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.

Related papers:

title: Survival of children with thyroid cancer in Europe 1978--1989.
abstract: Thyroid cancers are rare in childhood with between 0.4 and 1.5 cases per million, 2--3 times as frequent in girls as in boys. However, following the Chernobyl accident, a remarkable incidence increase was observed in children exposed to radioactive iodine fall-out. Survival after thyroid cancer in childhood is thus of interest. In the EUROCARE II study, excluding most of Eastern Europe, a total of 165 childhood thyroid cancers were reported during the period 1978--1989, of which 134 were aged 10--14 years. The childhood cancer registry in England and Wales contributed 39% of the cases, and another 24% came from the Nordic countries, the rest from other parts of west, south, east and central Europe. The 5-year survival was for both genders combined 97% (95% confidence interval (CI): 93--99), 98% (95% CI: 91--100) for boys and 97% (95% CI: 91--99) for girls, with no significant difference between the genders. Survival was high during the entire study period, and variations influenced by the small numbers. As for adults, long-term follow-up beyond 10--20 years is needed to clearly demonstrate excess mortality as a consequence of the cancer.

title: Insular carcinoma of the thyroid in an adolescent: a case report and review of the literature.
abstract: A 15-year-old girl was referred for a thyroid gland mass, which rapidly enlarged in the brief interval between initial evaluation and surgery. Fine needle aspiration of the mass suggested a diagnosis of papillary thyroid carcinoma. Upon pathological examination of this aggressive tumor, an "insular" pattern of tumor was identified. Insular carcinoma of the thyroid gland is unusual in the pediatric age group, however its aggressive nature and prognosis have important management implications for those physicians involved in the care of affected patients. Aggressive surgical debulking, very close observation of the course of disease, and adjunctive radioiodine therapy may all be indicated as were performed in this case. A description of the pathology of this condition, and a review of the clinical experience with insular carcinoma in childhood and adolescence are presented.

title: Differentiated thyroid carcinoma in children and adolescents
abstract: From 1936 to 1990, 89 children and adolescents (72 girls and 17 boys) were treated for differentiated thyroid carcinoma at the University of Michigan Medical Center; 58 of these patients were first reported in 1971. Thirty (34%) patients had previously received external irradiation to the head and neck, although only 1 (3%) patient of the last 33 patients seen had this history. Patients first presenting from 1971 to 1990 had less advanced disease than those seen earlier. Also, during this time period, the rate of initial palpable cervical adenopathy fell from 63% to 36%, local infiltration of primary cancer from 31% to 6%, and initial pulmonary metastases from 19% to 6%. The incidence of cervical nodal metastases has remained 88% for 54 years. Papillary or the follicular variant of papillary carcinoma was found in 93% of all patients. Seventy-nine (89%) patients had total or completion total thyroidectomy. Surgical management of lymphatic metastases varied from regional excision of nodes to radical neck dissection. The overall rate of permanent accidental recurrent laryngeal nerve palsy and hypoparathyroidism was 4.5%, although neither has occurred in a child or adolescent undergoing surgery at the center in the past 25 years. The most recent 33 patients had a low rate of local/regional persistence or recurrence. Cervical nodal persistence occurred in 21%; there were no thyroid recurrences. Eighty-two percent of patients received131I. The long-term mortality rate was 2.2%. We continue to advocate total thyroidectomy, cervical lymph node dissection, and postoperative131I therapy as the most conservative treatment regimen for children with differentiated thyroid carcinoma.RésuméEntre 1936 et 1990, 89 enfants et adolescents (72 filles et 17 garons) ont été traités pour cancer différencie de la thyroïde au Centre Médical de l'Université de Michigan. Cinquante huit d'entre eux ont fait l'objet d'une publication en 1971. Trente de ces patients (34%) avaient eu une radiothérapie externe au niveau de la tête et/ou du cou, mais ce facteur n'a été retrouvé que chez un des 33 derniers patients (3%). Les patients vus entre 1971 et 1990 avaient une maladie moins avancée. Pendant cette période, le taux d'adénopathies cervicales palpables est passée de 63 à 36%; le pourcentage de patients ayant une infiltration locale, de 31 à 6%, et celui de métastases pulmonaires de 19 à 6%. L'incidence des métastases ganglionnaires cervicales, par contre, est restée de 88% depuis 54 ans. Le cancer était papillaire ou folliculaire dans 93% des cas. Soixante-neuf patients (89%) ont eu une thyroïdectomie totale, soit d'embl%ee soit secondairement. La thérapeutique des métastases ganglionnaires a varié depuis l'exérèse régionale et le curage ganglionnaire cervical. Le taux global de paralysie récurrentielle et de l'hypoparathyroïde était de 4.5%, mais aucune de ces deux complications n'a été observée pour les enfants opérés dans notre centre au cours des 25 dernières années. Parmi les 33 derniers patients, le taux de tissu résiduel ou de récidive était bas. Dans 21% des cas, il persistait du tissu néoplasique après chirurgie, sans récidive. Quatre-vingt pour cent de ces patients ont eu un traitement par l'iode 131. La mortalité à distance était de 2.2%. Nous continuous de recommander une thyroïdectomie totale, une lymphadénectomie cervicale et une iodothérapie post-opératoire par l'iode 131 comme le traitement les plus conservateurs du cancer différencié de la thyroïde chez l'enfant.ResumenOchenta y nueve niños y adolescentes (72 de sexo femenino y 17 de sexo masculino) fuiron tratados por carcinoma tiroideo diferenciado en el Centro Médico de la Universidad de Michigan; 58 de estos pacientes fueron reportados por primera vez en 1971. Treinta pacientes (34%) tenían historia de irradiación a la cabeza y el cuello; sin embargo, solamente uno de los últimos 33 (3%) presentó tal historia. Los pacientes vistos entre 1971 y 1990 exhibían enfermedad menos avanzada que aquellos vistos previamente. Así mismo, la incidencia de adenopatías cervicales palpables descendió de 63% a 36%, la de infiltración local por cáncer primario de 31% a 6% y la de metástasis pulmonares iniciales de 19% a 6%. La incidencia de metástasis ganglionares cervicales se ha mantenido en 88% por 54 años. La variante papilar o folicular del carcinoma papilar se encontró en 93% de los pacientes de la serie. Setenta y nueve pacientes (89%) fueron sometidos a toroidectomía total o a reoperación para completar la tiroidectomía total. El manejo quirúrgico de las metástasis linfáticas varió desde la resección regional de los ganglios hasta la disección radical del cuello. La tasa global de lesión accidental, permanente o temporal, del nervio recurrente laríngeo y de hopoparatiroidismo fue 4.5%, aunque ninguna de estas complicaciones ha ocurrido en un niño o en un adolescente sometido a cirugía en nuestro centro médico en los últimos 25 años. Los últimos 33 pacientes exhibieron una tasa reducida de persistencia o de recurrencia local/regional. La persistencia ganglionar cervical se presentó en 21% de los casos; no hubo recurrencias tiroideas. Ochenta y dos por ciento de los pacientes recibió131I. La tassa de mortalidad a largo plazo fui 2.2%. Nuestro grupo continúa preconizando tiroidectomía total, disección ganglionar cervical y terapia postoperatoria con131I como la modalidad terapéutica más conservadora en carcinoma diferenciado de la glándula tiroidea en la niñez.

title: Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective.
abstract: Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies.



We analysed recent literature on the follow-up of DTC.



Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC.



We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.

title: A prospective study of thyroid nodular disease in children and adolescents in western Poland from 1996 to 2000 and the incidence of thyroid carcinoma relative to iodine deficiency and the Chernobyl disaster
abstract: In Poland, where soil is deficient in iodine, supplementation of iodine was introduced in 1935, discontinued in 1980, and then re‐introduced in 1997. One of the effects of inadequate iodine intake, prior to 1997, was an increase in the prevalence of thyroid nodular disease (TND) in children. Chernobyl, located in the neighbouring country of Ukraine, suffered a catastrophic nuclear explosion in April 1986.

title: Increased incidence of thyroid carcinoma in france: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee.
abstract: Thyroid cancer (TC) incidence, in France, has dramatically increased over the last two decades. In order to try and account for this observation, the French Department of Health requested the Public Health Agency to coordinate a multidisciplinary Thyroid Cancer Committee (TCC). The TCC analysed the temporal incidence trend in France, evaluated the contribution of changes in diagnostic practices of thyroid diseases to the observed increase of TC, and set up guidelines to improve the national surveillance system of TC. The increased incidence of TC is real (8.1% and 6.2% per year in women and in men, respectively), mainly due to papillary type with an epidemic of microcarcinomas (43% of operated cancers, period 1998-2001) associated to the extensiveness of thyroidectomies. Multicentric studies showed a significant increase, from 1980 to 2000, in ultrasonographic (3 to 84.8%) and cytological procedures (8 to 36% of patients with thyroid nodules) as well as a significant association between the increase in TC prevalence among operated patients (12.5 to 37%) and the spread of fine needle aspiration. Epidemiological evidence does not favour any link with the Chernobyl accident. The TCC recommended a national registry dedicated to thyroid cancer of the youths ( <18 years old). For adults, in addition with the strengthening of the French regional registries, a continuous registration of incident cases through the National Hospital Discharge Survey that covers all the territories is proposed. Such system, matched with pathological data derived from a national standardized collection, will provide a relevant model for epidemiological surveys of TC.

title: Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies.
abstract: The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

title: Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence
abstract: Recent data indicate that the risk of developing a thyroid neoplasm clearly is increased after high‐dose, therapeutic radiation therapy during childhood. To better understand the time course, natural history, and histopathology of thyroid lesions that develop after high‐dose irradiation, the authors undertook a retrospective study of all survivors of childhood and adolescent malignancies who were treated at Memorial Sloan‐Kettering Cancer Center and who developed a clinically apparent thyroid neoplasm.

title: Thyroid carcinoma presenting in childhood or after treatment of childhood malignancies: An institutional experience and review of the literature.
abstract: Thyroid carcinomas can occur as a primary malignancy (PTM) or secondary after another malignancy (STM). Information about the presentations and outcomes of patients with STM are limited. The authors sought to compare the clinical characteristics, course, and outcomes of patients with primary or secondary thyroid malignancies.



The authors reviewed the medical records of 8 children with PTM and 17 children with STM referred to St Jude Children's Research Hospital between February 1962 and February 2002 for evaluation and treatment of malignant thyroid carcinoma.



The 8 children who had primary thyroid carcinoma had it diagnosed at a median age of 12.5 years (range, 7.3 to 16.3 years). Seven patients had papillary carcinoma, and 1 patient had follicular carcinoma. Three of the 8 (37.5%) had metastatic disease involving regional lymph nodes; 2 patients (25.0%) had lung metastases. Six patients required radioactive iodine (I 131) ablation for residual or metastatic disease after surgical resection. All 8 patients remain alive a median of 22.6 years after diagnosis (range, 0.7 to 30.5 years); 1 continues to receive radioactive iodine (I 131) ablation for persistent disease. Seventeen patients had thyroid carcinoma as a second malignant neoplasm after treatment for acute lymphoblastic leukemia (n = 6), Hodgkin's disease (n = 5), central nervous system tumor (n = 2), Wilms' tumor (n = 1), retinoblastoma (n = 1), non-Hodgkin's lymphoma (n = 1), or neuroblastoma (n = 1). Patients with secondary thyroid carcinoma presented at a median age of 21.5 years (range, 15.3 to 42.6 years), a median of 16.2 years (range, 0.9 to 29.2 years) after diagnosis of the primary cancer. Twelve of the 17 patients (70.6%) had received radiation to the thyroid gland during therapy for the primary cancer. Four patients (23.5%) had metastatic disease involving regional lymph nodes. Six patients (35.3%) required I(131) ablation for residual or metastatic disease after thyroidectomy. At the time of this report, all 17 patients are alive and in continue to be free of disease.



Pediatric thyroid carcinoma is uncommon and responds well to current therapy. Given the limited period of follow-up of our cohort of secondary malignant thyroid tumors that arise after childhood cancer, these lesions appear to have similar presentations and outcomes when compared with primary carcinomas and can therefore be managed in the same manner.

title: Thyroid cancer incidence trends in Belarus: examining the impact of Chernobyl.
abstract: While prior studies of thyroid cancer incidence within Belarus have increased since the 1986 Chernobyl reactor accident, the magnitude of increase is not well quantified.



Using Belarussian national cancer registry data, trends in average annual age-adjusted thyroid cancer incidence rates were examined by calendar year and gender. Incidence rates were also examined across specified time intervals, for specific age groups at diagnosis, and in 'higher exposure' regions compared with 'lower exposure' areas.



Age-adjusted thyroid cancer incidence rates (adjusted to the WHO 2000 world population) have increased between 1970 and 2001 from 0.4 per 100 000 to 3.5 per 100 000 among males (+775%) and from 0.8 per 100 000 to 16.2 per 100 000 among females (+1925%). The relative increase among males (+1020%) and females (+3286%) in 'high exposure' areas exceeded increases among males (+571%) and females (+250%) in 'lower exposure' areas of Belarus. Dramatic increases in thyroid cancer incidence rate ratios were noted among both males and females and in all age groups. The highest incidence rate ratios were observed among people from 'higher exposure' areas ages 0-14 yr at time of diagnosis.



Marked increases in the incidence of thyroid cancer have occurred over a relatively limited period of observation in all areas of the Republic of Belarus and among all age categories. The greatest increases have occurred among children, suggesting that a high prevalence of pre-existing iodine deficiency in combination with unique susceptibility among younger people might have contributed to potential carcinogenic exposures to the thyroid.

title: Thyroid cancer has increased in the adult populations of countries moderately affected by Chernobyl fallout.
abstract: The incidence of thyroid carcinoma increased among children affected by Chernobyl fallout. Less evidence exists for a corresponding effect in adolescents and adults. The Cancer Registry of the Czech Republic provides an opportunity to study various determinants of the occurrence of thyroid cancer.



Anonymous population-based incidence data on thyroid carcinoma of the Czech Republic from 1976 to 1999 were obtained from the Czech Statistical Office (CSO) and the Institute of Health Information and Statistics (IHIS). This study covers 247 million person-years. Linear logistic regression models allowing for possible changes in slope (change-points) are suggested for the trends of incidence proportions.



From 1976 to 1999 a uniform annual increase of 2.0% per year was found in the directly age-standardized thyroid cancer incidence proportion (95%-CI: 1.3-2.7, p<0.0001). From 1990 on, we observed an additional significant increase in the thyroid cancer incidence of 2.6% per year (95%-CI:1.2-4.1, p=0.0003). This effect (change-point) is essentially independent of age but dependent on gender: females 2.9% per year (95%-CI: 1.3-4.7, p=0.0006), males 1.8% per year (95%-CI: -1.0-4.7,p=0.2127). The estimated minimum latency period for the population as a whole is 4 years.



Although the Czech Republic received only a relatively moderate amount of radioactive fallout,an unexpected uniformly accelerated increase of thyroid cancer in all age categories is seen from 1990 onwards. Therefore one should look carefully at collective dose and at the group of persons low in individual organ dose but high in number.

title: Age-dependent thyroid absorbed doses for radiobiologically significant radioisotopes of iodine.
abstract: In light of the post-Chernobyl increase in pediatric thyroid cancer incidence, among other recent events, there is renewed interest in radioiodine thyroid dosimetry and effects. Among the radioiodines produced in fission of 235U, only 131I [(T1/2)p = 8.04 d], 132I (2.3 h), 133I (20.3 h), and 135I (6.7 h) may undergo significant environmental dispersion. Age-dependent thyroid absorbed dose estimates for these radiobiologically significant radioiodines and for the "medical" radioisotopes 123I (13.2 h) and 125I (60 d) have been derived, incorporating the effect of absorption following inhalation or ingestion. This effect has generally been ignored in previously derived estimates of radioiodine absorbed doses to the thyroid. Based on the latest ICRP lung and gut models, inhaled radioiodine is absorbed at a rate of 0.175 h(-1) and exhaled at 0.101 to 0.118 h(-1) (depending on age) and ingested radioiodine is completely absorbed in the stomach at a rate of 1 h(-1). Whole-body compartmental models (SAAM II) were fit to previously published 24-h thyroid uptakes, thyroid half-times, and 48-h plasma concentration of protein-bound iodine. The resulting fitted models were used to calculate thyroid residence times of radioiodine. The mean thyroid absorbed doses [cGy/37 kBq (rad/microCi) injected intravenously] were then calculated using the age-dependent S(thyroid<--thyroid) factors (MIRDOSE III), with the highest doses (from 0.49 for 123I to 36 for 131I) in newborns and the lowest doses (from 0.014 for 123I to 1.4 for 131I) in adults in inverse relation to the thyroid mass. Although the thyroid absorbed dose for inhalation is substantially (30 to 70%) less than that for injection for all radioiodines and at all ages, it is markedly (25%) less for ingestion only for short-lived 132I.

title: Thyroid cancer 15 years after Chernobyl
abstract: ratios, monotonically increased with showing a dose-response relation significant at less than 0·01. Among children in Gomel district who underwent thyroid assessments in the Chernobyl Sasakawa Health and Medical Cooperation Project from 1991 to 1996, 7546 boys and 7946 girls were aged 5–13 years at the time of examination and thyroid cancer was detected in ten boys and 21 girls. The expected number of thyroid cancers in group I under a logistic model fitted to group III, with sex and age as covariates, was 6·3 and 20·4 for boys and girls, respectively, whereas no thyroid cancers were reported in boys and girls of group I. Therefore, the prevalence of thyroid cancer differed significantly between groups I and III. Finally, elaborate thyroid dose estimates, which are quite difficult to establish, are essential for a casecontrol study to be successful.

title: A comparison of thyroid carcinoma in those who have and have not had head and neck irradiation in childhood.
abstract: Among 1324 patients with well differentiated (papillary, follicular, Hurthle cell) thyroid carcinoma treated at the University of Texas M. D. Anderson Hospital and Tumor Institute between January 1950 and July 1984, 125 had a history of external irradiation to the head and neck region during childhood. This study was a comparison of the characteristics and disease course of thyroid carcinoma in these patients with those of patients who had not received such irradiation. Each irradiated patient was matched to 3 nonirradiated patients by age, sex, and extent of disease. The groups had similar distributions of histological type of lesion, surgical procedures, and number of patients who received radioactive iodine as part of their initial treatment. The two groups' recurrence and mortality rates were similar as well, although patients who had head and neck irradiation as children more often presented with thyroid cancer not limited to the thyroid gland and bilateral thyroid lobe involvement (P less than 0.005). The data indicate that patients who received head and neck irradiation have, at the time of diagnosis, more extensive thyroid carcinoma. However, the prognosis of well differentiated thyroid carcinoma in patients who have a history of head and neck irradiation is similar to that in patients without such a history.

title: Childhood thyroid cancer. Characteristics and long-term outcome in children irradiated for benign conditions of the head and neck.
abstract: To determine the characteristics and long-term outcome of radiation-induced thyroid cancer in children.



Retrospective review of a cohort of 4296 irradiated patients who received childhood radiation treatment to the head and neck area at the same hospital.



Forty-one children who were younger than 20 years when thyroid cancer developed in them and 77 adults in whom thyroid cancer developed. All 118 cases were diagnosed before 1974 and were followed up for a median of 19.4 years.



Children presented with clinically palpable lymph nodes more often than adults (30.7% vs 15.1%, P = .05) and had more recurrences (39% vs 16%, P = .05). Despite these frequent recurrences, only one patient (an adult) died of thyroid cancer. Seventy percent of the recurrences occurred during the first 10 years of follow-up, but recurrences continued after 20 years. The adults had previously identified factors that predicted the risk of recurrences, but none could be identified in the children.



The presentation and relatively good outcome of radiation-induced thyroid cancer in children is similar to that in nonirradiated children. Frequent and late recurrences call for lifelong follow-up.

title: Pediatric thyroid cancer after the chernobyl disaster. Pathomorphologic study of 84 cases (1991–1992) from the republic of Belarus
abstract: During the initial period after the Chernobyl accident, large amounts of radioactive iodine were released in fallout, resulting in serious exposure to the thyroid gland in the residents of areas around the nuclear power station. Beginning in 1990, a definite increase in the incidence of thyroid cancer was noted in children of the Republic of Belarus.

title: Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades.
abstract: Fifty-eight children (18 boys, 40 girls) less than 17 years of age, undergoing initial surgery because of papillary thyroid carcinoma (PTC) at Mayo Clinic from 1946 through 1975 and followed up for a median time of 27.6 years were compared with 981 adults (323 men, 658 women) treated during the same period and followed up for a median period of 19.5 years. At initial evaluation, mean tumor size (+/- SD) was greater in children (3.1 +/- 1.7 cm) than in adults (2.1 +/- 1.7 cm) (p less than 0.001); tumor DNA content was nondiploid in 10% of 39 children and in 25% of 110 adults (p = 0.047). Neck node metastases at diagnosis were detected in more children (89.7%) than adults (34.7%) (p less than 0.0001), but extrathyroidal invasion was not significantly more frequent in children (24.1%) than adults (15.8%) (p = 0.095). Distant metastases at diagnosis were detected in more children (6.9%) than adults (2.1%) (p = 0.022). Postoperatively, neck node metastases recurred more frequently in children (30%) than in adults (7%) (p less than 0.001), but local neck recurrences were not significantly more frequent in children (12%) than in adults (5%) (p = 0.083). Postoperative distant metastases occurred with similar frequency in children (6%) and adults (5%) (p = 0.98). Survival (all causes of death) for both adults and children up to 30 years after the initial surgery was no different from expected survival rates. Only adults aged more than 40 years had a significantly higher mortality from PTC than did children (p less than 0.0001). Fourteen percent of children had died of PTC by 15 years after diagnosis of distant metastases, whereas 68% of similarly affected adults were dead at 15 years (p = 0.014). PTC was more often metastatic to neck nodes and lungs before initial surgery and more often recurrent in neck lymph nodes postoperatively. However, PTC tended to be less fatal in children, and this may be related to the infrequency of nondiploid DNA content in the childhood PTC tumors.

title: Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma. A clinicopathologic study of 105 consecutive patients
abstract: Multiple thyroid involvement (MTI) in papillary thyroid carcinoma was clinicopathologically studied in 105 non‐selected, consecutive patients. Whole thyroids resected by total thyroidectomy were sectioned at intervals of 2–3 mm (mean number of slices per gland, 19.2) and histologically reviewed. The intraglandular cancer foci, other than the tumor regarded as the primary focus, were demonstrated in 82 (78.1%) of 105 patients. The foci were usually small (less than 4 mm) and were not accompanied by sclerotic fibrous stroma or by a fibrous capsule. These small foci were distributed around the primary lesion and also were found frequently (61.0%) in the opposite lobe as bilateral disease. In the opposite lobe, a similar incidence (approximately 30%) of disease was obtained in each of the three parts (upper, middle, and lower). The mean number of foci in patients with MTI was statistically correlated to age, the presence of lymph node metastases, and the presence of solid areas or psammoma bodies in the primary tumor. It was concluded that MTI could be regarded as one of the most striking and important biologic characteristics of papillary thyroid carcinoma.

title: Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia.
abstract: Rearrangements involving the RET protooncogene have been implicated in the development of papillary thyroid carcinoma (PC). Transgenic mice, expressing thyroid-targeted RET/PTC-1, develop PC; but the clinical significance of this oncogene remains uncertain. We examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PC to determine its role in early stage vs. developed PC and to examine the diversity of RET/PTC in multifocal disease. RNA was extracted from paraffin-embedded microcarcinomas and clinically evident PCs; the results obtained from paraffin-embedded tissue were confirmed on RNA from corresponding snap-frozen tissue of clinically evident PCs. RT and PCR was performed using primers for RET/PTC-1, -2, and -3; PGK-1 (the housekeeping gene) analysis was used to ensure integrity of the RNA and efficiency of the RT reaction. PCR products were resolved by gel electrophoresis, and Southern hybridization was performed with RET/PTC-1, -2, and -3 probes. A polyclonal antibody to the carboxyterminus of RET was used for immunohistochemistry on paraffin sections. Thirty-nine occult papillary thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors (77%) positive for RET/PTC rearrangements, 12 were positive for RET/PTC-1, 3 for RET/ PTC-2, 6 for RET/PTC-3, and 9 for multiple RET/PTC oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements. Immunohistochemistry demonstrated close correlation with RT-PCR-derived findings. RET/PTC expression is highly prevalent in microcarcinoma and occurs more frequently than in clinically evident PC (P < 0.005). Multifocal disease, identified in 17 of the 21 patients, exhibited identical RET/PTC rearrangements within multiple tumors in only 2 patients; the other 15 patients had diverse rearrangements in individual tumors. Our results indicate that RET/PTC oncogene rearrangements may play a role in early-stage papillary thyroid carcinogenesis, but they seem to be less important in determining progression to clinically-evident disease. In multifocal disease, the diversity of RET/PTC profiles, in the majority of cases, suggests that individual tumors arise independently in a background of genetic or environmental susceptibility.

title: Completion thyroidectomy in 131 patients with differentiated thyroid carcinoma.
abstract: To evaluate the prognostic factors that influence survival and recurrence after "completion" thyroidectomy (removal of the total thyroid remnant after diagnosis of carcinoma has been made in a specimen that was incompletely excised for a benign condition).



Open study.



Teaching hospital, Germany.



131 Patients (65 with papillary and 66 with follicular thyroid cancer) who underwent completion thyroidectomy after primary subtotal resection.



Indications for further operation were: tumour stage worse than pT1 ( n = 116), tumour stage pT1 and the suspicion of persistence of the tumour (n = 13), and incompletely resected tumour (n = 2). Multivariate analysis by Cox's proportional hazards model.



Recurrence, development of metastases, and length of survival.



Patients who underwent their completion thyroidectomies within six months of the primary operation had significantly fewer recurrences, fewer lymph node metastases, fewer haematogenous metastases and survived significantly longer than those in whom the second operation was delayed for longer than six months. The age at the time of diagnosis and the stage of the tumour influenced survival, whereas sex and type of tumour did not.



Completion thyroidectomy as soon as possible after incomplete resection of the tumour may improve prognosis in differentiated thyroid cancers the stage of which is worse than pT1 or in patients whose recurrent tumour is diagnosed at follow-up.

title: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer.
abstract: To determine the long-term impact of medical and surgical treatment of well differentiated papillary and follicular thyroid cancer.



Patients with papillary and follicular cancer (n = 1,355) treated either in U.S. Air Force or Ohio State University hospitals over the past 40 years were prospectively followed by questionnaire or personal examination to determine treatment outcomes. Outcomes were analyzed by Kaplan-Meier survival curves and Cox proportional-hazard regression model.



Median follow-up was 15.7 years; 42% (568) of the patients were followed for 20 years and 14% (185) for 30 years. After 30 years, the survival rate was 76%, the recurrence rate was 30%, and the cancer death rate was 8%. Recurrences were most frequent at the extremes of age (< 20 and > 59 years). Cancer mortality rates were lowest in patients younger than 40 years and increased with each subsequent decade of life. Thirty-year cancer mortality rates were greatest in follicular cancer patients, who were more likely to have adverse prognostic factors: older age, larger tumors, more mediastinal node involvement, and distant metastases. When patients with distant metastases at diagnosis were excluded, follicular and papillary cancer mortality rates were similar (10% versus 6%, P not significant [NS]). In a Cox regression model that excluded patients who presented with distant metastases, the likelihood of cancer death was (1) increased by age > or = 40 years, tumor size > or = 1.5 cm, local tumor invasion, regional lymph-node metastases, and delay in therapy > or = 12 months; (2) reduced by female sex, surgery more extensive than lobectomy, and 131I plus thyroid hormone therapy; and (3) unaffected by tumor histologic type. Following 131I therapy given only to ablate normal thyroid gland remnants, the recurrence rate was less than one third the rate after thyroid hormone therapy alone (P < 0.001). No patient treated in this way with 131I has died of thyroid cancer. Low 131I doses (29 to 50 mCi) were as effective as high doses (51 to 200 mCi) in controlling tumor recurrence (7% versus 9%, P = NS). Following 131I therapy, whether given for thyroid remnant ablation or cancer therapy, recurrence and the likelihood of cancer death were reduced by at least half, despite the existence of more adverse prognostic factors in patients given 131I. At 30 years, the cumulative cancer mortality rate following 131I therapy, regardless of the reason for its use, was one third that in patients not so treated (P = 0.03).



Over the long term, for tumors > or = 1.5 cm that are not initially metastatic to distant sites, near-total thyroidectomy followed by 131I plus thyroid hormone therapy confers a distinct outcome advantage. This therapy reduces tumor recurrence and mortality sufficiently to offset the augmented risks incurred by delayed therapy, age > or = 40 at the time of diagnosis, and tumors that are much larger than 1.5 cm, multicentric, locally invasive, or regionally metastatic.

title: Differentiated thyroid carcinoma in childhood: long term follow-up of 72 patients.
abstract: Seventy-two children with differentiated thyroid cancer who were 16 years old or younger at the time of initial treatment were followed for a median time of 13 yr. Initially, 18% had lung metastases, and 74% had palpable lymph nodes. Capsular invasion was found in 67%, and histological lymph node involvement in 90%. The recurrent laryngeal nerve chain and the jugulo-carotid chain were involved with the same frequency (greater than 80%). The anterior superior mediastinum was involved only in patients with involvement of the recurrent laryngeal nerve chain. Forty-three patients had a complete remission after initial treatment. In patients without distant metastases for whom surgery was macroscopically incomplete, relapses occurred 5 times more frequently than in patients whose surgery was complete. Six patients died from thyroid carcinoma at ages ranging from 19-44 yr, 12-33 yr after initial treatment, and 1 died from intercurrent disease. Despite favorable long term survival (90.3% at 20 yr), the standardized mortality ratio was equal to 8.1. This study underlines the need for complete surgical treatment and compulsive follow-up, which should be continued throughout the patient's life, in order to detect and effectively treat relapses of thyroid cancer.

title: Brain metastases from papillary thyroid carcinoma.
abstract: In their recent article, Parker et al 1 stated that distant metastasis in cases of papillary thyroid cancer (PTC) typically involves "the lung, bone, or liver" and, in reviewing 1346 reported PTC cases, they found only two (0.15%) examples of brain metastasis. In a recently completed study 2 of 859 patients with PTC, treated at the Mayo Clinic, Rochester, Minn, during a 25-year period and followed for up to 39 years, 11 patients (1.3%) with brain metastases were identified. In 40 patients developing postoperative metastasis, the principal sites of involvement were lungs (70%), mediastinum (24%), bone (23%), and brain (15%). Of 56 patients dying of PTC, 11 patients (20%) died as a consequence of metastasis to the brain or the spinal cord. Both of the patients described by Parker et al 1 were males; one patient was found to have brain metastasis 33 years after the initial

title: Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma.
abstract: We assessed the therapeutic benefits of 131I treatment in patients with distant metastases of differentiated thyroid carcinoma.



Of 2200 patients treated for differentiated thyroid carcinoma at our institution, 394 had lung and/or bone metastases.



Two-thirds of the patients had 131I uptake in their metastases, but only 46% achieved a complete response. Prognostic factors for complete response were: younger age, presence of 131I uptake in the metastases and small extent of disease. The survival rate was 33% at 15 yr. As shown by multivariate analysis, favorable prognostic factors for survival were: younger age and time of metastases detection, well-differentiated histologic type of the thyroid tumor, presence of 131I type uptake in the metastases, small extent of the disease and year of discovery of metastases.



In terms of survival, the benefits of 131I therapy cannot be demonstrated by prospective controlled studies. The present study clearly demonstrates, however, that treatment with 131I is one of the factors which accounts for survival; patients whose metastases concentrated 131I and who could be treated with radioiodine had higher survival rates. Patients who achieved complete response following treatment of distant metastases had a 15-yr survival rate of 89%, while those who did not achieve complete response had a survival rate of only 8%. The survival rate improved with the year of discovery of distant metastases, after 131I total-body imaging and serum thyroglobulin measurements were routinely used.

title: Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of the Children's Cancer Group.
abstract: Young patients with differentiated thyroid cancer typically present with regional lymph node involvement (60% to 80%), and 10% to 20% have distant metastases. This study characterizes the clinical presentation, treatment, and outcome in patients with differentiated thyroid cancer who were less than 21 years of age at diagnosis and who presented with distant parenchymal metastases.



A retrospective, multi-institutional data base that included 327 patients in this age group with differentiated thyroid carcinoma was searched for patients who presented with distant metastases, and 83 cases (25%) were found. The median time to first disease progression was 2.4 years (range, 0.1 to 12.4 years) and the overall median follow-up was 10.9 years (range, 1.0 to 42.1 years).



The median age at diagnosis was 14.6 years (range, 6.6 to 20.8 years); 69% were girls and 92% were white. In 12%, there was a history of prior head and neck irradiation, and 10% of these patients had a family history of carcinoma. Preoperative needle biopsies were performed in 25%. Regional lymph nodes were positive in 90%, and extrathyroidal extension occurred in 48%. The site of distant metastases included the lungs in all patients. Total thyroidectomy, subtotal thyroidectomy, lobectomy, and nodule excision was done in 66%, 24%, 3%, and 8% of patients, respectively. There was no residual cervical disease after surgery in 75%, whereas 14% had microscopic and 11% had gross residual. Histopathologic subtypes included papillary-follicular (48%), papillary (42%), and follicular (10%). The median tumor size was 3.0 cm (range, 0.4 to 11.0 cm). In this group, 100% of patients received adjuvant iodine 131I therapy, and the overall survival rate at 10 years was 100%. The progression-free survival rate was 76% at 5 years and 66% at 10 years from diagnosis.



A significant number of young patients with thyroid cancer present with distant metastases and will require radioiodine therapy. This should be considered when planning the surgical approach because total or subtotal thyroidectomy facilitates 131I imaging and treatment. Although about one third of these patients will experience relapse or disease progression, the overall mortality rate is low.

title: Results of radioactive iodine treatment in children from Belarus with advanced stages of thyroid cancer after the Chernobyl accident
abstract: Exposure of the thyroid to ionising radiation leads to an increased cancer risk. Whereas the average excess relative risk after external exposure amounts to approximately 8 per Gy, this relative risk is lower by a factor of 2 after exposure to radioiodine. The risk is greatest in newborns and small children below age of 5, intermediate in adolescents and questionable in adults. Papillary thyroid cancer with a relative incidence of approximately 80% per se is typical for thyroid cancer in childhood and adolescence; however, after exposure to radioiodine, this relative frequency is increased close to 100%. Bilateral involvement, multicentric growth and cancer not limited to the thyroid gland seem to be characteristic for radiation-induced thyroid cancer. Up to now, approximately 1500 cases of thyroid cancer in children below age of 15 have been diagnosed between 1990 and 2000 after the Chernobyl accident in Belarus, the Ukraine and Russia. Histologically, 94% of the tumors were classified as papillary thyroid cancer and tumors with stage pT1 in 26%, pT2 in 28%, pT3 in 1% and pT4 in 45%. Between 1st of April 1993 and 31st of December 2000, 209 children from Belarus with most advanced stages of thyroid cancer have been treated totally with 755 courses of radioiodine therapy in Germany. Of those selected cases, 71% were staged as pT4, 97% as pN1 and 46% as pM1. Disseminated miliary spread was typical for lung metastases detectable in 97 of those children. Up to now, complete remissions of tumor disease could be achieved in 84% of the whole group (and in 67% of the children with distant metastases). Fortunately, in no single case treated with radioiodine progressive disease or a recurrence has been observed up to now.

title: Lung metastases from differentiated thyroid carcinoma. A 40 years' experience.
abstract: Retrospective studies have been carried out to estimate the survival of 96 patients with lung metastases from differentiated thyroid carcinoma, observed from 1958 to 2000.



All patients had undergone total thyroidectomy. Case histories were analysed with respect to age at diagnosis, sex, histology, local lymph node involvement, size of lung metastases and 131I uptake by metastases. Survival functions were calculated. Cox regression was performed.



There was no statistically significant difference in histological type and lymph node involvement, whereas a significantly longer survival time was observed in patients under 45 years of age at diagnosis (p= or <0.0001), in those with metastases concentrating 131I (p= or <0.0001) and in those with fine miliaric metastases (p=0.0037). Multi-variate analysis revealed that the risk of death increases about 5.4-fold in patients over 45 years old, whereas 131I treatment is likely to reduce this risk to nearly 1/6.  In conclusion, in patients with lung metastases from differentiated thyroid carcinoma, young age at diagnosis and 131I uptake by metastases are the most important factors positively affecting survival time. Radioiodine therapy, also with high cumulative 131I activity, can lead to longer survival time or complete recovery.

title: Expression of the Sodium Iodide Symporter and Thyroglobulin Genes Are Reduced in Papillary Thyroid Cancer
abstract: Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 ± 41 picogram equivalents [pg Eq]), than did benign nodules (829 ± 385 pg Eq), or normal tissues (1907 ± 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40–96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2–96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 ± 245 pg Eq vs. 1854 ± 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

title: Sodium iodide symporter and pendrin expression in human thyroid tissues.
abstract: Thyroid cells synthesize thyroid hormones through a multistep process during which iodide is transported through the basolateral and the apical membranes of thyrocytes. Two genes that participate in these transports and the corresponding proteins, namely sodium iodide symporter (NIS) and pendrin, the product of the Pendred syndrome gene, have recently been characterized. We studied NIS and pendrin expression at the mRNA and protein levels by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method and by single and double immunostaining in normal and pathological human thyroid tissues. In normal tissue, NIS and pendrin were detected in about 20% and 40%-60% of thyrocytes, respectively. The number of NIS- and pendrin-positive cells was much higher in hyperfunctioning tissue from Graves' disease or toxic adenoma. In hypofunctioning adenomas and carcinomas, the number of NIS- and pendrin-positive cells was low or nonexistent. Three types of follicular cells were observed in positive tissues: NIS-negative/pendrin-negative cells, NIS-positive/pendrin-positive cells, and NIS-negative/pendrin-positive cells. The first two types of cells appear to be resting and active cells, respectively, but the functional status of NIS-negative/pendrin-positive thyrocytes remains to be determined.

title: Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas.
abstract: Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.

title: Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters.
abstract: Iodide transport by thyrocytes involves two transporters, namely the Na(+)/I (-) symporter located at the basolateral pole and possibly pendrin in the apical membranes of the cell. Recently, we identified a human gene and its protein product, designated hAIT, as a putative new transporter involved in iodide transfer across the apical membrane of thyrocytes. In the present report, we analyzed both hAIT gene and protein expressions in a large series of benign and malignant human thyroid tissues. Using immunohistochemistry, hAIT staining was detected in normal thyroid tissue in about 10% of follicles; in positive follicles, 10-40% of thyrocytes, mostly the tall cells, were stained. In thyroid tissues obtained from patients with Graves' disease and toxic adenomas, hAIT mRNA and protein levels were similar to those found in normal tissue. In hypofunctioning adenomas, hAIT mRNA levels were slightly decreased, and apical iodide transporter (AIT) immunostaining was similar to that observed in normal thyroid tissue. AIT staining was stronger in Hürthle cell adenomas and in microfollicular adenomas. In thyroid carcinomas, the mean and median hAIT mRNA levels were significantly decreased. Expression of AIT protein was undetectable in most papillary carcinomas and was weak but detectable in most follicular carcinomas; it was negative in anaplastic carcinomas.

title: Relationship between expression of the sodium/iodide symporter and 131I uptake in recurrent lesions of differentiated thyroid carcinoma.
abstract: The sodium/iodide symporter (NIS) is known to be responsible for the active accumulation of iodide within the thyroid gland. We evaluated the relationship between the expression of NIS in primary or lymph node lesions and iodine-131 uptake in recurrent lesions of differentiated thyroid cancer. In 67 patients with differentiated thyroid cancer (5 follicular and 62 papillary carcinomas), the expression of NIS was analysed by immunohistochemical staining using polyclonal antibodies against human NIS. We used paraffin block tissues of primary tumours or metastatic lesions, and also assessed 131I uptake in recurrent lesions of thyroid cancer on post-operative 131I whole-body scan. Immunohistochemical staining was positive in 22 patients (32.8%), including 2 of 5 follicular and 20 of 62 papillary carcinomas. Recurrence was confirmed in 40 patients pathologically or clinically by serum thyroglobulin, 131I scan, fluorine-18 fluorodeoxyglucose positron emission tomography and/or computed tomography. Among these 40 patients, 28 showed positive uptake on 131I scan. Fourteen tumour specimens out of 28 (50%) were positive by NIS immunohistochemical staining. The remaining 12 patients with recurrent cancer showed negative 131I scans, and all specimens were negative by NIS immunohistochemical staining. Thus, NIS immunohistochemical staining predicted 131I uptake in recurrent cancer with a 100% positive predictive value and a 46.2% negative predictive value. There was no difference in the positivity of NIS according to the site of recurrence on 131I scan. Outcome of 131I therapy could be assessed in 22 of the 28 patients who showed 131I uptake in recurrent lesions. Patients with positive NIS immunostaining responded to 131I therapy better than did patients with negative immunostaining (P<0.05). In conclusion, NIS immunohistochemical staining showed a high positive predictive value in predicting iodine uptake. Positive immunohistochemical staining of human NIS in primary or lymph node lesions may predict 131I accumulation and effectiveness of 131I therapy in recurrent lesions.

title: Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin.
abstract: The incidence of differentiated thyroid cancer (DTC) has increased in many places around the world over the past three decades, yet this has been associated with a significant decrease in DTC mortality rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse rates remain high, in the order of 20-40%, depending upon the patient's age and tumor stage at the time of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment, but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumors that are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 ((131)I), followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regression modeling of 1510 patients without distant metastases at the time of initial treatment and including surgical and (131)I treatment, the likelihood of death from DTC is increased by several factors, including age >45 years, tumor size >1.0 cm, local tumor invasion or regional lymph-node metastases, follicular histology, and delay of treatment >12 months. Cancer mortality is favorably and independently affected by female sex, total or near-total thyroidectomy, (131)I treatment and levothyroxine suppression of TSH. Treatments with (131)I to ablate thyroid remnants and residual disease are independent prognostic variables favorably influencing distant tumor relapse and cancer death rates. Delay in treatment of persistent disease has a profound impact on outcome. Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New paradigms, however, provide alternative pathways to prepare patients for (131)I treatment and to optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease can now be identified within the first year after initial treatment by recombinant human (rh)TSH-stimulated serum Tg concentrations greater than 2 microg/l, without performing DxWBS. These new follow-up paradigms promptly identify patients with lung metastases that are not evident on routine imaging, but which respond to (131)I treatment. In addition, rhTSH can be given to prepare patients for (131)I remnant ablation or (131)I treatment for metastases, especially those who are unable to withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH fails to increase.

title: Follicular-cell derived thyroid cancer in children.
abstract: Thyroid carcinoma is a rare disease in children, and is mostly of the papillary histological type. It is often extended at presentation with frequent lymph node metastases. Treatment includes surgery (total thyroidectomy and lymph node dissection) and radioiodine therapy in case of extensive disease. Life long thyroxine treatment is given to all patients and when carefully controlled is devoided of adverse effects. Long term prognosis is favorable, but a few deaths have been reported some decades after initial treatment. Adverse prognostic indicators are younger age at discovery and presence of distant metastases.

title: Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review.
abstract: Current treatment strategies for pediatric patients with nonmedullary, well-differentiated thyroid carcinoma (WDTC) are derived from single-institution clinical cohorts, reports of extensive personal experience, and extrapolation of several common therapeutic practices for this tumor in adults. Because pediatric WDTC is an uncommon malignancy, the issues of its optimal initial and subsequent long-term treatment and follow-up remain controversial. Pediatric patients with WDTC can be divided into two groups: children younger than 10 years of age and teenagers/adolescents between 10 and 18 years of age because these groups have different recurrence and mortality rates. We hereby present our views and interpret them in the light of the pertinent literature. Our recommendations on treatment strategies are more relevant for younger children. After midpuberty, optimal treatment is adequately addressed in the relevant literature on adults. For the majority of patients, total/near-total thyroidectomy is currently recommended as the standard initial therapy for WDTC. This is commonly followed by administration of radioiodine (RAI; (131)I) therapy to destroy residual normal thyroid tissue (remnant). Routine (131)I remnant ablation has been shown to: (1). decrease the risk of local recurrences, (2) increase the sensitivity of subsequent diagnostic RAI whole-body scanning (WBS), and (3) render serum thyroglobulin (Tg) a highly sensitive marker for recurrent/residual disease during long-term follow-up. We recognize that the above practices are not universally adhered to in children and adolescents, because the risk stratification and intensity of applied therapeutic measures are influenced by institutional traditions and personal experience. In our view, aggressive initial management, followed by evaluations at regular intervals after thyroidectomy and (131)I remnant ablation, in conjunction with long-term thyroid hormone suppressive therapy (THST), result in decreased recurrence rates in pediatric patients with WDTC. Follow-up examinations should include a diagnostic RAI ((131)I or (123)I) WBS and measurement of serum Tg, both performed under conditions of TSH stimulation, as well as neck ultrasonography (US). Our strategy is corroborated by data from retrospective clinical cohort studies. In this malignancy, no evidence of disease (NED) status can be defined as the combination of a negative diagnostic WBS and the presence of undetectable or low serum Tg levels, both tested under TSH stimulation. These findings should be accompanied by the absence of anatomically definable disease by standard imaging modalities, e.g., neck US or chest computed tomography (CT). Although the long-term survival rates are good overall in this disease, selected patients may require further surgery or (131)I therapy for the eradication or clinical control of metastases. Finally, and importantly, because the duration of follow-up is lifelong, the care of children with prior diagnosis of WDTC should be transferred to an adult endocrinologist after they reach adulthood, even if they have achieved NED status by that time.

title: Thyroid cancer in children: the Royal Marsden Hospital experience.
abstract: The first child with well-differentiated thyroid cancer treated at the Royal Marsden Hospital presented in 1917. Since that time 30 children under the age of 16 years have been treated over a period during which many new treatments have been introduced. We have reviewed their management and outcome. The median follow-up is 22.5 years (range: 1-66). The median time to recurrence was 7 years (range: 2-44). There were events up to 44 years after presentation. The risk of recurrence was higher in children aged 10 years or younger [HR 3.45, 95% CI (1.04-11.11) P = 0.03]. Thyroid stimulating hormone (TSH) suppression was the only intervention to be shown to reduce the recurrence rate [HR 11, 95% CI (2.27-50) P = 0.0003]. The median overall survival is 53 years. The only presenting feature predictive of poorer survival was the presence of metastases (HR 28.96, 95% CI 2.51-334, P < 0.001). Patients who developed recurrence had a higher risk of death (HR 9.90, 95% CI 0.98-100, P = 0.02) and a shorter median survival of 30 years. No therapeutic intervention could be shown statistically to impact on survival. Our recommendation for treatment is total or near-total thyroidectomy for all patients and radioiodine ablation for all except those with early T stage node-negative disease aged over 10 years. Modified neck dissection is recommended for children with clinically positive neck nodes and TSH suppression for all. Follow-up with serial thyroglobulin measurement should be lifelong.

title: Mechanisms and pathogenesis of thyroid cancer in animals and man.
abstract: The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.

title: RET/PTC oncogene activation is an early event in thyroid carcinogenesis.
abstract: RET/PTC oncogene activation occurs in about 20% of human thyroid papillary carcinomas. However, it is not known yet whether it is an early or late event in the process of thyroid carcinogenesis. Here we demonstrate, by using a combined immunohistochemical and reverse transcriptase-polymerase chain reaction based approach, that RET/PTC activation is present in 11 out of 26 occult thyroid papillary carcinomas analysed. Therefore, we conclude that it represents an early event in the process of thyroid cell transformation.

title: High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.
abstract: Thyroid papillary cancers (PTCs) are associated with activating mutations of genes coding for RET or TRK tyrosine kinase receptors, as well as of RAS genes. Activating mutations of BRAF were reported recently in most melanomas and a small proportion of colorectal tumors. Here we show that a somatic mutation of BRAF, V599E, is the most common genetic change in PTCs (28 of 78; 35.8%). BRAF(V599E) mutations were unique to PTCs, and not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). Moreover, there was no overlap between PTC with RET/PTC, BRAF, or RAS mutations, which altogether were present in 66% of cases. The lack of concordance for these mutations was highly unlikely to be a chance occurrence. Because these signaling proteins function along the same pathway in thyroid cells, this represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem.

title: Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma.
abstract: Oncogenic rearrangements of RET and NTRK1 proto-oncogenes are frequently detected in papillary thyroid carcinomas. Several studies have shown an association between ionizing radiation and development of this tumor type. In addition in vitro irradiation of tumor cell lines induced rearrangements of RET similar to those observed in human papillary thyroid carcinomas. These two observations could be related to the reported increased incidence of papillary thyroid carcinomas in children living in contaminated areas around Chernobyl, given that it has been demonstrated that about 60% of them presents a RET oncogenic activation. However, this high frequency of RET positivity in radiation exposed children does not rule out the possibility that age could also play a role in the development of RET positive tumors. To assess this possibility we looked for a relationship between the presence of RET and NTRK1 oncogenic rearrangements and age at surgery in a sample of 92 consecutive patients. Our results show that, in papillary thyroid carcinoma, the frequency of RET and NTRK1 activation is significantly higher in the group of patients aged 4-30 years, thas supporting the concept that age could be contributing to this thyroid specific carcinogenic process.

title: Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.
abstract: In this study, we compare the morphological and genetic characteristics of 38 post-Chernobyl thyroid papillary carcinomas from Belarussian children 5-18 years old with those of 23 sporadic papillary carcinomas from the same age children without history of radiation exposure from Los Angeles and Cincinnati. Among radiation-induced tumors, solid variant of papillary carcinoma was found in 37%, follicular in 29%, typical papillary in 18%, and mixed and diffuse sclerosing variants in 8% each. In the sporadic group, a typical papillary pattern was prevalent in 70%, follicular in 17%, diffuse sclerosing variant in 9%, and solid in 4%. In both groups, the prevalence of ret rearrangements was high, but the frequency of specific types of rearrangement was significantly different. Among radiation-induced tumors, ret/PTC3 was found in 58%, ret/PTC1 in 16%, and ret/PTC2 in 3%, whereas among sporadic tumors, ret/PTC1 was found in 47% (P < 0.05), and ret/PTC3 was found in 18% (P = 0.01). The morphological variants of papillary carcinoma showed different prevalence of the specific types of ret rearrangement. Seventy-nine % of solid variant tumors had ret/PTC3, whereas only 7% had ret/PTC1 (P = 0.0007). Among typical papillary tumors, ret/PTC1 was found in 38%, ret/PTC3 in 19%, and ret/PTC2 in 5%. Thus, ret rearrangements are highly prevalent in pediatric papillary carcinomas from children exposed to radiation and in those occurring sporadically. However, the types of ret/PTC vary between these two populations, with ret/PTC3 present more commonly in post-Chernobyl tumors. Furthermore, solid variants have a high prevalence of ret/PTC3, whereas typical papillary carcinomas do not, suggesting that the different types of ret rearrangement confer neoplastic thyroid cells with distinct phenotypic properties.

title: Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas.
abstract: A high prevalence of the activating BRAF mutation, BRAF(T1796A), is observed in adult papillary thyroid carcinomas (PTCs). The prognosis of childhood PTCs is generally fairly good despite the fact that distant metastases are often documented in these cases. To investigate the differences between the characteristics of childhood and adult PTCs, we analyzed both BRAF(T1796A) and RAS mutations in 31 Japanese and 48 post-Chernobyl Ukrainian thyroid carcinomas. In the 31 Japanese childhood cases, BRAF(T1796A) was found in only one instance (3.2%), and no RAS mutations were detected. In the Ukrainian subjects, of the 15 childhood and the 33 adolescent and young adult PTCs examined, the BRAF(T1796A) mutation was found in zero and eight cases, respectively, and RAS mutations were found in two of the young adult cases. In addition, 17 of the 48 Ukrainian cases showed expression of the RET tyrosine kinase region, indicating the existence of RET/PTC rearrangements. Unlike adult PTCs, we could detect no positive association between BRAF(T1796A) mutations and clinical parameters in the childhood carcinomas, suggesting that a low prevalence of BRAF(T1796A) is a common feature of PTCs in children regardless of radiation exposure levels. The differences in the prevalence of BRAF(T1796A) mutations between childhood and adult cases of PTC may well reflect inherent differences in the clinical features of these cancers between the two age groups.

title: ret rearrangements in Japanese pediatric and adult papillary thyroid cancers.
abstract: Oncogenic rearrangements of the ret proto-oncogene (ret/PTC) are found uniquely in papillary thyroid carcinomas. The prevalence of ret/PTC in these tumors varies widely, from 0% to 87%, among patient series from different geographical regions. The differences in the prevalence of ret rearrangement have been ascribed to age, genetic, and/or environmental factors. The very high prevalence of ret/PTC in tumors arising in children after the Chernobyl nuclear accident has generated speculation that this oncogene may be an indicator of overt or inadvertent radiation exposure. In Japan, the prevalence of ret activation is reportedly quite low (0% to 9%). Here we examined the frequency of ret rearrangements in papillary carcinomas from Japanese adults and children by means of reverse transcription polymerase chain reaction (RT-PCR) followed by Southern hybridization. Ret rearrangements were detected in 4 of 11 (36%) tumors from the adult population, and in 3 of 10 (30%) pediatric tumors. One child with a solid variant papillary carcinoma had a ret-PTC3 rearrangement, further supporting the association between the solid variant histotype and this particular rearrangement of ret. The present data do not support a major geographic difference in the prevalence of ret/PTC rearrangements in papillary carcinomas between Japan, the United States, and Italy.

title: RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features.
abstract: The papillary carcinoma family (PCF) of thyroid tumors includes a wide variety of neoplastic entities regarded as well-differentiated, poorly differentiated, and undifferentiated papillary thyroid carcinomas. Recent studies have established the presence of alternative oncogenic rearrangements of the RET and NTRK1 genes in a consistent fraction (< or = 50%) of papillary thyroid tumors. RET oncogenic rearrangements are also very frequent (approximately 60%) in Chernobyl radiation-associated papillary thyroid neoplasias, which show an increased aggressiveness in terms of pathological stage at disease onset. These observations prompted us to study the relationship between the presence or absence of RET and NTRK1 oncogenes and the clinicopathological features (age, sex, histopathology, and pTNMC2 staging) of 76 consecutive, non-radiation-related tumors of the PCF. As previously reported, statistical univariate analysis revealed a correlation between the combination of RET and NTRK1 (RET/NTRK1) positivity and young age of patients at diagnosis. In addition, a significant association was found between RET/NTRK1 positivity and locally advanced stage of disease at presentation (pT4: P < 0.015). The multivariate analysis confirmed that RET/NTRK1 activation parallels an unfavorable disease presentation, which may correlate with a less favorable disease outcome. Furthermore, within the PCF, the frequency of RET/NTRK1 positivity was not influenced by the different neoplastic subtypes or the tumor versus degree of differentiation.

title: Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study.
abstract: To screen and validate the global gene expression in papillary thyroid carcinoma (PTC) using cDNA expression arrays and immunohistochemistry on tumor tissue microarrays in an attempt to find genes that may be of importance in the molecular pathogenesis and malignant progression of PTC.



Eighteen PTC tissue specimens were compared with three morphologically normal thyroid specimens by applying Atlas Human Cancer 1.2 Array membranes printed with cDNAs of 1176 human genes involved in cancer. Results for selected genes were confirmed by reverse transcription-PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 107 PTCs and compared with histologically normal thyroid tissue samples.



By cDNA arrays, two genes [c-MET and matrix metalloproteinase (MMP)-11] were expressed only in tumor tissue, where they were present in >50% of cases. Ten genes [macrophage inhibitory cytokine-1, CGD, fibronectin (FN), hypoxia-inducible factor 1, Fc-epsilon-receptor gamma-chain, lactate dehydrogenase A, HLA-DBP1, AH receptor, tissue inhibitor of metalloproteinase (TIMP-1), and glycyl-tRNA-synthetase] were found to be up-regulated >2-fold in 40-100% of cancers, whereas 9 genes (GADD153, polykystic kidney disease-1, CYR61, DPC4, HBA1, gravin, DLG3, protein tyrosine phosphatase sigma, and heterochromatin protein 1 homologue-alpha) were down-regulated to <50% of their normal levels in 40-94% of cases. Conventional reverse transcription-PCR gave consistent results with the cDNA array findings for all four genes selected to be studied (c-MET, FN, TIMP-1, and GADD153). Immunohistochemistry for three selected proteins, FN, MMP-11, and TIMP-1, showed positive staining in 81, 87, and 68% of the tumor samples, respectively.



Several novel and previously undetected tumor promoting/inhibiting genes may be of importance in the molecular pathogenesis and malignant progression of PTC. Transcription of these genes may result in overexpression of proteins, such as c-MET, MMP-11, TIMP-1, and FN, which may contribute to the pathogenesis of PTC.

title: Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications.
abstract: The study looked for an optimal set of genes differentiating between papillary thyroid cancer (PTC) and normal thyroid tissue and assessed the sources of variability in gene expression profiles. The analysis was done by oligonucleotide microarrays (GeneChip HG-U133A) in 50 tissue samples taken intraoperatively from 33 patients (23 PTC patients and 10 patients with other thyroid disease). In the initial group of 16 PTC and 16 normal samples, we assessed the sources of variability in the gene expression profile by singular value decomposition which specified three major patterns of variability. The first and the most distinct mode grouped transcripts differentiating between tumor and normal tissues. Two consecutive modes contained a large proportion of immunity-related genes. To generate a multigene classifier for tumor-normal difference, we used support vector machines-based technique (recursive feature replacement). It included the following 19 genes: DPP4, GJB3, ST14, SERPINA1, LRP4, MET, EVA1, SPUVE, LGALS3, HBB, MKRN2, MRC2, IGSF1, KIAA0830, RXRG, P4HA2, CDH3, IL13RA1, and MTMR4, and correctly discriminated 17 of 18 additional PTC/normal thyroid samples and all 16 samples published in a previous microarray study. Selected novel genes (LRP4, EVA1, TMPRSS4, QPCT, and SLC34A2) were confirmed by Q-PCR. Our results prove that the gene expression signal of PTC is easily detectable even when cancer cells do not prevail over tumor stroma. We indicate and separate the confounding variability related to the immune response. Finally, we propose a potent molecular classifier able to discriminate between PTC and nonmalignant thyroid in more than 90% of investigated samples.

title: Thyroid carcinomas that express telomerase follow a more aggressive clinical course in children and adolescents
abstract: With each cell division, DNA is lost from the telomeres, limiting the number of divisions, and leading to senescence. Malignant tumors maintain immortality by expressing a specific DNA repair enzyme, telomerase, that replaces this DNA. We hypothesized that tumors which express telomerase would have the highest recurrence risk and we tested this by determining telomerase expression in 27 papillary thyroid carcinomas (PTC), 5 follicular thyroid carcinomas (FTC) and 13 benign thyroid lesions from children and adolescents. Patients were 6–21 yr of age (mean±SE=16.6±4.1 yr) and followed from 0–14.1 yr (mean±SE=4.71±3.5 yr). Original tumors were sectioned, and immunostained for telomerase. Telomerase-specific staining was determined by two independent, blind examiners and graded from absent (Grade 0) to intense (Grade 3). Telomerase was detected in a similar majority of benign (11/13, 85%) and malignant tumors (24/32, 75%). However, the intensity of telomerase expression was greater among FTC (mean±SE=2.4±0.5 relative intensity) followed by PTC (mean±SE=1.9±1.0 relative intensity) and benign tumors (mean±SE=1.8±1.0 relative intensity). Autoimmune lesions had lower telomerase expression (mean±SE=1.25±0.5 relative intensity) compared to FTC (p=0.01), PTC (p=0.06) and benign lesions (p=0.15). Among PTC, 19 (70%) expressed telomerase, and 8 (30%) did not. Direct invasion (no.=4, 21%), distant metastasis (no.=2, 10%) and recurrence (no.=7, 37%) developed exclusively in PTC that expressed telomerase (p=0.02). Disease-free survival was also shorter for PTC that expressed telomerase (p=0.06). Recurrence developed in 1/2 (50%) FTC that expressed telomerase. We conclude that childhood thyroid cancers which express telomerase have an increased risk of tissue invasion, metastasis, and recurrence.

title: Fas ligand expression in thyroid carcinomas: a potential mechanism of immune evasion.
abstract: Fas ligand (FasL) induces apoptosis by cross-linking the Fas receptor and is expressed by cells of the immune system. Recently, FasL was found in malignant tumors, suggesting that it helps them escape immune surveillance by eliminating infiltrating lymphocytes. We investigated the presence of FasL immunohistochemically in 48 thyroid carcinomas and by Western blotting and RT-PCR in 5 thyroid carcinoma cell lines. We found that in contrast to normal thyroid tissue, FasL was highly expressed in all papillary, follicular, and Huerthle carcinomas. Medullary carcinomas lacked or had minimal FasL expression. In papillary carcinomas, high levels of expression correlated independently with aggressive histology and unfavorable clinical presentation. FasL was also present in all thyroid cell lines. Thyroid carcinoma cells killed Fas-sensitive targets in a FasL-dependent manner in a coculture experiment. Cross-linking of Fas induced apoptosis in thyroid carcinoma cells only in the presence of cycloheximide. We conclude that FasL is specifically expressed in thyroid carcinomas of follicular epithelial origin, may help them evade the immune system, and may have prognostic implications in papillary carcinoma, as it is associated with a more aggressive phenotype. Thyroid carcinoma cells avoid Fas-mediated suicide possibly by expressing an inhibitor of the Fas apoptotic pathway.

title: The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland.
abstract: Ninety-five patients with papillary thyroid carcinoma (PTC) who received primary surgical treatment in 1983 at Kuma Hospital and were followed until 1992 were the subjects of this study. Initial therapy was tumor resection for 5 patients, lobectomy for 23 patients, total thyroidectomy with unilateral modified neck dissection for 60 patients, and total thyroidectomy with bilateral modified neck dissection for 7 patients. Clinical stage at diagnosis was as follows. Class I included 28 patients with intrathyroidal disease, class II included 60 patients with positive cervical lymph nodes, and class II included 7 patients with tumor invasion into tissue outside of the thyroid gland. Recurrence of the tumor was evaluated according to lymphocytic infiltration in the thyroid gland. Group A consisted of 36 patients with PTC associated with lymphocytic infiltration, 26 with infiltration surrounding the tumor, 3 with infiltration inside of the tumor, and 7 with both. Group B consisted of the remaining 59 patients with PTC with no lymphocytic infiltration. There were no differences in age, sex, initial tumor size, or initial treatment between groups A and B. Antithyroglobulin antibody and/or antimicrosomal antibody were positive in 16 patients from group A and 4 patients from group B (P < 0.001). Class I included 14 patients from each group, class II included 22 patients from group A and 38 patients from group B, and class III included 7 patients, all from group B. Recurrence of the tumor was found in only 1 group A patient (2.8%), but in 11 patients of group B (18.6%). The percentage of patients free from recurrence over the 10 yr of follow-up in group A was significantly higher than that in group B (by Cox-Mantel test, P < 0.01). The time between initial treatment and recurrence was 2-10 yr. In comparing the clinical stage at the time of initial treatment, recurrence was found in 1 class II patient from group A (4.5%) and in 1 class I (7.1%), 6 class II (15.8%), and 4 class III (57.1%) patients from group B. No patients died during the 10 yr of follow-up. In conclusion, 1) lymphocytic infiltration surrounding the tumor or inside the tumor in PTC might be of use as a means for predicting a favorable prognosis; and 2) class II or class III patients with no lymphocytic infiltration had a high rate of recurrence.

title: Influence of lymphocytic thyroiditis on the prognostic outcome of patients with papillary thyroid carcinoma.
abstract: Both the association between lymphocytic thyroiditis (LT) and papillary thyroid carcinoma (PTC), and the prognostic significance of lymphocytic infiltrate in patients with thyroid malignancy, remain controversial. We examine the above relationships by retrospectively reviewing our series of patients treated for differentiated nonmedullary thyroid carcinoma at University of California-San Francisco over a 25-yr period (1970-1995). Of the 631 patients with complete data for analysis, 128 patients (20.3%) showed concomitant histologic evidence of LT and 503 patients (79.7%) had no evidence of LT. Prognostic outcome was assessed using Kaplan-Meier survival plots and analysis of risk factors by Cox's proportional-hazard modeling. The cohort with LT revealed a higher frequency of PTC (97.7% vs. 87.3%) and female patients (85.2% vs. 66.8%), a lower frequency of extrathyroidal invasion (7.8% vs. 23.3%) and nodal metastases (25.8% vs. 43.3%), and absence of distant metastases (0% vs. 4.8%), respectively, compared with those without LT. At initial surgery, a significantly greater proportion of patients with LT belonged to lower pathological tumor-node-metastasis stages, compared with those without LT (stage 1, 86.7% vs. 73%; stage 2, 4.7% vs. 8.3%; stage 3, 8.6% vs. 15.3%; and stage 4, 0% vs. 3.4%). Over a mean +/- SE follow-up period of 11.1 +/- 0.4 yr, patients with LT had significantly lower cancer recurrence rate (6.3% vs. 24.1%; P < 0.0001) and cancer mortality rate (0.8% vs. 8.0%; P = 0.001), respectively, compared with those without LT. In summary, our series showed a relatively common occurrence of LT in patients with PTC, and we believed that lymphocytic infiltration developed mainly in response to the tumor itself. We also found a more favorable course of PTC in the presence of LT; this supports the hypothesis that lymphocytic infiltration represents a form of immune reaction to control tumor growth and proliferation.

title: Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes.
abstract: The immune response appears to be important in preventing metastasis and recurrence of thyroid cancer. We previously showed that papillary thyroid carcinoma (PTC) from children and adolescents that contain the most numerous proliferating lymphocytes have the best prognosis. However, the types of lymphocytes involved are not yet known. To further define this, we examined 21 PTCs from patients 21 yr of age or younger (52% were 18-21 yr of age) for the presence of CD4+ (helper), CD8+ (killer), CD19+ (B cells), and CD56+ (natural killer) cells as well as proliferating lymphocytes (Ki-67+). Nearly half the PTCs contained CD4+ (9 of 21, 43%), CD8+ (8 of 21, 38%), or CD19+ (10 of 21, 48%) lymphocytes. Only one PTC (1 of 21, 5%) contained CD56+ lymphocytes, and none contained all four cell types. By dual staining, none of these lymphocytes were proliferating (Ki-67+). However, PTCs containing either CD8+ cells (n = 8) or a combination of CD4+, CD8+, and CD19+ cells (n = 5) contained more numerous proliferating lymphocytes than did PTCs containing any other combination (14.2-fold increase, P = 0.03 and 13.1-fold increase, P = 0.003, respectively). During follow-up, none of the PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes recurred. However, the cohort is too small and the follow-up inadequate to provide accurate information on the clinical impact of these immunological findings. We conclude that the immune response against PTC is important and also complex, involving more than one type of lymphocyte.

title: Infiltration of differentiated thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival for children and young adults.
abstract: An immune response directed against thyroid cancer might be important in preventing metastasis and recurrence. This idea is supported by previous observations showing that adults with autoimmune thyroiditis or lymphocytic infiltration surrounding papillary thyroid carcinoma (PTC) have improved disease-free survival. The long-term outcome for differentiated thyroid cancer is even more favorable for children and young adults. If the immune response is important, we hypothesized that tumor-associated lymphocytes with a high proliferation index would be found in thyroid cancers from children and young adults and would be associated with improved disease-free survival. Using immunohistochemistry, we examined 39 childhood PTC, 9 follicular thyroid carcinomas, 2 medullary thyroid carcinomas, 11 benign thyroid lesions, and 2 normal thyroid glands for the presence of lymphocytes (leukocyte common antigen) and lymphocyte proliferation (proliferating cell nuclear antigen, Ki-67). The majority of PTC (65%) and follicular thyroid carcinomas (75%) from children and young adults contained lymphocytes in the immediate vicinity of thyroid cancers, but only 7 (18%) patients with PTC also had a diagnosis of autoimmune thyroiditis. Disease-free survival did not correlate with the presence or number of lymphocytes per high power field. In contrast, disease-free survival was significantly improved (P = 0.01) for thyroid cancers with the greatest number of Ki-67-positive lymphocytes per high power field. The number of lymphocytes per high powered field was greater for multifocal PTC (P: = 0.023), and the number of proliferating lymphocytes was greatest for PTC with regional lymph node involvement (30.5 +/- 12.3 vs. 6.8 +/- 5.0; P = 0.047). We conclude that proliferation of tumor-associated lymphocytes is associated with improved disease-free survival for children and young adults with thyroid cancer.

title: Intense expression of the b7-2 antigen presentation coactivator is an unfavorable prognostic indicator for differentiated thyroid carcinoma of children and adolescents.
abstract: Previous observations suggest that an immune response against thyroid carcinoma could be important for long-term survival. We recently found that infiltration of thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival, but the factors that control lymphocytic infiltration and proliferation are largely unknown. We hypothesized that the antigen presentation coactivators (B7-1 and B7-2), which are important in other immune-mediated thyroid diseases, might be important in lymphocytic infiltration of thyroid carcinoma. To test this, we determined B7-1 and B7-2 expression by immunohistochemistry [absent (grade 0) to intense (grade 3)] in 27 papillary (PTC) and 8 follicular (FTC) thyroid carcinomas and 9 benign thyroid lesions. B7-1 and B7-2 were expressed by the majority of PTC and FTC (78% of PTC and 100% of FTC expressed B7-1; 88% of PTC and 88% of FTC expressed B7-2). B7-1 expression was more intense in PTC (1.4 +/- 0.2; P = 0.01) and FTC (2.6 +/- 0.2; P < 0.001) than in benign tumors (0.57 +/- 0.30) or presumably normal adjacent thyroid (0.07 +/- 0.07) and was more intense in carcinoma that contained lymphocytes (1.95 +/- 0.21) than in carcinoma that did not (1.08 +/- 0.26; P = 0.016). B7-2 expression was of similar intensity in benign and malignant tumors (PTC, 1.6 +/- 0.2; FTC, 2.1 +/- 0.4; benign, 1.86 +/- 0.4), but was more intense than in presumably normal adjacent thyroid (0.64 +/- 0.25; P </= 0.013). B7-2 expression also correlated with the number of tumor-associated lymphocytes per high power field (r = 0.38; P = 0.02). Recurrence developed exclusively from tumors that expressed B7-2, and intense B7-2 expression was associated with a reduced probability of remission (P = 0.04). In conclusion, these data support the hypothesis that the antigen presentation coactivators B7-1 and B7-2 may be important for lymphocytic infiltration and the immune response against thyroid carcinoma.

title: Differentiated thyroid cancer in children and adolescents: Clinical outcome and mortality after long‐term follow‐up
abstract: Children and adolescents with differentiated thyroid cancer (DTC) have a good prognosis and prolonged survival even when extensive regional disease or lung metastases are present at the diagnosis; very‐long‐term follow‐up is needed to appreciate what, if any, impact the disease may exert on the ultimate outcome.

title: The changing role of radioiodine in the management of differentiated thyroid cancer.
abstract: This article discusses several aspects of the evaluation and management of differentiated thyroid carcinoma that are changing or may change in the near future. Although conventional treatment of this disease is highly effective, some modification may improve the welfare of patients and the overall results. Because the symptoms of hypothyroidism are vexing, there has been great interest in using recombinant human thyroid-stimulating hormone (rhTSH) to prepare patients for iodine 131 imaging. rhTSH has been about as effective as thyroid hormone withdrawal for diagnostic imaging so that approval for this use is expected. Another topic of interest is the administration of 131I therapy to patients whose serum thyroglobulin levels are abnormal but whose diagnostic 131I scans are negative. Because the 131I scans after therapy are often abnormal in these patients and a reduction of serum thyroglobulin can occur, this approach seems effective. The long-term impact of this therapy on recurrence and survival, however, is unknown. A third issue that is currently under review is the amount of 131I that should be used for diagnostic scanning. Although past opinion favored larger doses, "stunning" of thyroid remnant and tumor can occur with diagnostic 131I imaging. Substituting iodine 123 is an alternative for postthyroidectomy scanning, but when administered as 300 uCi it is less accurate than 131I for recurrent disease or distant metastases. Related to these issues, two other topics are reviewed: the use of other radiopharmaceuticals for imaging patients with thyroid cancer, and 131I dosimetry.

title: The British Thyroid Association guidelines for the management of thyroid cancer in adults
abstract: IntroductionThyroid nodular disease is common in the UK (8.6%) and 50% of nodules are considered solitary. They are more common in women and the problem increases with age. Although the commonest way for thyroid cancer to present is as a solitary thyroid nodule in a euthyroid patient when the incide

title: Frequent adverse events after treatment for childhood-onset differentiated thyroid carcinoma: a single institute experience.
abstract: Since the mortality rate for childhood differentiated thyroid carcinoma is nearly zero, the focus must be to minimise morbidity following treatment. Our aim was to analyse early and late adverse events. Twenty-five of 26 children treated between 1962 and 2002 were evaluated. Median follow-up was 14.2 years (range 0.9-39.4 years). All underwent total thyroidectomy, 15 (60%) with lymph node dissection and 15 (60%) with adjuvant radio-iodide therapy. Mortality was zero. Seven developed recurrent disease, two developed a third recurrence. Twenty-one (84%) had > or =1 adverse event. Eight had permanent hypoparathyroidism (PH), six permanent recurrent nerve paralysis (PRNP) and two Horner's syndrome. Risk factors for PH and PRNP were total thyroidectomy with lymph node dissection (RR: 6.45, P = 0.015) and recurrent nerve tumour encasement (RR: 8.00, P = 0.001), respectively. Other adverse events were fatigue (n = 5), scar problems (n = 4) and chronic myeloid leukaemia (n = 1). These results emphasise the need to improve treatment strategies.

title: Impact of parathyroid status and Ca and vitamin-D supplementation on bone mass and muscle-bone relationships in 208 Belarussian children after thyroidectomy because of thyroid carcinoma.
abstract: This observational study analyzes Ca-P metabolism and its impact on bone mass accrual and density and the muscle-bone mass/mass relationships in male and female children and adolescents who were parathyroidectomized because of thyroid carcinoma. Two hundred and eight children and adolescents (119 girls and 89 boys) from Gomel city (Belarus) and its rural surroundings were referred to our institution after having undergone total thyroidectomy for the treatment of advanced papillary thyroid cancer. A subgroup of children with demonstrated primary hypoparathyroidism received dihydrotachysterol (AT-10) and/or Ca supplementation. Among routine procedures over a maximum follow-up period of 5 years (average 3.7 years, maximum 8 visits), whole-body scans were taken using dual energy X-ray absorptiometry (DXA) at each visit in order to determine whole-body bone mineral content (TBMC), projected "areal" bone mineral density (TBMD), total lean mass (TLM) and total fat mass (TFM). The average serum Ca, P and AP concentrations over the whole observation period were significantly different between the groups; however, TBMC z-scores for all studied children were statistically similar in all visits. In girls, no between-group differences in height- and weight-controlled TBMC and TBMD or the TBMC/TLM ratio were observed (ANCOVA) and supplementation exerted no effect on these data, suggesting that the total bone mass accrual was not impaired by PTH deficiency in the studied conditions. However, non-supplemented boys showed lower values of the TBMC/TLM ratio than girls, and supplementation normalized these values in direct correlation with the induced improvement in serum P availability to bone. Results indicate that the primary impairment in parathyroid function and bone metabolism indicators in the thyroidectomized children was unrelated to any measurable change in crude bone mass values. However, in boys this condition impaired the TBMC/TLM ratio in such a way that the administered supplementation could normalize it as a function of improved P availability. Girls' skeleton seemed to have been naturally protected against the negative metabolic effect of the studied condition. An estrogen-induced enhancement of the biomechanical impact of muscle contractions on bone mass and structure could not be excluded in this group.

title: Quantitative radioiodine therapy in the treatment of differentiated thyroid cancer.
abstract: Radioiodine therapy is used in the treatment of patients with differentiated thyroid cancer both to ablate residual thyroid tissue after initial surgery and to treat residual, recurrent, or metastatic cancer. In most institutions, therapy remains based on empirically determined, fixed amounts of radioiodine that do not account for individual differences in the mass of tissue to be treated and in radioiodine kinetics. Over the last 25 years, we have developed and refined techniques based on pre-therapy, diagnostic quantitative radiation dosimetry and imaging with 131I that permit individualized treatment which balances the success of the treatment and the risk of serious acute adverse effects on the bone marrow and lungs. In this manuscript we discuss patient selection and preparation for radioiodine therapy and outline in detail methods for performing quantitative dosimetry studies. Guidelines for the application of these results to the treatment of individual patients are presented.

title: Efficacy of I131 ablation therapy using different doses as determined by postoperative thyroid scan uptake in patients with differentiated thyroid cancer.
abstract: The optimal dose of I(131) for ablation of functioning residual thyroid tissue after surgery is controversial. The current study was conducted to determine the optimal dose of I(131) for remnant postoperative ablation. A review of the literature is included.



A total of 238 patients with papillary and follicular carcinoma were treated with I(131) for ablation of a postoperative thyroid remnant. The I(131) dose was based on the 24-h percentage of neck uptake in the postoperative thyroid scans. Patients with < 5% uptake received a median of 85 mCi; 6-10% uptake, a median of 80 mCi; 11-15% uptake, a median of 60 mCi; 16-20% uptake, a median of 50 mCi; and > or =21% uptake, a median of 30 mCi. The ablation results were compared with the prognostic factors.



Complete ablation was observed in 40 (92%) of 43 patients receiving 85 mCi, in 31 (94%) of 33 who received 80 mCi, in 39 (95%) of 41 who received 60 mCi, in 51 (93%) of 55 who received 50 mCi, in 37 (94%) of 39 who received 30 mCi, and in 18 (96%) of 19 who received 30 mCi. The overall successful ablation rate was 94% (95% confidence interval, 89-100%).



Our findings suggest that patients with differentiated thyroid cancer can be treated with doses of I(131) according to the percentage of neck uptake of postoperative total body scan, with high complete ablation rates, without exposing patients to higher dose levels of I(131).

title: Efficacy of low-dose iodine-131 ablation of post-operative thyroid remnants: a study of 69 cases.
abstract: Low-dose iodine-131 of mean activity 1117 MBq was used to ablate post-operative thyroid remnants in 69 patients with differentiated thyroid cancer. Successful ablation was defined as uptake of less than 1% at 48 h and absence of visible image on the post-ablation scan. Ablation by one dose was successful in 95% of patients after total or subtotal thyroidectomy, and 56% of patients after partial or hemithyroidectomy. All patients with uptake of 10% or less on the pre-ablation scan had successful ablation. The results are compared with other reports using low-dose radioiodine ablation and the significance of the findings discussed.

title: Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.
abstract: To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy.



One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined.



Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin.



Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

title: Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation?
abstract: Measuring serum Tg and performing a diagnostic whole body scan (DxWBS) has become the standard for follow-up of patients with differentiated thyroid carcinoma. The primary aim of this study was to determine whether recombinant human TSH (rhTSH)-stimulated Tg alone is sufficiently sensitive to identify residual cancer in patients with no clinical evidence of disease and undetectable or very low serum Tg levels during thyroid hormone (TH) therapy. A secondary aim was to investigate the frequency of tumor in such patients. One hundred and seven consecutive patients, aged 10.9-85.3 yr (median, 36.3), at the time of initial surgery who had Tg levels on TH therapy that were undetectable (95% < or =0.5 ng/ml) or low (4% 0.6 ng/ml, 1% 1.0 ng/ml) and who underwent rhTSH-stimulated testing 10 months to 35 yr (median, 3.5 yr) after initial thyroidectomy and (131)I ablation were retrospectively studied. Many (50%) were at high risk of tumor recurrence, and 5 had distant metastases during the course of their disease. In response to rhTSH, Tg ranged from 0.5 or less to 17.9 ng/ml, remaining at 0.5 ng/ml or less in 68 (64%) patients and increasing to levels between 0.6 and 2 ng/ml in 19 (18%) others and to levels higher than 2 ng/ml in 20 (19%) patients. Eleven patients (10%), all of whom had rhTSH-stimulated serum Tg levels above 2 ng/ml, were found to have persistent tumor in lung (4 patients), lymph nodes (5 patients, 3 with cervical central compartment, 1 bilateral cervical, and 1 with mediastinal nodes) identified by fine needle cytology, surgical pathology, posttherapy whole body scans, or computed tomography and, in two patients, with high serum Tg values alone (4.6 and 7.0 ng/ml after rhTSH and, respectively, 28.5 and 70.6 ng/ml after TH withdrawal), although in neither could the tumor site be identified. Thirteen patients (12%) were treated with surgery or (131)I, and in some cases both, as a result of the rhTSH studies; 10 had tumor, 1 had residual uptake in the thyroid bed visible on rhTSH-stimulated diagnostic whole body scan (DxWBS), and 2 had high serum Tg levels, presumably originating from a tumor site that could not be identified. A patient's tumor status, even in retrospect, usually was not predictable on the basis of Tg during TH therapy or tumor node metastasis status: among patients found to have tumor after rhTSH, serum Tg during TH therapy was 0.5 ng/ml or less in 55% and 0.6 ng/ml in 36%, and tumor node metastasis status was T2N1 or less in 82%. In no case did the rhTSH-stimulated DxWBS show the site of persistent tumor. There were correlations between visible thyroid bed uptake on DxWBS and quantitated (131)I uptake (r(2) = 0.11; P = 0.001), between DxWBS and rhTSH-stimulated Tg (r(2) = 0.54; P = 0.001), and between rhTSH-stimulated Tg and (131)I uptake (r(2) = 0.66; P = 0.0001). There was no statistically significant difference (P = 0.4) in bed (131)I uptake in patients with rhTSH-stimulated serum Tg levels of 0.5 ng/ml or less compared with that in subjects with higher rhTSH-Tg levels. An rhTSH-stimulated Tg level greater than 2 ng/ml had a sensitivity of 100%, a negative predictive value of 100%, and a false positive rate of 9%. The rhTSH Tg had a substantially better performance than the other studies; the false negative rates were 64% for Tg higher than 0.5 ng/ml on TH therapy, 73% for rhTSH-stimulated DxWBS showing uptake, and zero for an rhTSH-stimulated Tg more than 2 ng/ml. In conclusion, of 107 patients who were clinically free of disease, 10% had persistent tumor (4 with pulmonary metastases and 5 with regional disease) that was only identified with an rhTSH-stimulated serum Tg level greater than 2 ng/ml. This study shows that tumor amenable to early therapy may be found when rhTSH-stimulated serum Tg rises above 2 ng/ml without performing a DxWBS, which merely provides data concerning the completeness of thyroid ablation, but not persistent tumor. An elevated rhTSH-stimulated Tg greater than 2 ng/ml warrants further study.

title: Clinical comparison of whole-body radioiodine scan and serum thyroglobulin after stimulation with recombinant human thyrotropin.
abstract: Sensitive monitoring for thyroid cancer recurrence or persistence includes whole-body radioiodine scanning (WBS) and measurement of serum thyroglobulin (Tg) after endogenous or exogenous thyrotropin (TSH) stimulation. We reviewed our experience using recombinant human thyrotropin (rhTSH) in 83 patients to compare the clinical relevance of a positive WBS and/or Tg. Ten patients had a positive WBS; eight of these patients had activity limited to the thyroid bed. rhTSH-stimulated Tg was 2 ng/mL or more in 25 and 5 ng/mL or more in 13 patients. Of the patients with a negative WBS, 11 of 20 patients with a Tg 2 ng/mL or more and 7 of 9 patients with a Tg 5 ng/mL or more received therapy or further evaluation based on the Tg alone. Conversely, only 1 of 5 patients with a serum Tg less than 2 ng/mL received therapy or further evaluation based on a positive WBS alone. Three of the patients who did not receive therapy or further evaluation, had subsequent negative WBS 10-12 months later, suggesting lack of clinically significant disease. Twenty patients had a negative WBS and serum Tg 2 ng/mL or more. Eleven of 20 patients had a Tg less than 5 ng/mL and 4 of these patients had further evaluation with a neck ultrasound. One patient had a biopsy-proven recurrence (rhTSH-stimulated Tg 4 ng/mL). Subsequent evaluations (> or = 6 months later) have been negative for 8 patients. Of the nine patients with a Tg 5 ng/mL or more and a negative WBS, 7 had further evaluation and 6 of 7 had identified disease. In summary, rhTSH-stimulated WBS and Tg are complementary, but Tg is a more sensitive indicator of disease recurrence or persistence. In our practice, an rhTSH-stimulated Tg greater than 4-5 ng/mL often resulted in further evaluation, while a Tg less than 4 ng/mL rarely resulted in further immediate evaluation.

title: A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma.
abstract: Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

title: Pulmonary metastases in children and adolescents with well-differentiated thyroid cancer.
abstract: In this study, 27 patients less than 18 yr old with pulmonary metastases from well-differentiated thyroid carcinoma were evaluated to determine their response to (131)I therapy.



Of 121 children and adolescents treated with (131)I between 1963 and 1996, 27 patients had pulmonary metastases associated with nodal disease. Treatment response from (131)I was measured by three parameters: chest radiograph, scintigraphic images and serum thyroglobulin levels. Total activity of (131)I administered ranged from 4.6 GBq (125 mCi) to 38.7 GBq (1.05 Ci). Four patients were given one treatment, 8 were given two treatments, 4 were given three treatments and 11 were given more than three treatments. Radiation doses to the lungs were estimated in 14 patients using the MIRD methodology. The minimum duration of follow-up was 6 mo.



At the time of initial presentation, diagnostic (131)I studies revealed bilateral radioiodine uptake in the lungs in 19 (70.4%) patients, whereas 12 (44.4%) patients had abnormal chest radiographs. One patient was lost to follow-up and was excluded from the study. Of the 26 patients studied, complete ablation of pulmonary metastases was observed in 8 (30.8%), partial ablation in 17 (65.4%) and there was no response to treatment in 1 (3.8%). Dosimetric parameters such as radioiodine uptake as a percentage of therapeutic activity, effective half-life and radiation dose delivered to the lungs were evaluated with each therapy. There was a progressive decline in each of these parameters with successive therapies. No correlation was observed between the radiation dose delivered and the response of pulmonary metastases to therapy. The number of therapies and amount of radioiodine administered had no influence on the ablation response. Of the 26 patients, 13 had a follow-up duration of less than 5 yr, 7 had 5-10 yr and 6 had more than 10 yr. One patient developed new metastases after 7 yr of diagnosis and treatment. One patient died of the disease after 4 yr. All surviving patients were asymptomatic and leading normal lives.



Complete response of pulmonary metastases after (131)I therapy is difficult to achieve. A partial response with reduction of metastatic disease is possible and, in general, the patients had a good quality of life with no further disease progression and a low mortality rate.

title: Ablation of thyroid residues with 30 mCi (131)I: a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal.
abstract: The aim of the study was to assess whether stimulation by recombinant human TSH (rhTSH) may be used in patients with differentiated thyroid carcinoma for postsurgical ablation of thyroid remnants using a 30-mCi standard dose of (131)I during thyroid hormone therapy. The rate of ablation was prospectively compared in three groups of patients consecutively assigned to one of three treatment arms: in the first arm, patients (n = 50) were treated while hypothyroid (HYPO); in the second arm, patients (n = 42) were treated while HYPO and stimulated in addition with rhTSH (HYPO + rhTSH); in the third arm, patients (n = 70) were treated while euthyroid (EU) on thyroid hormone therapy and stimulated with rhTSH (EU + rhTSH). The outcome of thyroid ablation was assessed by conventional HYPO (131)I scan performed in HYPO state 6-10 months after ablation. Basal serum TSH was elevated in the HYPO and HYPO + rhTSH groups. In the EU + rhTSH group, basal serum TSH was 1.3 +/- 2.5 micro U/ml (range, <0.005-11.9 micro U/ml). After rhTSH, serum TSH significantly increased in the HYPO + rhTSH group and the EU + rhTSH group. Basal 24-h radioiodine thyroid bed uptake was 5.8 +/- 5.7% (range, 0.2-21%) and 5.4 +/- 5.7% (range, 0.2-26%) in the HYPO and HYPO + rhTSH groups, respectively. In the HYPO + rhTSH group, mean 24-h thyroid bed uptake rose to 9.4 +/- 9.5% (range, 0.2-46%) after rhTSH (P < 0.0001). The 24-h uptake after rhTSH in the EU + rhTSH group was 2.5 +/- 4.3% (range, 0.1-32%), significantly lower (P < 0.0001) than that found in the HYPO and HYPO + rhTSH groups. The rate of successful ablation was similar in the HYPO and HYPO + rhTSH groups (84% and 78.5%, respectively). A significantly lower rate of ablation (54%) was achieved in the EU + rhTSH group. Mean initial dose rate (the radiation dose delivered during the first hour after treatment) was significantly lower in the EU + rhTSH group (10.7 +/- 12.6 Gy/h) compared with the HYPO + rhTSH group (48.5 +/- 43 Gy/h) and the HYPO group (27.1 +/- 42.5 Gy/h). In conclusion, our study indicates that by using stimulation with rhTSH, a 30-mCi standard dose of radioiodine is not sufficient for a satisfactory thyroid ablation rate. Possible reasons for this failure may be the low 24-h radioiodine uptake, the low initial dose rate delivered to the residues, and the accelerated iodine clearance observed in EU patients. Possible alternatives for obtaining a satisfactory rate of thyroid ablation with rhTSH may consist of increasing the dose of radioiodine or using different protocols of rhTSH administration producing more prolonged thyroid cells stimulation.

title: Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.
abstract: We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

title: Possible limited bone loss with suppressive thyroxine therapy is unlikely to have clinical relevance.
abstract: To determine the effect of suppressive doses of thyroxine (T4) on bone mass, we studied 50 women on suppressive doses of T4 for 3-27 years (mean of 11 years). Twenty-five had nontoxic goiter and 25 had well-differentiated thyroid carcinoma. Fifty controls were matched for age, menopausal status, and body mass index. Bone mineral density (BMD) was measured in the lumbar spine (LS), femoral neck (FN), trunk (TK), and extremities (EXT) by dual-energy X-ray absorptiometry (DXA). In addition, the trunk area was measured by neutron activation analysis and recorded as a calcium bone index (CaBI). Twenty-one patients were restudied with DXA measurements at a mean of 1.5 +/- 0.5 (1 SD) years. The total population of 50 patients showed no difference in bone mass from controls. In patients with nontoxic goiter, there was no evidence of any loss in bone mass. Cancer patients showed insignificant reductions of 2-5% in BMD of LS, FN, and TK and a significant 5% reduction in BMD of EXT, compared to controls, and a 12% reduction in CaBI compared to goiter patients. Cancer patients had a slightly higher (p < 0.001) mean daily dose of T4 than goiter patients (0.23 vs 0.15 mg/day) but had a similar degree of TSH suppression. BMD and CaBI values did not correlate with free T4 index) with the daily T4 dose, accumulative dose, or with duration of T4 therapy. There were no significant changes in bone mass in either goiter or cancer patients restudied after a mean of 1.5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropin-suppressive doses of L-thyroxine.
abstract: Biondi, Fazio, and colleagues recently reported that long term T4 treatment to suppress serum TSH markedly affects cardiac function. T4-treated patients had more symptoms [12.2 +/- 3.9 (+/-SD) vs. 4.2 +/- 2.3 by quantitative questionnaire], higher mean heart rate, increased incidence of atrial extrasystoles, increased interventricular septal thickness and left ventricular mass index (LVMi), and significant diastolic dysfunction. The severity of cardiac abnormalities was highly correlated with scores of a rating scale used for assessing symptoms of thyrotoxicosis. We have duplicated their studies in 17 athyreotic patients (mean age, 45 +/- 10 yr; range, 27-63 yr) without heart disease or hypertension whose dose of T4 was titrated to suppress serum TSH to less than 0.01 microU/mL. The mean duration of T4 treatment was 9.2 +/- 5.4 yr. Controls were healthy volunteers matched for sex and age (+/-3 yr). The mean T4 dose was 2.8 +/- 0.9 micrograms/kg (0.192 +/- 0.058 mg/day). By questionnaire, patients had minimal symptoms, although their symptom score was significantly greater than the control value (4 +/- 3 vs. 2 +/- 1; P < 0.05; maximum score, 36). No differences in mean heart rate or in atrial or ventricular extrasystoles were noted. In patients, indexes of systolic and diastolic function and interventricular septal thickness were similar to control values. The mean LVMi was normal in both groups. However, the mean LVMi in patients (117 +/- 35 g/m2) was higher than that in controls (92 +/- 31; P < 0.05). In conclusion, patients were minimally affected by TSH-suppressive doses of T4. They had few symptoms and no increase in extrasystoles or basal heart rate. Based on current knowledge, the increase in LVMi observed in patients without associated significant systolic or diastolic abnormalities does not have clinical or prognostic importance. Therefore, in the absence of symptoms of thyrotoxicosis, patients treated with TSH-suppressive doses of L-T4 may be followed clinically without specific cardiac laboratory studies.

title: Is thyroid hormone suppression therapy prothrombotic?
abstract: The purpose of this study was to determine whether chronic thyroid hormone suppression therapy (THST) is prothrombotic. We obtained blood samples from 14 thyroid cancer patients while on THST and after they had become hypothyroid for radioiodine whole-body scanning and therapy. Prothrombin fragment 1 + 2, fibrinogen, factor VIII, antithrombin, tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor 1 (PAI-1), PAI-1/tPA, and C-reactive protein were significantly (P < 0.05) higher in the hyper- than in the hypothyroid state, whereas protein C and plasmin-antiplasmin complexes were significantly lower during the hyperthyroid period. When the 10 female patients were hyperthyroid, their levels of prothrombin fragment 1 + 2, fibrinogen, protein S, antithrombin, tPA, PAI-1, and PAI-1/tPA were significantly higher (P </= 0.05) than in healthy female controls, whereas when the female patients were hypothyroid, their antithrombin and plasmin-antiplasmin were lower and their protein S was higher than in controls. Factor II, plasminogen, and D-dimer were not significantly affected by the thyroid status in either assessment. In conclusion, we found evidence that the majority of patients treated with THST have a prothrombotic profile.

title: Chronic thyrotropin-suppressive therapy with levothyroxine and short-term overt hypothyroidism after thyroxine withdrawal are associated with undesirable cardiovascular effects in patients with differentiated thyroid carcinoma.
abstract: To evaluate cardiovascular functionality in patients with thyroid cancer, we have performed echocardiography and ambulatory blood pressure monitoring in 19 women with differentiated thyroid carcinoma during thyroxine withdrawal, at three time points: the last day on TSH-suppressive thyroxine doses (subclinical or mild hyperthyroidism), 4-7 days after withdrawal (normal free thyroxine (FT4) and free triiodothyronine (FT3) levels), and before 131I whole body scanning (overt hypothyroidism). Twenty-one healthy euthyroid women served as controls. When compared with the values at visit 2, when patients had normal serum FT4 and FT3 levels, night-time systolic and mean blood pressure were increased when the patients were mildly hyperthyroid, and night-time systolic, diastolic and mean blood pressure were increased during overt hypothyroidism. The proportion of nondippers (absence of nocturnal decline in blood pressure) was markedly increased compared with healthy controls (7%), when patients were hyper- or hypothyroid (58% and 50% respectively), but not when patients had normal FT4 and FT3 levels (12%). No changes were observed in office blood pressure or in daytime ambulatory blood pressure readings. Diastolic function worsened during thyroxine withdrawal (E and A waves (early and late mitral flow) decreased, and the E/A ratio and the isovolumic relaxation time increased), and cardiac output decreased in parallel with the decrease in heart rate and systolic blood flow. In conclusion, the chronic administration of TSH-suppressive doses of thyroxine and the withdrawal of thyroxine frequently used for the management of differentiated thyroid carcinoma, are associated with undesirable cardiovascular effects.

title: The effect of levothyroxine therapy on bone mineral density: a systematic review of the literature.
abstract: Currently debate still exists about the effects of thyroid hormone therapy on skeletal integrity, that is the safety of levothyroxine use with respect to bone mineral density.



A systematic review of the effects of TSH-suppressive and replacement levothyroxine therapy on bone mineral density evaluated main causes of conflicting results and its implications for clinical practice, and suggested directions of future research.



A MEDLINE search identified English-language studies assessing bone mineral density under levothyroxine therapy published from 1990 to 2001.



The studies were grouped by design and type of intervention. Outcomes were qualitatively analysed. Subgroup analysis assessed heterogeneity between studies.



Of 63 identified studies, 31 studies reported no effects of levothyroxine on bone mineral density, 23 studies showed partial beneficial or adverse, and 9 studies overall adverse effects. A significant dose-response was not found. There was a tendency towards peripheral cortical bone loss, suggesting a site-specific effect. In adolescents, men, and premenopausal women evidence for levothyroxine influence was weaker than in postmenopausal women. However, also findings in postmenopausal women remained unclear. The extent and etiology of underlying thyroid diseases also contributed to inconsistent results. Further, controversial results were due to substantial heterogeneity of studies. Above all, studies were limited by moderate quality, small size, and inadequate control for confounders.



Based on current studies there is insufficient evidence about effectiveness of levothyroxine on bone mineral density. All conclusions, however, must take into account the important methodical drawbacks. Present data may only be proved by longitudinal, high quality studies in homogeneous patients with sufficient sample size, clinical implication of future research remains questionable, though.

title: [Evaluation of effects of L-thyroxine therapy in differentiated thyroid carcinoma on the cardiovascular system --prospective study].
abstract: 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.

title: Long‐term results and prognostic factors in patients with differentiated thyroid carcinoma
abstract: A multivariate analysis of the prognostic factors was carried out on a series of 546 differentiated thyroid cancers followed for 8 to 40 years. For survival, the highest risk factor was associated with age; tumors diagnosed in patients younger than 45 years had higher relapse‐free survival (RFS) and total survival (TS) rates and a slower growth rate. In children, although the RFS and TS at 15 years were high, they decreased later. The second independent prognostic factor was histology. There was no difference between papillary and follicular well‐differentiated (FWD) tumors, but follicular moderately differentiated (FMD) had lower TS and RFS. Among FMD cancers, relapses occurred earlier and the interval between relapse and death was shorter. The third factor was sex. Tumors tended to disseminate more in male than in female patients. The survival rate after relapse was the same, however, suggesting that the growth rates are not different. The presence of palpable lymph nodes also had a significant independent impact on both TS and RFS. Patients treated after 1960 have a better outcome than patients treated earlier, although they did not differ in age distribution, histologic characteristics, sex ratio, or incidence of palpable lymph nodes. The distribution of time intervals between treatment and relapse was not compatible with an exponential failure time model but fit with a log‐logistic model. Relapses can occur as late as 30 years or more after initial treatment. Elevated levels of circulating thyroglobulin have been observed in about 12% of the patients who had been in complete remission for longer than 20 years.

title: Current Therapy for Childhood Thyroid Cancer: Optimal Surgery and the Legacy of King Pyrrhus
abstract: Follicular cell-derived thyroid cancer is far less common in children than adults and accounts for approximately 1% of all pediatric malignancies. Compared with adults, children and adolescents with differentiated papillary and follicular thyroid cancer are more likely to have advanced or multicentric disease and metastatic dissemination of cancer to regional lymph nodes and distant tissues at the time of initial diagnosis. Cancer recurrence is also more common in children with differentiated thyroid cancer (DTC) than in adults. On the other hand, despite the advanced stage of their cancers, children and adolescents with DTC have an excellent prognosis and enjoy very low mortality rates. This striking dissonance suggests that late diagnosis rather than aggressive behavior may account for the more extensive disease at presentation. Still, there may be fundamental differences in the biology of childhood and adult thyroid cancer that have potentially important clinical implications. For example, the juvenile thyroid gland exhibits enhanced sensitivity to radiation-induced genetic change and neoplasia, which could relate to the increased propensity to multicentric disease. Nikiforov et al.1 demonstrated that approximately 70% of pediatric papillary thyroid cancers contained RET/PTC oncogene rearrangements regardless of a history of radiation exposure. By contrast, only 20% of sporadic adult papillary cancers contain a RET/PTC  Regardless of patient age, management of DTC generally includes surgery, total thyroidectomy if the tumors are larger than 1.5 cm or metastases are detected, and resection of enlarged cervical lymph nodes. Surgery is generally followed by administration of radioactive iodine to eradicate any remaining normal and malignant thyroid tissue. After this initial ablative therapy, patients are treated with supraphysiological doses of L-thyroxine to suppress pituitary secretion of thyrotropin, a trophic hormone that can promote growth of thyroid cancer cells. Patients are subsequently monitored to detect any evidence of recurrence or progression of thyroid cancer, most commonly by whole body iodine-131 (I) scintigraphy and measurement of serum levels of thyroglobulin after administration of recombinant thyrotropin or after induction of hypothyroidism via withdrawal of L-thyroxine therapy. In selected patients additional tests might include ultrasound examination of the neck or magnetic resonance imaging, computed tomography, and positron emission tomography scans. Recurrent or persistent cancer is then treated with additional surgery, radioactive iodine, or external beam radiation, either alone or in combination. Do the available data support aggressive initial surgery in the management of childhood DTC? Are the benefits worth the risks of permanent hypothyroidism and laryngeal nerve dysfunction? Exchange scalpel for sword, and the exploits of Pyrrhus, the courageous if imprudent warrior king of the Hellenistic kingdom of Epirus, come to mind. In 281 BC, Pyrrhus assembled an army of 25,000 men and 20 elephants to march against Rome and establish a kingdom of Sicily and lower Italy. Although successful, his many battles were so costly that he was forced to withdraw from Italy, remarking, “Another such victory and I shall be ruined.” By analogy, clinicians must ask whether our surgical victories over thyroid cancer come at too great a morbidity. A conclusive answer is not yet available, and the impact of initial surgical therapy on outcome in patients with DTC continues to be a very controversial topic. Management of adult patients with DTC is based on the results of large, Received November 1, 2002; accepted November 8, 2002. From the Section of Endocrinology (MDR), Washington Hospital Center/MedStar Research Institute, Washington, DC; and the Division of Pediatric Endocrinology (MAL), Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to: Michael A. Levine, MD, Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, 211 Park Building, 600 N. Wolfe St., Baltimore, MD 21287; Fax: 410-955-9773; E-mail: mlevine@jhmi.edu.

title: A report of six cases of familial papillary thyroid cancer.
abstract: Familial occurrence of papillary thyroid cancer is uncommon. The purpose of this study was review our own experience in a series of 267 papillary thyroid cancers.



We analysed the clinical records of 267 consecutive patients operated on for papillary thyroid cancer (PTC) in our hospital between June 1980-March 2000.



We identified a family history in three families (6 patients), which results in a 2.25% familial papillary thyroid carcinoma (FPTC) rate. Pathology findings revealed that the tumour was multifocal and bilateral in 2 patients. Lymph-node metastases were found in 4 patients. They are all alive with a mean time of follow-up of 74.3 months (range 2-120).



We recommend that patients with familial disease should be treated according to the disease stage and other risk factors, similar to those with sporadic differentiated papillary thyroid cancer. We encourage the further reporting and pedigree analysis to identify patients affected by FPTC.

title: The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients.
abstract: This study analyzed the impact of prognostic variables of age, sex, histopathological diagnosis, extent of disease at diagnosis, and surgical intervention on well differentiated thyroid carcinoma and how surgical treatment, radioactive iodine, and radiotherapy influence the patients' outcomes. There have been 1599 patients with well differentiated thyroid cancer treated and followed at the University of Texas M.D. Anderson Cancer Center from 1948 to 1989. The median follow-up for all patients was 11.0 yr, with the maximum follow-up being 43 yr and the minimum follow-up being 1 yr. The patients were predominantly female (2.3:1), with papillary (81%) and intrathyroidal carcinomas (42%) at the time of diagnosis. Sixty-six percent of the patients had a total thyroidectomy, 7% received external radiotherapy, and 46% had radioactive iodine as part of the treatment of the original disease; the overall recurrence rate was 23%, and the death rate was 11%. This study showed that treatment with radioactive iodine was the single most powerful prognostic indicator for increased disease-free interval (P less than 0.001) and that its use significantly increased survival as well. No benefit was obtained from treatment with external radiotherapy. Children had the best overall survival, but of the adult patients, females who had intrathyroidal papillary disease treated with total thyroidectomy, who had been given radioactive iodine, and whose disease had been diagnosed between 20-59 yr of age had the best prognosis.

title: Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer
abstract: The aim of this study was to review the outcome of ablative radioiodine treatment on ovarian function in young women treated for differentiated thyroid carcinoma. Of 1398 patients with differentiated thyroid cancer, 496 were women under the age of 40 at the time of diagnosis who had received radioiodine therapy. Of these, 322 received a single 3 GBq ablation dose of radioiodine while the remainder received subsequent treatment with 131I with a cumulative activity of 8.5–59 GBq for residual, recurrent, or metastatic disease. Transient amenorrhoea or menstrual irregularities lasting up to 10 months were experienced in 83 patients (17%). No cases of permanent ovarian failure were recorded. There were 427 children born to 276 women; only one patient wishing to achieve a successful pregnancy outcome has been unsuccessful. Four premature births and 14 miscarriages occurred but no congenital abnormalities were reported. The risk of permanent damage to the ovaries after ablative radioiodine treatment appears to be low and patients can be reassured they can have normal pregnancies after this treatment.

title: The impact of clinical guidelines on surgical management in patients with thyroid cancer.
abstract: Thyroid cancer is an uncommon but highly curable disease if treated optimally. The aim of this study was to determine whether clinical guidelines introduced locally at the beginning of 1999 were associated with better surgical outcome, using radioiodine uptake as a surrogate measure of completeness of thyroidectomy.



We reviewed the medical records of all patients with thyroid cancer referred to a cancer centre (n=176) 3 years before and 3 years after the introduction of guidelines. The uptake of radioiodine in the thyroid bed after thyroidectomy and before radioiodine ablation was used to assess the completeness of primary surgical treatment.



The number of new cases referred to our centre increased from 80 in the 1996-1998 period to 94 during 1999-2001. This was largely because of an excess of papillary thyroid cancers. Documentation in the medical records of the pathological primary tumour size improved from 47.5% to 80.8% following the introduction of guidelines. A significant reduction in radioiodine uptake in the thyroid bed was observed following the introduction of guidelines (5.03% +/- 6.82 (SD) vs 2.75% +/- 5.10 (SD); P=0.005). Linear regression analysis of clinical variables indicated that the year of surgery was the only significant factor influencing radioiodine uptake in the thyroid bed (P=0.014). Twelve hospitals within the Northern Cancer Network carried out thyroid surgery for thyroid cancer in the pre-guideline era compared with seven hospitals in the post-guideline era. Surgeons who were members of the regional multidisciplinary thyroid cancer team operated on 35% of cases in the 1996-1998 period and 56.4% in the 1999-2001 period (P<0.01).



The introduction of clinical guidelines in 1999 was associated with a reduction in the size of thyroid remnant after primary surgical treatment. This was accompanied by fewer hospitals undertaking thyroid surgery and more patients being operated on by surgeons who were members of the thyroid cancer multidisciplinary team.

title: Surgical therapy of the thyroid papillary carcinoma in children: experience with 56 patients < or =16 years old.
abstract: This article is an anatomic, clinical, therapeutic, and prognostic assessment of 56 children 16 years of age or younger, who underwent a surgical operation for thyroid papillary carcinoma from April 1988 to December 2001 in the Department of General Surgery at the University of Pisa. Of these 56 patients, 22 are Belarus children (39%) in whom carcinoma developed after the nuclear accident in Chernobyl in April 1986, whereas 34 (61%) are children with differentiated nonirradiated tumors. The purpose of this work was to compare the group of children who had radiation-induced thyroid carcinoma with the group affected by non-radiation-induced carcinoma to evaluate if there are significant clinical, anatomic, and prognostic differences between them and to identify the best surgical strategy to adopt.



At the time of clinical presentation, the tumor was limited to the thyroid gland in 28 cases (50%), whereas in the others, in 24 cases (43%) metastases in the neck lymph nodes were present or had infiltrated the extrathyroid tissues as was seen in 4 cases (7%). The surgical operation was a total thyroidectomy in 37 cases (66%), whereas in 19 patients with radiation-induced carcinoma it was a hemithyroidectomy followed by a completion of thyroidectomy in Pisa (34%). The histologic examination showed multifocal sites of papillary adenocarcinoma in the gland in 23% of cases, and both lobes of the thyroid gland were involved with tumor in 23% of patients. The postsurgical follow-up showed a mortality rate of 0% and a recurrence rate of 33.5% (64% radiation-induced carcinoma v 3% non-radiation-induced carcinoma; P < .0001). At the moment, 8 of 22 cases (36%) with radiation-induced carcinoma are free of disease versus 33 of 34 (97%) with non-radiation-induced carcinoma (P < .0001).



These findings show carcinoma of the thyroid in children has a low risk of mortality but a high risk of recurrence. Children with radiation-induced thyroid carcinoma are more likely to have a recurrence of the disease. Total thyroidectomy for the treatment of both radiation-induced and non-radiation-induced carcinomas appears to represent, on the basis of these results, the best therapeutic option.

title: Papillary thyroid cancer with pulmonary metastases beginning in childhood: clinical course over three decades.
abstract: We present a case of childhood papillary thyroid cancer with persistent but stable pulmonary metastases for over three decades in order to highlight the natural history and clinical features of this unusual disease entity. A nine-year-old girl had thyroidectomy and cervical lymph node dissection followed by neck irradiation for invasive papillary thyroid cancer. Diffuse pulmonary metastases were present at the time of diagnosis and were treated with radioactive iodine 10 and 30 years later; both the chest radiographs and the patient remained stable throughout. This case illustrates the potential indolence of thyroid cancer when it presents during childhood.

title: Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis.
abstract: Papillary thyroid cancer (PTC) in young patients may rarely be encountered with pulmonary metastases. Previous studies have suggested that, in the pediatric population, this may not portend a lethal outcome. Our present study, children with pulmonary metastases, was designed to clarify this issue.



Fourteen children and young adolescents (mean age, 13.5 years; range, 9.8-17 years) with PTC and pulmonary metastases were treated at our institution between 1937 and 1998. Surgical treatment consisted of total thyroidectomy (n = 10 patients), subtotal thyroidectomy (n = 3 patients), and a biopsy only procedure (n = 1 patient). All patients who underwent thyroidectomy also underwent a variety of cervical lymph node dissections, and all patients proved to have regional nodal disease. After the operation, 12 patients were treated with ablative doses of (131)I, 1 patient was treated with external beam irradiation, and all patients were placed on suppressive thyroid hormone therapy. The mean length of follow-up was 19.3 years (range, 1-45 years).



Regional recurrent disease developed in 2 patients (15%). No patient experienced the development of worsening pulmonary disease or extra-pulmonary metastases. All patients with recurrent disease underwent selective nodal resections. No patient died of metastatic PTC. Seven patients (50%) remain completely free of disease and are probably cured; 7 patients (50%) are asymptomatic with residual pulmonary disease.



A stepwise treatment approach allows long-term survival and frequent cure for young patients with PTC and concomitant pulmonary metastases.

title: Current Strategies for Surgical Management and Adjuvant Treatment of Childhood Papillary Thyroid Carcinoma
abstract: Childhood papillary thyroid carcinoma is associated with more locally aggressive and more frequent distant disease than its adult counterpart. Recurrence rates tend to be higher in children, but cause-specific mortality remains low. Optimal initial treatment of childhood papillary thyroid carcinoma should include total or near-total thyroidectomy and central compartment node clearance. Modified neck dissections should be performed for biopsy-proven lateral neck disease. Every effort should be made to maintain parathyroid and laryngeal nerve function. Radical neck dissections are to be avoided. Radioiodine remnant ablation (RRA), appropriate thyroid hormone suppressive therapy (THST), and judicious use of therapeutic doses of 131I are applied to achieve a disease-free status, which is most often confirmed by negative neck ultrasonography, negative whole-body scan (either withdrawal or recombinant human thyroid-stimulating hormone-stimulated), and extremely low levels of serum thyroglobulin. Appropriate utilization of 131I, THST, repeat surgery, external beam radiotherapy, and rarely chemotherapy may provide long-term palliation and some cures in patients with recurrent/persistent disease. Follow-up should be lifelong, and the care of children after age 17 should subsequently be transferred to adult-care endocrinologists with expertise in managing thyroid neoplasia. Optimal surgical management can be achieved if adequate operations are routinely carried out by “high-volume” thyroid surgeons with expertise in the care of children. Nowhere is a multidisciplinary approach (endocrinologists, surgeons, nuclear medicine physicians, pediatricians, pathologists, oncologists) more critical than in the long-term management of papillary thyroid carcinoma that presents during childhood.

title: Tumor Size and Extent of Disease at Diagnosis Predict the Response to Initial Therapy for Papillary Thyroid Carcinoma in Children and Adolescents
abstract: Treatment of papillary thyroid carcinoma (PTC) in children and adolescents is controversial. We previously showed that large tumor size, multifocal disease, and extensive disease at diagnosis predict recurrence. We examined 47 patients with PTC to determine whether these features predict response to treatment. Overall, 70% of the patients (33/47) remitted with initial treatment. 79% (15/19), of Class I, 86% (12/14) of Class II, and 100% (6/6) of Class III, but none of Class IV patients (n = 8) (p < 0.001) achieved remission. Tumor size for patients who entered remission (2.0 +/- 0.2 cm) was less than for patients with persistent disease (4.2 +/- 0.4) (p < 0.0005). Extent of disease at diagnosis correlated with the number of radioactive iodine (RAI) treatments (p = 0.022) and dose (p = 0.002) required to achieve first remission. We conclude that extensive disease at diagnosis and larger tumor size predict failure to remit after initial treatment of PTC in children and adolescents.

title: AMES, MACIS and TNM prognostic classifications in papillary thyroid carcinoma.
abstract: The need for total thyroidectomy and extended for lymphadenectomy and the need for postoperative radioiodine ablation in the treatment of papillary thyroid carcinoma is continuously debated. Since less aggressive treatment in low-risk patients has been suggested, several scoring systems have been developed to identify low-risk patients. In the current study, we compared the AMES, MACIS and TNM staging systems in predicting carcinoma-specific mortality in papillary thyroid carcinoma. Between 1967 and 1994, 495 patients with papillary thyroid carcinoma were treated at the Department of Surgery, Helsinki University Central Hospital. Carcinoma-specific mortality in the AMES low-risk group, comprising 89.7% of these patients, was 2.4%. Corresponding figures for the MACIS were 89.9%, and 2.4%, and for the TNM 85.9% and 1.2%. The mortality ratio, at 10 years, between low-risk and high-risk patients was 22.2 for the AMES, 25.0 for the MACIS and 41.8 for the TNM system. The proportion of explained variance in the Cox model was 16.3 for the AMES, 30.0 for the MACIS taken as a conitinuous variable and 28.9 for the TNM stage. The TNM stage was on average superior to the MACIS or AMES score in predicting cancer-specific mortality of patients with papillary thyroid carcinoma. This may be explained by the fact that the TNM system includes the prognostic effect of nodal metastases, which is included in neither the MACIS nor AMES systems.

title: Clinical review 170: A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer.
abstract: Radioactive iodine remnant ablation destroys residual thyroid tissue after surgical resection of papillary or follicular thyroid cancer. We systematically reviewed 1543 English references to determine whether remnant ablation decreases the risk of thyroid cancer-related death or recurrence after bilateral thyroidectomy for papillary or follicular thyroid cancer. In 13 cohort studies in which the analysis of thyroid cancer-related outcomes was statistically adjusted to a variable degree for prognostic factors or cointerventions, rates of recurrences of thyroid cancer-related outcomes were significantly decreased in the following: one of seven studies examining thyroid cancer-related mortality, three of six studies examining any tumor recurrence, three of three studies examining locoregional recurrence, and two of three studies examining distant metastases. Thyroid hormone suppressive therapy was not adjusted for in the majority of these analyses. In 18 cohort studies not adjusted for prognostic factors or interventions, the benefit of radioactive iodine ablation in decreasing the thyroid cancer-related mortality and any recurrence at 10 yr was inconsistent among centers. However, pooled analyses were suggestive of a statistically significant treatment effect of ablation for the following 10-yr outcomes: locoregional recurrence (relative risk of 0.31, 95% confidence interval, 0.2, 0.49) and distant metastases (absolute decrease in risk 3%, 95% confidence interval, risk decreases 1-4%). In conclusion, radioactive iodine ablation may be beneficial in decreasing recurrence of well-differentiated thyroid cancer; however, results are inconsistent among centers for some outcomes, and the incremental benefit of remnant ablation in low-risk patients treated with bilateral thyroidectomy and thyroid hormone suppressive therapy is unclear.

title: Functioning pulmonary metastases of thyroid cancer: does radioiodine influence the prognosis?
abstract: Functioning pulmonary metastases are the most common distant lesions of differentiated thyroid cancer. About 50% of patients with such metastases die within 10 years. The impact of iodine-131 therapy is controversial. In this study we examined: (1) the early diagnostic value of post-surgery 131I ablation for lung invasion and (2) the survival of patients receiving periodic 131I therapy. Between January 1970 and December 1995 we provided initial treatment for 509 patients with thyroid cancer. Most of them (74%) underwent total thyroidectomy and 131I ablation. Functioning pulmonary metastases occurred in 20 patients. All these patients received periodic 131I therapy for as long as 131I uptake persisted. Additional therapy consisted of lung surgery in three patients and local treatment of bone lesions in four patients. Follow-up data were recorded up to December 2001. Functioning pulmonary metastases occurred late in one patient, and were visible on the post-surgery 131I therapy scan in the other 19 patients. At diagnosis of lung invasion, 11 patients had negative chest X-ray findings, and serum thyroglobulin levels were not suggestive of metastatic disease in 56% of these cases. One of the 11 patients with negative chest X-ray findings died with a neck recurrence, two have persistent pulmonary 131I uptake, and the other eight are in apparent remission after receiving an average cumulative 131I activity of 338 mCi (12.51 GBq). The nine patients with positive chest X-ray findings received an average of 939 mCi (34.74 GBq); two of them died, five are continuing to receive therapy and two are in apparent remission. Overall survival at 10 years is 84%. The average follow-up of the 17 survivors is 12.7 years. These results suggest that patients with functioning pulmonary metastases, even in advanced stages, may survive for many years on 131I therapy. Early diagnosis, during post-surgery 131I scanning, of radiologically inapparent metastases is associated with a better prognosis.

title: Dosimetrically determined doses of radioiodine for the treatment of metastatic thyroid carcinoma.
abstract: In the absence of definitive studies relating radioiodine dose to outcomes, selection of a dose of radioiodine to treat metastatic thyroid carcinoma is problematic, and several approaches have been used. These include empiric fixed doses and doses used on dosimetric approaches specific for each patient. This paper is a review of the rationale and technique for dosimetrically-determined doses of radioiodine for the treatment of metastatic thyroid carcinoma. This review (1) discusses the alternatives for selection of a dose, (2) discusses the two major approaches for determining radioiodine doses dosimetrically, (3) briefly reviews several modifications of these approaches, (4) reviews the literature regarding the results, (5) discusses the side effects of these different approaches, and (6) concludes with recommendations for patient management and future research. This review does not address use of dosimetrically-determined doses of radioiodine for the initial ablation of thyroid tissue postoperatively.

title: 131‐I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma
abstract: Pulmonary metastases from papillary thyroid carcinoma shorten the survival of the hosts. Treatments with 131‐I have been reported to induce disappearance of these tumors in a large proportion of afflicted patients. In this study, consecutive patients with diffuse micronodular lung metastases from papillary thyroid carcinoma were examined to determine if disappearance of tumor occurred, and how much disappeared, after substantial amounts of 131‐I were administered.

title: Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables.
abstract: We studied 134 patients with differentiated thyroid cancer and pulmonary metastases. All were treated with total or near total thyroidectomy, radioiodine and L-thyroxine. The prognostic value of the following variables in three groups of patients were evaluated by univariate and multivariate analysis: age at diagnosis, sex, histologic type, tumor extension, cervical lymph node metastases, mediastinic metastases, presence of metastases in distant sites other than lungs (multiple distant metastases) and morphological (chest x-rays) and functional (131I uptake) features of lung metastases. Univariate analysis identified patient age (p < 0.0001), morphological and functional features of lung metastases (p < 0.0001), presence of multiple distant metastases (p < 0.0001) and histologic type (p = 0.04) as significant prognostic factors. Multivariate analysis showed only morphological (p = 0.0014) and functional (p < 0.0001) features of lung metastases and the presence of multiple distant metastases (p = 0.01) as significant and independent variables. The data show that early (pre-radiological) scintigraphic diagnosis and 131I therapy of lung metastases appear to be the most important elements in obtaining both a significant improvement in survival rate and a prolonged disease-free time interval in these patients.

title: Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine
abstract: From 1969 to 1990 there were 309 patients with differentiated thyroid carcinoma (241 papillary and 68 follicular) treated with radioactive iodine for functioning node metastases alone (n=191) or distant metastases (n=118) with or without node metastases. These patients represented 32.7% of 945 patients treated in our institution during the same period. Initial treatment included near-total thyroidectomy and 131I ablation of postsurgical thyroid residue, followed by L-thyroxine suppressive therapy. At the end of follow-up (mean 5.8 years), 146 patients (76.4%) in the group with nodal metastases were considered cured, as assessed by clinical and laboratory evaluation including whole body scan (WBS) and serum thyroglobulin (Tg) levels; 32 patients (16.7%) had persistent disease. Loss of 131I uptake in persistent metastatic lesions occurred in five patients (2.6%), and newly developed distant metastases occurred in eight patients (4.2%). Of the patients with distant metastases, 36.4% were cured by 131I. Distant metastases from papillary carcinomas had a higher cure rate than follicular carcinomas (p<0.01). The metastases of four patients (5.2%) lost the property to take up radioiodine. Lung and bone metastases detectable by WBS but not by radiography were most likely to be cured by 131I. The overall survival at the end of follow-up was 95.8% in patients with only lymph node metastases and 76.0% in those with distant metastases. Tumor-related deaths were 3.6% and 23.7%, respectively. Our data indicate that 131I therapy is highly effective in the treatment of lymph node metastases from differentiated thyroid carcinoma. To a variable extent, distant metastases may also benefit from radioiodine therapy, definitive cure being much more likely during the early phase of metastatic involvement.RésuméEntre 1969 et 1990, 309 patients ayant un cancer différencié de la thyroïde (241 cancers papillaires et 68 cancers folliculaires) ont été traités par l'iode radioactif pour stériliser des métastases ganglionnaires (n=191) ou des métastases à distance (n=118) avec ou sans métastases ganglionnaires fixant l'iode. Ces patients représentaient 32.6% des 945 patients traités dans notre institution pendant la même période. Le traitement initial était une thyroïdectomie presque totale et l'administration d'iode 131 en postopératoire, suivie enfin d'une opothérapie suppressive par la l-tyroxine. A la fin du suivi (moyen = 5.8 ans), 146 patients (76.4%) du groupe ayant des métastases ganglionnaires ont été considérés comme guéris, d'après la clinique et l'évaluation paraclinique comprenant une scintigraphie du corps entier (SCE) et un dosage de la thyroglobuline alors que 32 patients (16.7%) avaient encore du tissu cancéreux. Cinq patients (2.6%) avaient des localisations métastatiques qui ont cessé de fixer l'iode et 8 patients (4.2%) ont développé de nouvelles métastases à distance. Parmi les patients ayant des métastases à distance, 36.4% ont été stérilisés par l'iode 131. Le taux de stérilisation des métastases à distance à partir des cancers papillaires était plus élevé que celui des métastases des cancers folliculaires (p<0.01). La fixation des métastases a cessé chez quatre patients (5%). Les métastases pulmonaires et osseuses détectables par la SCE, mais pas par radiographie, sont plus susceptibles d'être stérilisées par l'iode 131. La survie globale à la fin du suivi était de 95.8% chez les patients n'ayant que des métastases ganglionnaires et de 76.0% chez ceux ayant des métastases à distance. La mortalité en rapport avec le cancer était respectivement de 3.6% et de 23.7%. Nos résultats indiquent que l'iode 131 est très efficace dans le traitement des métastases ganglionnaires des cancers différenciés de la thyroïde. Avec une efficacité variable, les métastases peuvent également être traitées par l'iode 131, la guérison définitive étant beaucoup plus probable en début de période métastatique.ResumenEntre 1969 y 1990, 309 pacientes con carcinoma diferenciado de la tiroides (241 papilares y 68 foliculares) fueron tratados con yodo radioactivo por metástasis ganglionares funcionantes solas (n=191) o metástasis distantes (n=118) con o sin metástasis ganglionares. Estos pacientes representaban el 32.6% de 945 que fueron tratados en nuestra institución durante el mismo período. El tratamiento inicial incluyó tiroidectomía casi total y ablación con 131-I del tejido tiroideo residual postquirúrgico, seguida de terapia de supresión con l-tiroxina.Al final del período de seguimiento (promedio 5.8 años), 146 pacientes (76.4%) en el grupo con metástasis ganglionares fueron considerados como curados, a juzgar por evaluación clínica y de laboratorio que incluyó escanografía de cuerpo entero (ECE) y niveles séricos de tiroglobulina (Tg), en tanto que 32 pacientes, (16.7%) presentaban enfermedad persistente. Se observó pérdida de la captación del 131-I en lesiones metastásicas persistentes en 5 casos (2.6%) y la aparición de nuevas metástasis distantes en 8 (4.2%). De los pacientes con metástasis distantes, 36.4% fueron curados con 131-I. Las metástasis distantes de los carcinomas papilares exhibieron una mayor tasa de curación que las de los carcinomas foliculares (p <0.01). Las metástasis de 4 pacientes (5.2%) perdieron la propiedad de captar yodo radioactivo. Las metástasis pulmonares y óseas detectables por ECE pero no por rayos X aparecieron como las de más probable curación con 131-I.La tasa de sobrevida global al final del período de seguimiento fue de 95.8% en los pacientes con sólo metástasis ganglionares y de 76.0% en aquellos con metástasis distantes. Las tasas de mortalidad relacionadas con el tumor fueron de 3.6% y 23.7% respectivamente.Nuestros datos indican que la terapia con 131-I es altamente efectiva en el tratamiento de las metástasis ganglionares del carcinoma diferenciado de la tiroides. Hasta cierto punto las metástasis distantes también pueden beneficiarse con la terapia con yodo radioactivo, siendo la probabilidad de curación definitiva mucho más alta en la fase precoz de la afección metastásica.

title: 131I therapy for elevated thyroglobulin levels.
abstract: Assuming that the fractional uptake is the same, both after the administration of a diagnostic and a therapeutic activity, 131I uptake too low to be detected with 2-5 mCi may become detectable after the administration of 100 mCi. This should be performed routinely in patients with thyroglobulin levels above approximately 5 ng/mL during L-Thyroxine (LT4) treatment or 10 ng/mL off LT4 treatment for three main reasons: 1) in 80% of these patients, a post-therapy 131i total body scan showed foci of uptake in the neck or at distant sites, whereas in the other patients, metastases emerged clinically some years later; 2) 131I is not the only treatment modality, and, for instance, lymph node metastases may warrant further surgery; and 3) from a dosimetric point of view, the relevant parameter is the concentration of 131I, i.e., the ratio between the uptake and the mass of functioning tissue: a low uptake in a small metastasis may result in a higher 131I concentration than a higher uptake in a much larger metastasis.

title: Surgical Experience in Children With Differentiated Thyroid Carcinoma
abstract: The optimal surgical treatment in children with well-differentiated thyroid carcinoma remains an important point of discussion. In this study, we evaluated our surgical experience and reviewed the literature accordingly to identify the most adequate treatment.
 Methods: We retrospectively analyzed 21 children, all under the age of 18 years at the time of diagnosis, with differentiated thyroid carcinoma (17 papillary, 3 follicular, and 1 Hürthle cell carcinoma). Total thyroidectomy was performed, followed by radioiodine therapy, as a part of the initial treatment in all patients. The results were compared with data from the literature.
  Eleven children (52%) who presented with cervical lymph node metastases were treated by a modified radical neck dissection. Pulmonary metastases were seen at diagnosis in three patients. Six patients developed temporary complications. During follow-up, with a median of 11 years (range, 2–26 years), two patients (10%) developed recurrences, and no patient died during this observation period. A literature search confirmed our experience of excellent results without an increase of complications in the more aggressively treated patients.
  In children with differentiated thyroid cancer, treatment should consist of total thyroidectomy, followed by a modified radical neck dissection (when indicated) and iodine-131 ablation treatment. This aggressive approach seems to be justified because of the high incidence of nodal involvement and the low complication and recurrence rate after surgery.

title: 131I treatment of 131I negative whole body scan, and positive thyroglobulin in differentiated thyroid carcinoma: what is being treated?
abstract: Several aspects of the management of differentiated thyroid cancer cause considerable controversy. Among these is the role of 131I therapy in patients after thyroidectomy. There is no controlled study to demonstrate whether this treatment reduces the recurrence rate or improves mortality. Because of the overall excellent prognosis, it is unlikely that a controlled study will ever be conducted. Most frequently, patients have a diagnostic scan with 131I to determine whether radioiodine would be an appropriate therapy and to judge much to be prescribed, based on the extent of abnormalities seen on the scintiscan. Serum thyroglobulin (Tg) has been found to be a valuable tumor marker, with very good sensitivity and specificity. In most patients, the result of whole-body 131I scintiscan and Tg measurement give concordant results. However, in some patients, Tg is measurable, but the diagnostic scan with 131 is normal. There has been data published about treatment of these patients with therapeutic doses of 131I. The author questions whether this treatment is appropriate, prompted by seeing and hearing of patients who were treated with therapeutic doses of 131I, but had no abnormal uptake of the therapeutic doses and who had no improvement in serum Tg level. These patients have no clinical evidence of disease, and the only abnormality is measurable Tg. Since large doses of radioiodine are not without problems, a controlled clinical trial should be developed to evaluate efficacy in this situation.

title: Effects of therapeutic doses of 131I in thyroid papillary carcinoma patients with elevated thyroglobulin level and negative 131I whole‐body scan: comparative study
abstract: Previous studies have shown a high rate of visualization of uptake and a decrease in serum thyroglobulin (Tg) after therapeutic doses of 131I in well‐differentiated thyroid cancer patients with elevated thyroglobulinaemia but negative diagnostic 131I whole‐body scan (DxWBS), but its therapeutic effect remains controversial. We evaluate the effect of therapeutic doses of 131I in patients with elevated thyroglobulin level but negative DxWBS.

title: Anaplastic changes associated with p53 gene mutation in differentiated thyroid carcinoma after insufficient radioactive iodine (131I) therapy.
abstract: Thirty-two patients with differentiated thyroid carcinomas with distant metastasis were examined using a radioactive iodine (131I) tracer dose prior to 131I therapy and followed up for 10 years or until death (whichever occurred first). Nineteen patients who received 131I therapy had an accumulation of 131I in the metastases (group I) and 15 of those patients were alive more than 10 years after the first 131I treatment. In contrast, all 13 patients in whom the metastases did not show accumulation of 131I died within 10 years. Of the latter group, eight patients had received 131I therapy (group II), four of whom died with anaplastic changes within 5 years of treatment. p53 gene mutation was identified by immunohistochemistry in primary thyroid carcinoma tissue from patients with anaplastic changes that were evident during total thyroidectomy. Five patients did not receive 131I therapy (group III), of whom one, who also had a p53 gene mutation in the original tumor, died with anaplastic change 10 years after thyroidectomy. Seven patients in group I had p53 gene mutations in their thyroid carcinoma tissues, but none showed anaplastic changes. Our results suggest that 131I therapy may be useful for patients with distant metastases, with or without p53 gene mutations, which show accumulation of 131I from tracer and therapeutic doses. In contrast, 131I therapy is apparently not effective in patients who do not show sufficient accumulation of 131I, but rather, may cause early anaplastic changes with a p53 gene mutation.

title: Does radioiodine therapy have disadvantageous effects in non‐iodine accumulating differentiated thyroid carcinoma?
abstract: Although radioiodine therapy in differentiated thyroid carcinoma without radioiodine accumulation has not been considered harmful, increased thyrotrophin levels during thyroxine withdrawal without the benefit of radiotoxicity as well as the selection of de‐differentiated cells may have disadvantageous effects on tumour course.

title: Recombinant human TSH-aided radioiodine treatment of advanced differentiated thyroid carcinoma: a single-centre study of 54 patients
abstract: We sought to evaluate the efficacy, biochemical effects, safety and outcome of recombinant human thyroid-stimulating hormone (rhTSH) as an adjunct to radioiodine treatment of advanced differentiated thyroid carcinoma (DTC). We also sought to determine whether rhTSH is useful as an adjunct to radioiodine treatment following isotretinoin re-differentiation therapy of DTC metastases that have lost function. Therefore, in 54 consecutive patients who had retained bulky metastatic and/or locoregional lesions of DTC despite the exhaustion of other therapeutic options, we gave one to four courses of two consecutive daily intramuscular injections of rhTSH, 0.9 mg, followed by a therapeutic activity of 131I per os on day 3. Fifty patients had received prior radioiodine treatment aided by l-thyroxine (T4) withdrawal. We included in the study 23 patients who had received a trial of isotretinoin therapy for re-differentiation of confirmed de-differentiated metastases. In a blinded, within-patient comparison of post-therapy whole-body scans after the first rhTSH-aided and latest withdrawal-aided treatments in patients with functional metastases at baseline, 18 of 27 (67%) scan pairs were concordant, four (15%) were discordant in favour of the rhTSH-aided scan and five (19%) were discordant in favour of the withdrawal-aided scan. In total, 37 (74%) of 50 paired scans were concordant, eight (16%) favoured rhTSH and five (10%) favoured withdrawal. All differences appeared to be attributable to clinical causes, not to any difference between endogenous and exogenous TSH stimulation. Reflecting the biochemical activity of rhTSH and the release of thyroglobulin (Tg) due to tumour destruction, median serum Tg concentration rose approximately fourfold between baseline and day 6 of the rhTSH-aided treatment course. rhTSH was well tolerated, with mostly minor, transient toxicity, except for neck oedema in three patients with neck infiltrates and pathological spine fracture in one patient with a large vertebral metastasis. At 6 months, complete response occurred in one (2%), partial response in 12 (26%) and disease stabilisation in 19 (40%) of 47 evaluable patients. The rate of complete + partial response was 41% and that of disease stabilisation, 30%, in the 27 evaluable patients with functional metastases at baseline; the corresponding rates were 10% and 55% in the 20 evaluable patients with non-functional metastases at baseline. Although within-patient comparison of early outcome after both modalities is limited by a significantly greater median number of courses and a greater median cumulative activity of radioiodine given under withdrawal, response to rhTSH-aided and withdrawal-aided treatment was similar in 23 (52%) of 44 evaluable patients, superior with rhTSH in 12 (27%) and superior with withdrawal in seven (16%). In two patients, a superior response was obtained after isotretinoin pretreatment and rhTSH and attributed to re-differentiation therapy. In conclusion, our study provides preliminary evidence that rhTSH safely and effectively aids radioiodine treatment of advanced DTC, and does so to an at least equivalent degree as does T4 withdrawal.

title: rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review.
abstract: Traditionally, withdrawal of thyroid hormone has been used to attain the increase in serum TSH concentrations that are believed to optimize the trapping and retention of radioiodine for diagnostic procedures, thyroid remnant ablation and treatment of patients with differentiated thyroid cancer (DTC). However, withdrawal frequently causes clinical hypothyroidism, with resultant cognitive impairment, emotional dysfunction, physical discomfort, health risks in patients who are elderly, frail or have concomitant illness, and impaired quality of life and ability to work. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and the associated morbidity. rhTSH has been approved as an adjunct for diagnostic procedures in patients with DTC, but is currently an experimental aid in thyroid remnant ablation and the treatment of thyroid tumours. In the period 1997-2004, nearly 30 medical centres worldwide have reported on almost 400 patients with DTC who were given rhTSH in preparation for radioiodine ablation of thyroid remnants or treatment of local tumours of metastatic disease. We have analysed and summarized the findings reported in this literature. Ablation aided by the standard course of rhTSH, two consecutive daily injections of 0.9 mg, had success rates better than 84% in 90 patients given radioiodine activities in excess of 4000 MBq. However, when 1110 MBq was administered, success rates were 81.2% in 16 patients given the standard course of rhTSH and 4-day withdrawal of thyroid hormone around the time of radioiodine administration in one study, but 54% in 70 patients in another study. rhTSH-aided treatment of persistent or recurrent local or metastatic cancer, or both, with from one to six courses of radioiodine 1000-19055 MBq, achieved 2% complete remission, 36% partial response and 27% disease stabilization rates, for a 65% clinical benefit rate, in 115 primarily elderly, late-stage patients for whom responses were reported. Twelve of these patients died as a result of progressive disease or were discharged from hospital into hospice care. Generally, rhTSH was very well tolerated. However, in a minority of patients with central nervous system, spinal or bone metastases, or bulky thyroid remnant or neck lesions with or without poor pulmonary reserve, administration of rhTSH, like thyroid hormone withdrawal, was found to stimulate expansion of the tumour, with ensuing compression of key anatomical structures and neurological, respiratory or other clinical complications. The rapid onset, response to glucocorticoids and radiological findings of peritumoural oedema or, less commonly, haemorrhage in the published cases, strongly suggest that the tumour expansion was the result of swelling rather than growth. As in the case of thyroid hormone withdrawal, special attention and glucocorticoid premedication are thus warranted when rhTSH is given to patients known or suspected to have the above characteristics. Dosimetric data suggest that whole-body and whole-blood radioiodine clearance may be faster in euthyroid patients after administration of rhTSH. In theory, the faster clearance could allow, or demand, increased radioiodine activities when rhTSH is used, but clinical data to date suggest that this may be unnecessary. The faster clearance also might result in safety or convenience benefits with the use of rhTSH, such as decreased exposure of extrathyroid areas to radiation, and shorter hospital stays. In conclusion, in preliminary results from open-label studies, both rhTSH-aided tumour ablation and treatment have been well tolerated and have shown efficacy in substantial proportions of patients. rhTSH-aided ablation merits further study. rhTSH-aided treatment may be preferred in patients who are at greater risk of hypothyroid complications from withdrawal of thyroid hormone or are unable to produce sufficient endogenous TSH, and warrants additional investigation in younger patients at earlier stages of thyroid cancer.

title: Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma
abstract: Iodine kinetics were studied in patients with differentiated thyroid cancer while euthyroid under exogenous thyroid stimulating hormone (TSH) and while hypothyroid to detect differences in radioiodine uptake, distribution and elimination. Nine patients with total or near-total thyroidectomy on thyroid hormone suppressive therapy received two or three daily doses of 0.9 mg recombinant human TSH (rhTSH) followed by administration of a diagnostic activity of 2 mCi (74 MBq) iodine-131. After the biokinetics assessments had been performed, patients stopped taking thyroid hormones to become hypothyroid. A second 2 mCi (74 MBq) diagnostic activity of 131I was administered, followed by a second set of biokinetics assessments. One week later the patients underwent remnant ablation with a therapeutic activity of 131I. A comparison of the 131I kinetics in the patients while euthyroid and while hypothyroid showed major differences in the doses to the remnant as well as in residence times and radiation exposure to the blood. In the first diagnostic assessment the remnant dose was higher in eight of the nine patients and clearance of the activity from the blood was faster in all of them. The data from this study suggest that radioiodine administration is potent and safe when administered to euthyroid patients following rhTSH administration. Enhanced residence time in the remnant and decreased radiation exposure to the blood were noted when patients were euthyroid compared to when they were rendered hypothyroid. However, all patients received diagnostic activities in the same order: first while euthyroid, followed by hypothyroidism. It is quite possible that "stunning" from the radioiodine administered in the initial uptake study inhibited the subsequent uptake of radioiodine by the remnant lesions in the second uptake study.

title: Influence of body surface area on serum peak thyrotropin (TSH) levels after recombinant human TSH administration.
abstract: Recombinant human TSH (rhTSH) has been proposed as an alternative method to the withdrawal of thyroid hormones in the follow-up of differentiated thyroid cancer. The aim of the present study was to evaluate the influence of several demographic and anthropometric parameters [age, body weight, height, body mass index, and body surface area (BSA)] on serum peak TSH levels after rhTSH administration. rhTSH was administered to 112 patients with differentiated thyroid carcinoma according to the conventional two-dose schedule (0.9 mg/d). Serum TSH levels were measured 24 h before and after the first administration of rhTSH, and then 24, 48, and 72 h after the second administration of rhTSH. In one severely obese patient, serum peak TSH values did not reach a valid stimulation range. Serum peak TSH levels were negatively related to body weight (r = -0.69; P < 0.0001), body mass index (r = -0.51; P < 0.0001), and BSA (r = -0.72; P < 0.0001). In a multivariate regression analysis including demographic and anthropometric variables, only BSA was independently associated to serum peak TSH concentrations (standardized beta coefficient = -0.721; P < 0.0001). In conclusion, body size seems to influence serum peak TSH levels after rhTSH administration. Future studies should evaluate the possibility of using personalized rhTSH doses, adjusted in relation to BSA.

title: Hemiplegia after thyrotropin alfa in a hypothyroid patient with thyroid carcinoma metastatic to the brain.
abstract: E radioiodine treatment of thyroid cancer is dependent on an increase in serum TSH concentration in response to LT4 withdrawal. The major disadvantage to thyroid hormone withdrawal is the development of symptomatic hypothyroidism. More concerning, although not common, is the potential for accelerated tumor growth mediated by TSH (1–8). The use of recombinant human TSH (TSH alfa) without LT4 withdrawal prevents the development of hypothyroidism and has been approved in diagnostic radioiodine scanning (9, 10). It is unknown whether short-term administration of TSH results in growth of thyroid cancer in patients. We report a patient with follicular thyroid cancer metastatic to the skeleton, brain, and clivus. Hypopituitarism resulted from a metastatic clival lesion that involved the pituitary gland. TSH alfa, in a compassionate use protocol, was administered before radioiodine treatment. Forty-eight h after TSH alfa administration, the patient developed hemiplegia.

title: Near-lethal respiratory failure after recombinant human thyroid-stimulating hormone use in a patient with metastatic thyroid carcinoma.
abstract: A patient with widely metastatic differentiated thyroid cancer who had been heavily pretreated with (131)I was given recombinant human thyroid stimulating hormone (rhTSH) prior to (131)I treatment. Clinical and physical data from both this case and the literature suggest that the recombinant hormone, not the (131)I, may have caused a significant portion of the tumor swelling, which in turn was the most likely cause of the patient's symptoms. The potential effect of (131)I-induced tumor swelling and direct radiation effect on the lung is also analyzed. We review the potential hazards associated with rhTSH in patients with metastasis and propose means of minimizing this risk.

title: Treatment of Recurrent Papillary Thyroid Carcinoma in Children and Adolescents
abstract: Mortality for children with papillary thyroid carcinoma (PTC) is low (< or = 10%), but recurrence is frequent (20%). In adults, recurrent PTC has a poor prognosis (50% remission) and a high mortality (16-63%). We hypothesized that treatment of recurrent PTC would be more effective in children than in adults. We reviewed the clinical course of 42 children with PTC in remission. Seven (7/42, 17%) recurred and records were available for six. All six received RAI (median = 130 mCi), and one had a cervical node removed. Five of the six (83%) achieved remission (median duration 67 mo, range 10-99 mo), one had a second recurrence and a third remission, and one patient (17%) had persistent disease. There were no deaths. In conclusion, although we had only one child less than 10 years of age in our study, these and previous data suggest that treatment of recurrent PTC in children is generally effective.

title: Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH.
abstract: This study tested the hypothesis that administration of human recombinant thyroid-stimulating hormone (rhTSH: Thyrogen, thyrotropin alpha) could promote iodine-131 ((131)I) uptake in the therapy for metastatic or locally invasive differentiated thyroid cancer (DTC), obviating L-thyroxine suppressive therapy (L-T4) withdrawal and hypothyroidism in patients with advanced disease.



Twelve totally (or almost completely) thyroidectomized adults, nine of whom had received earlier therapy after L-T4 withdrawal, underwent (131)I treatment while euthyroid on L-T4, after rhTSH administration. Nine underwent diagnostic whole-body scanning (WBS) after two consecutive daily i.m. injections (0.9 mg) of rhTSH. They then received an identical second course of rhTSH to promote therapeutic (131)I uptake. Post-therapy WBS was performed one week later. Three patients received only rhTSH (131)I therapy.



Administration of rhTSH promoted (131)I uptake in all patients, as demonstrated by post-therapy WBS. Administration of rhTSH also promoted a significant increase in serum thyroglobulin (Tg) concentrations. According to the most recent measurements, 3-12 months after therapy, serum Tg levels fell in four, and stabilized in two out of eleven patients. Upon additional rhTSH-WBS 8 months post-study, a reduction in one metastatic site was noted in one patient. The rhTSH was well tolerated, with mild, transient fever and/or nausea occurring in only a minority of patients. Individuals with bone metastases experienced degrees of peritumoral pain and swelling that were similar (though more short-lived) to those seen in the same or other patients after L-T4 withdrawal.



Administration of rhTSH is a safe, successful tool for inducing (131)I uptake in local and metastatic DTC lesions, and avoids L-T4 withdrawal, preserving metabolic homeostasis and preventing the debilitating effects of hypothyroidism.

title: Pulmonary metastases in differentiated thyroid carcinoma. Study of 58 cases with implications for the primary tumor treatment
abstract: Fifty‐eight cases of pulmonary metastases (PM) from 831 cases of differentiated thyroid carcinoma (DTC) were studied. PM were found in about 10% of follicular and 5% of papillary tumors. 131I uptake was found in 55% of the cases, irrespective of histology. Twenty‐one patients were treated by 131I only and 12 were cured. Micronodular metastases, 92% papillary, with 86% positive 131I uptake and 77% 8‐year survival rate, are the most favorable forms. In others the influence of PM size/age, uptake, delay of appearance, presence of cervical or mediastinal lymph nodes is discussed. Occurrence of late PM according to treatment of the primary tumor was 1.3% thyroidectomy + 131I; 3% thyroidectomy; 5% partial thyroidectomy + 131I; 11% partial thyroidectomy only. Thus prevention in DTC of severe PM (28% 8‐year survival rate) can best be achieved by complete thyroidectomy + 131I ablation dose.

title: Radioactive iodine and the salivary glands.
abstract: Radioactive iodine ((131)I) targets the thyroid gland and has been proven to play an effective role in the treatment of differentiated papillary and follicular cancers. Simultaneously, this radioisotope hones in on the salivary glands where it is concentrated and secreted into the saliva. Dose related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, stomatitis, candidiasis, and neoplasia. Prevention of the (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Recently, amifostine has been advocated to prevent the effects of irradiation. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration.

title: Nasolacrimal Obstruction Secondary to I131 Therapy
abstract: To report the finding of nasolacrimal drainage system obstruction associated with I131 therapy for thyroid carcinoma from an updated and expanded cohort.  Patients with a history of epithelial derived thyroid carcinoma who had tearing were offered referral for evaluation by an oculoplastic surgeon. Patients underwent nasolacrimal probing and irrigation procedures with localization of their nasolacrimal obstruction. Therapy for the site of obstruction was instituted.  Clinically significant tearing was identified in 26 patients, all of whom had previously undergone I131 therapy (n = 563). Nineteen patients were evaluated and confirmed to have nasolacrimal drainage system obstruction; 7 have yet to be formally evaluated. Areas of obstruction included nasolacrimal duct, common canaliculus, and, rarely, distal upper and lower canaliculi. Patients were treated with a variety of modalities including silicone intubation, balloon dacryoplasty, dacryocystorhinostomy, and conjunctival dacryocystorhinostomy.  The use of I131 for thyroid carcinoma is associated with a 3.4% incidence of documented nasolacrimal drainage obstruction and an overall 4.6% incidence of documented or suspected obstruction. The true incidence may be higher, since-I131 treated individuals were neither systematically evaluated nor questioned about tearing. It has yet to be established if the obstructions result from local toxicity caused by the passive flow of radioactive iodine containing tears through these tissues or the active uptake and concentration of I131 in lacrimal drainage system tissues through the sodium/iodide supporter.

title: Coexistent parathyroid adenomas and thyroid carcinoma. Can radiation be blamed?
abstract: The coexistence of parathyroid adenomas and thyroid cancer in a substantial number of patients with primary hyperparathyroidism has led to speculation implicating ionizing radiation as a possible cause. Experience with a group of 40 individuals harboring both tumors was reviewed and evidence of roentgen ray exposure to the head and neck was found in only one of these patients. Association of parathyroid adenomas and thyroid carcinoma cannot be explained on the basis of prior irradiation to the neck.

title: Outcome of pregnancy after radioactive iodine treatment for well differentiated thyroid carcinomas
abstract: This study sought to determine the outcome of pregnancy in female patients with differentiated thyroid carcinoma who became pregnant after radioactive iodide treatment. A total of 779 female thyroid cancer patients were treated at Chang Gung Medical Center in Linkou between January 1977 and December 1995. The medical records of these patients were reviewed retrospectively. Thirty-seven of these patients had well differentiated thyroid carcinoma receiving 131I treatment and conceived at a mean age of 27.97±3.49 year-old. A total of 58 pregnancy episodes were recorded during this study period. Among these 37 patients, 3 episodes of artificial abortion, 8 episodes of spontaneous abortion and 2 threatened abortions were observed. These patients delivered a total of 47 babies including 3 premature babies. Seven of these patients conceived within 6 months after the last administration of 131I, including 2 cases within 1 month, 4 cases within 4 months, and 1 patient within 5 months. Of these 7 patients, only one patient who conceived within 6 months after the last administration of 131I (14.3%) had a spontaneous abortion. The present results suggest that previous administration of 131I in female patients with well differentiated thyroid cancer does not result in demonstrable adverse effects in subsequent pregnancies. However, further studies involving long-term follow-up of children delivered by mothers who became pregnant within 6 months after the last administration of 131I is needed to further elucidate the possible chronic effects and sequelae of 131I therapy on subsequent pregnancies.

title: Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine.
abstract: The aim of the present study was to assess whether 131I therapy for differentiated thyroid carcinoma (DTC) can affect endocrine testicular function.



Serum follicle-stimulating hormone (FSH) and testosterone (T) concentrations were measured in 103 patients periodically submitted for radioiodine therapy for residual or metastatic disease. Mean follow-up was 93.7 +/- 54 mo (range 10-243 mo).



Mean FSH values in 131I-treated patients tested after their last treatment were 15.3 +/- 9.9 mU/ml, significantly higher than those of 19 untreated patients (6.5 +/- 3.1 mU/ml). Considering the mean +3 s.d. FSH of untreated subjects as the upper limit of normal range, 36.8% of the patients had an abnormal increase in serum FSH. Longitudinal analysis performed in 21 patients showed that the behavior of FSH in response to 131I therapy was not universal. Six patients had no change or a slight increase in serum FSH after 131I administration; eleven patients had a transient increase above normal values 6-12 mo after 131I treatment, with return to normal levels in subsequent months. The administration of a second dose was followed by a similar increase in FSH levels. Finally, four patients, followed for a long period of time and treated with several 131I doses, showed a progressive increase in serum FSH, which eventually became permanent. Semen analysis, performed in a small subgroup of patients, showed a consistent reduction in the number of normokinetic sperm. No change was found in serum T levels between treated and untreated patients.



Our results indicate that 131I therapy for thyroid carcinoma is associated with transient impairment of testicular germinal cell function. The damage may become permanent for high-radiation activities delivered year after year and might pose a significant risk of infertility.

title: Second primary malignancies in thyroid cancer patients
abstract: The late health effects associated with radioiodine (131I) given as treatment for thyroid cancer are difficult to assess since the number of thyroid cancer patients treated at each centre is limited. The risk of second primary malignancies (SPMs) was evaluated in a European cohort of thyroid cancer patients. A common database was obtained by pooling the 2-year survivors of the three major Swedish, Italian, and French cohorts of papillary and follicular thyroid cancer patients. A time-dependent analysis using external comparison was performed. The study concerned 6841 thyroid cancer patients, diagnosed during the period 1934–1995, at a mean age of 44 years. In all, 17% were treated with external radiotherapy and 62% received 131I. In total, 576 patients were diagnosed with a SPM. Compared to the general population of each of the three countries, an overall significantly increased risk of SPM of 27% (95% CI: 15–40) was seen in the European cohort. An increased risk of both solid tumours and leukaemias was found with increasing cumulative activity of 131I administered, with an excess absolute risk of 14.4 solid cancers and of 0.8 leukaemias per GBq of 131I and 105 person-years of follow-up. A relationship was found between 131I administration and occurrence of bone and soft tissue, colorectal, and salivary gland cancers. These results strongly highlight the necessity to delineate the indications of 131I treatment in thyroid cancer patients in order to restrict its use to patients in whom clinical benefits are expected.

title: Radiation dose assessments in radioiodine (131I) therapy. 1. The necessity for in vivo quantitation and dosimetry in the treatment of carcinoma of the thyroid.
abstract: In order to destroy thyroid cancer metastases by radioiodine an average tissue dose of 80-300 Gy is needed. Such high doses can be expected, following the administration of the conventional 5.5 GBq of 131I, only if both the percentage uptake per gram in the target tissue and the effective half life of the radioiodine in it are higher than well-defined threshold values, and if every dimension of the tissue exceeds several millimeters. The fulfillment of such favourable conditions in actual clinical cases can only be confirmed by in vivo quantitation of the absorbed dose achieved as a result of the administration of radioiodine.

title: Patient-specific dosimetry for 131I thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software.
abstract: Compared with conventional, whole-organ, S-factor-based dosimetry, 3-dimensional (3D), patient-specific dosimetry better accounts for radionuclide distribution and anatomic patient variability. Its accuracy, however, is limited by the quality of the cumulated activity information that is provided as input. This input has typically been obtained from SPECT and planar imaging studies. The objective was to implement and evaluate PET-based, patient-specific, 3D dosimetry for thyroid cancer patients.



Three to 4 PET imaging studies were obtained over a 7-d period in 15 patients with metastatic thyroid carcinoma after administration of (124)I-NaI. Subsequently, patients were treated with (131)I on the basis of established clinical parameters. Retrospective dosimetry was performed using registered (124)I PET images that were corrected for the half-life difference between (124)I and (131)I. A voxel-by-voxel integration, over time, of the resulting (131)I-equivalent PET-derived images was performed to provide a single 3D dataset representing the spatial distribution of cumulated activity values for each patient. Image manipulation and registration were performed using Multiple Image Analysis Utility (MIAU), a software package developed previously. The software package, 3D-Internal Dosimetry (3D-ID), was used to obtain absorbed dose maps from the cumulated activity image sets.



Spatial distributions of absorbed dose, isodose contours, dose-volume histograms (DVHs), and mean absorbed dose estimates were obtained for a total of 56 tumors. Mean absorbed dose values for individual tumors ranged from 1.2 to 540 Gy. The absorbed dose distribution within individual tumors was widely distributed ranging from a minimum of 0.3 to a maximum of 4,000 Gy.



(124)I PET-based, patient-specific 3D dosimetry is feasible, and sequential PET can be used to obtain cumulated activity images for 3D dosimetry.

title: Increasing efficacy and safety of treatments of patients with well-differentiated thyroid carcinoma by measuring body retentions of 131I.
abstract: There is no consensus on the amount of (131)I for treatment of patients with well-differentiated thyroid carcinoma; usual amounts vary widely. Body retention of (131)I has been shown to be a valuable index of radiation toxicity. If a broad range of body retentions occurs among patients, then high and low retentions will be a basis for modifying the usual prescriptions for (131)I to ensure safety and increase efficacy.



After withdrawal of thyroid hormone in 87 patients, the fractional retention of diagnostic (131)I in each body was measured at 2 d by a scintillation probe. In 43 patients, the retention was measured 2 d after therapeutic (131)I.



Diagnostic retention varied from 0.01 to 0.51, with a median of 0.15. These retentions did not correlate with any index of health, thyroid hormone, or carcinoma status. Seventeen patients, previously treated with (131)I, exhibited a significantly lower mean retention. In 43 patients, retention of diagnostic (131)I was highly correlated with retention of therapeutic (131)I: diagnostic predicted therapeutic retention with a mean error of 0.04. In 10 patients receiving thyroxine, the mean retention of diagnostic (131)I after recombinant human TSH (rhTSH) was strikingly lower, 0.06, with a range of 0.016-0.16.



Body retentions of (131)I are easily measured and vary considerably among patients. Because increased therapeutic (131)I will impart greater irradiation of tumor, and body retention has been accepted as an index of toxicity from (131)I, the use of body retention could enable prescriptions of therapeutic (131)I that enable increased efficacy while ensuring safety. If tumor retention is not proportionally decreased with the body retention of (131)I after rhTSH, then rhTSH may enable increased therapeutic efficacy.

title: Tumour dosimetry and response in patients with metastatic differentiated thyroid cancer using recombinant human thyrotropin before radioiodine therapy
abstract: The development of recombinant human thyrotropin (rhTSH) has given clinicians new options for diagnostic follow-up and treatment of patients with differentiated thyroid cancer (DTC). This paper evaluates the tumour dosimetry and response following -iodine-131 treatment of metastatic thyroid cancer patients after rhTSH stimulation instead of classical hormone withdrawal-induced hypothyroidism. Nineteen consecutive 131I treatments in 16 patients were performed after rhTSH stimulation. All patients had undergone a near-total thyroidectomy followed by an ablative dosage of 131I. They all suffered from metastatic or recurrent disease showing tumoral 131I uptake on previous post-treatment scintigraphy. Dosimetric calculations were performed using 131I tumour uptake measurements from post-treatment 131I scintigrams and tumour volume estimations from radiological images. Response was assessed by comparing pre-treatment serum thyroglobulin (Tg) level with the Tg level 3 months post treatment. In 18 out of 19 treatments, uptake of 131I in metastatic or recurrent lesions was seen. The median tumour radiation dose was 26.3 Gy (range 1.3–368 Gy), and the median effective half-life was 2.7 days (range 0.5–6.5 days). Eleven of 19 treatments (10/16 patients) were evaluable for response after 3 months. 131I therapy with rhTSH resulted in a biochemical partial response in 3/11 or 27% of treatments (two patients), biochemical stable disease in 2/11 or 18% of treatments and biochemical progressive disease in 6/11 or 55% of treatments. Our study showed that although tumour doses in DTC patients treated with 131I after rhTSH were highly variable, 45% of treatments led to disease stabilisation or partial remission when using rhTSH in conjunction with 131I therapy, without serious side-effects and with minimal impact on quality of life. RhTSH is therefore adequately satisfactory as an adjuvant tool in therapeutic settings and is especially suitable in advanced recurrent or metastatic DTC patients who may be intolerant to TSH stimulation by levothyroxine withdrawal.

title: "High-dose" radioiodine therapy in advanced differentiated thyroid carcinoma.
abstract: There is yet no consensus concerning the appropriate regimen of the application of [131I]sodium iodine (Nal) activities to patients suffering from advanced differentiated thyroid carcinoma. We report on a total of 167 applications of [131I]Nal, including 78 applications of 11.1 GBq. Response to high-activity radioiodine therapy (RIT) is correlated to the course of the disease as well as to the reaction of thyreoglobulin and acute/subacute side effects of radiation.



Following radioablation of thyroid remnants using 1.85 to 3.7 GBq[131I]Nal, 26 patients with advanced differentiated thyroid carcinoma (follicular, 11; papillary, 4;mixed-cell thyroid carcinoma, 11) were treated with repeated activities of 11.1 GBq[131I]Nal. Initial tumor staging according to UICC showed T4 in 54%, T3 in 19%, T2 in 19% and was not obtained in 8%. Differentiated thyroid carcinoma was multifocal in 23% of patients. Applied accumulated activities ranged from 14.8 to 99.9 GBq with a mean of 55.5 GBq per patient.



Mean post-diagnostical follow-up was 73 mo, mean follow-up after diagnosis of metastatic spread was 48 mo. Follicular thyroid carcinoma remained as stable disease in 7 of 11 patients, 6 of whom showed metastatic disease after a mean of 20 mo, and only 1 complete remission was achieved using high-dose therapies, with progressive disease in the remaining patients. Overall, 73% of follicular thyroid carcinoma had progressive disease without major response to high-activity RIT. In contrast, only 20% of papillary thyroid carcinoma/mixed-cell thyroid carcinoma showed progressive disease, and complete remission was achieved in 47% of patients. Pulmonary and lymph node metastases in the majority of patients showed good response to therapy, whereas local recurrences and bone metastases showed minor reactions to RIT. After low-activity therapies 8% of patients showed WHO grade I hematotoxic reactions. After high-activity therapies, 38% of patients had WHO I, 8% WHO II and one patient had WHO III toxicity (4%).



Use repetitive high-activity RIT with a maximum of 44.4 GBq applied during 1 yr and a maximum of 99.9 GBq accumulated activity resulted in a significant increase of hematotoxicity. However, during the follow-up period (mean, 4 yr), no clinical symptoms possibly related to low blood counts were seen in patients with advanced differentiated thyroid carcinoma. Initiation of high-activity RIT in reaction to metastatic tumor outspread to achieve complete remission was found to be useful in treating papillary thyroid carcinoma and mixed-cell thyroid carcinoma, but only in a minority of follicular thyroid carcinoma patients.

title: Influence of diagnostic and therapeutic doses on thyroid remnant ablation rates
abstract: Radioiodine ablation of thyroid tissue after subtotal thyroidectomy has been shown to decrease recurrence in certain subsets of patients with well-differentiated thyroid cancer. In a substantial percentage of cases (20-30%), initial ablation of the thyroid remnant fails, necessitating a second treatment. The factors associated with ablation failure are not fully understood. In particular, it is not certain whether the use of doses higher than 3.70 GBq would result in any additional benefit, or whether there is a ‘stunning’ effect of the diagnostic dose of 131I on the subsequent ablation rate. A retrospective analysis was performed of all patients (n = 389) with well-differentiated thyroid cancer treated at our institution between 1992 and 2001. Remnant ablation success was determined by a whole-body radioiodine scan. The following factors, thought to be associated with thyroid remnant ablation, were studied by logistic regression analysis: age, gender, tumour histology, stage, pre-therapy neck uptake of 131I, diagnostic dose, ablation dose, time between diagnostic and therapeutic dose (T1), time between therapeutic administration and the first follow-up whole-body scan (T2) and the thyroid-stimulating hormone (TSH) level measured at the time of therapy. Follow-up whole-body scans were available in 214 patients. We found no association with age, gender, histology, TSH level, neck uptake, diagnostic dose and successful ablation. The therapeutic dose was the only variable found to be associated with success (odds ratio, 1.96 per 1.85 GBq increment; 95% confidence interval, 1.11-3.46). Our results confirm the presence of a significant percentage of ablation failures (24.4%) despite the use of high ablative doses (3.70-7.40 GBq). Higher therapeutic doses are associated with higher rates of successful ablation, even when administered to patients with more advanced stages. Using our protocol, higher diagnostic doses were not associated with higher rates of ablation failure.

title: The nonimpact of thyroid stunning: remnant ablation rates in 131I-scanned and nonscanned individuals.
abstract: Thyroid stunning has been reported as the temporary impairment of thyroid tissue after a 111-MBq or greater diagnostic 131I dose that decreases the final absorbed dose in ablative therapy. Concerns regarding the reality of stunning have arisen in part due to a flawed study design in prior reports. To assess whether a stunning effect has any impact on therapeutic outcomes, we compared initial treatment ablation rates in patients who received 111- to 185-MBq 131I diagnostic scans (n = 37) before ablative doses of 3700-7400 MBq with ablation rates in patients who did not receive any 131I before the initial treatment dose (n = 63). Ablation rates were 64.9% for scanned patients and 66.7% for nonscanned patients, a nonsignificant difference. Nonscanned patients with metastatic lesions (n = 23) were ablated at a higher rate (78.3%) than scanned patients (n = 9) (66.7%), but the difference was not significant (P = 0.50). It is possible that the reported stunning phenomenon, specifically its impact in temporarily impairing tissue, has been overemphasized.

title: Impact of 131I diagnostic activities on the biokinetics of thyroid remnants.
abstract: Recent publications described many discrepant findings about thyroid "stunning" after the administration of (131)I diagnostic activities to patients with differentiated thyroid carcinoma. Stunning may play a major role in reducing the therapeutic efficacy of high (131)I activities given for ablation therapy.



Participation in a multicenter study to investigate differences in iodine biokinetics in the hypothyroid state and after the application of recombinant human thyroid-stimulating hormone enabled us to study quantitative changes in thyroid iodine biokinetics after the administration of 74 MBq of (131)I twice within 6 wk and an ablation activity of 3-4 GBq 7-12 d after the second diagnostic administration of (131)I in 6 patients.



The uptake and half-life of the first 74 MBq of (131)I were significantly reduced to a mean of 44% and a mean of 51%, respectively, after the second diagnostic administration and further reduced to a mean of 40% and a mean of 30%, respectively, during ablation therapy. The residence times were reduced to 25% in the second dosimetric assessment and to 10% during therapy compared with the value in the first assessment. For one patient, an estimated absorbed dose as high as 38 Gy was found in the first diagnostic study. The mean dose for all patients after the first assessment was 15 Gy; after each further assessment, the dose was reduced according to the decrease in residence time.



This study shows a severe impact of 74 MBq of (131)I on the biokinetics of thyroid remnants during subsequent radioiodine therapy.

title: Influence of scanning doses of iodine-131 on subsequent first ablative treatment outcome in patients operated on for differentiated thyroid carcinoma.
abstract: The therapeutic outcome after (131)I first ablative treatment in patients operated on for nonmedullary differentiated thyroid carcinoma was compared after both the currently used scanning dose of 111 MBq (131)I and a scanning dose of 37 MBq (131)I.



Two-hundred twenty-nine consecutive patients with no known metastases were retrospectively studied. They were divided in two populations according to the scanning dose (127 patients with 111 MBq and 102 patients with 37 MBq). All patients received 111 or 37 MBq (131)I for diagnostic purposes and 3.7 GBq (131)I for ablative therapy 9 days later. To assess the efficacy of the treatment, all patients were studied with (131)I and with thyroglobulin plasma assays 6-17 mo later.



Successful outcome was significantly more frequent after a scanning dose of 37 MBq (131)I than after a scanning dose of 111 MBq (76% versus 50%, p < 0.001). The treatment efficacy was particularly enhanced after 37 MBq in patients with associated lymphocytic thyroiditis.



In patients with no known metastases, our data suggest that the impairment of the treatment efficacy observed after a scanning dose of 111 MBq (131)I is related to a stunning effect on the thyroid remnants. The threshold amount above which this effect begins to occur in thyroid remnants could be between 37 and 111 MBq (131)I. Consequently, a scanning dose of only 37 MBq (131)I could be recommended before first ablative treatment. The absence of metastatic patients in our study prevents any conclusion about the possible stunning of the neoplastic tissue. Nevertheless, we must suspect such an effect and try to avoid it, especially during follow-up after first radioiodine therapy. For instance, one may consider postponing radioiodine treatment several weeks or even months after scanning dose administration or using only thyroglobulin measurement for patients who are likely to receive a subsequent radioiodine treatment.

title: Superiority of Iodine-123 Compared with Iodine-131 Scanning for Thyroid Remnants in Patients with Differentiated Thyroid Cancer
abstract: Iodine-123 is a pure gamma emitter and has excellent characteristics for imaging with modern scintillation cameras. The goal of this study was to compare the performance of I-123 and I-131 as imaging agents for whole-body scanning in patients with differentiated thyroid cancer undergoing ablation for thyroid remnants after initial surgery.  Fourteen patients with differentiated thyroid cancer who had undergone near-total thyroidectomy and had serum thyroid-stimulating hormone levels greater than 40 mU/l underwent diagnostic scanning 5 hours after administration of 48 to 56 MBq (1.3 to 1.5 mCi) I-123 and 48 hours after administration of 111 MBq (3 mCi) I-131. After receiving ablative I-131 therapy, they also underwent whole-body planar imaging 7 days later. The diagnostic I-123 and I-131 scans were compared with each other and with the post-therapy images by two nuclear medicine physicians and one endocrinologist.  The diagnostic scans revealed 35 foci in the thyroid bed and neck. The I-123 images showed all 35 foci, but only 32 of the 35 foci (91%) were seen on the I-131 scans. The findings of pre- and post-therapy scans were concordant in 11 of 13 patients, and the same general sites of uptake (left and right thyroid bed, midline) were revealed on both sets of images. In one patient, a focus seen on the diagnostic I-123 and I-131 images was not visualized on the post-therapy scan and was thought to represent possible stunning. An additional area of uptake in the lower right neck and upper mediastinum was present on the post-therapy scan of another patient, but it was not seen on diagnostic images.  These results show improved quality of imaging with 50 MBq (1.5 mCi) I-123 compared with 111 MBq (3 mCi) I-131 for whole-body scanning in patients with differentiated thyroid cancer undergoing thyroid remnant ablation. I-123 imaging may prove to be the preferred procedure in such settings in patients with differentiated thyroid cancer.

title: Sensitivity of 123I whole-body scan and thyroglobulin in the detection of metastases or recurrent differentiated thyroid cancer
abstract: Primary treatment of differentiated thyroid carcinoma consists of total thyroidectomy followed by ablation of thyroid tissue remnants and possible metastases by means of radioactive iodine. After complete destruction of remnants, metastases or recurrence can be detected by measurement of the serum thyroglobulin level as well as by radionuclide methods. Here we report on the sensitivity of diagnostic 123I scintigraphy and serum thyroglobulin measurement for tumour detection in patients with proven recurrence or metastases. Fifty-five patients who received their first high activity (1,850–5,550 MBq) of 123I therapy after total thyroidectomy and 131I ablation were included in the study. The thyroglobulin level was measured both during TSH-suppressive L-thyroxine therapy (Tg-on) and 4–6 weeks after L-thyroxine withdrawal (Tg-off, TSH>20 mU/l). Prior to treatment, whole-body scanning (WBS) was performed 24 h after the administration of 111–370 MBq 123I. The therapeutic activity of 1,850–5,550 MBq 131I was administered within 24 h after diagnostic scanning. The mean interval between 131I therapy and post-therapeutic WBS was 8.6 days (range 3–15 days). The sensitivity of WBS, Tg-on and Tg-off was 75%, 82% and 98%, respectively. The overall sensitivity of the combination of Tg-on with WBS and of Tg-off with WBS was 95% and 100%, respectively. In 12 out of 51 cases either Tg-off or Tg-on or both Tg-on and Tg-off levels were elevated while 123I-WBS was negative. More lesions were visible on the post-therapeutic 131I scan than on the corresponding diagnostic 123I scan (n=13). Tg values increased significantly (P<0.0001) after thyroid hormone withdrawal. Early treatment of distant metastases or tumour remnants of differentiated thyroid carcinoma is favoured and 131I treatment should also be considered in patients with a negative WBS but positive serum Tg level. The finding of a positive Tg-off level, which is clearly above the corresponding Tg-on value, is sufficient to make this decision. Additional diagnostic 123I WBS will not improve sensitivity.

title: Comparison of (123)I and (131)I for whole-body imaging in thyroid cancer.
abstract: We compared the diagnostic sensitivities of (123)I and (131)I whole-body imaging in differentiated thyroid cancer.



Twelve thyroidectomized patients (3 previously treated with (131)I) were studied. After a period of thyroid hormone withdrawal, whole-body imaging was performed approximately 24 and 72-96 h after administration of 74-185 MBq (2-5 mCi) (123)I and 111-185 MBq (3-5 mCi) (131)I, respectively.



Both (123)I and (131)I revealed residual thyroid tissue, present in 9 patients. (131)I detected metastases in 5 studies of 4 patients. In 4 of 5 studies, (123)I missed metastases shown by (131)I in 8 body regions including the neck, mediastinum, lungs, and bone and detected 3 other sites of metastasis only in retrospect. No lesion was better seen with (123)I than with (131)I.



Although (123)I is adequate for imaging residual thyroid tissue, it appears to be less sensitive than (131)I for imaging thyroid cancer metastases.

title: Effects of low‐iodide diet on postsurgical radioiodide ablation therapy in patients with differentiated thyroid carcinoma
abstract: objective Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low‐iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly.

title: Reevaluation of the impact of a stringent low-iodine diet on ablation rates in radioiodine treatment of thyroid carcinoma.
abstract: Prior analyses of the impact of stringent, preablative low-iodine diets (LIDs) on ablation in patients with differentiated thyroid cancer postthyroidectomy are dated. We retrospectively reviewed first-time, short-term ablation rates for 44 LID patients and 50 patients following a regular diet (RD) who were verbally instructed to avoid salt, seafood, and multivitamins containing iodine. Patients who had undergone ablation were given between 100 and 200 mCi of 131I, depending on the presence of metastases. We found a 68.2% ablation rate for LID patients, compared to a 62.0% rate for RD patients, a nonsignificant difference (p = 0.53). We observed a dose-response relationship for both patient groups, with higher ablation rates corresponding to higher doses of radioiodine administered. We also measured iodine levels in spot urine samples from 7 matched LID patients and 7 matched RD adherents (healthy volunteers) prediet and postdiet as well as 39 healthy volunteers. LID patients had a lower mean urinary iodine level postdiet (173.9 microg/L; range, 45-1,217 microg/L; standard deviation [SD] = 127.7) than the RD patients (mean, 381.4 microg/L; range, 140-630 microg/L; SD = 196.3) or the 39 normal controls (444.0 microg/L; range, 50-1,690 microg/L; SD = 413.4). Whereas the LID lowered urinary iodine levels by 69.4% from prediet values, the RD reduced urinary iodine by 23.6%. Although differences in the reduction of urinary iodine levels between the LID and the RD were substantial, both groups experienced equivalent outcomes. The level of iodine in the American diet has progressively decreased, and may be much lower now than when prior LID studies were conducted. We suggest that prescribing a refined, less stringent diet that avoids high-iodine-containing foods would offer equivalent outcomes with increased patient convenience.

title: EANM Procedure Guideline for Therapy with iodine-131
abstract: 1. I-131 is a beta-emitting radionuclide with a physical half-life of 8.0 days, a principal gamma ray of 364 keV and a principal beta particle with a maximum energy of 0.61 MeV, an average energy of 0.192 MeV and a range in tissue of 0.8 mm. 2. Therapy in this context means the oral administration of 131I as sodium iodide. 3. Benign conditions in this context mean Graves’ disease (diffuse toxic goitre), toxic or non-toxic goitre, solitary hyperfunctioning toxic thyroid nodule or benign thyroid remnants from cancer surgery. 4. Malignant conditions include differentiated thyroid cancer that accumulates radioiodine or functioning thyroid cancer metastases.

title: Gene expression in papillary thyroid carcinoma reveals highly consistent profiles
abstract: Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase–PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase–PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.