Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present

Câncer de tiróide na infância na Bielorússia, Rússia, e na Ucrânia, após Chernobil e atualmente

REVISÃO

Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present

Câncer de tiróide na infância na Bielorússia, Rússia, e na Ucrânia, após Chernobil e atualmente

Yuri E. Demidchik^I; Vladimir A. Saenko^II; Shunichi Yamashita^{II, III}

^IDepartment of Oncology, Belarusian State Medical University and Thyroid Cancer Center, Minsk, Belarus

^IIDepartment of International Health and Radiation Research and Department of Molecular Medicine

^IIIAtomic Bomb Disease Institute, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan

^{Address for correspondence}

ABSTRACT

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

Keywords: Childhood thyroid cancer; Chernobyl; Surgery; Radioiodine; Histotype; Molecular genetics

RESUMO

O câncer de tiróide é habitualmente raro em crianças, mas em indivíduos expostos a radiação o risco da doença aumenta consideravelmente. Cerca de uma década após o acidente de Chernobil, em 1986, foi registrado um aumento de mais de 10 vezes na incidência de câncer de tiróide, resultando cumulativamente em mais de mil novos casos diagnosticados em crianças que viviam nos territórios da Bielorrússia, Russia, e Ucrânia, afetadas pela chuva radioativa. A experiência com essa epidemia resultou em conhecimento substancial de oncologia pediátrica clínica, patologia e ciências básicas. Este artigo analisa a epidemiologia, os achados clínicos, os resultados do tratamento e a evolução de pacientes pediátricos com câncer de tiróide induzido pela radiação de Chernobil, em comparação com casos esporádicos diagnosticados atualmente. Adicionalmente, serão discutidos tópicos de patologia e achados moleculares no carcinoma de tiróide infantil.

Descritores: Câncer de tiróide infantil; Chernobil; Cirurgia; Radioiodo; Histotipo; Genética molecular

THYROID CANCER AFFECTS EVERY year 0.1–2.2 individuals per million of all aged under 15 years old worldwide. Exposure to external or internal radiation at young age, however, increases risk of thyroid malignancy dramatically.

After the accident on April 26, 1986, at the Chernobyl nuclear power station, which is located at the north of Ukraine close to the borders of Belarus and Russia, over 10¹⁸ Bq of radioactivity were released into the environment (1). Due to changeable weather conditions, radioactive pollutions have been detected to some extent in many European countries and even in the North America, but the heaviest contamination occurred in Belarus, Ukraine, and western parts of Russia (figure 1). The spectrum of ejected isotopes included over four hundred of different radionuclides with large amounts of radiologically important ¹³¹I and ¹³⁷Cs.

Although inhalation of some radionuclides from air was possible in the affected regions, the main route of radioactive iodine entry into the human body has been primarily through ingestion of contaminated milk. In total, millions of peoples including hundreds of thousand children were exposed. According to the estimates, only in Belarus several thousand children have accumulated ¹³¹I thyroid doses exceeding 2 Gy (1). Given the thyroid in children is particularly radiosensitive compared to adults (2), a group of risk included cumulatively a very large number of young individuals.

There has been a sharp increase in the incidence of thyroid cancer in exposed children in 1990–1993 (3-12) that peaked about a decade ago in the three most affected countries displaying an order-scale raise. Since the phenomenon of Chernobyl, childhood thyroid cancer has been recognized by the international medical and scientific communities, numerous epidemiological, clinical and molecular studies have been done. These investigations have established a compelling link of disease with radioactive iodines released to the environment, and addressed distinctive features of clinicopathological characteristics and underlying molecular changes of Chernobyl tumors. An unprecedented increase in the number of diagnosed childhood thyroid cancers led to a rapid accumulation of experience in the treatment of this otherwise rare malignancy.

Nowadays, 20 years after the Chernobyl tragedy, incidence of thyroid cancer in children in the affected countries decreased to the levels just somewhat elevated compared to the pre-accident rate. There are no justified reasons to suspect radiation etiology of thyroid cancer in the individuals born in 1987 or later around Chernobyl, and such newly diagnosed cases are considered sporadic. Since the number of young patients with sporadic thyroid cancer is currently approaching the score of a hundred only in Belarus, it seemed to be timely to compare the clinical course and other relevant peculiarities of these cases to those observed earlier in patients with radiation-induced cancer.

EPIDEMIOLOGY OF CHILDHOOD THYROID CANCER

The most detailed information on the incidence of thyroid malignancies in childhood was published by the International Agency for Research on Cancer (IARC) in 1999 (13). It included data from major world cancer registries except Belarus, Russia, and Ukraine, which were affected by radioactive fallouts at the time of the Chernobyl accident. The total number accounted for less than a thousand of pediatric patients and, according to the results obtained, the crude and age standardized incidence rate (ASR) for sporadic thyroid carcinomas in the age group under 15 years old was 0–2.2 per one million (table 1). Of note, pooled data included only 21 pediatric patients less than 5 years old, while the majority of patients were aged more than 10 years.

Similar observations were done in the EUROCARE II study that included series from 45 cancer registries of 17 countries (14). For the period between 1978 and 1989, 165 childhood thyroid cancer cases were diagnosed in Western Europe. Of them, 134 (81%) patients were 10–14 years old and the remaining thyroid malignancies were diagnosed in younger individuals.

In a recent series published by Steliarova-Foucher et al., the estimated rate for childhood thyroid cancer ranged between 0.3 and 2.0 per million depending on region and patients’ gender (15). These data were based on 151 cases diagnosed during 1988–1997 as collected from 61 European cancer registries excluding Belarus. The cumulative mean ASR was 0.5 per million.

Incidence of disease in Belarus, northern Ukraine, and western regions of Russian Federation was comparable to that determined in the above-mentioned studies before the Chernobyl disaster (4,7,8). Only five childhood patients with thyroid malignancies were diagnosed in Belarus between 1978 and 1985, while a slight annual increase of primary adult cases was observed. Since 1990, a sharp elevation in the number of patients was documented, initially in the southern, mostly contaminated, regions of the country. In 1993, the crude incidence in Gomel and Brest regions (located closer to the Chernobyl nuclear power plant) reached 9.4 and 6.7 per 100,000, respectively (4). It was recognized as the highest worldwide, but firstly these observations were attributed to the undertaken screening programs (table 2). Indeed, the mass application of thyroid ultrasonography and fine-needle aspiration biopsy in early years after Chernobyl disaster revealed an unexpectedly great number of childhood patients with thyroid malignancies. One of the concerns about these findings was that these carcinomas had been diagnosed before than they would have manifested in older ages. However, subsequent screening of children born after the accident in the same regions demonstrated the absence of cancer in this age group.

Examination of the geographical distribution of diagnosed cases and the estimates of absorbed thyroid doses left no doubts that childhood thyroid cancer cases are associated with exposure to radiation, in particular with intake of ¹³¹I (19,20).

The increasing number of primary childhood cancer cases in Belarus was documented during seven years after the accident with the peak in 1996 (figure 2A). It is interesting to note that the major impact on the increased incidence of the short-latency cases (i.e. those diagnosed during the first decade after the accident) could be attributed to children diagnosed for cancer at the age below 10 years old (figure 2B). Since 1996, the incidence in children was gradually decreasing (figure 2A), and from 2001 only sporadic cases occurred in the age group under 15 (5). In total, 740 childhood patients with proven thyroid carcinomas from Belarus were reported for the period between 1986 and 2003 (21).

It is necessary to emphasize that the Belarusian experience with childhood thyroid cancers has been more substantial as compared to that in Ukraine and affected regions of Russian Federation, especially in terms of the total number of diagnosed cases. For instance, Ukrainian series of patients aged 0–14 years at diagnosis reported by Tronko et al. included 472 cases mostly from six northern regions that were heavily contaminated by iodine isotopes at the time of accident (9). In it, the crude incidence exceeded the average pre-Chernobyl level 11.4 times (1.9 per 100,000 children in 1996, peak) and had the dose-dependent pattern. Lushnikov et al. (22) published a series of 51 patients under 15 years old from the most affected Bryansk region of Russian Federation with the peak of incidence 12.6 per 100,000 in 1998. The reported cases from the three countries contaminated by radioactive fallouts are shown in table 3.

On the whole, observations in the reported Chernobyl childhood thyroid cancer series could be summarized as following: i) the majority of patients were residents of the regions proximal to the Chernobyl power plant and there is a significant association between cancer incidence and absorbed thyroid doses (23,24); ii) the highest risk for thyroid cancer was found in patients aged 0–4 years at the time of exposure; and iii) papillary thyroid carcinoma was the prevalent pathological type (94–98%) and most patients had an advanced stage of disease at presentation (21,25).

CLINICAL COURSE OF CHILDHOOD PATIENTS WITH THYROID CANCER

Thyroid carcinomas in childhood are usually asymptomatic with clinical signs of disease seen in only about 20% of cases. The prevalent manifestation of thyroid malignancy is neck mass with or without lymph node enlargement or palpable thyroid nodules. Advanced disease can be accompanied by hoarseness and sometimes labored breathing as a sign of recurrent laryngeal nerve or tracheal wall involvement, respectively. Other symptoms in young patients are rather occasional (25-31). Thyroid carcinomas in childhood do not cause hypo- or hyperthyroidism, the majority of patients are generally euthyroid. A moderate prevalence of disease in female patients is common.

As shown in table 4, papillary thyroid carcinoma is the major histological type of malignancy while follicular, medullary or undifferentiated cancers are rare. Childhood thyroid carcinomas are frequently locally invasive, positive neck lymph nodes can be found in up to 90% of the cases vs. 35% in adults (32). Data available from the literature also demonstrate a higher frequency of lung metastases in children as compared with adult cases (32). In a recent series, Chow et al. found pulmonary metastases in 15% of patients aged less than 21 years and 7.8% in the older individuals (33). In our experience, children with lung metastases usually have nodal disease with large thyroid nodules accessible by palpation without labored breathing in most instances. Pulmonary foci are frequently very small or diffuse that makes them virtually undetectable by routine chest X-ray or CT scan. Metastatic disease can be found as "snow storm" radiographs in isolated cases. Bone metastases in children are uncommon and usually associate with lung lesions.

Neck ultrasonography and fine-needle aspiration biopsy of thyroid nodules or enlarged lymph nodes are widely accepted methods of primary diagnosis of thyroid cancer. Distant metastases can be most correctly identified by whole-body scanning after total thyroidectomy.

Besides certain differences between clinicopathological characteristics of thyroid cancers in children and adults, there is a question whether some features may be specific to radiation-induced or sporadic pediatric tumors. Pacini et al. (34) performed a comparative study of Chernobyl thyroid carcinomas and sporadic thyroid malignancies from France and Italy. It was found that Belarusian cases developed during the first decade after exposure had the greater aggressiveness at presentation and were diagnosed at the younger age. Spinelli et al. (35) compared radiogenic and sporadic childhood cases of papillary thyroid carcinomas to demonstrate the frequency of recurrences of 64% and 3% in patients exposed and not exposed to radiation, respectively. In this work, the higher prevalence of distant metastases and recurrent local relapses were recognized to be particularly associated with the radiogenic thyroid malignancies.

In our recent study, comparison of patients with radiogenic (n= 686) and sporadic (n= 66) thyroid cancer did not reveal statistically significant difference in tumor size, and distributions of histological types and tumor stages between the two groups (36). With regard to disease relapse, in a series that included the greatest number of patients with radiation-related thyroid cancer, the frequency of local failures was registered in 9.9% cases, distant in 12.2% and a combination of local and distant recurrences in 5.5% (21). In a group of childhood thyroid cancers from Ukraine, a similar rate of distant (14.5%) and cervical relapses (6.8%) was demonstrated (25). Our analysis indicates that these data do not significantly differ from those cumulatively found in sporadic childhood thyroid carcinomas worldwide. Thus, at a moment there is no clear evidence that etiologically distinct childhood thyroid carcinomas are presented with different clinical course but this problem undoubtedly requires further investigations.

Despite childhood thyroid cancers frequently have advanced stage at diagnosis and recurrence rate may be high, 10- and 15-years cause-specific survival exceeds 95%.

TREATMENT STRATEGIES FOR CHILDHOOD THYROID CANCER

Surgery is the principal method of choice for the treatment of thyroid malignancies. Since the prognosis in childhood patients with well-differentiated thyroid cancer is excellent in most cases, extent of removal has been a matter of debate for many years. Clinicians generally consider lumpectomy insufficient but hitherto there is no valid evidence that survival rates are significantly different in individuals undergoing primary total thyroidectomy or lesser extracapsular resections (52,56).

The rationale for organ preserving surgery is a very low operative morbidity and good condition of patients after partial thyroidectomy at follow-up. By now, the accepted indications for thyroid lobectomy are cases of minimally invasive follicular carcinomas or encapsulated papillary microcarcinomas without intraglandular dissemination, nodal disease and history of exposure to radiation.

However, a safe surgical procedure frequently results in recurrences in thyroid remnants or lymph node involvement. In the Belarusian series every fourth patient had to undergo completion thyroidectomy for local relapse or residual carcinoma after primary lobectomy or subtotal thyroidectomy (21). Indeed, lymph node or thyroid remnant recurrence, especially diagnosed shortly after primary surgery, is likely to develop from malignant foci that initially were not removed. Since 1998, we routinely recommend total thyroidectomy, central compartment removal with simultaneous bilateral selective neck dissection for all childhood patients. Such a strategy ensures an overall curative benefit with a very low frequency of local relapses, improved staging and accurate diagnosis of metastases using whole body scanning and meaningful serum thyroglobulin measurements. In table 5 we summarized the major results of treatment approaches and associated complication and failures available from the literature.

A classical radical neck dissection is now uncommon and could be acceptable only for advanced medullary or poorly differentiated carcinomas, as well as in very rare cases with resectable anaplastic malignancies. The highly aggressive nature of such tumors normally requires extensive excision but fortunately such operations are exceptionally rare, if any, in young patients.

The purpose of radioiodine therapy is the ablation of thyroid remnants after near total thyroidectomy and elimination of residual foci of carcinoma, neck or mediastinal recurrences and distant metastases. This therapeutic option is indicated in all childhood patients with papillary or follicular carcinomas staged pT2-pT4 four or five weeks after total thyroidectomy when serum TSH level exceeds 30 mU/l. Activity of ¹³¹I for ablation of residual thyroid tissue and recurrences is 50 MBq/kg and 100 MBq/kg bodyweight, respectively. Before therapy, a 24-hour radioiodine uptake test has to be done (25 MBq/kg), and if the uptake value exceeds 20%, repeated surgery should be recommended to remove large thyroid remnants (64).

The results of radioiodine therapy are usually excellent. This therapeutic means undoubtedly improves prognosis for pediatric patients with well-differentiated thyroid cancer (21,41,62). The criteria of efficacy are very rigorous so that complete responders should display no evidence of ¹³¹I accumulation on whole body scanning and have serum thyroglobulin levels < 1 ng/l. Otherwise patients have to continue radioiodine administration. If there is no ¹³¹I uptake on whole body scanning and thyroglobulin levels ranges between 1 and 10 ng/l, criteria correspond to stable partial response while a combination of detectable isotope accumulation and elevated serum thyroglobulin levels is interpreted as a partial response.

Successful ablation of thyroid remnants usually requires one or two courses of radioiodine therapy whereas elimination of distant metastases could be achieved after three to five courses (21,60). Some patients with lung metastases in our series received a total of about 50 GBq during the period of more than ten years and still the complete response is not confirmed.

L-thyroxine suppressive therapy with the mean dose of 2.5 µg/kg bodyweight is recommended after radioiodine ablation. Although a comprehensive assessment of the results of lifelong treatment with L-thyroxine has not been done yet to our knowledge, in our experience stable serum TSH equal to or lesser than 0.1 mU/l could hardly be reached in childhood patients. TSH levels appear quite changeable depending on body weight of a growing organism and, perhaps, other individual characteristics. Our preliminary estimates indicate a quite low efficacy of suppressive therapy during which only 46% childhood patients in Belarusian series had permanently suppressed TSH at careful follow-up. Since hypothyroidism is significantly associated with the disease recurrence, issues of optimization of TSH suppression in children remain urgent and require further investigation.

PATHOLOGICAL CHARACTERISTICS OF CHILDHOOD THYROID CANCER

The WHO histological classification of thyroid tumors, 2004, indicates 12 types of thyroid carcinomas of which papillary, follicular, medullary, and undifferentiated carcinomas are the main entities (65).

In children, the differentiated types of thyroid carcinomas, i.e. papillary, follicular, and medullary, carcinomas are strongly prevalent compared with poorly differentiated and undifferentiated cancers. Childhood thyroid cancers are often presented with multifocal growth, frequent nodal disease, extraglandular invasion and distant metastases indicative of their more aggressive clinical course compared with disease in adults. Cases diagnosed in the Chernobyl countries, either those radiation-related or sporadic, correspond well with these observations.

Papillary thyroid carcinoma is the most common histological type (60–97% cases, mean 85%) observed in childhood patients with both sporadic and radiation-induced thyroid cancer. Morphological diagnosis of papillary thyroid carcinoma is based on specific features of tumor epithelial cells, first of all such as enlarged overlapping nuclei with ground glass appearance, nuclear grooves and pseudoinclusions, and psammoma bodies. Papillary thyroid carcinomas are usually non-encapsulated or partly encapsulated tumors except for the follicular variant of papillary carcinoma, which may be frequently seen as a nodule surrounded by a fibrous capsule. The main way of papillary thyroid cancer dissemination is lymphatic, manifesting in a high rate of regional lymph node involvement. Vascular invasion is observed in up to 30% of cases (43) with distant metastases documented in a somewhat lesser proportion (table 4).

There is an apparent age-dependent trend in the distribution of morphological patterns of sporadic papillary thyroid carcinomas in pediatric patients. In older children, classical papillary morphology is more frequent while the solid-type tumors are more characteristic for patients aged below 10 years (66). Papillary carcinomas with the solid growth pattern were found with an exceedingly high frequency (> 70%) in the Chernobyl patients diagnosed for thyroid cancer during the first decade after the catastrophe (67-72). However, in contrast to sporadic papillary thyroid carcinomas, in these radiation-induced cases solid morphology did not display a strict correlation with patients’ age. Instead, there has been a pronounced association with the shorter period of latency (72).

Follicular thyroid carcinoma, similarly to papillary carcinoma, develops from the follicular cells. It is diagnosed in 3–33% (12%, median) of childhood thyroid cancers and tends to occur in older children (73). From the adult thyroid cancer series it is known that follicular carcinoma is relatively more prevalent in the iodine-deficient areas (74). It is unclear, however, if it applies to childhood cases. For example in some series in Japan (iodine-rich region), the follicular cancer accounted for 12% (69), in England, Wales, and Italy (iodine sufficient) for 11–12% (26,66) and for 4–6% in the Chernobyl countries (mild iodine deficiency) (5,9). Most tumors are solitary, all encapsulated. Main route of dissemination is hematogenous with metastases occurring in the lungs, bones, liver, and brain. The morphologic criteria of follicular carcinoma include capsular and vascular (the blood vessels in or beyond the capsule only) invasion. Upon comparison, follicular thyroid carcinoma appears less advanced at presentation than papillary cancer in childhood patients (75) and its prognosis is favorable.

Medullary thyroid carcinoma occurs in about 2% of all childhood thyroid cancers but variations in some series may occur due to sampling bias or screenings (30,66). In adults, sporadic medullary carcinoma is diagnosed in 70–80% cases and 20–30% of cancers are hereditary, occurring either as familial medullary cancer or as a part of multiple endocrine neoplasia type 2 (MEN2) syndromes (76). Onset of the sporadic medullary cancer is usually observed in the patients aged over 30 years. Therefore, the proportion of inherited form of the disease in children may be expected to be substantially higher. Sporadic medullary cancer is usually presented with a solitary nodule. Inherited forms are often multifocal, C-cell hyperplasia beyond the tumor nodule(s) is prominent. Children operated on for medullary cancer, including those with MEN2 who have undergone prophylactic thyroidectomy, have more favorable prognosis compared with adults.

Poorly differentiated and undifferentiated thyroid carcinomas are exceptionally rare in young patients with only isolated instances reported in the literature (5,69,77,78).

ISSUES OF TUMOR STAGING

Papillary thyroid microcarcinoma has been a term to denote tumors measuring 1 cm or less. Tumors meeting this criterion have been found in 24% of childhood cases according to an earlier work (79) and currently in the Belarusian series this proportion is higher, 37% (36). It is necessary, however, to bear in mind that most pediatric cases have been identified during the screening programs in the countries affected by the Chernobyl accident. The definition of microcarcinoma builds up a difficulty in childhood cases, with the T category in particular, because of the smaller size of the thyroid in children. Human thyroid increases in volume until the age 22–24 years old. Therefore, the same absolute dimensions of a tumor in a child and in an adult would result in an under-staging in younger patients (79,80). According to the evaluation of age-adjusted tumor size vs. age-specific thyroid volume, a tumor measuring 1 cm in an adult corresponds to a tumor with a diameter of 4 mm in a 10-year-old individual (64). It has been proposed that an arbitrary size limit should not be used to define papillary microcarcinoma in childhood patients until a study correlating tumor size and other features to the disease prognosis is undertaken (81). Indeed, papillary microcarcinoma for many instances is an incidental pathological finding in the thyroid tissue removed for the reasons other than thyroid cancer. By contrast, carcinomas measuring less than 1 cm in diameter often display extrathyroid invasion and metastases in children. Thus, there may be a need for further revision of UICC classification for childhood thyroid malignancies in the future.

MOLECULAR PATHOGENESIS

In the papillary thyroid carcinoma, oncogenic RET/PTC, NTRK1, and AKAP9/BRAF gene rearrangements and point mutations of the BRAF gene and RAS family members are the best known molecular changes. There is a pronounced trend in the distribution of oncogenes among patients of different ages: rearrangement-type alterations are largely prevalent in childhood cancers whereas point mutations occur infrequently.

RET/PTC rearrangements have been reported with a frequency of 11–43% in sporadic papillary thyroid cancers (about 40% on average in childhood cases) and 38–87% in patients with a history of radiation exposure.

A strong link between rearrangement type of and tumor morphology was found in pediatric series. It has been shown that RET/PTC1 and RET/PTC3 associate with papillary thyroid carcinomas with the classic papillary and solid architecture, respectively (71,82,83). Interestingly, in children affected by the Chernobyl accident, RET/PTC3 was predominant (60% of all rearrangements) in the tumors developed during the first decade after the accident, while in those developed after the longer latency the most frequent rearrangement was RET/PTC1 (65%) (71). This observation corresponds well with the higher prevalence of papillary thyroid carcinomas with solid morphology developed after the shorter period of latency and an increasing proportion of tumors with classic papillary architecture observed in the later-onset cases. Some similarity in tumor genotype-phenotype correlations could be seen in sporadic childhood papillary thyroid carcinomas diagnosed in patients of different ages (84), but further investigations are necessary to clarify age-molecular-(clinico)pathological relationships including the prognostic value of gene rearrangements.

In a relatively small series of sporadic childhood papillary thyroid carcinomas diagnosed between 2001–2006 (n= 25, patients’ age 7–15 years old) that was available for molecular studies we found a 28% RET/PTC rearrangement rate and a 16% frequency of BRAF mutations (manuscript in preparation). Although based on a limited sample size, these observations are supportive of two characteristics of sporadic childhood papillary thyroid carcinomas: the greater prevalence of gene rearrangements compared to point mutations and the lower frequency of gene rearrangements compared to the radiation-induced cancers.

In the follicular variant of papillary carcinoma, one of the frequent gene abnormalities is the PAX8-PPARg fusion arising as a result of a translocation between chromosomes 2 and 3. In adults this gene alteration has been reported in 38–50% of corresponding tumors (85,86) but its prevalence in childhood follicular variant of papillary carcinoma, which is observed in about one-fifth of patients, remains to be established.

Point mutations of the RAS family genes [detected in 0–6% cases (87-89)], BRAF [0–16% (89-94)], GNAS [not detected (95)], and TP53 [0–23% (89,96-98)] genes are quite rare in childhood papillary thyroid carcinoma. Perhaps such an imbalance between rearrangement-type gene alterations and point mutations, more prevalent in pediatric and adult papillary thyroid carcinoma, respectively, may be a part of the explanation of the difference in the prognosis of disease in patients of different age.

Follicular thyroid carcinoma is associated with point mutations of the RAS genes and PAX8-PPARg rearrangement. In adult patients, prevalence of these genetic alterations is some 20–50% (99-102) and 14–35% (99,103-106), respectively. In childhood series, the frequency of these events remains to be determined.

Molecular pathogenesis of medullary thyroid cancer is associated with point mutations of the RET gene. More than 95% of patients with heritable form of medullary cancer have germline point mutations in the RET gene that enables prospective screening of individuals at risk. In sporadic medullary cancer, a somatic mutation at codon 918 may be expected in 25–50% cases in adults. In pediatric patients with sporadic medullary cancer, prevalence of point mutations in RET is not known exactly, but there is no reason to assume it will be too different from the elderly cases.

CONCLUSION

Experience from Chernobyl childhood thyroid cancer has substantially improved our understanding of the disease in several fields of knowledge, including clinical practice, pathology, and molecular carcinogenesis.

The vast majority of thyroid cancers registered in young patients were papillary adenocarcinomas. Comparison of radiation-related and sporadic cases demonstrated that, despite short-latency Chernobyl cancers have been more aggressive with a high rate of local lymph node involvement and elevated incidence of distant metastases, there is no clear evidence of the main difference in clinical course and prognosis on the whole. Radical thyroid surgery including total thyroidectomy combined with neck dissections followed by radioiodine ablation could be recommended as the method of choice for the eradication of tumor. Clinical approaches for radiation-induced childhood thyroid cancer could adequately be transferred and used in young patients with sporadic thyroid malignancy.

It is necessary to remember that cumulatively several million individuals have been exposed to radioactive fallouts in the affected countries during their childhood and adolescence. Although those who were even newborns at the time of the accident are not children or adolescents at present, risk of development of thyroid cancer remains elevated in such people for the lifespan. Therefore, further surveillance and thorough clinical, pathological, and molecular studies, such as those performed by the Chernobyl Tissue Bank (http://www.chernobyltissuebank.com, ref. 107), will be essential to clarify the late effects of Chernobyl in order to be better prepared for a superior medical care to both childhood and adult patients with thyroid cancer in the future.

ACKNOWLEDGEMENTS

This work was supported in part by Nagasaki University 21^st Century COE Program, International Consortium for Medical Care of Hibakusha and Radiation Life Sciences.

Recebido em 14/03/07

Aceito em 19/03/07

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Publication Dates

• Publication in this collection
  20 Sept 2007
• Date of issue
  July 2007

History

• Accepted
  19 Mar 2007
• Received
  14 Mar 2007