Extrathyroidal Sites Research Articles

Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers.

Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

Functional Water Channels Within the TSH Receptor - a new paradigm for TSH action with disease implications.

The TSH receptor (TSHR) transmembrane domain (TMD) lives in the plasma membrane consisting of lipids and water molecules. To understand the role of TSHR-associated water molecules we used molecular dynamic simulations of the TMD and identified a network of putative receptor associated transmembrane water channels. This result was confirmed with extended simulations of the full length TSHR with and without TSH ligand binding. While the transport time observed in the simulations via the TSHR protein was slower than via the lipid bilayer itself we found that significantly more waters traversed via the TSHR than via the lipid bilayer which more than doubled with the binding of TSH. Using rat thyroid cells (FRTL-5) and a calcein fluorescence technique we measured cell volumes after blockade of aquaporins 1 and 4, the major thyroid cell water transporters. TSH showed a dose-dependent ability to influence water transport and similar effects were observed with stimulating TSHR autoantibodies. Small molecule TSHR agonists, which are allosteric activators of the TMD, also enhanced water transport illustrating the role of the TMD in this phenomenon. Furthermore, the water channel pathway was also mapped across two activation motifs within the TSHR TMD suggesting how water movement may influence activation of the receptor. In pathophysiological conditions such as hypothyroidism and hyperthyroidism where TSH concentrations are highly variable this action of TSH may greatly influence water movement in thyroid cells and many other extrathyroidal sites where the TSHR is expressed thus affecting normal cellular function.

Pathologist-performed ultrasound-guided fine needle aspiration biopsies of extrathyroidal sites: An observational study.

Pathologist-performed ultrasound-guided fine needle aspiration (USFNA) biopsies have become an increasingly important component of the interventional cytopathologist's toolbox. However, its application varies between institutions, and there is limited literature describing its performance characteristics when utilized in extrathyroidal sites. Here we review our institutional experience within our pathologist-run FNA clinic. A retrospective review was conducted of pathologist-performed USFNAs of extrathyroidal sites over a 9-year period. Data collected included lesion site, size, patient age, patient gender, diagnostic category, and corresponding results from surgical resection when available. The diagnosis on surgical resection was considered the gold standard for determining discordance rates. A total of 143 pathologist-performed USFNAs of extrathyroidal lesions were performed from October 2011 to October 2020. These encompassed a wide range of sites, with most biopsies from the head and neck. The mean recorded size was 2.2cm, with a range of 0.6-6cm. Larger lesions (over 2cm) were more likely to be noted in challenging locations, demonstrate difficult features, or be cystic. Most (n =133) biopsies were sufficient for diagnosis, with a non-diagnostic rate of 7% (n =10). Accuracy when compared to subsequent surgical resection was high, with sensitivity of 89%, specificity of 93%, positive predictive value of 94%, and negative predictive value of 87%. Our experience supports that pathologist-performed USFNA of extrathyroidal lesions-even those with challenging features-can result in excellent diagnostic yield and accuracy. The addition of USFNA to the interventional cytopathologists' repertoire can be a valuable tool to enhance patient care.

Corrigendum to: Thyroid Disruptors: Extrathyroidal Sites of Chemical Action and Neurodevelopmental Outcome—An Examination Using Triclosan and Perfluorohexane Sulfonate

Corrigendum to: Thyroid Disruptors: Extrathyroidal Sites of Chemical Action and Neurodevelopmental Outcome—An Examination Using Triclosan and Perfluorohexane Sulfonate

Thyroid Disruptors: Extrathyroidal Sites of Chemical Action and Neurodevelopmental Outcome-An Examination Using Triclosan and Perfluorohexane Sulfonate.

Many xenobiotics are identified as potential thyroid disruptors due to their action to reduce circulating levels of thyroid hormone, most notably thyroxine (T4). Developmental neurotoxicity is a primary concern for thyroid disrupting chemicals yet correlating the impact of chemically induced changes in serum T4 to perturbed brain development remains elusive. A number of thyroid-specific neurodevelopmental assays have been proposed, based largely on the model thyroid hormone synthesis inhibitor propylthiouracil (PTU). This study examined whether thyroid disrupting chemicals acting distinct from synthesis inhibition would result in the same alterations in brain as expected with PTU. The perfluoroalkyl substance perfluorohexane sulfonate (50 mg/kg/day) and the antimicrobial Triclosan (300 mg/kg/day) were administered to pregnant rats from gestational day 6 to postnatal day (PN) 21, and a number of PTU-defined assays for neurotoxicity evaluated. Both chemicals reduced serum T4 but did not increase thyroid stimulating hormone. Both chemicals increased expression of hepatic metabolism genes, while thyroid hormone-responsive genes in the liver, thyroid gland, and brain were largely unchanged. Brain tissue T4 was reduced in newborns, but despite persistent T4 reductions in serum, had recovered in the PN6 pup brain. Neither treatment resulted in a low dose PTU-like phenotype in either brain morphology or neurobehavior, raising questions for the interpretation of serum biomarkers in regulatory toxicology. They further suggest that reliance on serum hormones as prescriptive of specific neurodevelopmental outcomes may be too simplistic and to understand thyroid-mediated neurotoxicity we must expand our thinking beyond that which follows thyroid hormone synthesis inhibition.

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

The thyroid stimulating hormone receptor (TSHR) is the key regulator of thyrocyte function. The gene for the TSHR on chromosome 14q31 has been implicated as coding for the major autoantigen in the autoimmune hyperthyroidism of Graves' disease (GD) to which T cells and autoantibodies are directed. The TSHR is a seven-transmembrane domain receptor that undergoes complex posttranslational processing. In this brief review, we look at the genetics of this important autoantigen and its influence on a variety of tissue functions in addition to its role in the induction of GD. There is convincing evidence that the TSH receptor gene confers increased susceptibility for GD, but not Hashimoto's thyroiditis. GD is associated with polymorphisms in the intron 1 gene region. How such noncoding nucleotide changes influence disease susceptibility remains uncertain, but is likely to involve TSHR splicing variants and/or microRNAs arising from this gene region. Whether such influences are confined to the thyroid gland or whether they influence cell function in the many extrathyroidal sites of TSHR expression remains unknown.

Molecular analysis of antigen receptor variable region repertoires in T lymphocytes infiltrating the intrathyroidal and extrathyroidal manifestations in patients with Graves' disease.

To determine whether T cells infiltrating thyroid, orbital and pretibial tissue of patients with Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD) represent a primary immune response that is directed against certain antigenic determinants shared between these involved tissues, we characterized these T cells at the molecular level. T cell antigen receptor (TcR) variable (V) region gene usage in thyroid, orbital, pretibial tissue and peripheral blood mononuclear cells of patients with GD, GO and PTD was assessed using RT-PCR and 22 V alpha and 23 V beta gene-specific oligonucleotide primers, followed by Southern hybridization analysis using TcR C-region-specific, digoxigenin-labelled oligonucleotide probes. In some instances, CDR3- and junctional regions of TcR V beta genes were sequenced. Marked restriction and similarities of V alpha and V beta gene usage were detected in samples derived from patients with active GO and PTD of recent onset. Moreover, sequence analysis of junctional domains of V beta families revealed oligoclonality of some intrathyroidal, orbital and pretibial T cell populations as well as the presence of conserved junctional motifs shared by T cells derived the thyroid gland and the extrathyroidal sites. These data suggest that similar antigenic determinants may be responsible for the recruitment and oligoclonal expansion of T cells both within the thyroid gland and at the involved extrathyroidal sites in Graves' disease.

Long-Term Outcome of Patients With Differentiated Thyroid Carcinoma: Effect of Therapy

To present an overview of current therapeutic practices and results in patients with differentiated thyroid carcinoma. Personal series of patients and selected studies reported in the literature are reviewed relative to outcome (tumor recurrence and cancer-related mortality) after treatment of differentiated thyroid cancer. In the United States, thyroid carcinoma ranks 14th in incidence among the major malignant tumors. Although many factors influence the long-term outcome with papillary and follicular thyroid carcinoma, the patient's age at the time of diagnosis, tumor stage, and initial treatment are the most important. The risk of death from thyroid cancer becomes substantially greater after age 40 years and increases dramatically after 60 years of age. Tumor recurrence is more prevalent before age 20 and after age 60 years. Delay in therapy for more than a year after initial manifestation also has been shown to have an adverse effect on outcome. The optimal initial treatment is usually near-total thyroidectomy and surgical excision of extrathyroidal tumor, when possible. For complete ablation of residual thyroid tissue, radioactive iodine therapy is usually necessary and should be followed by thyroid hormone suppression of serum thyrotropin concentrations. A schedule of 6-month follow-up intervals is recommended, until the serum thyroglobulin is undetectable and 131I whole-body scanning shows no uptake in the neck or extrathyroidal sites. An aggressive approach to management of differentiated thyroid carcinoma is likely to render about 90% of patients permanently free of disease.

T-cell restriction in thyroid eye disease.

Infiltrating immunocompetent cells act to establish and perpetuate the orbital autoimmune process in thyroid eye disease (TED). Until recently, it has remained unclear whether T cells infiltrating the orbital connective/fatty tissue and extraocular muscles represent a primary immune response that is specifically directed against orbital antigens. In addition, despite a close clinical and temporal association of the thyroidal and extrathyroidal manifestations in Graves' disease (GD), it has not been proven whether T cells infiltrating thyroid, orbital, and pretibial tissue in patients with TED and pretibial dermopathy (PTD) are directed against certain antigenic determinants shared between these anatomically distinct tissues. Using polymerase chain reaction (PCR)-based molecular analysis of T-cell antigen receptor (TcR) variable (V) region genes, we have demonstrated marked restriction of orbital and pretibial TcR Valpha and Vbeta genes in patients with active TED and PTD. In addition, molecular analysis of T cells in paired samples of extraocular muscle and orbital connective/fatty tissue revealed usage of similar TcR V genes. In contrast, TcR V gene restriction was either absent or much less pronounced in patients with longstanding TED and PTD. Comparison of TcR V genes in T cells obtained from thyroid gland, orbital tissue, pretibial tissue, and peripheral blood of three individual patients with active GD, TED, and PTD also revealed marked restriction and, in addition, striking similarities of TcR V gene usage. Sequencing of complementarity determining regions 3 (CDR3) and junctional domains of TcR Vbeta genes confirmed oligoclonality of intrathyroidal, orbital, and pretibial T cells. Moreover, several conserved junctional motifs were shared by T cells infiltrating the thyroid gland and the extrathyroidal sites. Taken together, these data suggest that, in patients with GD and extrathyroidal manifestations, similar antigenic determinants may be responsible for recruitment and oligoclonal expansion of T cells both within the thyroid gland and in the involved extrathyroidal sites.

TSH receptor transcripts and TSH receptor-like immunoreactivity in orbital and pretibial fibroblasts of patients with Graves' ophthalmopathy and pretibial myxedema.

Several lines of experimental and clinical evidence favor a close etiologic link between Graves' disease and its associated extrathyroidal manifestations, ophthalmopathy and pretibial dermopathy. The human TSHR represents a candidate antigen shared between the thyroid gland and the involved extrathyroidal sites in Graves' disease. Here, we demonstrate that ribonucleic acid encoding exons 1-10 of human TSHR can be detected in fibroblasts derived from the affected orbital and pretibial space in patients with Graves' ophthalmopathy and pretibial dermopathy. RNA prepared from cultured fibroblasts was reverse transcribed and the resulting cDNA amplified by the polymerase chain reaction using primers spanning exons 1 through 10 of TSHR. The predicted transcripts (1890 and 2092 bp, respectively) were obtained with cDNA derived from orbital and pretibial fibroblasts of all patients with GO and PTM, and orbital fibroblasts of one healthy individual, and confirmed by southern hybridization. Sequencing of TSHR transcripts confirmed their identity with the reported nucleotide sequence of the human TSHR. Immunostaining using both monoclonal and polyclonal antibodies directed against the recombinant human TSHR revealed specific TSHR-like immunoreactivity in fibroblasts and adipose/connective tissue derived from the orbital and pretibial space of patients with GO and PTD, but not in normal individuals or control tissues. Detection, within the orbital and pretibial tissues, of RNA encoding nonvariant hTSHR and of immunoreactivity for this important autoantigen in Graves' disease suggests that the pathogenic role of the TSHR may extend beyond the thyroid gland, and may include the associated extrathyroidal manifestations.

The effect of short term feeding of the antioxidant triethyleneglycol-bis-3(3-tert-butyl-4-hydroxy-5-methyl)propionate on serum thyrotropin and thyroid hormones in the male rat

Male rats were fed triethyleneglycol-bis-3(3-tert-butyl-4-hydroxy-5-methyl)propionate (TK 12627) admixed with the food at a concentration of 1000 ppm for 3, 6, 13, and 20 days. Treatment resulted in time-dependent and marked increases in serum levels of thyrotropin (TSH) and reverse triiodothyronine (rT 3). Serum levels of thyroxine (T 4) were slightly and transiently decreased, whereas triiodothyronine (T 3) levels decreased by 35–50% at all time periods. Treatment with 50, 150, 500, and 1000 ppm for 2 weeks resulted in dose-related increases in thyroid and liver weights, follicular hypertrophy of the thyroid, morphological changes of the pituitaries, liver hypertrophy, and similar changes in the serum parameters described above. At 50 ppm, no alterations in the weights and morphology of the liver, thyroid, or pituitary nor in the serum levels of TSH or T 4 were observed. The effects of TK 12627 observed at a dose of 1000 ppm for 2 weeks were reversible after cessation of treatment. Decreases in T 3, increases in rT 3, and no change in T 4 serum levels were also obtained when thyroidectomized T 4-substituted rats were treated with 1000 ppm TK 12627 for 28 days, indicating that the effects of TK 12627 are probably due to inhibition of the 5′ monodeiodination of T 4 to T 3 and rT 3 to diiodothyronine with compensatory increases in thyroid hormone conjugation at extrathyroidal sites.

Extrathyroidal effects of thiourea treatment in rainbow trout ( Salmo gairdneri) rapidly transferred from fresh water to dilute sea-water

1. 1. Exposure of yearling rainbow trout, Salmo gairdneri, to either 0.3 or 0.5‰ thiourea (TU) in fresh water (FW) or subsequently in dilute sea-water (SW); impaired osmoregulatory performance in both media. 2. 2. TU treatment resulted in depression of gill Na +/K +-ATPase activity in SW (in 0.5‰ TU) or delayed adaptive increase in ATPase activity (in 0.3‰ TU) following SW entry as compared to control fish. 3. 3. Plasma Na + and Cl − levels decreased in FW fish and increased in SW-acclimated fish exposed to TU. 4. 4. T 4 replacement did not abolish these effects. 5. 5. Neither did TU treatment depress circulating levels of total T 4, and the observed effects were probably associated with TU toxicity in extrathyroidal sites. 6. 6. The effectiveness of TU to block thyroid function in fish is discussed.

Presence of immunoreactive calcitonin in the hypothalamus and pituitary lobes of rats

We have found calcitonin-like immunoreactive material in extracts of hypothalami from six-month old, male rats. The level of this immunoreactivity, 0.21 ng/hypothalamus, is substantial considering out lower limit of detection of 0.006 ng of rat calcitonin. However, the hypothalamus contains less calcitonin-like immunoreactive material than either the anterior lobe (1.16 ng) or neurointermediate lobe (0.81 ng) of the pituitary. Taken together these three sources of calcitonin-like immunoreactive material contain less than one thousandth the immunoreactivity found in the thyroid. The exact nature of the calcitonin-like immunoreactive material found in these extrathyroidal sites and its physiological role, if any, remain to be discovered. The recent report of the occurrence of calcitonin receptors in the hypothalamus and other brain regions in conjunction with our finding of calcitonin-like immunoreactivity in the hypothalamus suggests that calcitonin-like molecules may be active within the brain.

STUDIES ON THE MECHANISM OF GOITROGENIC ACTION OF DIPHENYLTHIOHYDANTION

Diphenylthiohydantoin (DPTH) is a potent goitrogenic compound and produces a large goiter in rats. Like methimazole, DPTH depresses plasma thyroxine (T4) and triiodothyronine (T3) concentrations and elevates plasma TSH concentration. Unlike methimazole, however, DPTH does not suppress thyroidal radioiodine uptake and thyroid hormone synthesis. DPTH does not depress thyroidal radioiodine release nor augment the degradation of thyroid hormone. DPTH depresses an increase of plasma T3 and T4 in thyroidectomized, T4- and T3-maintained rats by augmenting fecal excretion of hormones. In addition, DPTH depresses peripheral conversion of T4 to T3 in vitro.It is suggested that DPTH is an unique goitrogen which acts on 2 different extrathyroidal sites, viz. fecal loss of thyroid hormone and conversion of T4 to T3.

Choice of thyroid function tests

IODINE METABOLISM AND THE THYROID - The thyroid gland concentrates iodide which is oxidised in the gland and later released as iodinated amino acids thyroxine (tetra-iodothyronine) (T4) and liothyronine (tri-iodothyronine) (T3) - mainly T4. T4 and T3 are transported in the blood almost completely bound to thyroxine binding globulin (TBG). Thyroid hormone release is regulated by thyroid stimulating hormone (TSH) from the pituitary, which is in turn controlled by thyrotrophin releasing factor from the hypothalamus. This mechanism responds to plasma levels of thyroid hormone. In hypothyroidism due to disease of the thyroid itself (primary hypothyroidism), blood levels of TSH are high; in hypothyroidism due to pituitary disease (secondary hypothyroidism) they are low. Iodide is largely excreted passively through the kidney. Extra-thyroidal sites of iodide concentration are not influenced by TSH, but may be relevant to the diagnostic and therapeutic use of radio-iodine, e.g. during lactation.

The metabolism of I131 by surviving slices of rat mammary tissue.

TWO juxtaposed, dissociable processes participate in the thyroidal manufacture of hormone. First, the thyroid transports inorganic iodide against a concentration gradient (VanderLaan and VanderLaan, 1947; Taurog, Chaikoff and Feller, 1947). Secondly, the accumulated anion is employed in organic iodinations within the thyroid gland (Morton and Chaikoff; 1943; Schachner, Franklin, and Chaikoff, 1944). Isolated similar functions have been reported in extrathyroidal sites. For example, concentration differentials for ionic iodide are regularly established in saliva and in gastric secretions (Lipschitz 1929; Schiff, Stevens, Molle, Steinberg, Kumpe and Stewart, 1947). As yet, an extrathyroidal model displaying both properties has not been described. In 1944, the classical experiments of Keston demonstrated the presence of soluble iodinating enzymes in unpasteurized milk. Van Middlesworth, Tuttle, and Haney (1954) have shown that such iodinations of milk proteins may also occur in vivo. Recently, Honour, Myant,...