Tall cell and diffuse sclerosing variants of papillary thyroid cancer: outcome and predicting value of risk stratification methods.

PURPOSE: Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification. METHODS: A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification). RESULTS: Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both. CONCLUSIONS: In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.

Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy.

PURPOSE: Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy. METHODS: A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU-treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed. RESULTS: The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy". CONCLUSIONS: While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy.

Parathyroid carcinoma: case report.

The authors present a case of parathyroid carcinoma in a patient with primary hyperparathyroidism. Following a literature review, the clinical and diagnostic profile, treatment and prognosis of this rare disease are discussed.

Toxic multinodular goitre. Personal case histories and literature review.

The authors reviewed their own case histories of surgical thyreopathy over the last 20 years in order to establish how many multinodular goitre (MNG) patients developed hyperthyroidism during the follow-up period. In agreement with the findings reported in literature, the authors observed that 220 out of 1117 patients with MNG developed hyperthyroidism caused by the appearance of hyperfunctioning nodules after 6-18 years from the initial diagnosis of MNG.

[Radio-guided parathyroidectomy]. / La paratiroidectomia radioguidata.

The Authors, after a careful review of literature about the instrumental diagnostic techniques (with particular attention to the nuclear-medical ones) and the surgical therapy of parathyroid diseases, report their experience on the use of the radio-guided mininvasive surgery with MIBI and gamma-probe for intraoperative localization of pathological glands. Once exposed their experience, the Authors conclude asserting that this technique is fast, slightly invasive and expensive, and certainly useful for the detection of pathological or ectopic glands. It can be widely employed because, in comparison to its numerous advantages, such as the reduction of the operating time and of the hospital-stay, the greater radicality and the possibility to use mininvasive techniques, it does not present significant technical limitations and/or radio-protectionistic problems.

Human galectin-3 immunoexpression in thyroid follicular adenomas with cell atypia.

Human galectin-3 (hgal-3) is a beta-galactoside binding protein involved in a number of physiological and pathological processes. Increasing hgal-3 immunoexpression has been reported in several human tumors, including thyroid carcinomas, but not in benign thyroid lesions. We analyzed the immunolocalization of hgal-3 in cell compartments of benign and malignant thyroid lesions. Hgal-3 immunoperoxidase reaction was carried out on 133 thyroid tissue samples obtained from 113 patients; 20 of these were normal (NT), 85 were benign thyroid lesions [20 colloid nodules (CN), 21 nodular hyperplasias (NH), 7 focal lymphocytic thyroiditis (FLT), 15 Hashimoto's thyroiditis (HT), 22 follicular adenomas (FA)], 25 differentiated carcinomas [15 papillary carcinomas (PC), 6 follicular carcinomas (FC) and 4 Hürthle cell carcinomas (HC)] and 3 anaplastic carcinomas (AC). Among the malignant thyroid lesions, hgal-3 was detected in 12/15 (80%) PC, 3/4 (75%) HC and in 4/6 (66.6%) FC, but in none of the 3 AC. Conversely, hgal-3 immunoexpression was absent in NT and in all benign thyroid lesions, but 1/15 HT and 10/22 (45.4%) FA. In the latter, hgal-3 was mostly expressed in microfollicular areas and in five of the six atypical FA. Hgal-3 cytoplasmic-perinuclear immunolocalization was observed in the majority of thyroid carcinomas and in more than half of the FA, theoretically suggesting an involvement of this protein in thyroid tumorigenesis throughout an antiapoptotic activity. Moreover, hgal-3 expression in FA might anticipate the likelihood of evolution of these benign lesions towards malignancy.

Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries.

Over a period of almost 10 yr, we carried out a prospective study of the neuropsychological development of the offspring of 16 women from a moderately iodine-deficient area (area A) and of 11 control women from a marginally iodine-sufficient area (area B) whose thyroid function had been monitored during early gestation. Attention deficit and hyperactivity disorder (ADHD) was diagnosed in 11 of 16 area A children (68.7%) but in none from area B. Total intelligence quotient score was lower in area A than in area B children (92.1 +/- 7.8 vs. 110 +/- 10) and in ADHD children when compared with both non-ADHD children from the same area and control children (88.0 +/- 6.9 vs. 99.0 +/- 2.0 and 110 +/- 10, respectively). Seven of 11 ADHD children (63.6%) were born to the seven of eight area A mothers who became hypothyroxinemic at early gestation, whereas only one of five non-ADHD children was born to a woman who was hypothyroxinemic at 20 wk of gestation. So far, a similar prevalence of ADHD has been reported only in children with generalized resistance to thyroid hormones. This might suggest a common ADHD pathogenetic mechanism consisting either of reduced sensitivity of the nuclear receptors to thyroid hormone (generalized resistance to thyroid hormones) or reduced availability of intracellular T3 for nuclear receptor binding. The latter would be the ultimate consequence of maternal hypothyroxinemia (due to iodine deficiency), resulting in a critical reduction of the source of the intracellular T3 available to the developing fetal brain.

Post-Chernobyl increased prevalence of humoral thyroid autoimmunity in children and adolescents from a moderately iodine-deficient area in Russia.

Circulating thyroglobulin antibodies (TgAb) and thyroperoxidase antibodies (TPOAb) were measured in 143 iodine-deficient children, 5 to 15 years of age, from the Region of Tula, Russia, who had been moderately contaminated after the Chernobyl disaster (37-185 GBq/km2 of caesium-137, [group A]) and in 40 sex- and age-matched subjects from an uncontaminated neighboring area (<3.7 GBq/km2 of caesium-137, [group B]). Increased thyroid size at sonography was found in 41% and in 45% subjects from group A and group B, respectively, associated with supranormal thyrotropin (TSH) values in 7.7% of group A and 7.5% of group B, without differences in average serum free thyroxine (FT4), free triiodothyronine (FT3) and TSH. Serum thyroperoxidase antibody (TPOAb)-associated or not with thyroglobulin-antibody (TgAb) as detected in 18.9% of children and adolescents from group A, about four-fold higher than in group B (5%, Fischer's exact test p<0.05). A 24% frequency was found in subjects whose age, at the moment of the disaster was 0-72 months or were in utero, but the frequency was about 7%, similar to that in group B, in those who had not yet been conceived at that time. Less than half of antibody-positive group A children were hyperthyrotropinemic, whereas no group B subclinical hypothyroid subject was antibody-positive, thus excluding the autoimmune etiology of the subclinical thyroid failure; more likely it is attributable to iodine malnutrition. The high prevalence of humoral thyroid autoimmunity phenomena in the investigated area suggests a combined role of iodine malnutrition in enhancing the effects of short lived iodine isotopes, particularly evident in pubertal individuals conceived or born immediately before the Chernobyl disaster.

Short-term effectiveness of low-dose radioiodune ablative treatment of thyroid remnants after thyroidectomy for differentiated thyroid cancer.

Twenty-five patients from a marginally iodine-deficient area with differentiated thyroid cancer who were referred to our unit between 1991 and 1997 had a residual thyroid uptake (RTU) at 24 hours of 5% or more after surgery. None of them underwent reoperation: 8 of 25 had RTU between 5% and 10% and were considered at low risk for both local recurrences and/or distant metastases; 17 of 25 had RTU greater than 10% and up to 30% and refused re-intervention. After detection of their cervical uptake by using a 131I tracer dose of 3.7 MBq (100 microCi), all 25 were treated with 1110 MBq (30 mCi) of 131I. A whole-body scan (WBS) performed 5 days later revealed 131I uptake corresponding to metastatic lymph nodes in the anterior part of the neck in 1 patient and the persistence of only RTU in 24 of 25 patients. RTU and thyroglobulin (Tg) levels were reevaluated 6 months later in all patients and compared to preradioiodine treatment values. RTU, ranging at presentation between 5% and 30%, decreased to below 1% in all but one patient. Serum Tg values, ranging between 1.6 and 108 ng/mL before radioiodine treatment, decreased to below 1.6 ng/mL in all but 4 of them (whose serum Tg was between 2 and 3.4 ng/mL). Our data indicate that 1,110 MBq of 131I can permit complete ablation of 80% of thyroid remnants concentrating up to 30% of radioiodine activity. A relation between this high success rate and iodine deficiency can be hypothesized because an increasing uptake of radioiodine by thyroid remnants could result in overestimation of their size. Therefore, our observations suggest that in iodine deficient areas, a hasty decision to carry out complete thyroidectomy should be avoided, even in the case of thyroid remnants with RTU up to 30%.

Increased risk of maternal thyroid failure with pregnancy progression in an iodine deficient area with major iodine deficiency disorders.

In an effort to assess the impact of moderate iodine deficiency on maternal thyroid function during pregnancy, we measured serum thyrotropin, total and free thyroid hormones, thyroid-binding globulin (TGB) at 8, 14, 20, 29, and 36 weeks of gestation, along with urinary iodide excretion, in 10 healthy women from a moderately iodine deficient region (group A), and compared them with 6 women from an iodine sufficient region (group B). Serum total thyroxine (T4) fell significantly in group A, and was significantly lower than in group B at 29 and 36 weeks (p<0.05). TBG saturation was significantly lower in group A throughout pregnancy, and declined in both groups as pregnancy progressed. Free thyroxine (T4) and triiodothyronine (T3) concentrations fell in both groups, and FT4 values were significantly lower in group A than group B in the third trimester (p<0.05). Urinary iodine excretion was lower in group A women with respect to group B and did not vary significantly in either group as gestation progressed. The serum T3/T4 molar ratio increased through pregnancy only in group B. Thyrotropin concentrations rose in both groups through pregnancy, and were higher in group A at term (p< 0.01). The incidence of isolated hypothyroxinemia or biochemical hypothyroidism doubled (30% to 70%) between midgestation and term in group A, suggesting that moderate iodine deficiency may result in maternal thyroid failure during the later stages of pregnancy.

Thyroid follicular oncogenesis in iodine-deficient and iodine-sufficient areas: search for alterations of the ras, met and bFGF oncogenes and of the Rb anti-oncogene.

To gain insights into the role of iodine deficiency in favoring thyroid tumorigenesis (particularly of the follicular histotype), 22 Sicilian patients with thyroid tumors were selected for having lived permanently in either one of two areas of different iodine availability. Eleven patients (age 46.1 +/- 14.6 years, mean +/- SD; 10 females and 1 male) were from the iodine-deficient (ID) areas of the provinces of Messina and Catania (mean urinary excretion of iodine = 48.1 micrograms/24 hours). Thyroid tumors were follicular or Hürthle cell adenomas (no. = 3), follicular carcinomas (FC, no. = 4), papillary carcinomas (PC, no. = 2) and anaplastic carcinomas (no. = 2). Eleven patients (age 47.1 +/- 15.2 years; 10 females and 1 male) were from the metropolitan area of Messina, an area of relative iodine-sufficiency (IS) (urinary excretion of iodine = 95.2 micrograms/24 hours). These 11 patients had serum levels of TSH that were significantly lower than the corresponding values of the 11 patients from the ID area (0.76 +/- 0.33 vs 1.80 +/- 1.22 mU/l, p = 0.01) The tumors of the 11 patients from the IS area were: follicular or Hürthle cell adenomas (no. = 6), Hürthle cell carcinoma (no. = 1), FC (no. = 2), PC (no. = 2). Molecular biology studies revealed that both the normal as well as the tumor tissue of all 22 patients did not harbor any of the three classical activating mutations (codons 12, 13 and 61) in any of the three ras oncogenes. Similar negative results were obtained as far as loss of heterozygosity of the retinoblastoma (Rb) anti-oncogene is concerned. Immunohistochemistry studies were performed to investigate expression of c-met and basic fibroblast growth factor (bFGF) proto-oncogenes. Only one Hürthle cell carcinoma and the two PC from the IS group, and one FC and the two PC from the ID group stained for the c-met oncogene. Expression of c-met was greater (3+) in the four PC (concerning 70-80% of the tumor cells) than in the other two cancers (1+; < 5% of the tumor cells). In the IS group, positivity for bFGF was detected in 3/6 adenomas, 1/2 FC, the Hürthle cell carcinoma and the two PC. In the ID group, positivity for bFGF was observed in 2/3 adenomas, 2/4 FC, the two PC and the two anaplastic carcinomas. The 8 positive cases from the ID group had a greater level of bFGF expression than the 7 positive cases from the IS group (intensity of staining = 2.0+ vs 1.57+). Interestingly, the greatest expression of bFGF was seen in the cases with peri-tumoral lymphocytic infiltration from either group. In the ID group correlations between (i.) pre-intervention serum TSH and intensity of tumoral staining for bFGF, (ii.) serum TSH and per cent of tumoral cells reactive with anti-bFGF and (iii.) between intensity of staining for bFGF and per cent of tumoral cells bFGF +ve were higher than in the IS group. We conclude that activating mutations of ras, loss of DNA from the Rb locus and over-expression of both c-met and bFGF are of no pathogenetic relevance in driving thyroid tumorigenesis of iodine-deficient areas.

Combined impairment of nutritional parameters and thyroid homeostasis in mildly iodine-deficient children.

The relation between thyroid homeostasis and the biochemical parameters of subclinical protein malnutrition has been analyzed in schoolchildren in a rural area in the south of Italy, known to be moderately iodine-deficient. The sera of 32 children (15 males and 17 females aged 6 to 11 years) have been analyzed. These children were divided into two groups, according to thyroid function: (1) 16 euthyroid children (mean thyrotropin [TSH] 2.38 +/- .35 mU/L; 6 with goiter) and (2) 16 subclinical hypothyroid children (mean TSH 7.32 +/- 1.68 mU/L; 6 with goiter). Retinol circulating complex (RCC) components were determined in serum by high-performance liquid chromatography (HPLC) and radial immunodiffusion and the essential and nonessential amino acid levels by ion exchange chromatography. Reduced retinol binding protein (RBP) and transthyretin (TTR) levels were recorded in the sera of 11 of 32 (34%) and in 5 of 32 (16%) patients, respectively. The linear regression analysis revealed that RBP and TSH levels were inversely correlated (r = -0.514; p < 0.0026). The RBP levels were subnormal in 2 of 16 euthyroid and in 9 of 16 hypothyroid patients (Fisher test p < 0.023), and the mean RBP levels were significantly reduced in the hypothyroid patients when compared with those of the euthyroid group (p < 0.0026). The retinol/RBP ratio was also significantly different between euthyroid and hypothyroid children (0.75 vs. 0.95; p < 0.0002). The mean essential amino acid levels, with the exception of methionine, were all in the normal range. The selected amino acid ratios confirmed that the patients were exposed to mild protein malnutrition. These results provide evidence that even mild protein-energy malnutrition may have detrimental effects on thyroid homeostasis in iodine-deficient areas.

[Iodine deficiency and pregnancy]. / Carenza iodica e gravidanza.

Iodine availability for maternal thyroid during pregnancy results from a combination of specific factors (increased urinary iodine loss, fetal-placental unit competition) and is critically reduced by the nutritional deficiency. Hyperestrogenism is associated with increased circulating thyroxine-binding globulin (TBG) levels and a higher binding capacity for T4 and T3, because of a reduced clearance rate of the protein. Our study carried out in a moderately iodine deficiency area from North-Eastern Sicily in pregnant women showed a inadequate synthesis of T4 not proportional to the increased TBG levels. The progressive decrease T4/TBG molar ratio implies the reduction of serum FT4 and the consequently increase of serum TSH. At delivery, about 70% of women showed a critical and transient biochemical hypothyroidism. Mental impairment and neurosensorial and neuromuscular disorders were observed in children born from those women. Therefore, short-term iodine prophylaxis with iodized salt in pregnant women does not correct nor prevent maternal hypothyroxinemia. L-T4 treatment is thus often required.

Iodine concentration by the thymus in thyroid carcinoma.

A 14-yr-old boy underwent a total thyroidectomy with bilateral neck dissection for a papillary carcinoma with lymph node metastases. Total-body scanning with 3.7 GBq 131I revealed radioiodine accumulation in the anterior mediastinum. CT and MRI demonstrated a mediastinal mass which corresponded to the area of increased radioactivity. Five months later, another therapeutic dose of 131I was followed by a sternotomy and removal of the thymus because a hand-held radiodetecting surgical probe demonstrated that the thymus was the mediastinal structure which concentrated iodine. Thymus histology was negative for thyroid cancer metastases (as further confirmed by the negative immunostaining) and showed cystic Hassall's bodies. Secondary ion mass spectrometry microscopy demonstrated that iodine was located only in the Hassall's bodies, bound to proteins. This finding suggests that an acquired "thyroid follicle-like" structure, as that observed in cystic Hassall's bodies, could be responsible for the epithelial cell iodine uptake. In conclusion, we have provided evidence for the iodine-trapping property of the cystic Hassall's bodies of the thymus, which may be a possible cause of misleading mediastinal radioiodine uptake.

Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders.

OBJECTIVE: Iodine deficiency is well known as the cause of several disorders such as endemic goitre and cretinism, along with a wide spectrum of psychoneurological development disorders including endemic mental deficiency and endemic cognitive deficiency, which are generally correlated to damage to the fetus. Such damage is, by inference, deemed a consequence either directly of iodine deficiency or of insufficient availability of thyroxine at the feto-placental unit level. Early pregnancy represents the crucial period for neurogenesis in the embryo. Several experimental studies have emphasized the direct role of maternal T4 in neurological embryogenesis, before the onset of fetal thyroid function and, therefore, its protective role in fetal thyroid failure. The objective of this study was to evaluate whether iodine deficiency may influence thyroid status of pregnant women throughout the first half of pregnancy. DESIGN: Thyroid function tests including total and free T4 and T3, TBG and TSH along with urinary iodine excretion were measured in the serum of pregnant women from an iodine deficient endemic goitre area in north-eastern Sicily, at 8, 13 and 20 weeks of gestation. The times of sampling were chosen to correspond approximately to a period prior to, coincident with and after the onset of fetal thyroid function, respectively. SUBJECTS: The longitudinal study was undertaken in 16 euthyroid pregnant women from the iodine deficient area in which major iodine deficiency disorders such as endemic cretinism and endemic cognitive deficiency in schoolchildren still persist (area A) and in 7 age matched volunteer pregnant women from a marginally iodine sufficient area (area B). MEASUREMENTS: Hormones and TBG were measured using commercial kits. Urinary iodine was measured by an automated method. RESULTS: The divergent changes in serum T4 and TBG with pregnancy progression induced a progressive TBG desaturation by T4 during the whole study period (from 22 to 17% in area A, ANOVA two-way F = 18.9, P < 0.0001; from 33 to 20% in area B, F = 20.7, P < 0.0005) in both areas. At 20 weeks, average FT4 levels were lower in area A than in area B (11.5 +/- 2.5 vs 14.3 +/- 2.4 pmol/l, t = 2.7 P < 0.01) and were below the normal range in 2/16 and borderline-low in 6/16 pregnant women. FT4 serum levels were inversely related to TSH concentrations (r = -0.54, P < 0.0001) which progressively increased, in area A, during the whole study period (F = 6.0, P < 0.01) and were abnormally high in the two women with low FT4, but not in area B. Also in area A (F = 3.4, P < 0.05) a significant T3/T4 molar ratio increase was observed. CONCLUSIONS: Iodine deficiency induces in early pregnancy a series of events (reduced synthesis of maternal T4, TBG desaturation by T4, critical decrease of FT4 levels with consequent TSH increase) responsible for overt or marginal biochemical hypothyroidism in about 50% of pregnant women. It is hypothesized that the imbalance of maternal thyroid hormone homeostasis during pregnancy as a consequence of endemic iodine deficiency may be responsible for the impaired psychoneurological development observed in children from that area so appropriate iodine and/or thyroxine prophylaxis to women in that region may prevent the neurobehavioural, cognitive and motor compromise of the population.