Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
Differentiated thyroid cancer (Dtc) is a rare disease, especially in children. Differences in the biology and clinical course of Dtc in children, when compared with adults, may be related both to pathogenesis as well as to clinical outcome of the disease. In childhood, the thyroid gland exhibits higher susceptibility to the carcinogenetic effect of ionizating radiation than in adulthood. Papillary thyroid cancer (Ptc) is more prevalent in children in comparison to adult patients. Among molecular events known to occur in papillary thyroid carcinoma, rEt/Ptc rearrangements exhibit higher prevalence in younger patients, while brAF mutations are very rare in this age group. cancer disease presents at a more advanced stage: 1) primary tumour at diagnosis is larger, especially in relation to the volume of the whole gland; 2) neck lymph node involvement is more commonly observed; 3) distant metastases are detected 3-4 times more frequently than in adults. the lungs are almost the sole distant metastatic site in children and pulmonary metastases are nearly always functional. Additionally, recurrence rates tend to be higher in children; nevertheless, cause-specific cancer mortality remains low. Up to now, thyroid cancer guidelines have been formulated on the basis of experience gained in the general population of patients. the peculiarities in childhood disease raise the question of whether it should be considered a distinct subtype, with specifically tailored therapy recommendations. A definitive answer to this question is not possible with the present state of knowledge. In the opinion of the authors, molecular analyses of childhood thyroid cancer may be crucial, as the clinical data have not satisfactorily answered this question.
Children, Differentiated thyroid cancer
Childhood cancer encompasses a spectrum of different malignancies varying by type of histopathology, site of disease origin, age and sex. In this age group, the vast majority of malignancies are due to non-epithelial malignant neoplasms: leukemias and lymphomas, central nervous system tumours, sarcomas or embryonal cancers such as neuroblastoma, retinoblastoma and Wilms’ tumours. Carcinomas—malignant tumours of epithelial origin—are very rare, particularly before the second decade of life, and comprise only about 9% of all childhood cancers. Interestingly, differentiated thyroid cancer (DTC) contributes to a markedly higher morbidity in children than carcinoma in any other localization (only malignant melanomas exhibit similar incidence).1 Additionally, the risk of malignancy in a thyroid nodule is distinctly higher in children than in adults.2,3
Incidence rates are practically negligible in very young children.4-6 The average annual rate of DTC per million increases sharply in adolescence, being at that period additionally influenced by sex.7 The age-specific incidence rates for males and females begin to diverge at age 10 years and from age 13 years the rates increase substantially for females.1,8,9
GENETIC PREDISPOSITION TO DIFFERENTIATED THYROID CANCER
Non-medullary thyroid cancer occurs rarely as an inherited disease. However, it is well known that PTC is diagnosed with a significantly high erincidence among the relatives of patients with this cancer histotype;10-14 however, the genetic mutations underlying the predisposition to familial non-medullary thyroid cancer have been only poorly defined.12,15-18 Non-medullary thyroid cancer in the course of familial adenomatous polyposis is well known but rarely diag-nosed. It may also occur in Cowden syndrome due to inactivating PTEN mutations, Werner syndrome and some other rare monogenic diseases. Generally, it is considered to be inherited as an autosomal dominant trait within complete penetrance and variable clinical expression.10 The existence of marked phenotypic differences indicates that there is a significant genetic heterogeneity and hence multigene contribution is probable. Recently, the CHEK2 polymorphism has been indicated as predisposing to PTC (with multiorgan involvement). Other single nucleotide polymorphismsites-based studies are on going and are expected to disclose additional contributing genes.19-21 To our knowledge, there are no data in dicating higher incidence of genetically determined disease among children diagnosed with DTC. In a population of 235 children and adolescents with DTC observed by us, only a few had a positive family history. On the other hand, it is well known that familial non-medullary thyroid cancer is more frequently multifocal and exhibits more advanced locoregional involvement, features considered to be characteristic for DTC in childhood. Thus, intensive studies of SNP polymorphisms in this subgroup are warranted.
RADIATION INDUCED THYROID CANCER
The increased risk of papillary thyroid cancer (PTC) in children exposed to ionizating radiation was documented for a wide range of doses, and a linear dose-response relation for doses from 0.1 Gy to up to 1-2 Gy has been described.22,23 Two distinct peaks are known in the incidence of radiation-induced thyroid cancer in children and young adults. The first rise was observed in the middle of the 20th century and was due to previous irradiation of head, neck and upper thorax as a form of therapy for a variety of mostly benign conditions.22-25 The risk of DTC was significantly elevated from 10-19 yr after exposure, peaking at 20-30 years and decreasing 40 years after exposure.26 After such radiation ceased to be used for the treatment of benign disease, the peak of thyroid carcinomas declined by half.27 Nevertheless, in some children radiation therapy for malignant disease is unavoidable and this subgroup constitutes an increased risk for later development of DTC if the radiation field encompasses the neck region.28
The second peak of thyroid cancer incidence in children, observed in some East European countries, was related to an uptake of radioiodine following the Chernobyl disaster in 1986.25,29 The increased DTC incidence started 4–5 years after exposure, reaching its maximum in the mid-1990s, and the disease developed mainly in children <5 years old at exposure.30,31 The accelerated onset, relative to external irradiation induced disease, is most probably related to radiation dose differences and to endemic iodine deficiency in Eastern Europe.31 Though only papillary thyroid cancers were initially diagnosed, a trend to increased rates of follicular tumours—follicular adenomas and follicular thyroid cancer— has now been reported with a markedly longer latency time.
The mechanisms responsible for a higher risk of thyroid cancer after radiation exposure in childhood than in adulthood are not well defined. However, a correlation with the growth pattern of thyroid cells seems the most probable mechanism. Thyroid cells proliferate actively only in early childhood and have very limited potential for proliferation during adult life. By using MIB-1 antibody that reacts with the Ki-67 nuclear antigen, found throughout the cell cycle but absent in resting (G0) cells, it was shown that the overall proliferative rate of normal adult thyroid cells is as low as 0.2%.32 Comparable findings (0.6%) were observed when another proliferative marker, proliferating cell nuclear antigen (PCNA)/cyclin, was studied in several normal thyroid glands.33 The recent analysis by Saad et al34 of histologically normal thyroid glands aged from 11 weeks of gestation to age 60 years, based on the expression of the Ki-67 nuclear antigen, showed the highest indices of cell proliferation in early fetal life, particularly at 11-15 and 16-20 weeks of gestation, when 16% and 12% of cells were labelled, respectively. There was a steep decline in the proliferation index during the subsequent fetal period and the first few postnatal months. The proliferation index remained within the range of 0.2-0.3% throughout childhood and adolescence and further decreased in the adult population, where it was close to 0.1%.34 There was an evidence of an overall trend for decreasing proliferative index with increasing age (p<0.01). The authors also compared the risks of radiation-related thyroid cancer and cell proliferation in the same age intervals and revealed a generally similar tendency for a decline in both parameters with age. However, a lack of correlation was noted between the slopes of risk and proliferative rate in the age group 0 to 9 years. This discrepancy suggests that additional and still unknown factors may further modify the risk of thyroid cancer in young children. One possibility would be a higher functional state of thyroid cells in early childhood. Indeed, Faggiano et al35 revealed that small, metabolically active follicles with high expression of NIS and pendrin predominate in children <12 years of age, a finding indicating that iodide transport mechanisms are more active in the thyroids of younger individuals.
AGE-RELATED DIFFERENCES IN THE MECHANISM OF PAPILLARY THYROID CANCER INITIATION
Many studies have shown that the distribution of molecular events leading to malignant transformation of thyroid cells differs between children and adults. In papillary thyroid cancer, which constitutes the main histotype diagnosed in children, there are two major initiating events, RET/PTC rearrangements and BRAF point mutation, both activating the same down-stream pathway, the mitogen activated protein kinase (MAPK) signalling pathway, the crucial intra-cellular cascade regulating cell growth, differentiation and survival in response to growth factors, hormones and cytokines.36 The other two mutations, NTRK1 rearrangements and RAS activating mutations, lie on the same pathway but occur rarely. Significantly, the frequency of RET/PTC and BRAF mutations show distinct age-related differences.37-40
RET activation in follicular thyroid cell is due to inversion or translocation, known as RET/PTC rearrangement, which breaks the RET gene and results in the fusion of its 3’ portion to the 5’ portion of several unrelated genes.41 Sixteen different types of RET/PTC have been reported to date with RET/PTC1 and RET/PTC3 accounting for the vast majority.42 In the mutated gene, RET tyrosine kinase domain is fused with the regulatory domains of other genes. The most frequent rearrangements are: RET/PTC1 (results from the fusion of RET with the gene CCDC6, formerly called H4 or D10S170) and RET/PTC3 (fusion of RET to the gene NcoA4, formerly called RET fused gene (RFG) or ELE1 or ARA70).36 Both of these genes are constitutively expressed in thyroid cells, contrary to the wild RET gene. Because mechanisms of transcription of their activation continue to operate, the transcription of the fusion gene is also activated and, in this way, a protein containing RET tyrosine kinase domain appears in the thyroid cell. The chimeric protein is found in cytoplasm (not in membrane, as the normal RET protein) and may be constitutively activated by dimerization (again, the regulatory domains of the gene fused with RET tyrosine kinase domain are responsible for this effect).36 Thus, the RET kinase starts to phosphorylate down-stream proteins and the MAPK cascade becomes activated, leading to the increased transcription of proliferation genes.
Activation of cell proliferation by RET/PTC rearrangement is only the initial event. The subsequent steps, leading to malignant transformation and development of papillary thyroid cancer, are much less known. Although it was observed that the rate of lymph node and distant metastases was higher in RET-positive papillary cancers, the overall prognosis is not affected or even considered more favourable in RET positive tumours.39,43 RET/PTC rearrange-ment has only rarely been found in anaplastic thyroid cancer, which may indicate that cancers initiated by RET rearrangement are not prone to this unfavourable course of PTC natural history.44 This view has recently been questioned by FISH studies showing the presence of RET/PTC in anaplastic cancer.45
The frequency of RET/PTC rearrangement differs substantially in various populations from less than 10% to more than 80% of cases.36 Many factors are responsible for these differences and may include methodological and ethnic differences. However, one of the most important is age difference: RET/PTC rearrangements are much more frequent in younger patients with PTC and especially in children. They constitute 40-70% of sporadic papillary carcinomas diagnosed in children and young adults.37-40,43 In fact, the highest frequencies of RET/PTC rearrangements in PTC, up to 87%,are encountered in the population of children with radiation-induced cancer developing after the Chernobyl catastrophe. This high detection rate was initially interpreted as the molecular fingerprint of radiation-induced cancer and only later was it related to the age of the patients.37-39,46,47 It is probably the shorter latency of RET/PTC induced tumours, which explains the high frequency of this mutation in cancers appearing 5-10 years after the Chernobyl accident. The frequency of RET/PTC3 is the highest in the earliest Chernobyl-induced PTCs, while the incidence of RET/PTC1 starts to rise later. RET/PTC1 has also been reported to be more frequent in exogenous radiation-induced thyroid cancer.48 The incidence of different RET rearrangements is age related, with RET/PTC3 being the most frequent in the youngest PTC patients.37-39,49 The presence of RET/PTC3 rearrangement correlates with solid PTC morphology, while RET/PTC1 is seen more frequently in the classical PTC variant. Interestingly, recent FISH studies indicate multiclonality of RET rearrangements in PTC, which raises the possibility that RET rearrangements may be an early but not initiating event.47
An alternative way of MAPK signalling pathway activation is induced by a mutation of the BRAF gene. A thymine to adenine inversion in the nucleotide 1799 is the prevalent one, resulting in a substitution of a valine with a glutamic acid at residue 600 of the protein, leading to a constitutive activation of BRAF kinase.50,51 To date, multiple studies have confirmed that BRAF mutation is the most common event in sporadic papillary carcinomas seen in adult patients. It occurs in approximately 40-60% of all cases.51,52 In contrast to adult papillary carcinomas, paediatric tumours (both sporadic and radiation-induced) have a low prevalence of BRAF mutations (0-12%).40,53-57 Kamagai et al58 observed only one case of BRAF mutation in 46 PTC patients diagnosed under the age of 15 years, and this was a rare case of poorly differentiated cancer. Indeed, BRAF mutations are found in thyroid anaplastic and poorly differentiated carcinomas, typically in those tumours that also contain areas of well differentiated papillary carcinoma.59 Mutant BRAF is detectable in both well differentiated and poorly differentiated or anaplastic tumour areas, providing evidence that it occurs early in tumorigenesis and predisposes to tumour dedifferentiation. Interestingly, BRAF mutations correlate with radiation dose in thyroid cancers occurring in atomic bomb survivors, which indicates that BRAF-positive PTCs may also be radiation-induced.60 Some BRAF activating mutations are due to a rearrangement.61
Apart from older age in several studies, the presence of BRAF mutation has been found to correlate with more frequent extrathyroidal extension, advanced tumour stage at presentation and tumour recurrence.42 BRAF mutation is an independent predictor of tumour recurrence, even in patients with stage I and II of the disease.62 Importantly, BRAF mutations have also been associated with a decreased ability of tumours to trap I-131 and with the treatment failure of the recurrent disease.62,63 However, the association between BRAF mutation and more aggressive tumour behaviour has not been found in some other studies.64 No multivariate analyses have thus far been performed, and hence it is not clear whether BRAF mutations are primarily related to poor prognosis or only occur in older patients, in whom other factors are primarily responsible for the poor outcome. It is a matter of future investigations to answer the question whether differences in mutations as a function of age account for the well documented but as yet poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma.
BRAF and RET mutations are related to very prominent differences in the gene expression profile of PTC.65 This suggests that the differences in the clinical course of BRAF-and RET-positive PTCs may be mediated by the induction of different molecular down-stream pathways.66 No data on the possible interaction with age are available. BRAF and RET mutations are believed to be alternative initiating events in PTC. In a general population of PTC patients, BRAF and RET mutations covered nearly all cases and those patients without any mutation identified constituted less than 20%. The last group was recently related to PDGFB amplification.67 However, in childhood PTC up to 40% of tumours might be caused by events other than RET/PTC and BRAF mutation, as neither one of these mutations can be found.38-41,50,55-58 Thus, it cannot be excluded that another molecular mechanism, characteristic for early onset of PTC, will be discovered in future studies.
ARE THERE OTHER DIFFERENCES IN THE MOLECULAR PROFILE OF THYROID CANCER IN CHILDREN?
Molecular studies in thyroid cancer are oriented on mutations initiating the process while further steps of tumorigenesis remain less known.68-70 Microarray-based gene expression profiling has documented that expression of several thousands of genes is changed in papillary thyroid cancer, when compared to the normal thyroid tissue.71 A distinct part of them is related to the immune response. Indeed, it is well known that many PTC tumours exhibit lymphocytic infiltration, well demonstrated in younger patients.72-76 Thus, it is conceivable that the better outcome in children’s DTC is related not only to differences in the molecular profile of cancer cells but additionally to the host anti-tumour immunity.75,76 Functional genomic studies may help to evaluate this hypothesis.
In the context of the molecular profiling of PTC, it is noteworthy that no major differences in the gene expression profile of radiation-induced cancer have thus far been detected compared to those unrelated to radiation.77
CLINICAL PRESENTATION AND OUTCOME
The age at diagnosis is preponderantly included in the clinical scoring system of differentiated thyroid carcinoma patients with distant metastases. Patients younger than 45 years are considered to be in stage II of disease, while those older than 45 are in stage IV. In fact, however, metastases are rare at diagnosis of DTC in patients between 21 and 45 years of age, while they are present in a significant number of younger patients, 20% in our experience in patients up to 18 years of age.78 The very favourable outcome in patients diagnosed in their first two decades of life is based on low mortality rate, with the specific overall survival approaching 100%.9,78 Cancer deaths nevertheless do occur in this age group.1
Although mortality rates in children and adolescents are much lower than in adults, DTC in childhood is often more advanced at presentation and there is a higher risk of disease recurrence.5,9,79-81 Papillary microcarcinoma, defined as a tumour less than 1-1.5 cm, is a rare diagnosis in children and in most studies accounts for less than 3% of sporadic PTC,82 while in adults up to 36% of thyroid cancers are below 1 cm.83 Zimmerman et al79 described 9% of tumours under 1 cm in children in comparison to 22% in adults. Nevertheless, Demidchik et al84 in their recent study of radiation-induced thyroid cancer reported that in 73% of children the thyroid cancer size was less than 2 cm in diameter.
Not only larger primary tumour but also a higher propensity for lymph node and distant metastases characterises childhood DTC.79,80 In sporadic PTC in children, the incidence of node metastases ranges from 40% to 60%. An extremely high propensity for lymph node metastases is seen in radiation induced PTC (>80%). In our study, where clinical outcome of DTC in children and adolescents younger than 18 years of age was compared with the outcome of young adults up to 30 years of age, we found that the incidence of lymph node and distant metastases was, respectively, two and four times higher in children than in young adults.80
The rate of distant metastases at diagnosis of PTC shows two peaks, the first in childhood and the second in patients older than 60 years.85 In children, distant metastases outside the lungs are very rare.86 Unlike adult lesions, pediatric pulmonary DTC metastases are overwhelmingly miliary and seldom nodular, and almost always functional.87-89 Among 95 Byelorussian children with radiation-induced DTC and lung metastases, 92 (97%) had disseminated and only 3 (3.15%) had nodular pulmonary radioiodine uptake.88 This type of lung metastases—disseminated involvement of miliary type—was also seen by other groups.90,91 In our group of 47 children and adolescents with primary (40 patients) or recurrent (7 patients) distant metastases, 44 had functional metastases.
The high prevalence of functional metastases in pediatric DTC may be related to differences in sodium iodide symporter (NIS) expression. While NIS expression is reduced in cancer cells, childhood tumours appear to have greater and more frequently detectable expression than adult tumours.92,93 In the absence of TSH stimulation, NIS expression is undetectable in ~65% of papillary and ~56% of follicular cancers in patients aged <20 years.93 In contrast, NIS expression is absent or reduced in ~90% of adult DTC, as assessed by reverse transcription polymerase chain reaction.92 Expression of other iodinetran sport-related molecules, pendrin and apical iodide transporter (AIT), has been found to be reduced in pediatric (Wiench, manuscript in preparation) as well as in adult DTC,94,95 but there are no data as to whether or not expression is greater in childhood DTC.
The greater NIS expression in pediatric than in adult DTC implies greater differentiation and radioiodine responsiveness in the former, which may be relevant to outcome. In young patients, recurrence risk was increased in NIS-negative versus NIS-positive tumours, even when TNM status and treatment were similar.93 The degree of NIS expression in primary DTC lesions correlated with subsequent radioiodine uptake in metastastases96 and the clinical response of recurrences to therapy.97
The net major characteristic of DTC diagnosed in children versus adults is a generally higher recurrence rate. With 16.6 years’ follow-up, this rate approaches 40% in patients with PTC diagnosed in subjects aged <20 years, versus ~20% in patients diagnosed at age 20-50 years.98 With more frequent application of radi-cal surgery and adjuvant radioiodine therapy, we have observed recurrence in 14% of our more than 200 DTC patients diagnosed prior to age 18 years and a median follow-up of 82.2 months.78
Overall survival is distinctly better in children than in adults, despite the more advanced disease at diagnosis and the frequent recurrences. Not more than 35 cause-specific deaths occurred among 2000 recently reported children and young adults.9 Despite the good overall survival prognosis, our own experience favours total thyroidectomy, modified lymphadenectomy in patients with lymph node metastases and adjuvant radioiodine treatment after radical surgery. We demonstrated in the multivariate analysis that all of these measures independently reduced the risk of thyroid and lymph node recurrence in young patients.78 Thus, in respect to the recommended treatment, we do not see any difference in comparison to older patients. However, in this age group special attention must be paid to avoid long-term complications related to therapeutic procedures applied.
While thyroid cancer guidelines are formulated on the basis of experience gained in the general population of patients,99,100 the peculiarities in childhood disease raise the question as to whether it should be considered a distinct subtype with specifically tailored therapy recommendations. In the opinion of the authors, molecular analysis of childhood thyroid cancer may be crucial as the clinical experience has not produced a satisfactory solution to pertinent questions.9,101,102 Future research directed towards a better understanding of the molecular mechanisms underlying pathogenesis of thyroid cancer will likely lead to molecularly oriented diagnosis, prognosis and therapy in children.
Our appreciation is extended to the expert secretarial assistance of Miss Monika Kowal. The paper has been partially supported by the European project GENRISK-T No. 036495
1. Bernstein L, Gurney J, 1999 Carcinomas and other ma-lignant epithelial neoplasms. In Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995. Cancer Statistics Branch, National Cancer Institute, Bethesda
2. Niedziela M, 2006 Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr Relat Cancer 13: 427-453.
3. Frates MC, Benson CB, Doubilet PM, et al, 2006 Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J Clin Endocrinol Metab 91: 3411-3417.
4. Harness JK, Thompson NW, McLeod MK, Pasieka JL, Fukuuchi A, 1992 Differentiated thyroid carcinoma in children and adolescents. World J Surg 16: 547-553.
5. Newman KD, Black T, Heller G, et al, 1998 Differentiated thyroid cancer: determinants of disease progression in patients<21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children’s Cancer Group. Ann Surg 227: 533–541.
6. Schlumberger M, Berg G, Cohen O, et al, 2004 Fol-low-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol 150: 105-112.
7. Steliarova-Foucher E, Stiller CA, Pukkala E, et al, 2006 Thyroid cancer incidence and survival among European children and adolescents (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 42: 2150-2169.
8. Harach HR, Williams ED, 1995 Childhood thyroid cancer in England and Wales. Br J Cancer 72: 777-783.
9. Jarzab B, Handkiewicz-Junak D, Wloch J, 2005 Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer 12: 773-803.
10. Sippel RS, Caron NR, Clark OH, 2007 An Evidence-based Approach to Familial Nonmedullary Thyroid Cancer: Screening, Clinical Management, and Follow-up.World J Surg 31: 924-933.
11. Hemminki K, Eng C, Chen B, 2005 Familial risks for nonmedullary thyroid cancer. J Clin Endocrinol Metab 90: 5747-5753.
12. Malchoff CD, Malchoff DM, 2002 The genetics of hereditary nonmedullary thyroid carcinoma. J Clin Endocrinol Metab 87: 2455-2459.
13. Pal T, Vogl FD, Chappuis PO, et al, 2002 Increased risk for nonmedullary thyroid cancer in the first degree relatives oprevalent cases of nonmedullary thyroid cancer: a hospital-based study.J Clin Endocrinol Metab 86: 5307-5312.
14. Handkiewicz-Junak D, Banasik T, Kołosza Z, et al, 2006 Risk of malignant tumors in first-degree relatives of patients with differentiated thyroid cancer - a hospital based study. Neoplasma 53: 67-72.
15. Malchoff CD, Malchoff DM, 2006 Familial nonmedullary thyroid carcinoma. Cancer Control 13: 106-110.
16. Charkes ND, 2006 On the prevalence of familial non-medullary thyroid cancer in multiply affected kindreds. Thyroid 2006 16:181-186. Erratum in: Thyroid 16: 520.
17. Tsilchorozidou T, Vafiadou E, Yovos JG, et al, 2005 A Greek family with a follicular variant of familial papillary thyroid carcinoma: TCO,MNG1, fPTC/PRN, and NMTC1 excluded as susceptibility loci. Thyroid 15: 1349-1354.
18. Yamashita S, Saenko V, 2007 Mechanisms of Disease: molecular genetics of childhood thyroid cancers. Nat Clin Pract Endocrinol Metab 3: 422-442.
19. Cybulski C, Gorski B, Huzarski T, et al, 2005 CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75: 1131-1135.
20. Stephens LA, Powell NG, Grubb J, et al, 2005 Investigation of loss of heterozygosity and SNP frequencies in the RET gene in papillary thyroid carcinoma. Thyroid 15: 100-104.
21. Rogounovitch TI, Saenko VA, Ashizawa K, et al, 2006 TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer. Oncol Rep 15: 949-956.
22. Ron E, Lubin JH, Shore RE, et al, 1995 Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 141: 259-277.
23. Cardis E, Kesminiene A, Ivanov V, et al, 2005 Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97: 724-732.
24. Lubin JH, Schafer DW, Ron E, Stovall M, Carroll RJ, 2004 Are analysis o fthyroid neoplasms I the Israeli tinea capitis study accounting for dose uncertainties. Radiat Res 161: 359-368.
25. Williams ED, 2006 Chernobyl and thyroid cancer. J Surg Oncol 94: 670-677.
26. Sadetzki S, Chetrit A, Lubina A, Stovall M, Novikov I, 2006 Risk of thyroid cancer after childhood exposure to ionizing radiation for tinea capitis. J Clin Endocrinol Metab 91: 4798-4804.
27. Catelinois O, Verger P, Colonna M, Rogel A, Hemon D, Tirmarche M, 2004 Projecting the time trend of thyroid cancers: its impact on assessment of radiation-induced cancer risks. Health Phys 87: 606-614.
28. Ronckers CM, Sigurdson AJ, Stovall M, et al, 2006 Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res 166: 618-628.
29. Williams D, 1996 Thyroid cancer and the Chernobyl accident. J Clin Endocrinol Metab 81: 6-8.
30. Farahati J, Demidchik EP, Biko J, Reiners C, 2000 In-verse association between age at the time of radiation exposure and extent of disease in cases of radiation-in-duced childhood thyroid carcinoma in Belarus. Cancer 88: 1470-1476.
31. Mahoney MC, Lawvere S, Falkner KL, et al, 2004 Thyroid cancer incidence trends in Belarus: examining the impact of Chernobyl. Int J Epidemiol 33: 1025-1033.
32. Katoh R, Bray CE, Suzuki K, et al, 1995 Growth activity in hyperplastic and neoplastic human thyroid determined by an immunohistochemical staining procedure using monoclonal antibody MIB-1. Hum Pathol 26: 139-146.
33. Shimizu T, Usuda N, Yamanda T, Sugenoya A, Iida F, 1993 Proliferative activity of human thyroid tumors evaluated by proliferating cell nuclear antigen/cyclin immunohistochemical studies. Cancer 71: 2807-2812.
34. Saad AG, Kumar S, Ron E, et al, 2006 Proliferative activ-ity of human thyroid cells in various age groups and its correlation with the risk of thyroid cancer after radiation exposure. J Clin Endocrinol Metab 91: 2672-2677.
35. Faggiano A, Coulot J, Bellon N, et al, 2004 Age-depen-dent variation of follicular size and expression of iodine transporters in human thyroid tissue. J Nucl Med 45: 232-237.
36. Santoro M, Melillo RM, Fusco A, 2006 RET/PTC activa-tion in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 155: 645-653.
37. Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA, 1998 RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 4: 223-228.
38. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA, 1997 Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57: 1690-1694.
39. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, TuttleRM, 2000 The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab 85: 1170-1175.
40. Kumagai A, Namba H, Saenko VA, et al, 2004 Low frequency of BRAFT 1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab 89: 4280-4284.
41. Grieco M, Santoro M, Berlingieri MT, et al, 1990 PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60: 557-563.
42. Ciampi R, Nikiforov YE, 2007 RET/PTC rearrangements and braf mutations in thyroid tumorigenesis. Endocrinology 148: 936-941.
43. Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M, 1998 Sporadic RET-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol 185: 71-78.
44. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, 1998 RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 4: 287-294.
45. Nakashima M, Takamura N, Namba H, et al, 2007 RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. Hum Pathol 38: 621-628.
46. Rabes HM, Demidchik EP, Sidorow JD, et al, 2000 Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6: 1093-1103.
47. Thomas GA, Bunnell H, Cook HA, et al, 1999 High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 84: 4232-4238.
48. Collins BJ, Chiappetta G, Schneider AB, et al, 2002 RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions. J Clin Endocrinol Metab 87: 3941-3946.
49. Wiench M, Wloch J, Oczko M, Gubala E, Jarzab B, 2001 Rearrangement of the RET gene in papillary thyroid carcinoma. Wiad Lek 54: Suppl 1: 64-71.
50. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA, 2003 High prevalence of BRAF muta-tions in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63: 1454-1457.
51. Davies H, Bignell GR, Cox C, et al, 2002 Mutations of the BRAF gene in human cancer. Nature 417: 949-995. 52. Xing M, 2005 BRAF mutation in thyroid cancer. Endocr Relat Cancer 12: 245-262.
53. Nikiforova MN, Ciampi R, Salvatore G, et al, 2004 Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 209: 1-6.
54. Lima J, Trovisco V, Soares P, et al, 2004 BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89: 4264-4266.
55. Penko K, Livezey J, Fenton C, et al, 2005 BRAF mutations are uncommon in papillary thyroid cancer of young patients. Thyroid 15: 320-325.
56. Powell N, Jeremiah S, Morishita M, et al, 2005 Frequency of BRAFT 1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol 205: 558-564.
57. Rosenbaum E, Hosler G, Zahurak M, Cohen Y, Sidransky D, Westra WH, 2005 Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma. Mod Pathol 18: 898-902.
58. Kumagai A, Namba H, Mitsutake N, et al, 2006 Childhood thyroid carcinoma with BRAFT1799A mutation shows unique pathological features of poor differentiation. Oncol Rep 16: 123-126.
59. Nikiforova MN, Kimura ET, Gandhi M, et al, 2003 BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. Junak Clin Endocrinol Metab 88: 5399-5404.
60. Takahashi K, Eguchi H, Arihiro K, et al, 2007 The pres-ence of BRFA point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose. Mol Carcinog 46: 242-248.
61. Ciampi R, Knauf JA, Kerler R, et al, 2005 Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115: 94-101.
62. Xing M, Westra WH, Tufano RP, et al, 2005 BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90: 6373-6379.
63. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Ca-bezas MA, Nistal M, Santisteban P, 2006 The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I-targeting to the membrane. Endocr Relat Cancer 13: 257-269.
64. Trovisco V, Soares P, Preto A, et al, 2005 Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness. Virchows Arch 446: 589-595.
65. Giordano TJ, Kuick R, Thomas DJ, et al, 2005 Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarrayanalysis. Oncogene 24: 6646-6656.
66. Polanski A, Polanska J, Jarzab M, Wiench M, Jarzab B, 2007 Application of Bayesian networks for inferring cause–effect relations from gene expression profiles of cancer versus normal cells. Math Biosci (In press).
67. Finn S, Smyth P, O’Regan E, et al, 2007 Low-level genomic instability is a feature of papillary thyroid carcinoma: an array comparative genomic hybridization study of laser capture microdissected papillary thyroid carcinoma tumors and clonal cell lines. Arch Pathol Lab Med 131: 65-73.
68. Cahilli S, Smyth P, Finn SP, et al, 2006 Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer 5: 70.
69. De Falco V, Castellone MD, De Vita G, et al, 2007 RET/ papillary thyroid carcinoma oncogenic signaling through the Rap1 small GTPase. Cancer Res 67: 381-390.
70. Kimmel RR, Zhao LP, Nguyen D, et al, 2006 Microarray comparative genomic hybridization reveals genome-wide patterns of DNA gains and losses in post-Chernobyl thyroid cancer. Radiat Res 166: 519-531.
71. Jarzab B, Wiench M, Fujarewicz K, et al, 2005 Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res 65: 1587-1597.
72. Mardente S, Lenti L, Lococo E, et al, 2005 Phenotypic and functional characterization of lymphocytesin autoimmune thyroiditis and in papillary carcinoma. Anticancer Res 25: 2483-2488.
73. Costello A, Rey-Hipolito C, Patel A, et al, 2005 Thyroid cancers express CD-40 and CD-40 ligand: cancers that express CD-40 ligand may have a greater risk of recurrence in young patients. Thyroid 15: 105-113.
74. Kebebew E, Treseler PA, Ituarte PH, Clark OH, 2001 Coexisting chronic lymphocytic thyroiditis and papillary thyroid cancer revisited. World J Surg 25: 632-637.
75. Modi J, Patel A, Terrell R, Tuttle RM, Francis GL, 2003 Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes. J Clin Endocrinol Metab 88: 4418-4425.
76. Gupta S, Patel A, Folstad A, et al, 2001 Infiltration of differentiated thyroid carcinoma by proliferating lymphocytesis associated with improved disease-free survival for children and young adults. J Clin Endocrinol Metab 86: 1346-1354.
77. Detours V, Wattel S, Venet D, et al, 2005 Absence of a specific radiation signature in post-Chernobyl thyroid cancers. Br J Cancer 92: 1545-1552.
78. Handkiewicz-Junak D, Włoch J, Roskosz J, et al, 2007 Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer. J Nucl Med 48: 1-10 (In press).
79. Zimmerman D, Hay ID, Gough IR, 1988 Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery 104: 1157-1166.
80. Handkiewicz-Junak D, Kalemba B, Roskosz J, et al, 2001 Prognostic factors for differentiated thyroid carcinoma in young patients. Nowotwory 51: 365-371.
81. Jarzab B, Handkiewicz-Junak D, Wloch J, et al, 2000 Multivariate analysis of prognostic factors for differentiated thyroid carcinoma in children. Eur J Nucl Med 27: 833-841.
82. Chow SM, Law SC, Mendenhall WM, et al, 2004 Dif-ferentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer 42: 176-183.
83. Sakorafas GH, Giotakis J, Stafyla V, 2005 Papillary thyroid microcarcinoma: a surgical perspective. Cancer Treat Rev 31: 423-438.
84. Demidchik YE, Demidchik EP, Reiners C, et al, 2006 Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus. Ann Surg 243: 525-532.
85. Mazzaferri EL, Jhiang SM, 1994 Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97: 418-428.
86. Schlumberger M, De Vathaire F, Travagli JP, et al, 1987 Differentiated thyroid carcinoma in childhood: long term follow-up of 72 patients. J Clin Endocrinol Metab 65: 1088-1094.
87. Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al, 1993 Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 71: 1348-1352.
88. Reiners C, Biko J, Demidchik EP, Demidchik YE, Drozd VM, 2002 Results of radioactive iodine treatment in children from Belarus with advanced stages of thyroid cancer after the Chernobyl accident. Elsevier International Congress Series 1234: 205-214.
89. Vermeer-Mens JC, Goemaere NN, Kuenen-Boumeester V, et al, 2006 Childhood papillary thyroid carcinoma with miliary pulmonary metastases. J Clin Oncol 24: 5788-5789.
90. Dottorini ME, Vignati A, Mazzucchelli L, Lomuscio G, Colombo L, 1997 Differentiated thyroid carcinoma in children and adolescents: a 37-year experience in 85 patients. J Nucl Med 38: 669-675.
91. Bal CS, Kumar A, Chandra P, Dwivedi SN, Mukhopad-hyaya S, 2004 Is chest x-ray or high-resolution computed tomography scan of the chest sufficient investigation to detect pulmonary metastasis in pediatric differentiated thyroid cancer? Thyroid 14: 217-225.
92. Ringel MD, Anderson J, Souza SL, et al, 2001 Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol 14: 289-296.
93. Patel A, Jhiang S, Dogra S, et al, 2002 Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents. Pediatr Res 52: 737-744.
94. Gerard AC, Daumerie C, Mestdagh C, et al, 2003 Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas. J Clin Endocrinol Metab 88: 4977-4983.
95. Lacroix L, Pourcher T, Magnon C, et al, 2004 Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters. J Clin Endocrinol Metab 89: 1423-1428.
96. Castro MR, Bergert ER, Goellner JR, Hay ID, Morris JC, 2001 Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake. J Clin Endocrinol Metab 86: 5627-5632.
97. Mian C, Lacroix L, Alzieu L, et al, 2001 Sodium iodide symporter and pendrin expression in human thyroid tissues. Thyroid 11: 825-830.
98. Mazzaferri EL, Kloos RT, 2001 Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 86: 1447-1463.
99. Cooper DS, Doherty GM, Haugen BR, et al, 2006 The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 162: 109
100.Pacini F, Schlumberger M, Dralle H, et al, 2006 European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154: 787-803.
101. Rachmiel M, Charron M, Gupta A, et al, 2006 Evidence-based review of treatment and follow up of pediatric patients with differentiated thyroid carcinoma. J Pediatr Endocrinol Metab 19: 1377-1393.
102.Gingalewski CA, Newman KD, 2006 Seminars: controversies in the management of pediatric thyroid malignancy. J Surg Oncol 94: 748-752.
Address for correspondence: Barbara Jarzab, M.D, Ph.D., 15 Wybrzeże Armii Krajowej Str., 44-100 Gliwice,
Poland, Tel.: +48 32 2789301, Fax: +48 32 2789325, e-mail: firstname.lastname@example.org
Received 30-05-07, Revised 20-06-07, Accepted 25-06-07