The Natural Thyroid Diet

Thyroid Factor

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Biology of Thyroid Hormone Receptors

Thyroid hormone receptors (TRs) play a major role in animal physiology. TRs are important and very interesting regulators of diverse aspects, including brain development, hearing, bone growth, morphogenesis, metabolism, intestine, and heart rate in vertebrates (Fig. 1). Aberrant functions of TRs induce tremendous defects in these pathways. For example, the human disease of Resistance to Thyroid Hormone (RTH) (see Chapter 8 by Yoh and Privalsky) is a genetically autosomal dominant inherited syndrome that is caused by mutations in the gene encoding the TR . The role of the ligand of TRs, the thyroid hormone, is to modulate the activity and functionality of TRs. Two separate genes encode two highly homologous TRs, TRa and TR . The TRa gene is localized on chromosome 17, while chromosome 3 harbors the TRp locus. Each gene encodes for several isoforms due to alternative splicing and alternative promoter usage (Fig. 2) (1-3). The expression patterns of TRa and TR are different, although...

General Categories Of Thyroid Problems

The general categories of thyroid problems are as follows Hypothyroidism the thyroid is unable to make and secrete adequate amounts of thyroid hormones to maintain a euthyroid state. Hyperthyroidism the thyroid is no longer under normal pituitary-hypothalamic control and produces and secretes excessive amounts of thyroid hormones. Thyroid nodules and goiter the thyroid may be working normally, but it enlarges (goiter) or develops lumps (nodules).

Classification of Follicular Derived Thyroid Carcinomas

Although the most important clinicopathologic predictors of aggressive clinical behavior for thyroid carcinomas are patient age, tumor size, and tumor stage, cytologic and histologic features that we recognize in daily practice can be used to divide neoplasms of thyroid follicular cells into three general categories that differ in clinical aggressiveness well- Well-differentiated thyroid carcinomas, representing the majority of thyroid cancers, have an excellent overall prognosis with mortalities in the range of 3 to 6 . In contrast, undifferentiated thyroid carcinoma, at the opposite end of the spectrum, is an extremely aggressive malignancy associated with greater than 90 mortality and a mean survival of only 2 to 6 months. Poorly differentiated carcinomas, insular carcinoma being the classic example, are characterized by a clinical behavior and mortality rate intermediate between that of the well-differentiated and undifferentiated thyroid carcinomas. These three groups of thyroid...

Approach To Evaluati On Of The Thyroid Patient

This section discusses the approach that I have used for many years in evaluating patients with possible thyroid disease. Because most of my patients are referred for suspected thyroid disease, it is easier for me to focus in on the problem. It is more difficult for the primary care physician (PCP) who must distinguish possible patients with thyroid problems from the large number of patients seen in the office every day. However, I think this general approach may be utilized by the PCP when thyroid disease is considered in the differential diagnosis. Age > 60 years Hyperthyroidism Other autoimmune disease Addison's disease Pernicious anemia Diabetes mellitus (type 1) Subacute thyroiditis (overt or silent) Head neck cancer (treated) Family member with thyroid disease Medication use Lithium carbonate Amiodarone Iodine (any form) Routine tests (if previously done) Hypercholesterolemia Thyroid tests (if previously done) TSH, thyroid-stimulating hormone TPO, thyroid peroxidase. (From...

Liver as Target for Thyroid Hormone

The liver is a major target organ of thyroid hormone. It has been estimated that approx 8 of the hepatic genes are regulated by thyroid hormone in vivo (1). We have used a quantitative fluorescent cDNA microarray to identify hepatic genes regulated by thyroid hormone. We sampled 2225 genes on the cDNA microarray, which represents approx 10 of the expressed genes in liver, assuming that the liver transcriptosome contains 10,000-20,000 genes (25). cDNA microarray hybridization is a powerful tool to study hormone effects on cellular metabolism and gene regulation on a genomic scale, as it enables simultaneous measurement and comparison of the expression levels of thousands of genes (26,27). Recently, cDNA microarrays have been used to study the gene expression due to fibroblast differentiation, oncogenesis, aging and caloric restriction of mouse muscle, cell cycle in yeast, and differentiation in Drosophila (28,30-34). Microarray technology is based on an approach where cDNA clone...

Thyroid Hormone and Brain Development

Among the most dramatic actions of thyroid hormone are those exerted on brain development and function. In the adult human brain, a deficiency or excess of thyroid hormone may lead to various psychiatric manifestations, but it is during development when thyroid hormone exerts its most varied and critical actions on neural tissue. In humans, a deficiency of thyroid hormone taking place during a critical period of development may lead to severe mental retardation and also to neurological defects (1). This critical period may extend from the start of the second trimester of pregnancy to the first few months after birth. During this period, the absence of thyroid hormone, if not corrected by early postnatal treatment, leads to irreversible damage with mental retardation. While in utero, the fetal brain is protected from thyroid deficiency by the maternal hormone. Severe thyroid hormone deficiency in the pregnant woman, especially if combined with fetal deficiency, leads to severe...

Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histoand Cytopathologists Working Together

Because thyroid cancer, in contrast to many other tumor types, is increasing slightly in frequency and the survival rates have not yet been optimized, this tumor needs continuous special attention. Therefore, in thyroid cancer too, early detection, regional node staging, and exact surgical treatment with the aim of R0 resection are all of great importance. The scintigraphically cold node is the indicator for further investigations in order to confirm or to rule out thyroid cancer disease.

Value of the SLN Concept in Thyroid Cancer Treatment

In the course of the last three decades there has been significant progress in locoregional clearance of thyroid cancers It must be pointed out that not only the follicular thyroid cancers show a positive reaction on 131 125I-scintigraphy, but also the papillary cancers, which synthesize thyroglobulin in more than 90 of cases. The paratracheal (retrothyroidal) lymph nodes above and below the isthmus of the thyroid gland

Dependence of Therapy Regimens on Sentinel Lymph Node Status in Thyroid Cancer Subtypes

In cases with papillary or follicular thyroid cancer classed as pT1aN0M0 no further adjuvant treatment is given, whereas in thyroid cancer classed as pT1a and higher pTsN1M0 and M+ a radioiodine treatment regimen is applied in institutes of nuclear medicine (see also Chapter 33). In papillary cancers with the highest rate of regional lymphatic spread, the adjuvant therapy problem is looked at in a different way. A large proportion of papillary thyroid cancers are seen clinically by reactions to radioiodine and, in addition, in reactions to antibodies directed to thyro-globulin, which are positive in more than 90 of cases. Therefore, radioiodine therapy is performed in more highly differentiated cases with cancer-infiltrated regional (sentinel) lymph nodes. In undifferentiated invasive thyroid cancers the sentinel node concept does not play any significant part, because of the diffuse regional cancer invasion. It must be made clear that in approximately 510 of cases cancer of the...

Cystic Lesions of the Thyroid

Thyroid cysts are common lesions that most often result from cystic degeneration in an adenomatous nodule. However, any type of thyroid nodule can undergo cystic degeneration, including follicular adenomas, follicular carcinomas, Hurthle cell neoplasms, and papillary thyroid carcinomas (PTCs). In some studies, as many as 15 to 25 of solitary thyroid nodules and up to 37 of all thyroid nodules are at least partially cystic. Often the cysts evolve secondary to hemorrhagic degeneration within the nodule. In addition to cystic degeneration of follicular-derived lesions, other nonfollicular cysts including thyroglossal duct cysts, branchial cleft-like cysts, and parathyroid cysts can also occur in or near the thyroid gland and are amenable to fine needle aspiration (FNA). The risk of malignancy in a thyroid cyst is low, occurring in less than 4 of purely cystic nodules, but the risk increases up to 14 for mixed solid and cystic lesions, cysts larger than 3 to 4 cm, and recurring cysts. By...

Papillary Thyroid Carcinoma

One of the most important roles of thyroid fine needle aspiration (FNA) is the diagnosis of papillary thyroid carcinoma (PTC). PTC is the most common malignancy of the thyroid, representing approximately 60 to 80 of thyroid malignancies. PTC occurs more often in women, and although it can occur at any age, even in childhood, the peak incidence is in patients between 30 and 50 years of age. PTC typically has an indolent clinical course and can be cured by thy-roidectomy and radioactive iodine therapy, even if metasta-tic. Because of these therapeutic implications, an accurate FNA diagnosis is essential. When metastatic, PTC spreads to regional cervical lymph nodes that drain the thyroid gland. Consequently, FNA can also be used to monitor patients for recurrence of PTC. An array of PTC variants are recognized, and some, such as the tall cell variant, columnar cell variant, and diffuse sclerosing variant, can display a more aggressive clinical course and may even develop resistance to...

Gene Regulation by Thyroid Hormone Receptors

Thyroid hormone functions by regulating gene expression through thyroid hormone receptors (TRs). TRs are DNA-binding transcription factors that belong to the steroid hormone receptor superfamily (5-7). Like most other members of this family, TRs consist of several distinct domains, including the From Methods in Molecular Biology, Vol. 202 Thyroid Hormone Receptors Methods and Protocols Edited by A. Baniahmad Humana Press Inc., Totowa, NJ TRs regulate gene expression mainly as heterodimers with 9-cis retinoid x receptors (RXRs) (5-9). TR RXR heterodimers are nuclear proteins that bind constitutively to thyroid hormone response elements (TREs) in chromatin (10,11). Current understanding suggests that TR RXR has dual functions repressing target gene expression in the absence of T3 and activating it when T3 is present (9,12). Both transcriptional repression and activation appear to be mediated by mul-ticomponent cofactor complexes. In the absence of thyroid hormone, TR RXR binds to...

Medullary Thyroid Carcinoma

Unlike most other carcinomas arising in the thyroid gland, medullary thyroid carcinoma (MTC) is a malignancy with neuroendocrine features, derived from the parafollicular C cell, which is of ectodermal neural crest origin. In most studies, MTC represents 3 to 12 of thyroid cancers, the majority of which are sporadic. However, in approximately 25 to 30 of cases, MTC is inherited, and is associated with one of three familial syndromes multiple endocrine neoplasia (MEN) syndrome type 2A, MEN type 2B, and familial medullary thyroid carcinoma (Table 10.1). In contrast to sporadic cases of MTC, germline RET proto-oncogene mutations are often detected in inherited cases, which may facilitate early diagnosis. Clinically, patients with sporadic MTC present with a solitary, circumscribed thyroid nodule, often in the mid- to upper half of the thyroid gland. Patients tend to be middle-aged adults, but in familial cases, patients often present at a younger age. Virtually all patients with MTC have...

Parathyroid hormone PTH

Other hormones including thyroid and pituitary hormones, and adrenal and gonadal steroids, also have major effects on the skeleton, as seen in clinical disorders in which their secretion is abnormally high or low. Many additional factors, notably cytokines and growth factors, also play a role in skeletal metabolism, in many cases by interacting locally with systemic hormones. Mechanical loading of the skeleton is also a major influence over bone remodelling.

Thyroid hormone and the hippocampus

Thyroid hormone receptors (TR) are expressed throughout the forebrain of the developing and adult rat. There are two gene products, TR alpha and TR beta, each of which has several alternately spliced variants. TR alpha 1 binds thyroid hormone, whereas the TR alpha 2 splice variant does not TR beta 1 and TR beta 2 have identical sequences in their DNA-binding, hinge-region, and ligand-binding domains and differ only at the amino terminal region as a result either of alternative splicing or alternative promotor usage (Lechan et al., 1993). In adult life, TR alpha 1 and TR alpha 2 mRNA are expressed at similar levels in olfactory bulb, hippocampus, and granular layer of the cerebellar cortex, whereas TR beta mRNAs were concentrated in the anterior pituitary and parvocellular paraventricular nucleus (Bradley, Young, and Weinberger, 1989). A related mRNA, REV-ErbA alpha, which fails to bind thyroid hormone, was concentrated in the cerebral cortex (Bradley, Towle, and Young, 1992 Bradley,...

Generation of Hypothyroid Rats and Mice

The induction of severe hypothyroidism is essential to observe changes in gene expression by thyroid hormone. Moderate hypothyroidism leads to physiological changes aimed at maintaining T3 concentrations in neural tissue within normal levels. The most important mechanism concerns deiodinase type 2 (D2). D2 is a selenoenzyme that catalyzes the removal of the iodine atom in the 5' position of T4 to generate the active hormone, T3. D2 activity is inhibited by T4 through a mechanism involving increased degradation of the enzyme in proteasomes. In situations of low T4, the increased expression and activity of D2, with the concomitant increased efficiency of T4 to T3 conversion, tends to maintain T3 concentrations constant (30). Therefore, only under very severe hypothyroid conditions are T3 concentrations low in the brain, in contrast with other tissues, such as the liver or kidney. Hypothyroidism can be induced in the rat by surgical or chemical means. Surgical thyroidectomy procedures...

The Thyroid Hormone Axis

TRH neurons are located in the paraventricular nucleus where the presence of the orexin-2, but not orexin-1 receptor mRNA has been reported (30). The presence of OX2R or OXjR receptors specifically on TRH neurons and orexin (hypocretin) projections to TRH neurons have not been reported. Nevertheless, an interaction between orexins and the thyroid axis is intriguing and requires further study since thyroid hormones are important in the regulation of energy expenditure and catecholaminergic responses and, the orexins also influence these systems. No changes in prepro-orexin mRNA or orexin receptor levels with medical thyroidectomy or hyperthyroidism, however, have been observed (31). The effects of thyroid hormone manipulations on peptide content and release have not been reported. Since the orexins have been shown to have profound effects on sleep, wakefulness, and locomotor activity, changes in orexin levels may parallel or oppose the effects of low thyroid hormone status on these...

Preliminary Results in Nstaging of Medullary Thyroid Cancer

For curative treatment of medullary thyroid cancer, accurate determination of the extent of disease and early identification of any metastases is of critical importance. There is no single sensitive imaging modality available for localizing metastases. Therefore, several imaging modalities, e.g. sonography, CT, MRI, and scintigraphy using pentavalent mtechnetium-dimercaptosuccinic acid (DMSA), thallium-201, mIn-pentetreotide, radiolabeled anti-CEA antibodies or 123I-metaiodobenzyl-guanidine (MIBG), are performed in patients with elevated calcitonin levels. (This does not apply for tumors of the pancreas and upper gastrointestinal tract, which can occasionally express calcitonin). Cai et al. (2001) compared the expression rates of cytokeratins 7 and 20 and thyroid-transcription factor 1 (TTF1) in cases with pulmonary, gastrointestinal, and pancreatic carcinoids in an attempt to find how discrimination might be improved in me-tastatic carcinoid cases when only metastatic tissue is...

Blood Elements And Foamy Macrophages In Thyroid Cyst

Macrophages Papanicolaou

Obtaining a sample from the solid portion of a thyroid cyst. For most types of cysts, both benign and malignant, the microscopic features of the cyst contents are similar and include a combination of abundant hemosiderin-laden macrophages, foamy histiocytes, blood, proteinaceous debris, watery colloid, and giant cells with foamy cytoplasm (Figure 8.2). Cholesterol crystals may also be present and are best visualized using Diff-Quik stains. The amount of background watery colloid will vary depending upon the nature of the cyst and may be difficult to appreciate. Cystic adenomatous nodules usually have more background watery colloid than cystic neoplasms. The cyst fluid in the aspirate can be clear yellow or bloody however, the gross color of the fluid is not predictive of whether the cyst is benign or malignant. A note of caution when evaluating thyroid cysts when an epithelial component is absent, the specimen should be con- Figure 8.2. Cyst contents. Aspiration of thyroid cysts...

Cystic Papillary Thyroid Carcinoma

Cystic papillary thyroid carcinoma. Despite the hypocel-lularity, rare epithelial groups are identified with diagnostic nuclear features of PTC. A multinucleated giant cell is also present. (Smear, Papanicolaou.) Figure 8.7. Cystic papillary thyroid carcinoma. Despite the hypocel-lularity, rare epithelial groups are identified with diagnostic nuclear features of PTC. A multinucleated giant cell is also present. (Smear, Papanicolaou.) Figure 8.8. Cystic papillary thyroid carcinoma. This aspirate consisted primarily of macrophages and did not contain sufficient epithelial groups to make a definitive diagnosis of PTC. (Smear, Papanicolaou.) Figure 8.8. Cystic papillary thyroid carcinoma. This aspirate consisted primarily of macrophages and did not contain sufficient epithelial groups to make a definitive diagnosis of PTC. (Smear, Papanicolaou.)

Thyroid Hormone

Thyroid hormone, isolated by Kendall in 1915, is one of the first hormones identified in the early last century. Its chemical structure has been known since 1925. Thyroid hormone is synthesized in the thyroid gland. It contains iodine atoms, and its synthesis is based on the amino acid tyrosine. The production of thyroid hormone is controlled by thyroid-stimulating hormone (TSH) secreted by the pituitary. TSH secretion itself is under the control of thyrotropin-releasing hormone (TRH), which is secreted from the hypothalamus. The production of thyroid hormone is negatively regulated in a feedback mechanism. Thereby, thyroid hormone, through binding to its nuclear receptors TRa and TR0, inhibits the genes coding for TSHa, TSH0, and TRH. This regulation and the feedback mechanism is referred to as the hypothalamus-pituitary-thyroid axis (see Chapter 8 by Yoh and Privalsky and Chapter 1 by Gauthier et al). Before the cloning of the receptors for T3, thyroid hormone was known to play a...

Thyroid Physiology

This brief discussion of thyroid-pituitary physiology will help the reader interpret thyroid test results. The thyroid gland produces the thyroid hormones, triiodothyronine (T3) and thyroxine (T4) under the control of the pituitary gland's secretion of thyroid-stimulating hormone (TSH). TSH secretion is also controlled by thyroid-releasing hormone (TRH) from the hypothalamus. A classic endocrine feedback loop (Fig. 1) functions to keep thyroid hormone levels normal in a patient without thyroid or pituitary disease. Thus, a small increase in thyroid hormones in the blood is detected by the pituitary gland (and hypothalamus), and secretion of TSH is decreased. When thyroid hormone levels fall, pituitary TSH secretion rises. The thyroid synthesizes and secretes both T4 and T3. However, much of the T4 that is secreted is deiodinated to T3 in the liver and other peripheral tissues. T3 is the active hormone at the level of the peripheral cell nuclei and at the pituitary and hypothalamic...

Thyroid Imaging

Nuclear Thyroid Scan This scan is often ordered along with the RAIU test. It has been used mainly in the diagnosis of thyroid nodules. The scan is done after administration of a radioactive tracer, either iodine 123 or technecium 99m. These tracers are concentrated in functioning thyroid tissue and can be imaged with a y-camera. In a patient with a thyroid nodule, the report will determine whether the nodule is functioning (warm or hot) or nonfunctioning (cold). Functioning nodules are rarely cancerous, whereas nonfunctioning nodules may harbor a cancer. The problem with this test is that only about 5 to 10 of cold nodules are cancerous the rest are benign. Thus, this test is sensitive but nonspecific. When Should You Order a Nuclear Thyroid Scan The first-line test in diagnosis of thyroid nodules is FNAB. However, when FNAB results indicate the possibility of cancer but are not definite (follicular neoplasm), the finding of a hot nodule on a nuclear scan would make cancer very...

Thyroid Dysfunction

The thyroid gland secretes hormones that control your metabolism, the rate at which your body burns energy. When the thyroid doesn't function properly, it can make your metabolism run too quickly or too slowly. Either problem can interfere with learning and memory. Research with animals demonstrates that changes in levels of thyroid hormones cause physiological changes in the hippocampus. An overactive thyroid (hyperthyroidism) can impair your memory and your ability to sustain attention. Hyperthyroidism is also associated with anxiety, insomnia, and tremor. An underactive thyroid (hypothyroidism) can cause generalized cognitive slowing, sluggishness, and psychiatric symptoms. If you suffer from thyroid problems, getting the proper medical treatment should help prevent or diminish memory difficulties.

Thyroid Cancer

Is the Sentinel Lymph Node Concept Practicable and Acceptable in the Diagnosis and Treatment of Thyroid Cancer In thyroid cancer, extensive neck dissection has long been discontinued rather so-called berry picking of nodes for intraoperative examination by imprint cytology or in frozen sections and paraffin embedding of the residual material with consecutive serial sectioning is practiced. Because no specific basins can be definitely related to particular parts of the thyroid gland. For instance, Kelemen and his colleagues (l998) injected O.l-O.8 ml of l isosulfan blue dye directly into suspicious thyroid masses and found that the blue dye passed along the lymphatics to the sentinel node within seconds. All sentinel nodes located in the paratracheal area were stained blue, while in two cases the jugular nodes were also stained. The authors suggested on the basis of their preliminary results that sentinel node biopsy could be helpful in further decision making. Papillary thyroid cancer...

Parathyroid Cysts

Parathyroid cysts, which can be either nonfunctioning or, less commonly, functioning, are occasionally mistaken for thyroid nodules and aspirated. The fluid obtained from a parathyroid cyst has a characteristic thin, clear, colorless appearance resembling water, reflecting the absence of cells, blood, colloid, and debris. Rarely, parathyroid adenomas can be cystic and contain yellow-brown fluid with occasional groups of parathyroid cells in microfollicles, crowded clusters, or papillary arrangements suggesting a thyroid neoplasm (Figure 8.11). When a parathyroid cyst is suspected based upon the

Thyroid Disease

Thyroid hormones, which are produced by the thyroid gland in the lower front of the neck, regulate the body's energy level. When levels of thyroid hormones are unusually high, a condition known as hyperthyroidism, the body burns energy faster and many vital functions speed up. Hyperthyroidism can make it hard to fall asleep, and night sweats cause nighttime arousals. The most common treatment is radioactive iodine, which stops excessive production of thyroid In other instances, levels of thyroid hormones can be abnormally low, a condition known as hypothyroidism. Feeling cold and sleepy during the daytime is a hallmark of this disorder. People with low thyroid levels tend to gain weight and their muscles don't work as well as they should both situations can bring about obstructive sleep apnea. Hypothyroidism can be treated with replacement doses of synthetic thyroid hormones. Because thyroid function affects every organ and system in the body, the symptoms can be wide-ranging and...

Transcriptional Control by TRs

The analysis of the transcriptional regulatory properties of TR is an exciting field. There are multiple levels of how the activity of TRs can be regulated in a cell. TRs have the interesting characteristic of silencing gene expression (active gene repression) in the absence of thyroid hormone (T3). Addition of T3 renders the receptor from a gene silencer to a gene activator. Thus, the hormone acts as a molecular switch controlling the repression and activation of target gene expression. All three transcription functions, silencing, hormone binding, and gene activation, are localized in the receptor carboxyterminus (15)(Fig. 2) (see Chapter 7 by Dotzlaw and Baniahmad). Lack of hormone binding capability with subsequent lack of target gene activation leads to deleterious defects in vertebrates. Interestingly, this general description of TR-mediated gene regulation is also modulated by the type of TR-binding sequence. Depending on its binding sites, TRs are also able to repress promoter...

Diseases and Developmental Role of TRs

Crystal structure of the TR HBD with the bound thyroid hormone. Crystal structure of liganded TRa HBD shows a predominantly a-helical structure with the pocket to bind thyroid hormone. The only two P-sheets are indicated as arrows. Kindly provided by R. Huber and R. J. Fletterick. Fig. 4. Crystal structure of the TR HBD with the bound thyroid hormone. Crystal structure of liganded TRa HBD shows a predominantly a-helical structure with the pocket to bind thyroid hormone. The only two P-sheets are indicated as arrows. Kindly provided by R. Huber and R. J. Fletterick. mone binding the helix 12 closes the hormone-binding cavity and is responsible for both corepressor dissociation and coactivator binding (19,24). Mutations in the gene encoding TRP, derived from patients with RTH, result in a complete loss or weakening of corepressor dissociation, despite the presence of hormone. Thus, it is expected that TR target genes regulated by classical TREs in patients with RTH are much more...

Introduction and Clinical Aspects

Over the past two decades, fine needle aspiration (FNA) has become an essential step in the evaluation of a thyroid nodule. The purpose of this book is to describe the application of FNA to the assessment of thyroid nodules, with particular emphasis on the key cytologic features that can be used to diagnose FNA specimens based upon a simple algorithmic approach. The clinical application of FNA as a primary diagnostic tool for thyroid nodules is widespread because thyroid nodules are quite common. Within the general population, palpable thyroid nodules are present in 4 to 7 of adults, and subclinical (nonpalpable) nodules are present in up to 70 of individuals. Of these thyroid nodules, 90 to 95 are benign, and include a wide variety of lesions such as adenomatous nodules, simple thyroid cysts, colloid nodules, follicular adenomas, and inflammatory and developmental conditions, among others. Benign Causes of Thyroid Nodules Simple thyroid cyst Chronic lymphocytic thyroiditis Focal...

Xu Feng Paul Meltzer and Paul M Yen 1 Introduction

Thyroid hormone receptors (TRs) and retinoic acid receptors (RARs) are nuclear hormone receptors that play crucial roles in embryogenesis, cell proliferation, differentiation, and metabolism. TRs and RARs repress basal transcription in the absence of ligand and activate transcription upon ligand binding in positively-regulated target genes (1-3). TRs and RARs mediate basal repression through interactions with corepressors, such as nuclear receptor corepressor (NcoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) (4,5). NCoR and SMRT are both 270 kDa proteins that have 43 amino acid homology (4,5). These corepressors have two nuclear hormone receptor interaction domains in the carboxy terminus and three transferable repression domains in the amino terminus (RD1, RD2, RD3) (3,6). RD1 and a region downstream of RD3 have been shown to recruit histone deacetylases (HDAC1 and HDAC2) through direct interaction with Sin3B (3,6-9). The TR corepressor sin3 HDAC causes...

Potential Mechanisms for NCoR Repression of Cell Proliferation

Another potential contributor to hepatocyte proliferation is bcl3 (61), which had increased mRNA expression in the transgenic mice. Bcl3, an IkB protein, interacts directly with NFkB homodimers (62). Bcl3 also interacts with transcription integrators such as SRC-1 and CBP p300 (61) and can function as a coactivator of retinoid X receptor and AP1-mediated transcription (61,63,64). Preliminary analysis of the bcl3 promoter showed that it contains potential myc and thyroid hormone response elements (65), suggesting that bcl3 could be a target gene of Myc Max Mad and TR. We recently showed that bcl3 is a target gene of thyroid hormone (35). Thus, the interaction of NCoR with members of both the nuclear hormone receptor and the Myc superfamilies raise the possibility that there may be cooperativity between the two pathways.

Complications and Contraindications

The most common complication following a thyroid FNA is a hematoma. Most cases of significant hematoma after thyroid FNA are caused by a tear in the capsule of the thyroid gland. This can occur if the patient swallows, speaks, or moves while the needle is in the gland. We also recommend that the needle track remain tightly confined to a narrow region for each pass, rather than utilizing a fanning motion, which can lead to increased tissue damage with associated bleeding. Figure 2.3. Ciliated respiratory epithelial cells. These may be obtained from inadvertent sampling of the trachea during a thyroid FNA. (ThinPrep, Papanicolaou.) Rarely during a thyroid FNA, the needle will pass into the trachea, but this should not be a cause for alarm. Signs that this occurred include cough and a loss of vacuum in the syringe. The patient will occasionally produce a small amount of blood-tinged sputum, but significant bleeding should not occur. Microscopically, the presence of ciliated...

Thin Layer Preparations

Although liquid-based preparations are not intrinsically inferior to smears, it should be recognized that cytologic features differ and that the diagnostic criteria for thyroid lesions are based largely on direct smear preparations rather than liquid-based thin-layer preparations. Specific morphologic differences between direct smears and thin-layer preparations are discussed in the subsequent chapters.

Cloning of the Human cDNA

The vector pCAGGS contains two EcoRI sites flanking a unique XhoI site, located just downstream of the intron of the chicken P-actin promoter (see Note 1). The vector was opened at the EcoRI positions and gel-purified. The pGEM3 vector (Promega), which contained the mutated human cDNA of the thyroid hormone receptor P1 was kindly provided by Stephen J. Usala. The complete coding region could be liberated from the vector backbone by EcoRI digestion and was also gel-purified. Following ligation and transformation of bacteria, clones that had the cDNA inserted in the right orientation were isolated, with the 5' end of the cDNA next to the chicken P-actin intron. Positive clones were verified by sequencing and amplified in LB-amp medium to prepare a plasmid

Assess General Components

Colloid is a proteinaceous substance (containing thyroglobu-lin and thyroid hormone) that is produced by thyroid follic-ular cells. The presence of abundant colloid within a thyroid lesion is generally a benign feature associated with adeno-matous nodules and colloid nodules. Thyroid FNA samples that contain numerous epithelial cells relative to the amount of colloid raise the possibility of a neoplasm. Such samples should be carefully screened for nuclear features of papillary carcinoma (fine chromatin, nuclear grooves, nuclear pseudoinclusions). If these are absent, the differential diagnosis for these lesions includes a follicular neoplasm and a cellular adenomatous nodule, as well as other nonfollicular neoplasms. Lesions that consist largely of macrophages indicate that the lesion is cystic. Most cystic lesions of the thyroid gland represent cystic degeneration of benign adenomatous nodules, but the differential diagnosis also includes cystic PTC. Consequently, it is important to...

Probing Northern Blots for Heart Specific Genes

In our analysis of the transgenic mice, we focused on genes that were known to be regulated by thyroid hormone. We used cDNA probes for SERCA2, rat thyroid hormone receptor a and GAPDH. For the myosin heavy chain genes a and P we used oligonucleotides to gain specificity and be able to distinguish the two isoforms (see Note 7).

Suggested Reading

Guidelines of the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. Mod Pathol 1996 9(6) 710-715. Goellner JR, Gharib H, Grant CS, Johnson DA. Fine needle aspiration cytology of the thyroid, 1980 to 1986. Acta Cytol 1987 31(5) 587-590. Hedinger CE. Histological typing of thyroid tumours. In Hedinger CE (ed) International histological classification of tumours, vol II. Berlin Springer-Verlag, 1988. Rosai J, Carcangiu ML, Delellis RA. Tumors of the thyroid gland. In Rosai J (ed) Atlas of tumor pathology. American Registry of Pathology,Third Series, Fascicle 5.Washington, DC Armed Forces Institute of Pathology, 1992. LiVolsi VA. Surgical pathology of the thyroid. Major problems in pathology, vol 22. Baltimore Saunders, 1990. De los Santos ET, Keyhani-Rofagha S, Cunningham JJ, Mazzaferri EL. Cystic thyroid nodules. The dilemma of malignant lesions. Arch Intern Med 1990 150(7) 1422-1427. Gharib H, Goellner...

Inflammatory Lesions and Lymphoma

Thyroiditis comprises a diverse group of inflammatory thyroid lesions and is one of the most common endocrine disorders in clinical practice. The most frequently encountered form is chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), first described in 1912, and a major cause of goiter and hypothy-roidism in the United States. Clinically, patients are young to middle-aged women who present with a moderately enlarged nodular thyroid that is nontender. Approximately 90 of patients have high circulating titers to thyroid peroxidase and, to a lesser extent, thyroglobulin. Hashimoto's thyroiditis is an autoimmune disorder that is thought to be caused by a derangement of suppressor T lymphocytes. Possible contributing factors to this disease include genetic associations with HLA-DR3,HLA-DR5, and HLA-B8 viral and infectious factors have also been proposed.Approximately 10 of cases are the fibrosing variant of Hashimoto's thyroiditis that presents as severe hypothyroidism in elderly...

General Diagnostic Approach

Using the algorithm (Figure 4.1), thyroid FNAs containing a predominance of inflammatory cells are divided into subsets of disorders based upon the specific types and combinations THYROID FNA of cells present. A variety of pathologically distinct inflammatory processes that affect the thyroid can be diagnosed by FNA. Hashimoto's thyroiditis is by far the most frequently encountered of these lesions, but other less common inflammatory lesions that can also be seen include acute thyroidi-tis, subacute thyroiditis, and Reidel's thyroiditis. In addition, when a predominance of lymphocytes is present in the thyroid aspirate, it is important to use ancillary studies such as flow cytometry to exclude the possibility of lymphoma.

Transcription Factors and Splicing Regulators

Some transcription factors have been found to be under thyroid hormone influence in vivo, including the early response gene NGFI-A (16), the orphan receptor RORa(17), and basic transcription element-binding protein (BTEB) (18). The regulation of transcription factors expression by thyroid hormone obviously should have far reaching physiological consequences. However, it is unknown how the regulated transcription factor target genes are modified in response to thyroid hormone deficiency or excess. In addition to regulation of transcription, recent data suggest that thyroid hormone could be involved in splicing mechanisms by modifying the expression of splicing regulators (19).

Differential Diagnosis and Pitfalls

A challenging diagnostic problem in thyroid cytology is the distinction of Hashimoto's thyroiditis from MALT lymphoma because of the heterogeneous population of lymphocytes in each. Cytologic differences between these two can be very subtle, but features favoring Hashimoto's thyroiditis include a combination of lymphocytes in all stages of maturation with a predominant population of small mature lymphocytes and admixed plasma cells, and lymphohistiocytic aggregates with tingible body macrophages and activated follicle-center cells. Because of the cytologic overlap between Hashimoto's thyroiditis and MALT lymphoma, the ultimate distinction between these two entities depends upon evaluation of light chain restriction through immunophenotyping by flow cytom-etry or immunocytochemistry. Cytologic Features Favoring Hashimoto's Thyroiditis Over MALT Lymphoma The presence of giant cells in thyroid aspirates raises a differential diagnosis that includes subacute thyroiditis as well as...

Clinical Management and Prognosis

For cases in which clinical hypothyroidism is present, chronic lymphocytic thyroiditis is managed by thyroid hormone replacement. Approximately 20 of patients with chronic lymphocytic thyroiditis are hypothyroid at presentation, and approximately 5 of the patients who are euthyroid progress to hypothyroidism each year. Surgical intervention is reserved for those cases in which the thyroid is so enlarged that the patient develops compressive symptoms. When dominant nodules or rapid diffuse thyroid enlargement occur in the setting of chronic lymphocytic thyroiditis, FNA is used to rule out the possibility of a neoplastic condition, particularly lymphoma and PTC. Subacute thyroiditis is a self-remitting painful disorder that in some cases can be associated with hypothyroidism lasting up to several months. Most cases are treated with nonsteroidal antiinflammatory drugs to manage the associated pain, but in some cases the pain is so severe that oral corti-costeroid therapy is needed. A...

Olivier Gandrillon 1 Introduction

The v-erbA oncogene is the most clear-cut case of an oncogene that acts by blocking a differentiation sequence (for a review, see ref. 1). It has been discovered as one of the two oncogenes carried by the avian erythroblastosis virus (AEV), a leukemia-inducing retrovirus. It is derived from the c-erbA proto-oncogene, which encodes the a form of the nuclear receptor for the thyroid hormone triiodothyronine (T3Ra) (2,3 for a detailed description of the structural differences between v-erbA and T3Ra, see ref. 4). Thyroid hormone receptors belong to the large superfamily of structurally and functionally related receptors that includes the receptors for thyroid hormone (T3R), retinoic acid (either all-ira s or 9-cis isoforms, RARs and RXRs) and vitamin D3 (VD3R), which are all lipophilic ligand-regulated transcription factors (5). From Methods in Molecular Biology, Vol. 202 Thyroid Hormone Receptors Methods and Protocols Edited by A. Baniahmad Humana Press Inc., Totowa, NJ

Colloid Predominant Lesions

The term goiter refers to any enlargement of the thyroid gland. However, most goiters are caused by a nonneoplastic, dynamic process in which there is hyperplasia and regression of the follicular epithelium and accumulation of colloid within the enlarged follicles. Grossly, this can lead to the development of multiple nodules of varying sizes within the gland, termed multinodular goiter. Often the largest or dominant nodule is the target of the fine needle aspiration (FNA). Iodine deficiency is a major cause of multinodular goiter in some countries however, in geographic areas where dietary iodine is sufficient, the etiology of multinodular goiter is unknown. It may involve abnormalities in thyroid hormone production and variable sensitivity of follicular cells to thyroid-stimulating hormone (TSH). For unclear reasons, multinodular goiters are more common in women and increase with age. Several synonymous terms have been used to describe these colloid-predominant, nonneoplastic...

Diagnostic Criteria Colloid

Identification of colloid is an important aspect of thyroid FNA evaluation because most colloid-predominant aspirates are benign. Unfortunately, the appearance of colloid is variable and is dependent on the FNA preparation method. Colloid is most easily appreciated in air-dried smears that papillary thyroid carcinoma nuclei papillary thyroid carcinoma nuclei -- I

Ancillary Techniques Thin Layer Preparations

The diagnostic criteria for adenomatous nodules were largely derived from direct smear preparations. Consequently, thyroid FNAs of adenomatous nodules that are processed for thin-layer slides have somewhat different features that must be considered. First, watery colloid in the specimen may be lost during processing, giving the thin-layer preparation a more highly cellular appearance than a smear preparation of the same sample. Some experts believe that colloid resembles a unique tissue-paper-like material on thin-layer preparations (Figures 5.9, 5.10). Because of this potential loss of watery colloid, it is particularly important to notice any fragments of dense colloid on the slide (Figure 5.11). Also, the architectural features of the epithelial fragments take on additional importance. Honeycomb sheets are derived from

Assessing the Role of Normal Receptors in the Differentiation Process

In the case of thyroid hormone action, the final potential source for confusion stems from redundancy. Indeed, we have shown that the potential sources of hormones activating both T3Ra and RARa have to be neutralized in order to obtain a significant decrease in the differentiation ability of the progenitors (41). Such a co-depletion was accomplished by preincubating the complete differentiation medium with the anti-T3 (monoclonal antibody from BioGenesis) at 0.3 (v v) and the RARa-specific antagonist Ro41-5253 at 10-7 M at 4 C for 1 h under constant agitation. Under those conditions, a 40 decrease in the percent of benzidine-positive cells should be observed (41).

Helmut Dotzlaw and Aria Baniahmad 1 Introduction

The transfection and overexpression of the cDNA encoding the thyroid hormone receptor (TR) in mammalian cells has shed light into several aspects of the function and biological characteristics of the TR in cells. Using this method, thyroid hormone and TR-responsive genes and response elements were identified. As well, the diversity of TR binding sequences and the effect of heterodimerization with retinoid x receptor (RXR) were elucidated. Furthermore, the functional domains of the TR, its activation domain, hormone-dependent transactivation function, nuclear localization, dimerization properties, and silencing domain could be identified and characterized (Fig. 1), for (reviews see refs. 1-3). The identification and analysis of functional domains of TR was accomplished mostly by generating fusion proteins of TR parts to a heterologous DNA-binding domain (DBD), such as that of the GAL4-DBD. These fusion proteins permitted the determination of amino acids required for a specific receptor...

Reporter Systems and Assays for Reporter Enzyme Activity

EMSA demonstrating the interaction of TR with the corepressor SMRT. COS cells were transfected with the cDNAs encoding the Gal-TR and or SMRT and treated with or without thyroid hormone (T3). Cell extracts from transfected CV1 cells were prepared and subjected to EMSA using a labeled UAS, the Gal4 binding site. Lane 2 contains a supershifted band of the SMRT Gal-TR UAS complex, demonstrating the hormone-sensitive interaction of SMRT with DNA-bound TR (27). Fig. 2. EMSA demonstrating the interaction of TR with the corepressor SMRT. COS cells were transfected with the cDNAs encoding the Gal-TR and or SMRT and treated with or without thyroid hormone (T3). Cell extracts from transfected CV1 cells were prepared and subjected to EMSA using a labeled UAS, the Gal4 binding site. Lane 2 contains a supershifted band of the SMRT Gal-TR UAS complex, demonstrating the hormone-sensitive interaction of SMRT with DNA-bound TR (27).


CAT Reporter Assay demonstrating the various forms of acetylated chloramphenicol. Hela cells were transfected with the cDNAs encoding TR and TR mutants in the presence of thyroid hormone together with a reporter construct containing TREs upstream of the CAT gene, TRE3x-tkCAT. Shown are the small spot of loading origin, the non acetylated, the two mono-acetylated, and the one di-acetylated forms of chloramphenicol separated by thin-layer chromatography. Increased expression of CAT leads to an increase in enzyme activity and to acetylation of chloramphenicol. Lane 1 shows low CAT expression and lane 3 shows high CAT expression. Fig. 3. CAT Reporter Assay demonstrating the various forms of acetylated chloramphenicol. Hela cells were transfected with the cDNAs encoding TR and TR mutants in the presence of thyroid hormone together with a reporter construct containing TREs upstream of the CAT gene, TRE3x-tkCAT. Shown are the small spot of loading origin, the non acetylated, the two...

Ancillary Techniques

Standard immunocytochemical markers for thyroglobulin and thyroid transcription factor-1 (TTF-1) are useful for distinguishing follicular-predominant lesions of the thyroid from metastatic tumors and nonfollicular thyroid neoplasms. It is disappointing, however, that a sensitive and specific molecular or immunocytochemical test to distinguish benign folli-cular lesions from FCs has yet to be discovered. Until this happens, FNA will remain a screening test rather than a diagnostic test for FC. Markers that have been investigated and which show some promise in a research setting as adjuncts to FNA cytology include galectin-3, thyroid peroxidase, p27 (KIP1), dipeptidyl aminopeptidase, and 3p25 rearrangements of the PPARgamma gene. However, to date, most potential marker studies have had significant limitations in their pre

Sunnie M Yoh and Martin L Privalsky 1 Introduction

Resistance to thyroid hormone (RTH) syndrome is an inherited human endocrine disease, which is manifested as a failure to respond properly to elevated circulating thyroid hormone (1-4). RTH syndrome behaves as an autosomal dominant trait, and has been mapped at the molecular level to a diverse array of mutations within the thyroid hormone receptor (TR)-P locus (1-4). As detailed elsewhere in this review series, TRs bind to specific DNA sequences, denoted thyroid hormone response elements (TREs) and regulate transcription of adjacent target genes in response to thyroid hormone (5-7). TRs typically repress transcription in the absence of hormone and activate transcription in the presence of hormone (8-10). These bipolar transcriptional properties of the receptor are mediated by the receptor's ability to recruit ancillary polypeptides, denoted corepressors and coactivators, to the target promoter (11-16). Corepres-sors and coactivators modulate transcription both by covalent modification...

Diagnostic Criteria General Features

Aspirates of thyroid cysts often contain numerous macrophages but little epithelium. For diagnostic purposes, it is critical to aspirate any solid portion of the nodule, especially to obtain adequate material for cases of cystic follicular neoplasms. Ultrasound-guided FNA is especially useful for

Molecular Cloning of TR Sequences from RTH Syndrome Patients

RTH syndrome patients are identified initially in the clinic as individuals manifesting aberrantly high levels of circulating T3 and T4 thyronine hormone, normal or elevated levels of thyroid-stimulating hormone (TSH), and overt or compensated hypothyroidism (1-4). Typically, once patients are diagnosed with RTH syndrome, genomic DNA is isolated from blood samples and subjected to PCR (PCR) so as to recover adequate material for molecular cloning and for sequence analysis (e.g. 34 ). These approaches generally focus on exons 4 to 10 of the TRP gene, which encode all but the first 8 amino acids of the open reading frame of the receptor. The sequences of the patient TRP genes are then compared to the wild-type TRP sequence to identify any specific base pair substitutions, deletions, or additions (see Note 1). Once a specific TRP mutation has been identified, it can be introduced into a variety of expression vectors for further experimental characterizations. Usually, the RTH syndrome...

Sashko Damjanovski Laurent M Sachs and YunBo Shi 1 Introduction

Thyroid hormone (T3) plays important roles during vertebrate development (1). In humans, T3 is detected in the embryonic plasma by 6 mo and rises to high levels around birth (2). During this postembryonic period, extensive tissue remodeling and organogenesis take place. T3 deficiency during human development leads to developmental defects, such as mental retardation, short stature, and in the most severe form, cretinism (1,3). Likewise, T3 is also critical for amphibian development. It is the controlling agent of anuran metamorphosis, a process that transforms a tadpole into a tailless frog (1,4). Blocking synthesis of endogenous T3 leads to the formation of giant tadpoles that cannot metamorphose, while addition of exogenous T3 to premetamorphic tadpoles causes precocious metamorphosis. Importantly, most, if not all, organs are genetically predetermined to undergo specific changes, and these changes are organ autonomous. Thus, T3 appears to act directly on individual metamorphosing...

Variants of PTC Follicular Variant FVPTC

Several variants of PTC are recognized, some because they can mimic other thyroid disorders, and others because they can be more clinically aggressive than conventional PTC. The most common variant is the follicular variant. Most PTCs contain some follicular structures, but the diagnosis of FVPTC is best reserved for aspirates of PTC containing a predominantly follicular architecture. Although it is not clinically necessary to distinguish classic PTC from FVPTC on an FNA, it is important to distinguish the FVPTC from a follicular neoplasm or adenomatous nodule. The FVPTC represents one of the more common causes of a false-negative diagnosis of PTC. Conversely, some aspirates diagnosed as a follicular neoplasm on FNA are called FVPTC in the corresponding resection specimen. Such discrepancies may result, in part, from the subjectivity of the histologic diagnosis of FVPTC. Until we have a better understanding of the biology and molecular features of FVPTC, we may continue to wrestle...

Use of Chromatin Immunoprecipitation for Investigating TR Action in Development

Anuran metamorphosis is controlled by thyroid hormones (T3). T3 exerts its effects on target tissues via binding to TRs. The presence of TRs in premeta-morphic as well as metamorphosing tadpoles, but not embryos, suggests several testable hypotheses regarding TR binding to its target sites in development and chromatin remodeling including histone acetylation as reviewed in the Subheading 1.

Jiemin Wong 1 Introduction

Genomic DNA in eukaryotic cells is packaged with histone and nonhistone proteins into chromatin structure. Both biochemical and genetic evidences indicate that chromatin structure imposes constraints on nuclear processes including transcription, replication, recombination and repair (1,2). Thus, a central question in study of transcription regulation is how transcription factors function in the context of chromatin. In recent years, it has become increasingly clear that chromatin structure has an important role in regulating gene expression and that transcription factors can actively recruit chromatin-remodeling enzymes to regulate transcription of their target genes positively or negatively (3-6). In this regard, thyroid hormone receptor (TR) is one of the best-studied transcription factors and has contributed its share of information to the current concept of transcription regulation (7-9). From Methods in Molecular Biology, Vol. 202 Thyroid Hormone Receptors Methods and Protocols...

Undifferentiated Anaplastic Carcinoma and Metastatic Disease

Unlike most thyroid carcinomas, undifferentiated carcinoma (anaplastic carcinoma) is an extremely aggressive malignancy with a poor prognosis. It generally occurs in elderly patients where it presents as a large, firm mass that infiltrates extrathy-roid tissues. For most undifferentiated carcinomas, surgical resection is not an effective treatment and only palliative therapies are used. Consequently, the pathologist may be called upon to establish the diagnosis of undifferentiated carcinoma by fine needle aspiration (FNA) to guide the clinical management (Figure 11.1). One of the key entities in the differential diagnosis of undifferentiated carcinoma is a metastasis. Metastatic disease involving the thyroid gland can present as diffuse thyroid enlargement, as multiple nodules, or as a solitary nodule, but it is quite uncommon, being detected in less than 0.1 of all thyroid FNAs. The most frequent metastatic tumors to the thyroid include kidney, colorectal, lung, breast, melanoma,...

Preparation of Nuclear Extract

Fig. 2. (Opposite page) FLAG epitope-tagging as a method for purifying TR-coregulatory protein complexes from mammalian cells. (A and B) Generation of a HeLa-derived cell line that stably expresses a FLAG-tagged human thyroid hormone receptor (f TR). A full-length TR cDNA (in this case, human TRa1) is first inserted inframe into the pFLAG(s)-7 plasmid (12) creating pFLAG-TRa. The FLAG-TRa gene is then subcloned into pBABEneo (13), which is a retroviral transfer vector confering G418-resistance. The pBABEneo-FLAG-TRa construct is subsequently transfected into yCRIP cells (an amphotrophic viral packaging cell line) (14). High titer recombinant virus is then used to infect HeLa cells followed by G418 selection. (C) Strategy for purification of TR-associated coregulatory proteins (e.g., TRAPs). f TR-expressing cells are cultured in media supplemented with thyroid hormone (T3) and then harvested for nuclear extract preparation. Anti-FLAG chromatography (M2-affinity resin), followed by...

Purification of the Trtrap Coactivator Complex from Nuclear Extract

1 mM Thyroid hormone (T3) stock solution dissolve 6.5 mg 3,5,3'-triiodothyro-nine (Sigma, cat. no. T2877) in 10 mL 10 mM NaOH. Filter-sterilize the solution through a 0.2-pm syringe filter and store at 4 C. The solution should be protected from light and is stable for 1-2 mo.

Diagnostic Criteria Undifferentiated Carcinoma

Aspirates of undifferentiated thyroid carcinoma are cytol-ogically high-grade malignancies due to their cellularity, necrosis, and malignant nuclear features. The cells are often dyscohesive and a dispersed single cell pattern is common, sometimes with numerous background naked nuclei. The microscopic appearance of the malignant cells is variable, ranging from squamoid cells, to spindle cells, to giant mult-inucleated tumor cells, or a combination of these cell types (Figures 11.3-11.5). Regardless of type, the nuclei of Figure 11.3. Undifferentiated thyroid carcinoma. A combination of squamoid, spindled, and giant cells is often present. (Smear, Papanicolaou.) Figure 11.3. Undifferentiated thyroid carcinoma. A combination of squamoid, spindled, and giant cells is often present. (Smear, Papanicolaou.) Figure 11.4. Undifferentiated thyroid carcinoma. Clusters of spindle cells with elongate nuclei can be seen. (Smear, Papanicolaou.) Figure 11.4. Undifferentiated thyroid carcinoma....

Ancillary Techniques Immunocytochemistry

An immunocytochemical panel on cell block material can also be useful for metastatic tumors of the thyroid because these tumors are negative for thyroglobulin and most are also negative for TTF-1. Because a majority of patients with metastatic disease have a history of malignancy, a focused immunocytochemical panel can be performed that includes S-100, HMB-45, and MART-1 for aspirates suspicious for malignant melanoma, CK20 for colon carcinoma, RCC and CD10 for renal cell carcinoma, and lymphoid markers for lymphoma.

Branchial Cleft Cysts and Ultimobranchial Body Cysts

Ultimobranchial Cyst

Branchial cleft-like cysts (lymphoepithelial cysts) and ulti-mobranchial body cysts (cystic solid cell nests) are rare in the thyroid gland, and when they do occur it is often in association with Hashimoto's thyroiditis. Aspirates of branchial cleft cysts of the neck and branchial cleft-like cysts of the thyroid are similar and contain turbid proteinaceous fluid and degenerate squamous cells, as well as glandular cells that may be mucin containing or ciliated.Variable amounts of background lymphocytes can be seen, but colloid and follicular cells are absent. Without clinical information, it may be impossible to distinguish a branchial cleft cyst from a thyroglossal duct cyst on the basis of cytologic features alone. An abundance of background lymphocytes and germinal center fragments favors a branchial cleft cyst, but lymphocytes are not always present. Figure 8.10. Ultimobranchial body cyst.The nuclei of cells from this rare thyroid cyst have pale chromatin and nuclear grooves,...

Diagnostic Categories

Diagnostic categories of thyroid fine needle aspirations (FNAs). Hashimoto's thyroiditis Thyroiditis (subacute, acute, Reidel's) Papillary thyroid The benign thyroid FNA category comprises approximately 70 of all thyroid FNAs. The majority of these nodules are adenomatous nodules or colloid nodules. Because the false-negative rate for malignancy in this category is low (less than 1 ), most of these patients are managed without surgical intervention. Thyroid FNAs that fall into the malignant category represent approximately 5 to 10 of all cases, and most of these are PTC. Because of the low (1 -3 ) false-positive rate within the malignant category, patients in this category are usually managed surgically, often by total thyroidectomy.

NCoRi Animal Model to Study Biological Function of NCoR in Liver


Hollenberg et al. (37) have reported that a variant form of NCoR, NCoRi, lacks the repression domains in the amino terminus, but retains the nuclear receptor interaction domains. NCoRi is derived from a 3.1 kb cDNA that was originally isolated from a human placental library. NCoRi protein contains the TR interaction domains and surrounding amino acids (AA 1539-2453), but lacks the repressor domains (AA 1-1120) present in full-length murine NCoR. It also has been shown that NCoRi has dominant negative activity on endogenous NCoR as it blocked basal repression by TR in in vitro transfection assays (37). To study the biological function of NCoR in vivo, we constructed an expression vector containing the NCoRi cDNA and the mouse albumin promoter to target expression of NCoRi to the liver (38) (Fig. 2). NCoRi mRNA was expressed 17 to 146 times higher than endogenous NCoR mRNA in transgenic mouse lines in the euthyroid state (38). Northern blot analysis of various tissues showed that NCoRi...

Indication Of Hyperthythroidism

Drug-Induced Thyroid Dysfunction Whereas most thyroid problems result from endogenous thyroid dysfunction, some problems are secondary to treatment of other medical conditions. The case discussed here demonstrates how challenging the treatment of drug-induced thyroid dysfunction may be in the face of other serious illness. This 52-year-old man was referred because of an abnormal TSH of less than 0.03. He had a long history of ischemic heart disease with serious arrhythmias. Over the previous several months, he had noted heat intolerance, shakiness, and a 30-lb weight loss despite increased food intake. He denied recent palpitations. His first coronary artery bypass graft surgery was at age 33 years and the second at age 45 years. More recently, he had noted recurrent chest pain requiring angioplasty. He had several episodes of ventricular fibrillation and was started on amiodarone 2 years previously. An implantable defibrillator was in place, but it had not fired for about 9 months....

Cell Blocks and Cytospins

Preparing direct smears from a thyroid FNA. It is important to place only a small volume of material on each slide (A), then use a second slide to create a thin smear in the center of the slide (B, C). The slides can be immediately immersed in 95 ethanol for subsequent Papanicolaou staining or air-dried for Diff-Quik staining. Figure 2.4. Preparing direct smears from a thyroid FNA. It is important to place only a small volume of material on each slide (A), then use a second slide to create a thin smear in the center of the slide (B, C). The slides can be immediately immersed in 95 ethanol for subsequent Papanicolaou staining or air-dried for Diff-Quik staining.

Cellular Adenomatous Nodule

Microfollicle Macrofollicle

Aspirates of thyroid nodules composed of follicular cells arranged in a predominantly macrofollicular pattern and lacking nuclear features of PTC are benign, and we diagnose them as adenomatous nodules (Figures 6.2-6.9). A variety of Figure 6.3. Macrofollicle. A feature of benign thyroid nodules, macrofollicles are characterized by an evenly spaced honeycomb arrangement of follicular cells. (Smear, Diff-Quik.) Figure 6.3. Macrofollicle. A feature of benign thyroid nodules, macrofollicles are characterized by an evenly spaced honeycomb arrangement of follicular cells. (Smear, Diff-Quik.) Figure 6.7. Adenomatous nodule. Occasional groups of follicular cells with enlarged nuclei, squamoid metaplasia, or nuclear grooves can be seen in benign thyroid nodules. (ThinPrep, Papanicolaou.) Figure 6.7. Adenomatous nodule. Occasional groups of follicular cells with enlarged nuclei, squamoid metaplasia, or nuclear grooves can be seen in benign thyroid nodules. (ThinPrep, Papanicolaou.) synonymous...

Thyroglossal Duct Cysts

Thyroglossal duct cysts occur from embryologic remnants of the thyroglossal duct, a midline structure associated with the hyoid bone. Although more common in childhood, they can also occur in adults. The fluid often has a mucinous appearance, but it can also be proteinaceous. In contrast to thyroid cysts, however, the fluid seldom has hemorrhagic features and colloid is absent. Aspirates of thyroglossal duct cysts can have a predominance of macrophages and background debris, but they are often more cellular than cystic follicular nodules of the thyroid. The epithelial component of the aspirate can include any combination of several cell types including squa-mous cells, glandular cells, and ciliated respiratory-type cells (Figure 8.9). The epithelial cells are cytologically bland with mild reactive-type atypia.

Wolfgang H Dillmann and Bernd R Gloss 1 Introduction

Thyroid hormone (T3) is an important signaling molecule for cardiac function. Chronic exposure of the heart to either elevated levels of thyroid hormone (hyperthyroidism) or lower thyroid hormone levels (hypothyroidism) have profound effects on cardiac output. Hyperthyroidism increases the risk of cardiac failure dramatically, and hypothyroidism is associated with a diminished contractile performance of the heart, which is frequently compensated by cardiac hypertrophy. The molecular mechanisms that underlie these complex changes in cardiac performance, which are dependent on thyroid hormone are not yet fully understood. We and others have identified key target genes for thyroid hormone that are expressed in the heart and can account for some of the cardiac phenotypes observed in hyper- and hypothyroidism. Because there are reports that thyroid hormone may have so-called extranuclear effects, and there may also be the possibility of indirect effects of thyroid hormone on the heart, we...

Expression of TR and RXR in Xenopus laevis and Its Implications in Frog Development

Interestingly, TRa and TRfi genes are differentially regulated during development. The TRfi genes have little expression prior to metamorphosis, but are themselves direct thyroid hormone-response genes (Fig. 1) (25,28,29). Their expression is up-regulated by the rising concentration of endogenous T3 during metamorphosis. In contrast, the TRa genes are activated shortly after the end of embryogenesis, and their mRNAs reach high levels by Stage 45, when tadpole feeding begins. The expression profiles together with the ability of TR to both repress and activate thyroid hormone-inducible genes in the absence and presence of thyroid hormone, respectively, suggest dual functions for TRs during development (24). That is, in premetamorphic tadpoles, TRs, mostly TRa, act to repress thyroid hormone response genes. As many of these genes are likely to participate in metamorphosis (30), their repression by unliganded TR will help to prevent premature metamorphosis and ensure a proper period of...

Joseph D Fondell 1 Introduction

Thyroid hormone receptors (TRs) are capable of both activating and repressing transcription from genes bearing TR-binding elements (TREs). In general, TRs function as activators in the presence of thyroid hormone (T3) and repressors in the absence of T3 (1). The ability of TRs to regulate transcription has been linked to their ability to recruit distinct types of transcriptional coregulatory factors, termed coactivators and corepressors, to target gene promoters (2,3). Remarkably, yeast 2-hybrid and conventional expression library screens have identified numerous TR-binding coregulatory factors (reviewed in refs. 2 and 3). The best characterized TR coactivators include members the p160 SRC family (2-4). While the precise mechanism of action of the p160 SRC proteins is still being defined, their ability to associate with histone acetyltransferases (HATs) such as the CREB-binding protein (CBP) and p300, and the presence of intrinsic HAT activity in some family members indicates a...

Rc655b69 2005

Thyroid Disease A Case-Based and Practical Guide for Primary Care, by Dr. Emanuel Brams, is a supremely readable cased-based approach to understanding the myriad of disorders that encompass thyroid disease. Using cases derived from his busy practice, Dr. Brams gives us the history and physical examination details of each case, along with test results. Then, through a series of questions similar to that which any good clinician asks while caring for a patient, Dr. Brams explains an optimal approach to diagnosis, treatment, and follow-up of thyroid disease, with an emphasis on the practical and common issues that primary care physicians see in their offices. This is an important book for primary care physicians because thyroid disease is common in the population we take care of and accounts for 3-5 of primary care visits. It is often cited as an area that primary care physicians find confusing. Dr. Brams clarifies thyroid disease and, through his generous sharing of cases, allows us to...


Research on TR is a very interesting and important field, which will provide exciting new information in the future. To shed light into mechanisms of how TRs exert their effects, the identification of TR target genes (genomics) is very important. Although a few TR target genes are known (see Chapter 5 by Bernal and Guadano-Ferrez), at the present stage, only little is known about the identity of genes regulated by TR. It still remains unclear which dysregulated genes are responsible for mental retardation, hearing disorders, bone growth, heart rate (see Chapter 4 by Dillmann and Gloss), morphogenesis (see Chapter 9 by Damjanovski et al.) and the induction of cancer by the oncogene product v-erbA (see Chapter 6 by Gandrillon). Also, further analyses need to be performed to analyze the cellular networking of TR in the context of other cellular factors, coregulators, and chromatin (see Chapter 10 by Wong and and Chapter 11 by Fondell), as well as the mechanisms of cross talk in the...


As with any patient, the first step is to obtain a good history (Fig. 1). Because most of the symptoms of thyroid dysfunction are nonspecific, the PCP must first think about possible thyroid disease from the presenting complaints. For example, the patient might present with weight loss. The physician might think about hyperthyroidism as a diagnostic possibility along with such entities as infection, neoplasm, and anorexia. The most important part of the examination is palpation of the thyroid gland. It is important to have the patient swallow while examining the neck. I usually give the patient a small cup of water to facilitate swallowing. Because the thyroid gland is attached to the thyroid cartilage, you can feel it move with swallowing. Check for nodules, tenderness, and consistency of the tissue. If the thyroid is enlarged, the odds of thyroid dysfunction as a cause of the complaints increase markedly. A careful cardiac exam may show increased heart tones or irregular rhythm. Ask...

PreFNA Evaluation

Historically, patients with a thyroid nodule have received a radionuclide scan as well as a thyroid ultrasound examination before an FNA. More recently, it is recognized that for many patients this is neither necessary nor cost-effective. The main purpose of a radionuclide scan is to rule out a hyperfunc-tioning thyroid nodule, as these are rarely malignant. Because a hyperfunctioning nodule will suppress thyroid-stimulating hormone (TSH) production by the pituitary, a sensitive serum test for TSH levels can be used in place of a radionuclide scan. An abnormally low serum TSH level suggests a hyperfunc-tioning nodule that can then be evaluated clinically before performing an FNA. Thyroid ultrasound examination is useful in the evaluation of small, difficult to palpate nodules and may give information about cystic areas and calcifications. However, ultrasound does not offer sufficient sensitivity or specificity for malignancy to eliminate the need for an FNA. Large, easily palpable...


The term incidentaloma has been coined for any small (less than 1cm) thyroid nodule that is incidentally discovered during a procedure intended for a different purpose, such as a computed tomography (CT) scan of the cervical spine or an ultrasound study of the carotid arteries. Because the incidence of malignancy in these small lesions is low, physicians should have a high threshold for performing an FNA on these nodules, particularly within a multinodular gland in patients without other indications.


For most patients with a thyroid nodule, their clinical history does not contribute significantly to the FNA diagnosis. Features of the clinical history that do raise the suspicion of a thyroid malignancy in patients with a thyroid nodule include male gender, age less than 20 years or greater than 70 years, dysphagia or hoarseness, a history of neck irradiation during childhood or adolescence, a family history of thyroid disease especially papillary thyroid carcinoma (PTC), medullary carcinoma (MC), or multiple endocrine neoplasia (MEN) , or a rapid increase in the size of a long-standing goiter. Other useful clinical information includes a history of Hashimoto's thyroiditis, a history of Graves' disease or 131I therapy, or a history of a nonthyroid malignancy. Clinical Features That Raise the Suspicion of Malignancy in a Thyroid Nodule Family history of thyroid disease, especially PTC or MC Family or personal history of an MEN syndrome Dysphagia or hoarseness

Physical Examination

Physical examination of the thyroid is an art that develops with experience. Often, large nodules can be seen as an asymmetric bulge in the neck, so careful observation is recommended before palpation. Some texts recommend the use of one's thumbs to examine the thyroid, but we find the first and second fingers to be more sensitive in identifying nodules. Rather than standing behind the patient and reaching around to palpate the thyroid (which can be impractical and unnerving for the patient), we recommend standing to the patient's right side as the patient sits upright on an examination table. The first and second fingers of the right hand are then used to palpate the thyroid gland (this position may be reversed for left-handed examiners). To palpate the thyroid, the practitioner should place his first and second fingers firmly and deeply into the angle formed between the trachea and the insertion of the stern-ocleidomastoid muscle into the sternum (Figure 2.2). While the fingers are...


Thyroid testing has come a long way in the past 50 years. The tests discussed here should help you sort out most thyroid problems. TSH is now the first-line test in evaluating patients suspected of having thyroid dysfunction and in thyroid screening. FNAB is the first-line test in evaluating most thyroid nodules. The other tests reviewed in this chapter are useful in specific patients. The problem of nonthyroidal illness in acutely ill patients is often difficult to sort out, but the points listed here should be helpful.

Patient Preparation

Once a thyroid nodule has been identified, and informed consent has been obtained, the patient should be asked to recline on the examination table. A pillow may be placed under the patient's shoulder blades to permit a slight hyperextension of the neck. Be aware that this maneuver is uncomfortable or impossible for patients with cervical spine sensitivity. Patients' necks should never be markedly hyper-extended for long periods. Once positioned, the patient's thyroid nodule should be repalpated with the left hand while

Selected Sources

Baloch Z, Carayon P, Conte-Devoix B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003 13 3-126. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination a decision and cost effectiveness analysis. JAMA 1996 276 285-292. LoPresti JS. Laboratory tests for thyroid disorders. Otolaryngol Clin North Am 1996 29 557-575 Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients a systematic review. Arch Intern Med 1999 159 658-665


Using universal precautions against blood contact, sterilize the skin above the nodule using an alcohol pad. Some aspirators use Betadyne, but we believe this is not necessary. Also, local anesthesia does not need to be used for palpation-guided thyroid FNAs however, this is up to the discretion of the practitioner. With the first finger of the left hand inferior to the nodule and the second finger superior to the nodule, the patient should be prepared for aspiration by saying, Please swallow (patient swallows) now don't swallow or speak while I'm taking the sample. While holding the nodule firmly in place with the first two fingers of the left hand, you should insert the needle with the right hand (see Figure 2.2). The insertion of the needle should be steady and smooth, rather than an abrupt stabbing motion, which can alarm the patient. Thyroid FNA Technique Adequate sampling is absolutely essential for accurate thyroid FNA. For this reason, we recommend a minimum of three passes...


The patient claimed that the heat intolerance was intermittent. She also admitted to diarrhea, nervousness, and a hyper feeling recently. She had gained 10 lb over the previous 9 months since she quit smoking. TSH was 0.1 (0.4-4.5). She denied any family history of thyroid disease, but her mother recalled that a cousin of the patient had Graves' disease and was treated with thyroid surgery. The patient's only medication was a P-blocker prescribed recently by her family doctor. Physical examination revealed a pulse of 120. Bilateral lid lag was present, but there was no proptosis and eye movements were normal. The thyroid was diffusely enlarged to twice the normal size. The heart showed a regular rhythm at 120 beats per minute. There was no tremor or muscle weakness. The patient is clinically hyperthyroid, as confirmed by the low TSH. Although Graves' disease is the most likely diagnosis, the differential diagnosis includes autoimmune (silent) thyroiditis and subacute thyroiditis...

Direct Smears

If direct smears are made, we recommend two to four smears per pass, with half air-dried for subsequent Diff-Quik staining and half placed immediately into 95 ethanol for subsequent Papanicolaou staining. We believe that the Diff-Quik and Papanicolaou stains are complementary in the analysis of thyroid FNAs (see Table 2.1). Air-drying and Diff-Quik staining highlights colloid and amyloid and offers the possibility of immediate diagnostic assessment. Ethanol fixation and Papanicolaou staining highlights nuclear details such as the pale chromatin, grooves, and pseudoinclusions of papillary carcinoma. One key to ideal preparation lies in the FNA procedure itself. As mentioned previously, it is important to minimize the volume of blood in the specimen through proper FNA technique. Unless the lesion is cystic, the specimen should not exceed the volume of the needle and the needle hub (approximately 200ml). With this volume, virtually the entire specimen can be expelled onto four slides,...


The vector pCAGGS was originally described by Niwa et al. (14) and was intended to be used in a slightly modified form, for transient and stable expression of cDNAs in cultured cells. The promoter and enhancer that were used in this vector were initially tested in front of a P-galactosidase gene and were compared with the Rous sarcoma virus (RSV) long terminal repeat (LTR) and the CMV immediate early enhancer in transient transfection experiments into four different cell lines. The unique combination of the chicken P-actin promoter and the CMV immediate early enhancer proved to be a strong driver of linked reporter genes in a variety of cell lines. We have used this vector (see Note 1) to insert a mutated cDNA of the human thyroid hormone receptor Pi as an EcoRI fragment illustrated in Fig. 3. 2. The plasmid containing the mutated cDNA of the human thyroid hormone recep- Fig. 2. Map of the plasmid construct from which the transgene, which consists of the CAGGS enhancer-promoter and a...

Assess Adequacy

The first step in the evaluation of a thyroid FNA is a rapid, low magnification review of all specimen slides to assess adequacy. The precise criteria for thyroid FNA adequacy have been frequently debated, but not rigorously studied. Although experts agree that the presence of follicular epithelial cells is the critical feature for a specimen to be adequate, the number of required epithelial cells varies. The most stringent guidelines require 10 groups of follicular cells,with at least 20 cells in each group. Other guidelines suggest a minimum of 5 to 6 groups of follicular cells, each group containing 10 cells. Some experts suggest that very large groups may be counted as multiple small groups of 10 cells each. Another source also suggests a minimum of 6 groups, but indicates that they should be present on at least two of six passes. Samples may also be considered inadequate due to obscuring blood, extensive air-drying artifact, or a thick smear with obscuring cellularity. Figure...

Case 1

This 34-year-old woman was referred by her family physician regarding a thyroid nodule and possible hyperthyroidism. She told me she had noted a lump in the left side of her neck 2 or 3 weeks previously. She denied pain in the area, but she had noted a slight pressure sensation. On questioning, she admitted to the recent onset of heat intolerance and intermittent palpitations. She felt hyper at times, but denied tremor. She was about 1 year postpartum with her second child and had suffered a miscarriage 6 weeks prior to this visit. She had not had a period since her dilation and curettage and thought she might be pregnant again. She had a strong family history of thyroid disease, including hyper-thyroidism in her mother and a cousin. Her grandmother and an aunt had surgery for goiter. She was on no medications. Laboratory studies that accompanied her included a thyroid-stimulating hormone (TSH) of less than 0.1, total thyroxine (T4) of 10.1 (4-12), and cholesterol of 107. Physical...

Case 2

Physical examination revealed a middle-aged man who appeared acutely ill. His pulse was 60, BP was 130 78. There were no thyroid eye signs. The thyroid gland was enlarged bilaterally to twice normal size. Both lobes were 4+ tender. TSH was 0.1, total T4 was upper-normal at 11.4. Thyroid peroxidase (TPO) antibody test negative. Subacute thyroiditis with mild hyperthyroidism. The painful, tender thyroid along with a low RAIU and very high sedimentation rate are typical of this disease. Subacute thyroiditis is a self-limited disease. Therefore, treatment is symptomatic. Options for treatment of the pain include salicylates, nonsteroidal anti- He returned to the office 10 days later. He was still quite ill with neck pain and night sweats. He was convinced to begin taking prednisone. He was started on 60 mg day and his symptoms cleared in 48 hours. Response to prednisone in this disease is quite dramatic. When seen several days later, his thyroid gland was smaller and no longer tender....

Case 3

This 49-year-old woman was referred with a 2-month history of pain in the jaw and ear and tightness in her lower neck with swallowing. She had noted fatigue, heat intolerance, sweating, palpitations, and shakiness for 2 mo, along with slight hair loss. She had no past or family history of thyroid disease. TSH was less than 0.1 (0.4-5), FT4 was 2.6 (0.8-1.8). Physical examination revealed a pulse of 84 and BP of 116 72. The eyes showed a slight stare. The thyroid gland was enlarged to twice normal size. The left lobe was larger than the right and 2+ tender. There was no tremor and muscle power was good. Reflexes were normal. The patient was given propranolol for the shakiness and palpitations. Tests were ordered. She returned 1 wk later. She was feeling better and did not take the propranolol. On examination, the thyroid was still bilaterally enlarged but no longer tender. Silent (autoimmune) thyroiditis with hyperthyroidism. The patient did not require the prescribed P-blocker for her...

Case 4

A 40-year-old woman was referred for thyroid evaluation. She had lost 15 lb over the previous month and complained of palpitations. She had been hot, shaky, and noted hair loss. She denied any history of thyroid problems. Her TSH was less than 0.03. Physical examination revealed a pulse of 80 and BP was 104 72. When I entered the room, she was moving restlessly in the chair. There were no thyroid eye signs. The thyroid gland was diffusely enlarged to about twice normal size and not tender. Slight tremor of her outstretched upper extremities was present. This woman was hyperthyroid on history and physical examination. The low TSH confirmed the diagnosis. The differential diagnosis was between Graves' disease and hyperthyroidism secondary to thyroiditis. Autoimmune (silent) thyroiditis with hyperthyroidism. Treatment of the hyperthyroidism in this case is symptomatic because the hyperthyroidism is usually self-limited. The patient was started on propranolol and the shakiness and...

Genes of Myelination

Myelination in the CNS is carried out by oligodendrocytes, a special type of glial cells whose terminal differentiation is greatly influenced by thyroid hormone (7). Accordingly all the genes encoding proteins of myelin (8), such as myelin basic protein (MBP), myelin-associated glycoprotein (MAG), proteo-lipid protein (PLP), and cyclic nucleotide phosphohydrolase (CNP) are under thyroid hormone control in vivo with a similar timing. Dependency of these genes from thyroid hormone is transient, so that in the hypothyroid neonatal rat there is a delayed accumulation of mRNA and protein, but eventually they reach normal levels even in the absence of thyroid hormone treatment and become thyroid hormone independent.


The diagnosis of primary lymphoma of the thyroid gland is usually apparent on aspirates because DLBCL account for 50 to 75 of cases. When diagnostic difficulties arise in the diagnosis of DLBCL, it is usually due to confusion with other nonlymphoid malignancies. The cells of DLBCL are malignant appearing and consist of cellular aspirates of large, highly atypical immature lymphoid cells, including a predominance of centroblast-like cells or immunoblasts in a background of scant to absent follicular cells (Figures 4.11, 4.12). The cells are generally two to three times larger than a small mature lymphocyte and have round to oval irregular nuclei with vesicular chromatin and basophilic cytoplasm. The centroblast-like cells have one to three peripheral nucleoli and scant cytoplasm, whereas the immunoblastic cells have a prominent central nucleolus and abundant cytoplasm. When immunoblastic cells predominate, they may appear plasma-cytoid. Lymphoglandular bodies are identifiable in the...


The cases discussed in this chapter represent a spectrum of thyroid ophthal-mopathy from very mild to severe. All of these patients were treated with RAI. Only case 4 showed worsening of eye complaints after RAI treatment, and the worsening was mild and transient. This is consistent with recent studies which suggest that progression of thyroid ophthalmopathy is more common after RAI therapy than after other modes of treatment of Graves' disease. However, progression tends to occur in only a small minority of patients treated with RAI and is most commonly mild and often transient. Most thyroidologists in the United States, including myself, feel that the advantages of RAI therapy in most patients should be weighed against the small risk. In most cases, I think RAI is still the treatment of choice. Concurrent steroid therapy and alternate means of treatment of the hyperthyroidism may be considered in patients with severe ophthalmopathy.

Follicular Lesions

Follicular carcinoma (FC) is the second most common malignancy of the thyroid after papillary thyroid carcinoma (PTC), representing approximately 15 of all thyroid carcinomas. Most FCs are minimally invasive and are categorized as well-differentiated tumors that have an excellent prognosis. A small subset of FCs, however, are widely invasive carcinomas (i.e., grossly recognizable as carcinomas) with a much more aggressive clinical course. In addition, the classic form of poorly differentiated thyroid carcinoma is insular carcinoma, a rare, aggressive follicular-derived tumor. Follicular neoplasms typically present as a solitary thyroid nodule. Whether FC can develop from a preexisting benign thyroid nodule is controversial, but it is interesting to note that there is an increase in the number of FCs in endemic goiter areas. Patients with follicular neoplasms are usually middle-aged women who are serologically euthyroid those with FC tend to be a decade older, with an average age of 40...

Insular Carcinoma

Insular carcinoma of the thyroid is rare, and represents the classic form of poorly differentiated thyroid carcinoma. Aspirates of insular carcinoma are cellular and are composed of crowded groups of follicular cells and some microfollicles in a background of very little or absent colloid (Figures 6.17,6.18).

Case 5

A 27-year-old woman was referred to me because of abnormal thyroid function tests. She had delivered her third child about 8 months previously and there was no history of thyroid problems with her previous pregnancies. After her last delivery, she noted mood swings, fatigue, and heat intolerance along with a 15-lb weight gain. She was having regular menses. There was no family history of thyroid disease. Physical examination revealed a pulse of 76 and BP of 114 72. No thyroid eye signs were noted. The thyroid gland was mildly enlarged. The remainder of the examination was normal. The initial thyroid studies at 6 months postpartum showed a TSH of less than 0.005 and FT4 of 1.7 (0.8-1.8). Thyroid ultrasound had been reported as normal. At the time of my evaluation, the patient was clinically euthyroid. She required no thyroid treatment but careful follow-up was required. This 27-year-old woman had clinical and laboratory evidence of mild PPT disease. Her thyroid tests at 6 months...

Chromatin Features

The chromatin pattern of PTC is unique among thyroid lesions and represents an important diagnostic feature. In ethanol-fixed, Papanicolaou-stained samples, the chromatin appears pale, finely textured, and evenly distributed (see Figure 9.5). This appearance presumably parallels the optically clear, so-called Orphan Annie eye appearance of PTC in histologic preparations. The molecular basis for this is unclear, but it may be linked to the overexpression of the RET proto-oncogene. It is also typical of PTC nuclei to contain a small, eccentrically placed nucleolus. The pale chro-matin of PTC is distinctly different from that of normal follicular nuclei, which is dark and coarsely granular. These chromatin differences are much more easily appreciated using ethanol-fixed Papanicolaou-stained preparations than air-dried Diff-Quik preparations.

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