Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review.

Well under 15% of differentiated thyroid carcinoma (DTC) is diagnosed at < or =18 years of age. The population is heterogenous and the differences between prepubertal children and pubertals and adolescents are to be considered. Although very little has been reported on children with sporadic DTC under the age of 10 years, juvenile DTC has at least some undeniable differences with adult DTC: (1) larger primary tumor at diagnosis; (2) metastatic pattern and features, namely: (a) greater prevalence of neck lymph node and distant metastases at diagnosis, (b) lungs almost the sole distant metastatic site, (c) pulmonary metastases nearly always functional; (3) closer-to-normal and more frequent sodium-iodide symporter (NIS) expression; and (4) higher recurrence rate but longer overall survival. These differences are especially distinct in prepubertal children. The goals of primary treatment of juvenile DTC are to eradicate disease and extend not only overall, but recurrence-free survival (RFS). Extending RFS is itself a desirable goal in children because it improves quality-of-life, alleviates anxiety during psychologically formative years, reduces medical resource consumption, and may increase overall survival. Primary treatment of DTC generally comprises a combination of surgery, radioiodine ((131)I) ablation, and thyroid hormone therapy applied at varying levels of intensity. Therapeutic decision-making must rely on retrospective adult and/or pediatric outcome studies and on treatment guidelines formulated mostly for adults. Differences between juvenile and adult DTC and physiology dictate distinct treatment strategies for children. We, and many others, advocate a routine intensive approach because of the more advanced disease at diagnosis, propensity for recurrence, and greater radioiodine responsiveness in children, as well as published evidence of significant survival benefits, especially regarding RFS. This intensive approach consists of total thyroidectomy and central lymphadenectomy in all cases, completed by modified lateral lymphadenectomy when necessary and followed by radioiodine administration. However, absence of prospective studies and of universal proof of overall cause-specific survival benefits of this approach have led some to propose more conservative strategies. Most European centers give radioiodine ablation to the vast majority of juvenile DTC patients. Ablation seeks to destroy any residual cancer, including microfoci, as well as healthy thyroid remnant. Large studies have documented the procedure to decrease cause-specific death rates and, in children, to significantly lessen locoregional recurrence rates (by factors of 2-11) independent of the extent of surgery. There is universal agreement on treating inoperable functional metastases with large radioiodine activities. Treatment is especially effective in small tumor foci up to 1 cm in diameter, and should be administered every 6-12 months until complete response, loss of functionality, or attainment of cumulative activities between 18.5-37 GBq (500-1000 mCi). Radioiodine therapy is generally safe. Short-term side effects include nausea and vomiting (more frequent in children than in adults), transient neck pain and edema, sialadenitis (<5% incidence), mild myelosuppression (approximately 25%), transient impairment of gonadal function both in females and males (sperm quality in boys), or nasolacrimal obstruction (approximately 3%), with most cases generally being asymptomatic-moderate, self-limiting, or easily prevented or treated. If pregnancy is ruled out before each (131)I administration, and conception avoided in the year afterward, radioiodine therapy appears not to impair fertility. However, therapeutic (131)I carries a small but definite increase in cancer risk, particularly in the salivary glands, colon, rectum, soft tissue and bone. To better guide primary treatment, different therapeutic combinations should be prospectively compared using RFS as the primary endpoint. Efforts also should be made to identify molecular signatures predicting recurrence, metastasis and mortality.

Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients.

PURPOSE: The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. PATIENTS AND METHODS: One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing. RESULTS: Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P <.05). CONCLUSION: The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.

High frequency of recurrent mutations in BRCA1 and BRCA2 genes in Polish families with breast and ovarian cancer.

Germ-line mutations in BRCA1 and BRCA2 genes result in a significantly increased risk of breast and ovarian cancer. Other genes involved in an increased predisposition to breast cancer include the TP53 gene, mutated in Li-Fraumeni syndrome. To estimate the frequency of germ-line mutations in these three genes in Upper Silesia, we have analyzed 47 breast/ovarian cancer families from that region. We found five different disease predisposing mutations in 17 (36%) families. Twelve families (25.5%) carried known BRCA1 mutations (5382insC and C61G), four families (8.5%) carried novel BRCA2 mutations (9631delC and 6886delGAAAA), and one family (2%) harbored novel mutation 1095del8 in the TP53 gene, which is the largest germline deletion in coding sequence of this gene identified thus far. The 5382insC mutation in BRCA1 was found in 11 families and the 9631delC mutation in BRCA2 occurred in three families. These two mutations taken together contribute to 82% of all mutations found in this study, and 30% of the families investigated harbor one of these mutations. The very high frequency of common mutations observed in these families can only be compared to that reported for Ashkenazi Jewish, Icelandic, and Russian high-risk families. This frequency, however, may not be representative for the entire Polish population. The observed distribution of mutations will favor routine pre-screening of predisposed families using a simple and cost-effective test.

Molecular changes in thyroid neoplasia.

All authors integrating the known facts into a model of thyroid carcinogenesis concur that two main histotypes of thyroid cancer exhibit different routes of molecular development. RET rearrangements are an initiating event in papillary carcinoma, and simultaneously the most characteristic mutation for this type of cancer. They are followed by further, not well recognized, mutations. RAS mutations are regarded as a crucial event in the development of follicular tumors already at the adenoma step, while in papillary cancer they belong to the spectrum of secondary mutations, enabling tumor progression. Aberrant DNA methylation, causing loss of P16 tumor supressor gene, may be a common event in both types of cancer. Aneuploidy is seen much more frequently in follicular than in papillary cancer, which also exhibits a low rate for loss of heterozygosity and microsatellite instability. Mutations of the P53 tumor supressor gene are a common feature of undifferentiated thyroid cancers and could be responsible for their aggressive phenotype. RET rearrangements have been proposed as identifying fingerprints for irradiation induced thyroid cancer in children. Our own data speak against this hypothesis. We noted a high frequency of RET/PTC3 mutations in a group of Polish children with papillary thyroid carcinoma, regarded as sporadic cancer.

The genetic background of medullary thyroid carcinoma in young patients.

The study was undertaken to evaluate the frequency of RET polymorphisms at codons 769 and 836 in young medullary thyroid carcinoma (MTC) patients in whom the presence of a known germline mutation has been excluded. 40 patients aged 10-29 were subjected to genetic analysis of RET exons 10, 11, 13, 14 and 16 and compared to 140 older patients. The hereditary component occurred to be very high in young MTC patients: 57% carry the germline mutation, other 28% exhibit at least one rare polymorphic variant of RET. The observed allelic frequencies were 38% for polymorphic variant L769CTG and 6% for variant S836AGT. The results were significantly higher than those obtained in the group of older patients: 20% and 1% for L769CTG and S836AGT, respectively. Our results speak in favour that the polymorphism in RET codon 769 and 836 may also be a factor predisposing to the development of MTC in young age.

[Early results of 131I therapy of differentiated thyroid carcinoma in children]. / Wczesne wyniki leczenia 131I zróznicowanego raka tarczycy u dzieci.

Between 1970-1995 because of thyroid carcinoma 105 children were diagnosed or treated by radioiodine at the Maria Sklodowska-Curie Institute of Oncology and Cancer Center in Gliwice, 101 of them with differentiated thyroid cancer (DTC). All children were operated, in 91% by total thyroidectomy. Papillary carcinoma was diagnosed in 73% of children, follicular cancer in 27%. Lymph node metastases were present in 58.5%. Complementary radioiodine was given to 62 children--to 44 children for thyroid ablation, to 18 for complementary treatment of lymph node metastases. Very good outcome of combined surgical and radioiodine treatment was observed in 95% of children. Post-therapy scans revealed pulmonary micrometastases in 3 patients. Twelve children with pulmonary metastases were treated by radioiodine. Complete remission was observed after radioiodine therapy in 9 of them, in others the treatment is continued.

[Early evaluation of results after total thyroidectomy in patients with thyroid cancer]. / Wczesna ocena wyników pierwotnego calkowitego wyciecia gruczolu tarczowego u chorych na raka tarczycy.

UNLABELLED: 219 patients (159 females, 60 males) operated in Clinic of Oncological Surgery in Gliwice between 1995 and 1999 were analyzed in this study. In 89% of cases differentiated thyroid carcinoma (DTC) was diagnosed. In other patients medullary cancer (8%) and anaplastic one (3%) were diagnosed. Total thyroidectomy with removal of the central cervical lymph nodes compartment was performed in all cases. In 86% of operations bilateral nodal biopsy was done. In 27% of cases modified cervical lymph node dissection was performed. 44 patients were in T4 stage. In 51% of cases cervical nodal metastases were observed. The operation was estimated as radical in 195 patients. Distant metastases occurred in 15 patients. Bilateral paresis of recurrent laryngeal nerve was not observed, unilateral was noticed in 8.7% of cases, permanent hypoparathyroidism appeared in 15% of patients. In postoperative scintigraphy radioiodine uptake was in the range of 0-10% in 206 cases and in the range of 0-3% in 2/3 of operated patients. 125 patients with DTC were treated with 131I. All patients with DTC were administered L-thyroxine to suppress TSH. In other types of cancer substitutive hormone therapy was introduced. In the entire group 8 deaths occurred and 13 cases of local recurrences were observed during the observation. CONCLUSION: The results prove the high effectiveness of the radical thyroidectomy performed in thyroid cancer.

[Evaluation of results after repeated radical surgery for differentiated thyroid cancer]. / Ocena wyników wtórnego radykalnego leczenia chirurgicznego chorych na zróznicowane raki tarczycy.

Total thyroidectomy is the treatment of choice in thyroid cancer. Unfortunately, the diagnosis is not always established before the first operation and the secondary radical surgery is necessary. The aim of this study was to analyze the effectiveness of secondary surgery in differentiated thyroid carcinoma. The randomized group of 768 patients with differentiated thyroid carcinoma, treated in Oncology Center Institute in Gilwice between 1986 and 1997 was analyzed. Among them 474 persons (56%) - 398 females and 76 males (median age 44 years) were operated more than once in different clinics in Poland. They were compared with 136 persons operated by less radical approach. Negative histobiological risk factors were noted in 4% to 33% of cases. Cervical lymph node metastases were observed in 18% of patients. Distant metastases occurred in 3% of cases. 373 persons were treated with 131(I). All patients administered hormonal therapy to suppress TSH. After secondary operation the rate of cancer foci was 28% (when radicalization was performed durning one year after primary surgery) and 56% when it was done later. This difference was statistically significant (p=0,0002). Locoregional recurrence was observed in 5% of patients. In the entire examined group the actual 5-year-survival was 98% and 10-year-survival was 92%. Complete remission was observed in 80% of patients. The incidence of multifocality in 1/3 of cases and the presence of neoplasm in the re-operated thyroid gland in 1/4 of cases have substantiated the decision for secondary surgery. The delay in radicalization surgery of more than 12 months has doubled the risk of multifocality in thyroid gland remnants. Our results have confirmed the necessity of the secondary surgery after nonradical primary thyroid resection in differentiated thyroid carcinoma.

[Clinical picture of differentiated thyroid carcinoma in the T1 stage]. / Obraz kliniczny zróznicowanego raka tarczycy w stopniu zaawansowania T1.

UNLABELLED: Patients with thyroid microcarcinoma have usually excellent prognosis. However, recurrences in neck and distant metastases have been reported. The optimal treatment for this group of patients is still discussed. The aim of study was to present the clinical and histopathological data of our group of patients with differentiated thyroid carcinoma of 1 cm or less in size diagnosed from 1990 to 2000. 146 patients (137 females and 9 males, mean age 47 years) with differentiated thyroid carcinoma up to 1 cm in the greatest dimension were analyzed. The median follow-up time was 3.5 years. The diagnosis was incidental (made after primary surgery) in 82% of cases. In 85% of patients papillary thyroid carcinoma was diagnosed (in 6% of them as follicular variant). Histopathological risk factors were noticed in 32 patients (21%). The patients were operated in different surgical clinics in Poland. 5% (8) of primary operations and 51% (33) of secondary ones were performed in our center. The most frequent primary operation was bilateral, subtotal strumectomy (62%). Total thyroidectomy was made in 14% of cases (21). Secondary radical operation was performed in 65 patients (44%). Residual cancer was found in 9% of reoperated patients. 47% of patients (69) were treated with 131I and all of them were administered hormonal therapy to suppress TSH. No recurrence and distant metastases were observed. Lymph node metastases were diagnosed and treated in 10 patients (7%). During observation period 1 patient died because of breast cancer. No statistically significant influence of clinical and histopathological risk factors or operation type on clinical outcome was observed. In the analyzed group secondary surgery was connected with the higher risk of complications. CONCLUSIONS: In thyroid papillary microcarcinoma total thyroidectomy is recommended for patients with multiple foci of neoplasm or with metastases (lymph node or distant). Establishment of optimal treatment in minimal follicular thyroid cancer is not possible on the basis of our data and published literature.

[Evaluation of surgical treatment results in patients with differentiated thyroid cancer from materials in the Oncologic Institute in Gliwice]. / Ocena wyników leczenia operacyjnego chorych na zróznicowane raki tarczycy w materiale Instytutu Onkologii w Gliwicach.

The optimal surgical treatment for patients with differentiated thyroid carcinoma is still controversial and discussed. The aim of this study was to analyze the effectiveness of treatment in differentiated thyroid carcinoma, to establish the prognostic value of histopathological type, clinical advancement, the extent of surgery and to estimate the therapeutic benefit rate of the radical approach. The randomized group of 768 patients with differentiated thyroid carcinoma, aged between 16 to 40 (median age 44), treated in Oncology Center Institute in Gliwice between 1986 and 1997 were analyzed. They were operated in different surgical clinics in Poland. The primary total thyroidectomy was performed in 153 of patients (20%), the secondary radical operation in 474 (62%). 136 persons were operated by less radical approach. Cervical lymph node metastases were observed in 26% of patients. Distant metastases occurred in 8% of cases. 610 persons were treated with 131I. All patients were administered hormonal therapy to suppress TSH. Locoregional recurrence occurred in 7.5% of patients. Complete remission was observed in 71.5% of persons (548 patients). The influence of distant metastases lymph node metastases and tumor size on the long-term prognosis was analyzed in univariate statistic analysis. There were no differences in survival in patients with papillary and follicular carcinoma. The 10-year survival was statistically significantly longer in patients who underwent radical surgical treatment (92%) than after non-total thyroidectomy (80%). Despite the relatively high risk of surgical complications the benefits of the radical approach were significant.

[Possibilities and limitations of intraoperative isotope detection for thyroid carcinoma]. / Mozliwosci i ograniczenia sródoperacyjnej detekcji izotopowej raka tarczycy.

Intraoperative probes become increasingly important in the surgical management of cancer. Attempts with gamma probe guided surgery to improve the completeness of surgical excision of radioiodine avid tissues in thyroid cancer have been performed through several decades. The first Polish results by Pomorski et al. have shown that gamma probe guided surgery after preoperative dose of 131I have allowed locating and increasing the completeness of thyroid excision. These results have been substantiated by other authors. However, in the evaluation of intraoperative gamma probe localization of 131I avid tissues one should remember of the limitations of the method. The article begins with a discussion of the statistical limitations of the radiation detection and of the key performance parameters that characterize detectors. Later on we continue with the description of specific aspects concerning gamma probe guided surgery in thyroid cancer.

[Results of treating medullary thyroid carcinoma: the differences between sporadic and inherited forms]. / Wyniki leczenia raka rdzeniastego tarczycy: róznice pomiedzy postaciami sporadyczna i dziedziczna.

Medullary thyroid carcinoma (MTC) can be divided into two subgroups: sporadic or inherited. Hereditary form of MTC is often believed to be form with better prognosis than sporadic one. In this study the differences in MTC prognosis in Polish population of patients was analyzed. The group of 169 patients with MTC was examined. Hereditary cancer was stated in 48 (28%) patients. The median age of disease onset was 41 years (from 7 to 71 years). Genetic examination of RET protooncogene was performed in all patients. The calcitonin and CEA serum level analysis and radiological and radioisotopic examinations were used for monitoring of the disease course. Nineteen cases of MEN 2A syndrome, 11 cases of MEN 2B one and 18 cases of non classified familial MTC were recognized among patients with inherited MTC. Significantly lower age of disease onset in inherited MTC than in sporadic one was observed (27 years vs. 43.7 years, p < 0.001). Local or nodal recurrence was observed in 22 (13%) patients, distant metastases were stated in 21 (12%) patients. Basal or stimulated serum calcitonin level was increased in 85 (50%) patients. No significant differences between sporadic and inherited disease were observed. Eight patients died during observation, including 3 patients with sporadic MTC and 5 patients with inherited MTC. The updated 10-year survival rate was 97% in patients with sporadic MTC; in hereditary MTC it was about 20% worse. The complications related to the presence of adrenal tumors were the main reason for death in MEN2 and no significant differences in the course of MTC itself were observed.

[Rearrangement of the RET gene in papillary thyroid carcinoma]. / Rearanzacje genu RET w raku brodawkowatym tarczycy.

The RET/PTC oncogenes, activated forms of the RET protooncogene, almost exclusively found in papillary thyroid carcinoma (PTC). What is more, the targeted expression of RET/PTC in mice leads to the development of thyroid tumors very similar to human PTCs. In all RET/PTC types the RET tyrosine kinase domain is fused to the N-terminus of ubiquitously expressed genes that is capable of ligand-independent dimerization. The majority of RET/PTC identified consists of two types which results from the inversion of chromosome 10: RET/PTC1 and RET/PTC3. The prevalence of RET/PTC in papillary thyroid carcinomas of thyroid varies widely from a few to about 80% with the highest frequency in tumors arising in children after ionizing radiation. In Polish population the frequency of RET rearrangements in papillary cancers is 27%, although, it was reported to be twice higher in young patients (50% in patients younger than 21 at operation). Correlation with clinical outcome as well as prognostic value of RET/PTC is controversial. Some authors suggest that it predicts metastases, others found rearranged RET in more favourable, slow growing tumors. RET/PTC3 seems to be associated with solid/follicular variant PTC and short latency period (it is found more frequently in children) whereas RET/PTC1--with classic PTC variant and long latency.

[Evaluation of effects of L-thyroxine therapy in differentiated thyroid carcinoma on the cardiovascular system --prospective study]. / Ocena wplywu leczenia supresyjnego L-tyroksyna w raku tarczycy na uklad krazenia--badanie prospektywne.

Patients with differentiated thyroid carcinoma are treated by thyreoidectomy, followed by radioiodine treatment. A life-time suppressive therapy with L-thyroxine is also indicated. However, it may cause cardiovascular side effects. The aim of the study was a prospective evaluation of the left ventricle hypertrophy in patients treated with suppressive doses of thyroxine. A significant rise in left ventricular mass and mass index was noted during the first year of therapy and could be prevented by a simultaneous treatment with low doses of bisoprolol.

[Consequences of clinical genetic analysis of RET proto-oncogene]. / Konsekwencje kliniczne analizy genetycznej protoonkogenu RET.

Preliminary results of treatment of inherited medullary thyroid carcinoma, diagnosed primarily with genetic analysis of mutation of protooncogene RET are presented. Among 16 carriers of mutation identical with mutation diagnosed earlier in proband, there were 4 patients with clinically obvious medullary thyroid carcinoma and 12 asymptomatic carriers. In all patients, in whom calcitonin level was increased preoperatively, its normalization was obtained. The paper summarizes these aspects of cooperation between geneticians and physicians in which diagnostic results influence clinical decisions (indication and time of thyroid and lymph nodes surgery and it's spectrum, range of diagnostic procedures towards pheochromocytoma and parathyroid hyperplasia in relation to the found mutation).

[Prognostic significance of selected oncogene and suppressor gene expression in follicular thyroid carcinoma]. / Prognostyczne znaczenie ekspresji wybranych onkogenów i genów supresorowych w raku pecherzykowym tarczycy.

Oncogene and suppressor gene expression (cyclin D, p21WAF1, nm23-H1, Rb1, p16INK4A, and p53) was evaluated in 23 follicular thyroid carcinomas diagnosed in 20 women and 3 men operated or reoperated in Institute of Oncology in Gliwice in years 1992-1999. Positive reaction with p16INK4A, Rb1 and cyclin D1 antibodies was observed in all tumors, with nm23-H1 in 22 cases. The presence of p21WAF1 was stated in 8 cases (34.8%) and p53 in 7 cases (30.4%). A simultaneous presence of expression of p53 and lack of expression of p21WAF1 was stated three times and in two cases were accompanied by distant metastases. This pattern of expression was only rarely observed in minimally invasive follicular cancer. The prognostic significance of simultaneous immunohistochemical analysis of p53 and p21WAF1 in follicular thyroid carcinoma is suggested and has to be proved in further studies.

Sorption rate and thermal barriers in a gas-zeolite system: investigation of n-hexane sorption in MFI-type zeolite.

The nonequilibrium gravimetric sorption method was used to determine diffusion coefficient values for n-hexane in MFI-type materials. Improvements in the measurement device and experimental conditions resulted in high values of the corrected diffusion coefficient, which are comparable to the literature data obtained by the methods of pulsed field gradient nuclear magnetic resonance (PFG NMR) and frequency response (FR). The results indicate that thermal effects of sorption affect practically neither the rate of the sorption nor the diffusion coefficient.