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Childhood thyroid cancer in Belarus
International Congress Series 1299 (2007) 32 – 38
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Childhood thyroid cancer in Belarus Yuri E. Demidchik a,b,⁎, Eugene P. Demidchik a,b , Vladimir A. Saenko c,d , Christoph Reiners e , Johannes Biko e , Svetlana V. Mankovskaya b , Shunichi Yamashita c,f,g a
Belarusian State Medical University, Minsk, Belarus b Thyroid Cancer Center, Minsk, Belarus c Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan d Medical Radiological Research Center RAMS, Obninsk, Russian Federation e Clinic for Nuclear Medicine, University of Würzburg, Würzburg, Germany f Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan g Department of Public Health and Environment, WHO Headquarters, Geneva, Switzerland
Abstract. The retrospective analysis was performed to compare the clinical course of radiogenic and sporadic childhood thyroid cancer. The entire series included 752 patients aged less than 15 years at diagnosis. Of them, 686 (91.2%) individuals had radiation history including 681 (90.6%) exposed at the time of the Chernobyl disaster and 5 (0.7%) children were previously treated for malignant lymphoma with an external beam therapy. The second group consisted of 66 (8.8%) unexposed patients. All the children underwent surgery and received suppressive thyroxine therapy with the mean dose of 2.0–2.5 μg/kg of body weight. Radioiodine therapy was performed in 464 (61.7%) cases. The comparison of patients with radiogenic and sporadic thyroid cancer did not reveal statistically significant differences in the distribution of tumor size, histological type or TNM stage. During follow-up time relapses were registered in 204 (27.1%) patients. The main sites of recurrence were the lung or lymph nodes whereas other lesions (thyroid remnants, the bone, soft tissues or CNS involvement) were uncommon. The disease-free survival ranged widely, 0–213 months after the date of primary surgery without significant difference between the radiogenic and sporadic cases. The observed 10-year survival was 99.5% for the entire series, including 99.5%
⁎ Corresponding author. Belarusian State Medical University, 83, Dzerzhinsky av., 220116, Minsk, Belarus. Tel.: +375 172 902971; fax: +375 172 966571. E-mail address: [email protected] (Yu.E. Demidchik). 0531-5131/ © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2006.09.005
Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
33
and 99.7% in patients with radiogenic and sporadic carcinomas, respectively. © 2006 Elsevier B.V. All rights reserved. Keywords: Pediatric thyroid cancer; Recurrence; Survival rate
1. Introduction Thyroid cancer in childhood is an extremely rare disease with the crude incidence of 0– 2.2 per 106 individuals under 15 years old [1]. To date, less than 2000 cases have been cumulatively described all over the world beyond Belarus [2]. The fact that radiation can promote thyroid carcinomas in childhood is known from the publication by Duffy and Fitzgerald [3] who first reported pediatric cases associated with irradiation for enlarged tonsils or thymus. After the Chernobyl accident, the increased incidence of this malignancy was initially claimed by two groups of investigators in 1992 [4,5]. Since that numerous scientific publications on epidemiology, risk factors, clinical presentation, pathology, results of therapy and prognostication have appeared [6–11]. At present there are two etiological types of pediatric thyroid cancer in Belarus. One of them is the radiogenic, associated with the incorporation of radioactive iodine. Earlier, we reported that the vast majority of these cases were papillary adenocarcinomas confined to the thyroid yet displaying a high frequency of lung metastases and elevated risk of neck relapse after curative surgery [12]. Another category is sporadic thyroid cancers occurring in the unexposed children. A high incidence of such cases has been noted since 2001. Hitherto there is no clear evidence whether carcinomas associated with isotope uptake after the Chernobyl disaster and sporadic thyroid carcinomas have a different biological behavior or clinical course. This study was performed to compare the clinical features of disease in the two groups of pediatric patients, exposed or unexposed to radiation. 2. Material and methods From August 1985 to October 2005, 757 consecutive patients aged less than 15 years underwent therapy and were followed up in Thyroid Cancer Center (Minsk, Belarus). Of them 4 (0.5%) children had hereditary medullary carcinomas not related to radiation exposure. As this type of malignancy is pathogenetically different from the majority of pediatric thyroid tumors, these cases were not included in the analysis. In addition one patient with papillary carcinoma refused therapy and was also excluded from the evaluation. Among the remaining 752 patients, radiation history was documented in 686 (91.2%) individuals, including 661 (87.9%) children of residents of Belarus born before the Chernobyl disaster, 20 (2.7%) cases exposed in utero (9 months period from the date of accident) and 5 (0.7%) patients previously treated for malignant lymphoma with chemotherapy followed by an external beam therapy. The second group consisted of 66 (8.8%) patients who had no history of radiation exposure. The majority of them (62 patients) were born after the Chernobyl Power Plant
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Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
disaster (the accepted date from January 31, 1987). Four children with sporadic thyroid carcinomas had developed cancer before the accident. All the patients underwent surgery, mostly total thyroidectomy with simultaneous selective neck dissection, and were maintained on thyroxine suppressive therapy with the mean dose of 2.0–2.5 μg/kg of body weight. Radioiodine therapy for thyroid remnants or lung metastases was performed in 464 (61.7%) cases. It is necessary to note that patients with sporadic carcinomas have been subjected on average to the more aggressive surgical interventions because since 1998 the standard operation includes total thyroid removal, neck dissection and precise lymph nodes mapping (Table 1). The tumors were classified according to TNM UICC, 6th edition [13]. Statistical evaluation was done by comparing data set from the exposed group to that from sporadic carcinomas using two tailed Fisher's exact test. The Kaplan–Meier method was used to estimate overall survival and disease-free interval. 3. Results At diagnosis, most patients had solitary, usually asymptomatic tumors measuring less than 2 cm in the largest diameter corresponding to T1 stage (548, 72.9%) with a high
Table 1 Clinical data on childhood patients Item
Entire series (n = 752)
Radiogenic (n = 686)
Sporadic (n = 66)
Follow-up time (months) Cases lost of follow-up Mean age at diagnosis (years) Gender Male Female Ratio (m/f) Pathology Papillary Follicular Primary surgery Total thyroidectomy Subtotal thyroidectomy Lobectomy Lumpectomy Neck dissection Bilateral with level VI Ipsilateral with level VI Central compartment only Not applied Radioiodine therapy (+)
132.4 ± 44.4 a 11 (1.5) b 11.7
139.4 ± 35.9 10 (1.4) 11.7
62.5 ± 59.5 1 (1.5) 11.6
284 (37.8) 468 (62.2) 1:1.6
262 (38.2) 424 (61.8) 1:1.6
22 (33.3) 44 (66.7) 1:2
723 (96.1) 29 (3.9)
661 (96.3) 25 (3.7)
62 (93.9) 4 (6.1)
439 (58.4) 55 (7.3) 250 (33.2) 8 (1.1)
384 (56.0) 55 (8.0) 240 (35.0) 7 (1.0)
55 (83.3) * 0 (0) * 10 (15.2) * 1 (1.5)
176 (23.4) 199 (26.5) 242 (32.2) 135 (17.9) 464 (61.7)
127 (18.5) 196 (28.6) 238 (34.7) 125 (18.2) 437 (63.7)
49 (74.2) * 3 (4.5) * 4 (6.1) * 10 (15.2) 27 (40.9) *
a
Mean ± standard deviation. Number of subjects (percentage). ⁎ p b 0.05. b
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Table 2 Pathology and clinical manifestations Item
Entire series
Radiogenic
Sporadic
p-value
Tumor size (mm) Microcarcinomas (≤10 mm) Large tumors (N40 mm) Type of malignancy Solitary Multifocal pTNM distribution T1 T2 T3 T4 TX N1 M1 Clinical manifestations Asymptomatic Symptoms + Unknown
14.9 ± 8.5 a 278 (37.0) b 8 (1.1)
14.9 ± 8.6 260 (37.9) 7 (1.0)
15.0 ± 8.3 18 (27.3) 1 (1.5)
0.1086 0.5222
608 (80.9) 144 (19.1)
553 (80.6) 133 (19.4)
55 (83.3) 11 (16.7)
0.7432
548 (72.9) 78 (10.5) 122 (16.2) 2 (0.3) 2 (0.3) 523 (69.6) 17 (2.3)
498 (72.6) 72 (10.5) 113 (16.5) 2 (0.3) 1 (0.2) 477 (69.5) 16 (2.3)
50 (75.8) 6 (9.1) 9 (13.6) 0 1 (1.5) 46 (69.7) 1 (1.5)
0.6647 0.8352 0.7262 1.0000 0.1679 1.0000 1.0000
574 (76.3) 163 (21.7) 15 (2.0)
518 (75.5) 156 (22.7) 12 (1.8)
56 (84.8) 7 (10.6) 3 (4.5)
0.0964 0.0193 0.1372
a b
Mean ± standard deviation. Number of subjects (percentage).
frequency of nodal disease (623, 69.6%). Microcarcinomas were detected in 278 (37.0%) cases. Comparison of patients with radiogenic or sporadic thyroid cancer did not reveal statistically significant difference between the two groups in the distribution of tumor size, histological types or TNM stages. Table 3 Sites of recurrence Patterns of failure Lung metastases (M1 cases included) Positive neck lymph nodes Relapse in thyroid remnants Soft tissue metastases Lymph nodes and thyroid remnants Neck lymph nodes and lung metastases Lymph nodes and soft tissue metastases Lymph nodes, lung and bone metastases Lymph nodes, lung and CNS metastases Lymph nodes, lung, bone and CNS Lymph nodes, lung and thyroid remnants Lung, bone and soft tissue metastases Lung and soft tissue metastases Lung metastases and thyroid remnants Total a
Number of subjects (percentage).
Total 89 (11.8) 59 (7.8) 3 (0.4) 1 (0.1) 10 (1.3) 26 (3.5) 2 (0.3) 1 (0.1) 1 (0.1) 1 (0.1) 5 (0.7) 1 (0.13) 2 (0.27) 3 (0.40) 204 (27.1)
a
Radiogenic
Sporadic
p-value
86 (12.5) 58 (8.5) 3 (0.4) 1 (0.2) 9 (1.3) 26 (3.8) 2 (0.3) 1 (0.2) 1 (0.2) 1 (0.2) 4 (0.6) 1 (0.15) 1 (0.15) 3 (0.44) 197 (28.7)
3 (4.5) 1 (1.5) 0 0 1 (1.5) 0 0 0 0 0 1 (1.5) 0 1 (1.5) 0 7 (10.6)
0.0697 0.0514 1.0000 1.0000 0.6032 0.1569 1.0000 1.0000 1.0000 1.0000 0.3691 1.0000 0.1679 1.0000 0.0012
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Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
Table 4 Mean time (months) of disease-free survival Radiogenic Local recurrence Neck lymph nodes Thyroid remnants Soft tissue metastases Distant metastases Lung Bone a b
40.4 (2.0) a 32.5–48.2 b 28.7 (3.3) 22.3–35.1 52.1 (11.8) 29.1–75.1 51.6 (21.8) 8.8–94.4 43.5 (5.2) 33.3–55.7 19.3 (2.2) 15.0–23.7 43.0 (20.9) 2.1–83.8
Sporadic 90.4 (53.0) 0.0–194.2 76.5 (69.8) 0.0–213.3 114.1 (101.9) 0.0–213.8 – 44.7 (33.4) 0.0–110.2 17.5 (12.1) 0.0–41.2 –
Estimate (standard error). 95% confidence interval.
Symptoms at presentation were mainly caused by the large thyroid nodules or enlarged lymph nodes. Neck mass or discomfort was a common complaint registered in 134 of 163 (82.2%) patients with clinical manifestations. Sporadic thyroid carcinomas appeared to be significantly less symptomatic than radiogenic malignancies (Table 2). During follow-up period, recurrent disease was diagnosed in 204 (27.1%) patients. The main sites of recurrence were the lung or lymph nodes whereas others (thyroid remnants, the bone, soft tissues or CNS) were uncommon and usually associated with positive neck nodes or pulmonary foci. Perhaps because of different follow-up period, patients with radiogenic carcinomas had a higher rate of recurrence as compared with sporadic cases but no significant difference was found in the frequency of local relapse or distant metastases for these groups (Table 3). The relatively common lymph node relapses in radiogenic cases were likely due to the prevalence of safe surgical procedures in the early years after the Chernobyl disaster. The disease-free interval ranged widely between 0 and 213 months after the date of primary surgery without significant difference between radiogenic and sporadic cases (Table 4). The observed 10-year survival was 99.5% for the entire series, including 99.5% and 99.7% in patients with radiogenic and sporadic carcinomas, respectively. 4. Discussion Our data indicate no evidence that two etiological types of pediatric thyroid cancer, ie. the radiogenic and sporadic, are distinct from the standpoint of the clinical course of disease. The only noticed fact that sporadic cases are commonly asymptomatic is likely to reflect the general tendency of decreasing frequency of palpable neck masses [14]. In a recent review, Thompson and Hay demonstrated that in the past nearly 50% of pediatric patients with thyroid cancer had a history of radiation exposure [2]. Nowadays this
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proportion decreased to less than 3% but in the literature there are a few publications comparing the clinical course of sporadic and radiogenic thyroid malignancies. Spinelli et al. have analyzed 22 radiogenic and 34 sporadic pediatric cases of papillary carcinomas [15]. The high prevalence of distant metastases and pertinacious local relapses were recognized as specific features of the radiation-associated thyroid malignancies. The rate of recurrence reached 64% and 3% for exposed and unexposed patients, respectively. By contrast, another series of 339 post-Chernobyl pediatric cases reported by Rybakov et al. demonstrated a noticeably lower frequency of distant metastases and local relapses in radiation related cancers [16]. In the present study we found that history of radiation exposure has no impact on the clinical course of pediatric thyroid carcinomas. The high incidence of lung lesions and recurrences after curative treatment has been extensively described in the literature [17–20] previously. An elevated risk of dissemination is mostly associated with the younger age of patients [12,19,21]. In conclusion, the observed excellent 10-year survival of pediatric patients with thyroid cancer, 99.5%, is indicative of the high efficacy of the current treatment strategy allowing cure in almost all children with differentiated thyroid carcinomas. References [1] D.M. Parkin, E. Kramarova, G.J. Draper, et al. (Eds.), International Incidence of Childhood Cancer, vol. II, IARC Scientific Publications No. 144, International Agency for Research on Cancer, Lyon, 1998. [2] G.B. Thompson, I.D. Hay, Current strategies for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma, World J. Surg. 28 (2004) 1187–1198. [3] B.J. Duffy, P.J. Fitzgerald, Cancer of the thyroid in children: a report of twenty eight cases, Cancer 3 (1950) 1018–1032. [4] V. Kazakov, E. Demidchik, L. Astakova, Thyroid cancer after Chernobyl, Nature 359 (1992) 21–22. [5] K. Baverstock, B. Egloff, A. Pinchera, C. Ruchti, D. Williams, Thyroid cancer after Chernobyl, Nature 359 (1992) 21–22. [6] E. Cardis, J. Howe, E. Ron, et al., Cancer consequences of the Chernobyl accident: 20 years on, J. Radiol. Prot. 26 (2006) 127–140. [7] P. Jacob, T.I. Bogdanova, E. Buglova, et al., Thyroid cancer among Ukrainians and Belarusians who were children or adolescents at the time of the Chernobyl accident, J. Radiol. Prot. 26 (2006) 51–67. [8] E. Cardis, E. Amoros, A. Kesminiene, et al., Observed and predicted thyroid cancer incidence following the Chernobyl accident evidence for factors influencing susceptibility to radiation induced thyroid cancer, in: G. Thomas, A. Karaoglou, E.D. Williams (Eds.), Radiation and Thyroid Cancer, World Scientific, Singapore, 1999, pp. 395–405. [9] E.P. Demidchik, V.S. Kazakov, L.N. Astakhova, A.E. Okeanov, Yu.E. Demidchik, Thyroid cancer in children after the Chernobyl accident: clinical and epidemiological evaluation of 251 cases in the Republic of Belarus, in: S. Nagataki (Ed.), Nagasaki Symposium on Chernobyl: Update and Future, Elsevier, Amsterdam, 1994, pp. 21–30. [10] F. Pacini, T. Vorontsova, E. Demidchik, et al., Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France, J. Clin. Endocrinol. Metab. 82 (1997) 3563–3569. [11] M. Ito, S. Yamashita, K. Ashizawa, et al., Histopathological characteristics of childhood thyroid cancer in Gomel, Belarus, Int. J. Cancer 65 (1996) 29–33. [12] Yu.E. Demidchik, E.P. Demidchik, C. Reiners, et al., Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus, Ann. Surg. 243 (2006) 525–532. [13] L.H. Sobin, C. Wittekind (Eds.), TNM Classification of Malignant Tumours, 6th edition, WHO, Geneva, 2002.
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[14] J.K. Harness, Childhood thyroid carcinoma, in: O.H. Clark, Q.-Y. Duh (Eds.), Textbook of Endocrine Surgery, Saunders, Philadelphia, 1997, pp. 75–81. [15] C. Spinelli, A. Bertocchini, A. Antonelli, P. Miccoli, Surgical therapy of the thyroid papillary carcinoma in children: experience with 56 patients ≤16 years old, J. Pediatr. Surg. 39 (2004) 1500–1505. [16] S.J. Rybakov, I.V. Komissarenro, N. Tronko, et al., Thyroid cancer in children of Ukraine after the Chernobyl accident, World J. Surg. 24 (2000) 1446–1449. [17] J.W. Haveman, K.M. van Tol, C.W. Rouwe, D.A. Piers, J.T.M. Plukker, Surgical experience in children with differentiated thyroid carcinoma, Ann. Surg. Oncol. 10 (2003) 15–20. [18] D. Giuffrida, C. Scollo, G. Pellegriti, et al., Differentiated thyroid cancer in children and adolescents, J. Endocrinol. Investig. 25 (2002) 18–24. [19] P.W. Grigsby, A. Galor, J.M. Michalski, G.M. Doherty, Childhood and adolescent thyroid carcinoma, Cancer 95 (2002) 724–729. [20] M.P. La Quaglia, T. Black, G.W. Holcomb, R.G. Azizkhan, G.M. Haase, K.D. Newman, Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases, a report from the Surgical Discipline Committee of the Children's Cancer Group, J. Pediatr. Surg. 35 (2000) 955–999. [21] A.J. Alessandri, K.J. Goddard, G.K. Blair, C.J. Fryer, K.R. Schultz, Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma, Med. Pediatr. Oncol. 35 (2000) 41–46.
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Childhood thyroid cancer in Belarus Yuri E. Demidchik a,b,⁎, Eugene P. Demidchik a,b , Vladimir A. Saenko c,d , Christoph Reiners e , Johannes Biko e , Svetlana V. Mankovskaya b , Shunichi Yamashita c,f,g a
Belarusian State Medical University, Minsk, Belarus b Thyroid Cancer Center, Minsk, Belarus c Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan d Medical Radiological Research Center RAMS, Obninsk, Russian Federation e Clinic for Nuclear Medicine, University of Würzburg, Würzburg, Germany f Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan g Department of Public Health and Environment, WHO Headquarters, Geneva, Switzerland
Abstract. The retrospective analysis was performed to compare the clinical course of radiogenic and sporadic childhood thyroid cancer. The entire series included 752 patients aged less than 15 years at diagnosis. Of them, 686 (91.2%) individuals had radiation history including 681 (90.6%) exposed at the time of the Chernobyl disaster and 5 (0.7%) children were previously treated for malignant lymphoma with an external beam therapy. The second group consisted of 66 (8.8%) unexposed patients. All the children underwent surgery and received suppressive thyroxine therapy with the mean dose of 2.0–2.5 μg/kg of body weight. Radioiodine therapy was performed in 464 (61.7%) cases. The comparison of patients with radiogenic and sporadic thyroid cancer did not reveal statistically significant differences in the distribution of tumor size, histological type or TNM stage. During follow-up time relapses were registered in 204 (27.1%) patients. The main sites of recurrence were the lung or lymph nodes whereas other lesions (thyroid remnants, the bone, soft tissues or CNS involvement) were uncommon. The disease-free survival ranged widely, 0–213 months after the date of primary surgery without significant difference between the radiogenic and sporadic cases. The observed 10-year survival was 99.5% for the entire series, including 99.5%
⁎ Corresponding author. Belarusian State Medical University, 83, Dzerzhinsky av., 220116, Minsk, Belarus. Tel.: +375 172 902971; fax: +375 172 966571. E-mail address: [email protected] (Yu.E. Demidchik). 0531-5131/ © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2006.09.005
Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
33
and 99.7% in patients with radiogenic and sporadic carcinomas, respectively. © 2006 Elsevier B.V. All rights reserved. Keywords: Pediatric thyroid cancer; Recurrence; Survival rate
1. Introduction Thyroid cancer in childhood is an extremely rare disease with the crude incidence of 0– 2.2 per 106 individuals under 15 years old [1]. To date, less than 2000 cases have been cumulatively described all over the world beyond Belarus [2]. The fact that radiation can promote thyroid carcinomas in childhood is known from the publication by Duffy and Fitzgerald [3] who first reported pediatric cases associated with irradiation for enlarged tonsils or thymus. After the Chernobyl accident, the increased incidence of this malignancy was initially claimed by two groups of investigators in 1992 [4,5]. Since that numerous scientific publications on epidemiology, risk factors, clinical presentation, pathology, results of therapy and prognostication have appeared [6–11]. At present there are two etiological types of pediatric thyroid cancer in Belarus. One of them is the radiogenic, associated with the incorporation of radioactive iodine. Earlier, we reported that the vast majority of these cases were papillary adenocarcinomas confined to the thyroid yet displaying a high frequency of lung metastases and elevated risk of neck relapse after curative surgery [12]. Another category is sporadic thyroid cancers occurring in the unexposed children. A high incidence of such cases has been noted since 2001. Hitherto there is no clear evidence whether carcinomas associated with isotope uptake after the Chernobyl disaster and sporadic thyroid carcinomas have a different biological behavior or clinical course. This study was performed to compare the clinical features of disease in the two groups of pediatric patients, exposed or unexposed to radiation. 2. Material and methods From August 1985 to October 2005, 757 consecutive patients aged less than 15 years underwent therapy and were followed up in Thyroid Cancer Center (Minsk, Belarus). Of them 4 (0.5%) children had hereditary medullary carcinomas not related to radiation exposure. As this type of malignancy is pathogenetically different from the majority of pediatric thyroid tumors, these cases were not included in the analysis. In addition one patient with papillary carcinoma refused therapy and was also excluded from the evaluation. Among the remaining 752 patients, radiation history was documented in 686 (91.2%) individuals, including 661 (87.9%) children of residents of Belarus born before the Chernobyl disaster, 20 (2.7%) cases exposed in utero (9 months period from the date of accident) and 5 (0.7%) patients previously treated for malignant lymphoma with chemotherapy followed by an external beam therapy. The second group consisted of 66 (8.8%) patients who had no history of radiation exposure. The majority of them (62 patients) were born after the Chernobyl Power Plant
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Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
disaster (the accepted date from January 31, 1987). Four children with sporadic thyroid carcinomas had developed cancer before the accident. All the patients underwent surgery, mostly total thyroidectomy with simultaneous selective neck dissection, and were maintained on thyroxine suppressive therapy with the mean dose of 2.0–2.5 μg/kg of body weight. Radioiodine therapy for thyroid remnants or lung metastases was performed in 464 (61.7%) cases. It is necessary to note that patients with sporadic carcinomas have been subjected on average to the more aggressive surgical interventions because since 1998 the standard operation includes total thyroid removal, neck dissection and precise lymph nodes mapping (Table 1). The tumors were classified according to TNM UICC, 6th edition [13]. Statistical evaluation was done by comparing data set from the exposed group to that from sporadic carcinomas using two tailed Fisher's exact test. The Kaplan–Meier method was used to estimate overall survival and disease-free interval. 3. Results At diagnosis, most patients had solitary, usually asymptomatic tumors measuring less than 2 cm in the largest diameter corresponding to T1 stage (548, 72.9%) with a high
Table 1 Clinical data on childhood patients Item
Entire series (n = 752)
Radiogenic (n = 686)
Sporadic (n = 66)
Follow-up time (months) Cases lost of follow-up Mean age at diagnosis (years) Gender Male Female Ratio (m/f) Pathology Papillary Follicular Primary surgery Total thyroidectomy Subtotal thyroidectomy Lobectomy Lumpectomy Neck dissection Bilateral with level VI Ipsilateral with level VI Central compartment only Not applied Radioiodine therapy (+)
132.4 ± 44.4 a 11 (1.5) b 11.7
139.4 ± 35.9 10 (1.4) 11.7
62.5 ± 59.5 1 (1.5) 11.6
284 (37.8) 468 (62.2) 1:1.6
262 (38.2) 424 (61.8) 1:1.6
22 (33.3) 44 (66.7) 1:2
723 (96.1) 29 (3.9)
661 (96.3) 25 (3.7)
62 (93.9) 4 (6.1)
439 (58.4) 55 (7.3) 250 (33.2) 8 (1.1)
384 (56.0) 55 (8.0) 240 (35.0) 7 (1.0)
55 (83.3) * 0 (0) * 10 (15.2) * 1 (1.5)
176 (23.4) 199 (26.5) 242 (32.2) 135 (17.9) 464 (61.7)
127 (18.5) 196 (28.6) 238 (34.7) 125 (18.2) 437 (63.7)
49 (74.2) * 3 (4.5) * 4 (6.1) * 10 (15.2) 27 (40.9) *
a
Mean ± standard deviation. Number of subjects (percentage). ⁎ p b 0.05. b
Yu.E. Demidchik et al. / International Congress Series 1299 (2007) 32–38
35
Table 2 Pathology and clinical manifestations Item
Entire series
Radiogenic
Sporadic
p-value
Tumor size (mm) Microcarcinomas (≤10 mm) Large tumors (N40 mm) Type of malignancy Solitary Multifocal pTNM distribution T1 T2 T3 T4 TX N1 M1 Clinical manifestations Asymptomatic Symptoms + Unknown
14.9 ± 8.5 a 278 (37.0) b 8 (1.1)
14.9 ± 8.6 260 (37.9) 7 (1.0)
15.0 ± 8.3 18 (27.3) 1 (1.5)
0.1086 0.5222
608 (80.9) 144 (19.1)
553 (80.6) 133 (19.4)
55 (83.3) 11 (16.7)
0.7432
548 (72.9) 78 (10.5) 122 (16.2) 2 (0.3) 2 (0.3) 523 (69.6) 17 (2.3)
498 (72.6) 72 (10.5) 113 (16.5) 2 (0.3) 1 (0.2) 477 (69.5) 16 (2.3)
50 (75.8) 6 (9.1) 9 (13.6) 0 1 (1.5) 46 (69.7) 1 (1.5)
0.6647 0.8352 0.7262 1.0000 0.1679 1.0000 1.0000
574 (76.3) 163 (21.7) 15 (2.0)
518 (75.5) 156 (22.7) 12 (1.8)
56 (84.8) 7 (10.6) 3 (4.5)
0.0964 0.0193 0.1372
a b
Mean ± standard deviation. Number of subjects (percentage).
frequency of nodal disease (623, 69.6%). Microcarcinomas were detected in 278 (37.0%) cases. Comparison of patients with radiogenic or sporadic thyroid cancer did not reveal statistically significant difference between the two groups in the distribution of tumor size, histological types or TNM stages. Table 3 Sites of recurrence Patterns of failure Lung metastases (M1 cases included) Positive neck lymph nodes Relapse in thyroid remnants Soft tissue metastases Lymph nodes and thyroid remnants Neck lymph nodes and lung metastases Lymph nodes and soft tissue metastases Lymph nodes, lung and bone metastases Lymph nodes, lung and CNS metastases Lymph nodes, lung, bone and CNS Lymph nodes, lung and thyroid remnants Lung, bone and soft tissue metastases Lung and soft tissue metastases Lung metastases and thyroid remnants Total a
Number of subjects (percentage).
Total 89 (11.8) 59 (7.8) 3 (0.4) 1 (0.1) 10 (1.3) 26 (3.5) 2 (0.3) 1 (0.1) 1 (0.1) 1 (0.1) 5 (0.7) 1 (0.13) 2 (0.27) 3 (0.40) 204 (27.1)
a
Radiogenic
Sporadic
p-value
86 (12.5) 58 (8.5) 3 (0.4) 1 (0.2) 9 (1.3) 26 (3.8) 2 (0.3) 1 (0.2) 1 (0.2) 1 (0.2) 4 (0.6) 1 (0.15) 1 (0.15) 3 (0.44) 197 (28.7)
3 (4.5) 1 (1.5) 0 0 1 (1.5) 0 0 0 0 0 1 (1.5) 0 1 (1.5) 0 7 (10.6)
0.0697 0.0514 1.0000 1.0000 0.6032 0.1569 1.0000 1.0000 1.0000 1.0000 0.3691 1.0000 0.1679 1.0000 0.0012
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Table 4 Mean time (months) of disease-free survival Radiogenic Local recurrence Neck lymph nodes Thyroid remnants Soft tissue metastases Distant metastases Lung Bone a b
40.4 (2.0) a 32.5–48.2 b 28.7 (3.3) 22.3–35.1 52.1 (11.8) 29.1–75.1 51.6 (21.8) 8.8–94.4 43.5 (5.2) 33.3–55.7 19.3 (2.2) 15.0–23.7 43.0 (20.9) 2.1–83.8
Sporadic 90.4 (53.0) 0.0–194.2 76.5 (69.8) 0.0–213.3 114.1 (101.9) 0.0–213.8 – 44.7 (33.4) 0.0–110.2 17.5 (12.1) 0.0–41.2 –
Estimate (standard error). 95% confidence interval.
Symptoms at presentation were mainly caused by the large thyroid nodules or enlarged lymph nodes. Neck mass or discomfort was a common complaint registered in 134 of 163 (82.2%) patients with clinical manifestations. Sporadic thyroid carcinomas appeared to be significantly less symptomatic than radiogenic malignancies (Table 2). During follow-up period, recurrent disease was diagnosed in 204 (27.1%) patients. The main sites of recurrence were the lung or lymph nodes whereas others (thyroid remnants, the bone, soft tissues or CNS) were uncommon and usually associated with positive neck nodes or pulmonary foci. Perhaps because of different follow-up period, patients with radiogenic carcinomas had a higher rate of recurrence as compared with sporadic cases but no significant difference was found in the frequency of local relapse or distant metastases for these groups (Table 3). The relatively common lymph node relapses in radiogenic cases were likely due to the prevalence of safe surgical procedures in the early years after the Chernobyl disaster. The disease-free interval ranged widely between 0 and 213 months after the date of primary surgery without significant difference between radiogenic and sporadic cases (Table 4). The observed 10-year survival was 99.5% for the entire series, including 99.5% and 99.7% in patients with radiogenic and sporadic carcinomas, respectively. 4. Discussion Our data indicate no evidence that two etiological types of pediatric thyroid cancer, ie. the radiogenic and sporadic, are distinct from the standpoint of the clinical course of disease. The only noticed fact that sporadic cases are commonly asymptomatic is likely to reflect the general tendency of decreasing frequency of palpable neck masses [14]. In a recent review, Thompson and Hay demonstrated that in the past nearly 50% of pediatric patients with thyroid cancer had a history of radiation exposure [2]. Nowadays this
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proportion decreased to less than 3% but in the literature there are a few publications comparing the clinical course of sporadic and radiogenic thyroid malignancies. Spinelli et al. have analyzed 22 radiogenic and 34 sporadic pediatric cases of papillary carcinomas [15]. The high prevalence of distant metastases and pertinacious local relapses were recognized as specific features of the radiation-associated thyroid malignancies. The rate of recurrence reached 64% and 3% for exposed and unexposed patients, respectively. By contrast, another series of 339 post-Chernobyl pediatric cases reported by Rybakov et al. demonstrated a noticeably lower frequency of distant metastases and local relapses in radiation related cancers [16]. In the present study we found that history of radiation exposure has no impact on the clinical course of pediatric thyroid carcinomas. The high incidence of lung lesions and recurrences after curative treatment has been extensively described in the literature [17–20] previously. An elevated risk of dissemination is mostly associated with the younger age of patients [12,19,21]. In conclusion, the observed excellent 10-year survival of pediatric patients with thyroid cancer, 99.5%, is indicative of the high efficacy of the current treatment strategy allowing cure in almost all children with differentiated thyroid carcinomas. References [1] D.M. Parkin, E. Kramarova, G.J. Draper, et al. (Eds.), International Incidence of Childhood Cancer, vol. II, IARC Scientific Publications No. 144, International Agency for Research on Cancer, Lyon, 1998. [2] G.B. Thompson, I.D. Hay, Current strategies for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma, World J. Surg. 28 (2004) 1187–1198. [3] B.J. Duffy, P.J. Fitzgerald, Cancer of the thyroid in children: a report of twenty eight cases, Cancer 3 (1950) 1018–1032. [4] V. Kazakov, E. Demidchik, L. Astakova, Thyroid cancer after Chernobyl, Nature 359 (1992) 21–22. [5] K. Baverstock, B. Egloff, A. Pinchera, C. Ruchti, D. Williams, Thyroid cancer after Chernobyl, Nature 359 (1992) 21–22. [6] E. Cardis, J. Howe, E. Ron, et al., Cancer consequences of the Chernobyl accident: 20 years on, J. Radiol. Prot. 26 (2006) 127–140. [7] P. Jacob, T.I. Bogdanova, E. Buglova, et al., Thyroid cancer among Ukrainians and Belarusians who were children or adolescents at the time of the Chernobyl accident, J. Radiol. Prot. 26 (2006) 51–67. [8] E. Cardis, E. Amoros, A. Kesminiene, et al., Observed and predicted thyroid cancer incidence following the Chernobyl accident evidence for factors influencing susceptibility to radiation induced thyroid cancer, in: G. Thomas, A. Karaoglou, E.D. Williams (Eds.), Radiation and Thyroid Cancer, World Scientific, Singapore, 1999, pp. 395–405. [9] E.P. Demidchik, V.S. Kazakov, L.N. Astakhova, A.E. Okeanov, Yu.E. Demidchik, Thyroid cancer in children after the Chernobyl accident: clinical and epidemiological evaluation of 251 cases in the Republic of Belarus, in: S. Nagataki (Ed.), Nagasaki Symposium on Chernobyl: Update and Future, Elsevier, Amsterdam, 1994, pp. 21–30. [10] F. Pacini, T. Vorontsova, E. Demidchik, et al., Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France, J. Clin. Endocrinol. Metab. 82 (1997) 3563–3569. [11] M. Ito, S. Yamashita, K. Ashizawa, et al., Histopathological characteristics of childhood thyroid cancer in Gomel, Belarus, Int. J. Cancer 65 (1996) 29–33. [12] Yu.E. Demidchik, E.P. Demidchik, C. Reiners, et al., Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus, Ann. Surg. 243 (2006) 525–532. [13] L.H. Sobin, C. Wittekind (Eds.), TNM Classification of Malignant Tumours, 6th edition, WHO, Geneva, 2002.
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[14] J.K. Harness, Childhood thyroid carcinoma, in: O.H. Clark, Q.-Y. Duh (Eds.), Textbook of Endocrine Surgery, Saunders, Philadelphia, 1997, pp. 75–81. [15] C. Spinelli, A. Bertocchini, A. Antonelli, P. Miccoli, Surgical therapy of the thyroid papillary carcinoma in children: experience with 56 patients ≤16 years old, J. Pediatr. Surg. 39 (2004) 1500–1505. [16] S.J. Rybakov, I.V. Komissarenro, N. Tronko, et al., Thyroid cancer in children of Ukraine after the Chernobyl accident, World J. Surg. 24 (2000) 1446–1449. [17] J.W. Haveman, K.M. van Tol, C.W. Rouwe, D.A. Piers, J.T.M. Plukker, Surgical experience in children with differentiated thyroid carcinoma, Ann. Surg. Oncol. 10 (2003) 15–20. [18] D. Giuffrida, C. Scollo, G. Pellegriti, et al., Differentiated thyroid cancer in children and adolescents, J. Endocrinol. Investig. 25 (2002) 18–24. [19] P.W. Grigsby, A. Galor, J.M. Michalski, G.M. Doherty, Childhood and adolescent thyroid carcinoma, Cancer 95 (2002) 724–729. [20] M.P. La Quaglia, T. Black, G.W. Holcomb, R.G. Azizkhan, G.M. Haase, K.D. Newman, Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases, a report from the Surgical Discipline Committee of the Children's Cancer Group, J. Pediatr. Surg. 35 (2000) 955–999. [21] A.J. Alessandri, K.J. Goddard, G.K. Blair, C.J. Fryer, K.R. Schultz, Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma, Med. Pediatr. Oncol. 35 (2000) 41–46.