in children at risk, i.e., children with cancer predisposition syndromes or following exposure to ionizing radiation is, however, an issue of debate.
Most patients with pediatric and adolescent PTC clinically present with a growing thyroid nodule or a persistent cervical lymph node., Almost 77.6% of our patients presented with palpable thyroid nodule with or without neck nodal swelling, whereas 19.4% of patients presented with an isolated neck nodal swelling. It is noteworthy to mention that thyroid nodules in the children are five times more likely to be malignant than in adults. Pediatric and adolescent PTC is believed to have no relationship with gender in prepubertal children, while after puberty, girls are 4–5 times more likely to have thyroid cancer than boys. Our series, however, showed a male:female ratio of 1:3 in patient's ≤10 years of age.
The clinical presentation of pediatric and adolescent PTCs differs from their adult counterparts in the following ways, namely, larger tumors, more frequent papillary histology, more frequent cervical lymph nodal involvement, and distant metastases which invariably localize in the lungs.,,, A similar trend in clinical presentation was noted in our series as well, with multifocal tumors seen in close to a quarter (25.37%) of the patients, ETE in more than half (52.23%) of the patients, and nodal positivity in 71.6% of patients, the vast majority (85.5%) harboring N1b disease. Further, 72.91% of node-positive patients had perinodal extension in the nodes. Nearly 27.08% of patients had ≤4 positive nodes while 45.83% of patients had more than 10 positive nodes. Eleven patients in our cohort had upfront lung metastasis at presentation, and further, in ≤10 years' age group, 3 out of the 4 patients had upfront lung metastases. Only one-fifth of lung metastases were identified in the chest X-ray whereas others were as the remaining was identified in the postoperative iodine-131 whole-body scans. Many other studies have shown that close to one third to half of the patients with lung metastases will have normal chest X-ray. In the Indian subcontinent, military tuberculosis can mimic lung metastases and are to be evaluated diligently to prevent delay in diagnosis of a possible malignancy.
With regard to histology, papillary carcinomas account for 70%–80% of the cases of pediatric and adolescent well-differentiated thyroid cancers. O'Gorman et al. has reported that follicular variant of papillary carcinoma occurs in 14.6% of childhood PTCs. Follicular variant and diffuse sclerosing PTCs are more frequently found in pediatric patients than in adults. In our series, we observed follicular variant of papillary thyroid carcinoma to constitute up to 28.4% of cases, which is a bit higher than the reported incidence in the literature, although this observation had no prognostic significance. Conventional PTCs were the most common histological variant in our series (67%) while there were 4 cases of tall cell variant (5.9%).
As pediatric and adolescent PTCs are relatively rare diseases, the management protocol for these patients is largely derived from experiences of the adult PTC population. Surgical resection remains the mainstay of management for all pediatric and adolescent PTCs, but there is still controversy regarding the extent of resection.,,,,,, There are retrospective data to suggest that patients with pediatric and adolescent PTCs, not undergoing a total thyroidectomy, are at a higher risk for developing recurrences., Further, the incidence of multifocal disease varied from 19% to 57% in the literature, further favoring the argument for a total thyroidectomy in pediatric PTCs. In our study, multifocality was observed in 25.4% of the patients. Three patients of the seven patients who had a hemithyroidectomy developed recurrences in the contralateral lobe. Therefore, many authors including us recommend a total thyroidectomy for the vast majority of the patients of pediatric PTCs. A central neck dissection should be performed when there is evidence of central and/or lateral neck metastasis or gross extrathyroidal invasion.
Many studies have observed a complication rate of 22%, including permanent recurrent nerve damage in 6.2% and permanent hypoparathyroidism in 12.3%, and also, children have higher endocrine-specific complication rates than adults after thyroidectomy (9.1 vs. 6.3%). As with many other specialized surgical procedures, complications can be minimized by the surgeons who perform thyroid surgeries at the high-volume centers. In our cohort of patients out of all the patients who had their initial surgeries done at low-volume centers (n = 30), more than half (53.3%) of the patients needed completion surgery at our institute, thus further stressing the need for specialized care.
The role of postoperative iodine-131 therapy in patients with pediatric and adolescent PTCs is also a matter of considerable debatable, especially among those children without either lymph node or distant metastasis. However, there is reasonable evidence to show at least an improvement in DFS in patients with lymph node and/or distant metastases., Recombinant human TSH preparation has not been formally tested for safety and efficacy in the pediatric population and its use is not recommended. The current recommendation of RAI by the American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer is for the treatment of nodal or other locoregional disease that is not amenable to surgery as well as distant metastases that are iodine-avid. Moreover, the RAI therapy can also be considered in children with T3 tumors or extensive regional nodal involvement. In our cohort, in pulmonary metastases, 91% of the patients had complete response with single iodine-131 ablation whereas one patient needed ablation in two settings and had complete response.
Studies suggest that the early side effects of I-131 therapy seem to be associated with the amount of administrated activities of each treatment while the late effects are associated with the cumulative activities of radioiodine. The potential side effects of I-131 therapy include xerostomia, lacrimal gland dysfunction, pulmonary fibrosis, and gonadal dysfunction in both sexes. The late effects of I-131 in pediatric PTCs are scarce, and there is a possibility of the same being underestimated. The risk of malignancy due to I-131 therapy in pediatric and adolescent PTC patients has not been clearly defined. It is well known that higher doses of I-131 can induce leukemia. Furthermore, there are reports to suggest that the risk of a second primary solid tumor could be elevated following I-131 therapy. A statistically significant high mortality rate due to nonthyroid malignancies in survivors of pediatric PTC first was reported in a study. However, it was noted that only a minority of patients received I-131 therapy, thereby suggesting that the excess mortality might have been due to other causes. A subsequent study from a large cohort of children and adolescents with high-risk radiation-induced PTC after the Chernobyl reactor meltdown did not observe secondary malignancies during a median follow-up of 11.3 years. Similarly, there were no documented secondary malignancies in our series as well.
It is extremely rare for pediatric and adolescent PTCs to become iodine-131 refractory; therefore, no evidence exists as to how to proceed in such scenarios. While newer multikinase inhibitors have shown modest results in the adult population with I-131 refractory disease, no similar studies are available in the pediatric and adolescent PTC population.
As in any postthyroidectomy patient, administration of thyroxine is obligatory in pediatric and adolescent PTC patients as well. Whether this should be a mere supplementation or TSH suppressive therapy is still a matter of debate.
In comparison to the adult PTC, although pediatric and adolescent PTCs have a seemingly aggressive biological behavior, the cause-specific mortality due to the disease is extremely low. Many studies have suggested BRAFV600E mutations to be associated with a more extensive and aggressive clinical behavior in adult PTC; however, this association does not seem to hold good for pediatric and adolescent PTCs.,, There are no clear explanations for the differences observed.
Demidchik et al. reported that neck lymph node metastases were a common type of relapse in their large series of 740 patients. The parameters associated with the risk of nodal disease include young age at diagnosis, multifocal carcinoma, N1 status, and lack of neck lymph node dissection. For lung metastases, the significant risk factors were female gender, young age at diagnosis, and presence of symptoms. More recent studies have the usefulness of the American Thyroid Association-based risk classification and dynamic risk stratification based on the response to initial therapy in pediatric PTCs., Another recent study showed that stimulated postoperative thyroglobulin displayed a high accuracy in predicting the risk of persistent disease in pediatric and adolescent PTCs.
The recurrence rate in our cohort was observed to be 16.5%, which is less than many of the reported series. More than half of the recurrences are in the regional nodal stations. Most of the patients were salvaged except one patient with neck nodal recurrence declining the treatment for the recurrence and subsequently expired after 16 years. In our series, the lung was the only site of systemic recurrence. Further, ETE (OR - 3.3, P = 0.038) and age ≤15 years (OR - 11.79, P = 0.021) correlate with nodal positivity in the univariate analysis and age ≤15 years (OR - 10.6, P = 0.03) correlate with the nodal positivity in the multivariate analysis implying the factors that can help in finding the risk factor for nodal metastases. The 10-year survival analysis of our patient cohort is comparable to other series in the literature,,, [Table 6].
|Table 6: Comparison of various studies on clinical presentations and disease outcomes|
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The limitation of our study was the modest numbers and the retrospective nature of the study which precludes us from making any firm recommendations. Our study does bring out certain unique demographic aspects, such as a female preponderance in prepubertal children, a relatively higher incidence of follicular variant of PTCs, and no reported secondary malignancies over a 104-month median follow-up. More importantly, our study further reiterates the excellent clinical outcomes of pediatric and adolescent PTCs, and we hope that this will add to the limited data available in literature and help clinicians better understand the differences in the biology, clinical course, and long-term outcomes in this population.
| » Conclusion|| |
Being a rare malignancy, pediatric and adolescent PTCs with seemingly aggressive clinical presentation tend to behave differently from adult PTC, however, are associated with excellent survival outcomes. Prospective multicenter trials with long-term follow-up of pediatric and adolescent PTCs are necessary for better understanding of the clinical behavior, management outcomes, and the late effects of the administered treatments.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]