Papillary thyroid carcinoma in a boy with familial tuberous sclerosis complex attributable to a TSC2 deletion-a case report.

Tuberous sclerosis complex (tsc), a phacomatosis, is a rare genetic disease (autosomal dominant; incidence: 1 in 6,800-17,300) associated with mutations in the TSC1 and TSC2 genes, 70% of which are sporadic. The disease causes benign tumours in the brain, kidneys, heart, lungs, skin, and eyes; thyroid lesions are extremely rare. A 13-year-old euthyroid boy with a hereditary form of tsc (del 4730G in TSC2, also seen in 2 sisters and the father) was admitted to hospital with a thyroid nodule. Physical examination revealed a nodular left lobe with increased consistency. Thyroid ultrasonography revealed a heterogeneous left lobe, predominantly hypoechoic with multiple microcalcifications and the presence of suspicious cervical lymph nodes on the left side. A macrocalcification was observed on the right lobe. Fine-needle biopsy results showed a few groups of cells with discrete atypical characteristics, including abundant cytoplasm, nuclei with conspicuous nucleoli, intra-nuclear inclusions, and nuclear grooves. The patient underwent total thyroidectomy with lymphadenectomy. Histopathology examination confirmed papillary thyroid carcinoma. The coincidence of endocrine neoplasia including thyroid cancer and tsc is rare, and tsc with papillary thyroid carcinoma has never been described in a child. Studies of mutations in the tumour suppressor genes TSC1, TSC2, and STK11, activating the mtor (mammalian target of rapamycin) pathway, might support their role in the pathogenesis of thyroid cancer.

Gene expression profiles for radiation-induced thyroid cancer.

The question whether radiation-induced thyroid cancer differs by its molecular biology from sporadic disease still remains. Studies on tissue from patients who developed thyroid cancer after the Chernobyl accident have provided a unique opportunity to look for biological consequences of low-dose irradiation by comparing the gene expression profile of sporadic papillary thyroid cancer (PTC), whose aetiology is unknown, and PTC induced by internal radiation. So far, four transcriptomic studies comparing radiation-induced and sporadic thyroid cancer have been reported. However, no final conclusion has been drawn regarding the presence of a radiation signature, as either no difference was noted or the reported differences were not sufficiently convincing due to the low number of cases analysed or to the presence of confounding factors. The list of putative biological and clinical factors that may influence the PTC gene expression profile is long, but there are sufficient data reported in the literature to link expression profiles with differing pathological variants of PTC. The comparison of expression profiles in the tumour samples allows the search for a radiation signature, whereas the comparison of expression profiles of the normal contralateral tissues offers a substantial opportunity for assessing the existence of a susceptibility to radiation that could be responsible for tumour development. We have undertaken this analysis as part of a European Union-funded project, GENRISK-T. Gene expression profiles were investigated in tumours that have arisen in the population exposed to fallout from Chernobyl (i.e. born before 26 April 1986) and were compared with profiles of tumours of similar pathology arising in an age-matched population, residing in the same geographical area (same ethnicity) and born after 1 January 1987. RNA samples from these tumours and their contralateral normal tissues were obtained from the Chernobyl Tissue Bank. Several lines of evidence suggest that the predisposition to developing cancer after radiation exposure is variable in the general population and may be measurable from gene expression.

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.

Combined treatment of glioblastoma patients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and temozolomide.

AIM: In a previous phase I-II study, the safety profile and anti-tumor efficacy of pre-targeting locoregional radioimmunotherapy (LR-RIT), based on the ''3 step'' method, was assessed in 24 high-grade glioma patients. The encouraging results in terms of low toxicity and objective response rate (25%) prompted us to continue our study. METHODS: An analysis of 73 patients with hystologically confirmed glioblastoma multiforme (GBM), treated with the ''3 step'' (90)Y-biotin based LR-RIT, is herein reported. All patients had a catheter implanted at 2(nd) surgery and underwent at least 2 cycles of LR-RIT (range 2-7) with 2 months interval. Thirty-five out of 73 patients were also treated with Temozolomide (TMZ). Two cycles of TMZ (200 mg/m(2)/day, for 5/28 days) were administered in between each course of LR-RIT. Overall survival (OS) and progression free survival (PFS) were retrospectively calculated. RESULTS: Stabilization of disease was achieved in 75% of patients, while 25% progressed. In the 38 patients treated with LR-RIT alone, median OS and PFS were respectively 17.5 months (95%CI=[17-20]) and 5 months (95%CI=[4-8]), while in the 35 treated with the combined treatment (LR-RIT+TMZ) respective values were 25 months (95%CI=[23-30]) and 10 months (95%CI=[9-18] (p<0.01). The addition of TMZ to LR-RIT did not increase neurological toxicity, and no major hematological toxicity was observed. CONCLUSION: These results confirm the safety and the efficacy of (90)Y LR-RIT in recurrent GBM patients; the addition of TMZ significantly improved the overall outcomes; a further controlled prospective, randomized study is fully justified.

90Y-DOTA-D-Phe1-Try3-octreotide in therapy of neuroendocrine malignancies.

Somatostatin receptors type 2 (sst(2)) are expressed in high concentration on numerous neudoendocrine tumors. The successful use of radiolabeled somatostatin analogs in imaging promoted further studies in utilizing them in radiopeptide therapy. The somatostatin analog [(90)Y-DOTA-D-Phe(1)-Try3]octreotide (DOTATOC) (DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) possesses favorable characteristic for its therapeutic use; shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3); high hydrophilicity; stable and facile labeling with (111) In and (90) Y. In this article we report our experience with (90)Y-DOTATOC in neuroendocrine tumors. Eighty-seven patients with neuroendocrine tumors were treated with a cumulated activity ranging from 7.4 to 20.2 GBq. Most patients responded with stabilization of disease (48%); however, objective responses were observed in 28% of patients (5% complete response). No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The dose limiting was bone marrow toxicity and the maximal tolerated dose was defined as 5.18 GBq.

[Geographic differences in iodine supply in the Silesia terrain in relation to thyroid cancer risk]. / Zróznicowanie geograficzne podazy jodu na ternie województwa slaskiego w aspekcie ryzyka raka tarczycy.

Risk factors associated with differentiated thyroid carcinoma depend on its histotype. Follicular carcinoma is described as a predominant type in the areas with iodine deficiency, in opposite to papillary thyroid cancer. The incidence of thyroid cancer and its histotypes varies considerably throughout Silesia (data obtained from the Institute of Oncology Cancer Register, Gliwice). The factors responsible for these differences are unknown. The aim of our study was to evaluate the present iodine supply in Silesia region and to relate it to the incidence of the various histotypes of thyroid carcinoma. Urinary iodine excretion observed in 7-11 year-old-children was used as a parameter of iodine supply and measured in the group of 1037 school children in sixteen localities, equally dispersed throughout Silesia. Urine samples were obtained to measure iodine concentration by the modified Sandell-Kolthoff's catalytic method. Mean incidence rates of papillary and follicular thyroid carcinoma were calculated for regions of Silesia by averaging the rates of the communities in each region. Despite the intensive iodine prophylaxis the persistent symptoms of iodine deficiency were observed. There were significant differences in children's ioduria among investigated regions. The percentage of low ioduria (lower then 100 micrograms/l) varied from 35.7% to 87.7%. We observed no correlation between age-adjusted rates for histotypes of thyroid carcinoma and the percentage of urine iodine below 100 micrograms/l, which served as an estimation of iodine deficiency. Our study indicates that Silesia is still an area of moderate iodine deficiency. We were unable to explain the factors responsible for the observed differences in the incidence rates of papillary and follicular thyroid carcinoma.

[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.

[Early evaluation of treatment effectiveness using 131I iodine radiotherapy in patients with differentiated thyroid cancer]. / Ocena wczesnej skutecznosci leczenia uzupelniajacego jodem promieniotwórczym 131I chorych na zróznicowane raki tarczycy.

UNLABELLED: This paper presents the preliminary results of a prospective randomized trial on early effectiveness of 30 mCi versus 60 mCi for ablation of thyroid remnants in patients with WDTC after total thyroidectomy. Since April 1998 to January 2000, 220 patients with papillary thyroid cancer in stage T1b-3, N0-x, M0 had entered the study. 106 patients received 60 mCi and 114 received 30 mCi as the first ablation dose. The subject for the analysis was the uptake over the neck, post-therapeutic whole body scintigraphy and Tg level 6 months after ablation. The early effectiveness of ablation was estimated using a 5-degree scale: 0--very good effect, 1--good effect, 2--dubious effect-required repetition of WBS and Tg assessment in 6-12 months, 3--insufficient ablation--required repetition of radioiodine treatment, 4--for evident dissemination or local recurrence. RESULTS: Grades 0 were obtained in 29 (53%) after 30 mCi (group I) and in 38 patients (86%) after 60 mCi (group II). Grades 1 were obtained in group I in 15 patients (28%) and in 4 patients (9%) of group II. Grades 2 were obtained in group I in 9 patients (17%) and in group II in 1 (2.3%). Grade 3 was obtained only in 1 (2%) patient after 30 mCi. Grade 4 was obtained in one patient after 60 mCi (2.3%). The difference in uptake over the neck in the two groups was statistically significant (p < 0.05), although the differences in early effectiveness between the both groups according to the 5-degree scale were on the borderline of significance (p = 0.075). There was a correlation between uptake before and after ablation in 30 mCi group, which was not seen present in 60 mCi group. CONCLUSION: For the ablation of thyroid remnants 60 mCi should be considered as a standard dose.

[Use of recombinant human TSH for stimulation of iodine radioisotope uptake in metastases of thyroid cancer during therapy with 131I]. / Zastosowanie rekombinowanego ludzkiego TSH do stymulacji jodochwytnosci przerzutów raka tarczycy w czasie terapii jodem promieniotwórczym 131I.

The diagnostics with the use of recombinant human TSH for the follow-up of differentiated thyroid carcinoma (DTC) has been already approved. In more than 400 diagnostic scans, rhTSH proved to be effective in promoting 131I uptake in thyroid remnants and DTC metastases in patients receiving suppressive doses of thyroxine. However, information about its application in radioiodine treatment of DTC are scarce, especially with respect to patients with metastatic disease. In this review we have described our own results obtained during rhTSH aided radioiodine treatment of 42 patients with advanced DTC with reference to current literature data about diagnostic and therapeutic application of rhTSH.

[Use of 13-cis retinoic acid for treatment of advanced differentiated thyroid cancer]. / Zastosowanie kwasu 13-cis-retinowego w leczeniu zaawansowanego zróznicowanego raka tarczycy.

UNLABELLED: Retinoids, a large group of compounds structurally related to vitamin A, are able to induce redifferentiation of thyroid cancer cells. The aim of the study is to present our early results of retinoids redifferentiation therapy of thyroid cancer patients. In 15 patients with advanced thyroid cancer, whose cancer foci did not concentrate radioiodine, 13-cis retinoic acid (Roaccutan) was given for 6 weeks before radioiodine treatment. Radioiodine therapy was performed under exogenous TSH stimulation (Thyrogen). Three patients were treated twice. The planned retinoid dose was delivered to 11 patients. In the other four patients the reduction of retinoids dose was necessary due to severe side effects. In post-therapeutic scintigraphy radioiodine uptake was visible in two out of seven patients (29%) with lung metastases, in 5 out of 9 (56%) with locoregional disease and in two with bone metastases. On the whole, in 50% of patients reinduction of radioiodine uptake was visible, however, in most patients only a very discrete one. Thyroglobulin concentration before and after retinoids therapy did not differ significantly. CONCLUSIONS: In a subgroup of patients 13-cis retinoic acid can induce radioiodine uptake, however, prospective studies in larger groups of patients are necessary to prove its clinical application.

[Prospective analysis of criteria for interpreting measurements of thyroglobulin serum concentration during conditions of endogenous TSH stimulation in serum of patients with differentiated thyroid carcinoma]. / Prospektywna analiza kryteriów interpretacyjnych oznaczania stezenia tyreoglobuliny w warunkach stymulacji endogennym TSH w surowicy chorych na zróznicowane raki tarczycy.

The aim of this study was the assessment of diagnostic value of thyroglobulin serum measurement in patients with DTC during endogenous TSH stimulation. Thyroglobulin was measured by immunofluorometric method (Delfia-Wallac) in patients after combined surgery and I131 ablation. Predictive values for two threshold levels 10 and 30 ng/ml were compared. At 5 years follow up it has been demonstrated, that Tg values higher than 10 ng/ml were the true signals of DTC relapse only in 46% patients. Tg values higher than 30 ng/ml were associated with disease progression in 65% of patients. Thus, we accept Tg concentration of 30 ng/ml measured during endogenous TSH stimulation as a good cut-off limit for the detection of DTC progression. Reduction of this threshold up to 10 ng/ml is associated with the increased risk of false positive results.

[Thyroglobulin RT-PCR method for detection of lymph node metastases during the course of differentiated thyroid cancers]. / Metoda RT-PCR dla tyreoglobuliny w wykrywaniu przerzutów nowotworowych do wezlów chlonnych w przebiegu zróznicowanych raków tarczycy.

UNLABELLED: In patients with a suspicion of recurrence of differentiated thyroid cancer with metastases to lymph nodes, detection of thyroglobulin (Tg) mRNA in fine needle biopsy material may support the interpretation of classic cytological examination in cases where it fails to detect lymph node involvement early enough. AIM: Prospective study of thyroglobulin mRNA detection in neck lymph nodes in patients with suspected differentiated thyroid cancer (DTC) metastases. MATERIAL: 70 nodes from 60 patients with suspected DTC recurrence were investigated. Patients with suspicion of lymph node metastases of other types of cancer were included as a control group. Thyroglobulin RT-PCR was conducted in residual material left after preparation of cytological smears from fine needle biopsy specimens. Primers spanning exons 3-5 were used with 39 cycles of PCR. RNA isolation control and cDNA amplification were carried out using GADPH starters. RESULTS: Classical cytology confirmed nodal involvement in 22 of DTC patients, RT-PCR Tg was positive in 20 of them (91%). Among 48 patients with a suspicion of DTC recurrence and negative cytology, Tg mRNA was found twice. One positive RT-PCR result was confirmed by repeated cytology conducted 4-6 months later and followed by surgery. No positive result of RT-PCR was obtained with other head and neck malignancies. The overall specificity was estimated with 98%. CONCLUSIONS: RT-PCR Tg shows sufficient specificity to be applied in further studies estimating its usefulness in fine needle biopsy for early detection of lymph node metastases in differentiated thyroid cancer.

[Evaluation of bone density in women after thyroid cancer surgery and treatment with suppressive doses of L-thyroxine]. / Ocena gestosci kosci u kobiet po operacji raka tarczycy, leczonych supresyjnie L-tyroksyna.

The aim of this work was to evaluate the degree of bone resorption and incidence of osteoporosis in female postmenopausal patients with differentiated thyroid cancer treated with suppressive doses of thyroxine. During the regular follow-up of women with differentiated thyroid cancer, densitometry of lumbar spine (L2-L4) and femoral head were performed. urine concentration of deoxypyridinoline and calcium-phosphate metabolism were also evaluated. Osteoporosis was diagnosed in 11% of patients, all without hormone replacement therapy (HRT). Mean bone density was significantly higher in patients treated with HRT. A decrease in bone mass was related to the duration of thyroxine therapy. The best results of bone mass density were obtained in patients on HRT and with short duration of thyroxine therapy. Deoxypiridinoline estimation did not exhibit significant differences between groups, however it was useful in the individual evaluation of bone resorption.

Multivariate analysis of prognostic factors for differentiated thyroid carcinoma in children.

At most centres, the standard treatment for differentiated thyroid cancer (DTC) comprises total thyroidectomy, radioiodine treatment and thyroid-stimulating hormone (TSH) suppressive therapy. There is, however, considerable disagreement over the appropriate treatment for DTC in children. Some dispute the use of total thyroidectomy and/or question the routine application of iodine-131 therapy in children. The aim of this study was to perform a retrospective analysis of treatment results and prognostic factors for DTC in children treated at our centre. The study included 109 children with DTC (aged 6-17 years). The primary treatment comprised total thyroidectomy in 81 cases, radioiodine therapy in 85 cases and TSH suppressive therapy with L-thyroxine in all patients. Uni- and multivariate analysis of prognostic factors for disease-free survival was performed using the Cox regression method. The actuarial survival rate was 100%, and the 5- and 10-year actuarial disease-free survival rates were 80% and 61% respectively. Univariate analysis revealed that older age, total thyroidectomy and radioiodine treatment had a positive impact on disease-free survival whereas there were no statistical differences with regard to the child's sex, histological type of cancer or lymph node status. On multivariate analysis, radical surgery was estimated to be the most significant factor (P=0.007) for disease-free survival, while less than total thyroidectomy increased the relative risk of relapse by a factor of 10. Radioiodine treatment decreased the relative risk of relapse by a factor of 5, but with borderline significance (P=0.07). Permanent postoperative complications were observed in 17% of children: in 11 laryngeal palsy occurred, in six there was hypoparathyroidism, and one suffered from both. It is concluded that total thyroidectomy and radioiodine treatment significantly improve recurrence-free survival in children and should be routinely applied even in young children as the primary treatment of DTC.

Recombinant human TSH for the treatment of differentiated thyroid cancer metastatic to the spine.

The diagnostic use of recombinant human TSH (rhTSH) in follow- up of differentiated thyroid cancer (DTC) is already approved, however its application in (131)I therapy is still to be evaluated. We report results obtained in four patients with DTC metastatic to central skeleton, in whom 5 courses of rtTSH aided 131I therapy were administered.

[The usefulness of MIBI scintigraphy for postoperative monitoring of patients with thyroid cancer]. / Przydatnosc scyntygrafii MIBI w monitorowaniu pooperacyjnym chorych na zróznicowanego raka tarczycy.

Metoxyizobutyloizonitrile labelled with technetium 99mTc is a radio-pharmaceutical that was shown to accumulate in benign and cancerous thyroid tissue. As it can be applied without thyroid hormone withdrawal this gave a stimulus to the investigations on its usefulness in diagnostic and follow up procedures for thyroid cancer patients. The goal of this study is to evaluate the efficacy and benefit of 99mTc-MIBI whole body scintigrams in post surgery follow-up of patients with differentiated thyroid cancer. One hundred and twenty eight 99mTc MIBI scintigraphy were performed and evaluated. Sensitivity of MIBI scans was the highest for bone metastases--79%. Good results were also obtained for lymph node metastases (sensitivity--73%, specificity--90%). In case of lung metastases the sensitivity and specificity were 21% and 94% respectively. Sensitivity of detection of clinically apparent recurrent disease in thyroid bed was 70% and specificity of visualization 78%. Results of our study demonstrate that 99mTC-MIBI is valuable tool in follow up of thyroid cancer patients, but can not replace 131I scintygraphy.