Synthesis of Thyroid Hormone

After uptake into the follicular cells through the basal membrane (Fig. 1-2), inorganic iodide is rapidly oxidized. Thyroid hormones are then synthesized by the combination of iodine with tyrosyl residues within the protein thyroglob-ulin. This reaction is catalyzed by thyroperoxidase in two principal steps. In the first reaction, iodide reacts with FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine...

Clinical and Pathologic Characteristics

Although it may arise sporadically, MEN 2B more frequently occurs as a familial disorder inherited in an autosomal dominant fashion. MEN 2B is less common than MEN 2A. FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes. Vertical bars within the diagram indicate sites of cysteine codons....

Pathology

Pancreatic endocrine tumors are commonly termed neuroendocrine tumors. However, some researchers indicate that it is unclear whether these tumors originate from the pancreatic islets.3 Pancreatic endocrine tumors may contain ductu-lar structures may produce hormones that are not produced by the normal pancreas, including gastrin and vasoactive intestinal polypeptide (VIP) and may produce more than one hormone.35 These findings suggest that pancreatic endocrine tumors originate from...

Surgical Treatment of Recurrent or Persistent Medullary Thyroid Cancer

Because of the lack of success reported for other modalities in the treatment of persistent or recurrent MTC, surgical FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on and just beneath the surface of the liver,...

Image Diagnosis of Medullary Cancer

All patients with a preoperative diagnosis of medullary cancer of the thyroid should be tested for a ret protoonco-gene germline point mutation and also be screened for pheochromocytoma and hyperparathyroidism (see other chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer secretes calcitonin and carcinoembryonic antigen (CEA) and occasionally neuron-specific enolase, serotonin, chromogranin, gastrin-releasing peptide, substance P,...

Imaging of Metastases of Thyroid Cancer with Fluorine 18 Fluorodeoxyglucose

FDG is a D-glucose analog, which is converted in cells to FDG-6-phosphate by hexokinase. FDG-6-phosphate is metabolically trapped and accumulates in tissue where glucose-6-phosphatase is lacking. Metabolic trapping is the key factor responsible for the biodistribution of 18F-2-deoxyglucose.109 Because other enzymes that act on glucose-6-phosphate have only a negligible affinity for FDG-6-phosphate and membrane permeability is low, the rate of accumulation of FDG-6-phosphate is proportional to...

Molecular Carcinogenesis

The pathogenesis of radiation-induced thyroid cancer has not yet been elucidated. Gene rearrangements may play an important role in the process. Nikiforova and associates found that radiation-induced tumors had a 4 prevalence of BRAF point mutations and a 58 prevalence of RET PTC rearrangements, and sporadic papillary thyroid cancers demonstrated a 37 prevalence of BRAF point mutations and only a 20 prevalence of RET PTC rearrangements.34 Similarly, RET PTC3 rearrangement was found in...

NonMEN Familial Hyperparathyroidism and Parathyroid Cancer

Both parathyroid cancer and NMFH are rare parathyroid disorders. The association of these rare conditions suggests a common cause. Until 2002, 29 patients with NMFH and parathyroid cancer in 22 families were reported.16,21,23,27*33,35,43 Sixteen of these families have NMFH-JT or FIH-JT, and about one fourth of reported NMFH families have one or two affected members suffering from parathyroid cancer. Endocrinologists and surgeons should be aware of this association for proper management of these...

Adenoma

Adenomas are the most common benign tumors of the thyroid gland. They are of follicular cell origin, encapsulated with varying histology. They have been subdivided according to their histology, but no additional information is gained by this practice. Thyroid adenomas are probably common because of the inability of pathologists to separate consistently cellular adenomatous nodules in nodular goiters from adenomas. The majority of adenomas are most likely adenomatous nodules. The atypical...

Adrenal Medulla

The adrenal medulla constitutes about 15 of the adrenal and is surrounded by the cortex. The major constituent of the medulla, the catecholamine-containing cells, are of two types the norepinephrine and the epinephrine cells. These cells are often called chromaffin cells because they stain with chromium salts, and this was an early method used to detect these cells.5 Chromaffin cells in adults are primarily confined to the adrenal medulla, although they also occur in extra-adrenal locations....

Anatomy

Most humans have four parathyroid glands. The percentage of individuals with supernumerary glands varies from 2.5 to 22 . The presence of as many as eight parathyroid glands has been reported, and different series have determined that there is a wide variation in the number of individuals with fewer than four glands. The exact number of individuals with fewer than four glands may be impossible to determine because the surgeon or researcher may not be able to find one or more glands, and a...

Anatomy of Parathyroid Glands

The presence of four parathyroid glands is most common in humans. In dissection studies of 428 human subjects by Gilmour, four parathyroid glands were found in 87 of all patients and three parathyroids in 6.3 .5 Akerstrom and colleagues reported comparable rates in an autopsy study of 503 cases.6 Four parathyroids were found in 84 and three parathyroids in 3 of all patients in this study. The occurrence of supernumerary parathyroid glands is a rare entity that nevertheless has important...

Arterial Blood Supply to the Parathyroids

On the basis of the study of 357 parathyroid gland pedicles, Flament and colleagues14 found a single artery supplying the parathyroids in 80 of the cases. This artery was simple in 65 of the cases, bifurcated before its entry into the gland in 30 , and divided into three branches in 5 . In 15 of the total group, two distinct arteries were observed, in 4 three were seen, and in 1 , even four separate arteries were found. The length of the artery is variable, usually between 8 and 12 mm. When...

Assessment of Cure and Followup

Several reports suggest that at least one half of all Z-E syndrome patients explored, with the expectation to extirpate tumor and cure, continue to have hypergastrinemia postoperatively.84'96 Typically, a small duodenal gastrinoma or lymph node containing tumor has been excised, but an elevated serum gastrin level indicates that more tumor remains. A follow-up plan is needed for such patients. Should such a patient be re-explored or monitored Should re-exploration be done only when localizing...

Autonomy

Thyroid nodules that function in the presence of a suppressed blood TSH level are referred to as autonomous or hot nodules. Autonomous function and autonomous growth may or may not be related. Thus, cold nodules and hot nodules within a nodular goiter may have exactly the same growth potential and may respond or be refractory to TSH-suppressive T4 treatment.21 Some thyroid follicular cells take up and organify iodine in the absence of TSH, causing hot or autonomous nodules. As previously...

Autoregulatory Mechanisms

The thyroid can also control its own stores of thyroid hormone by intrinsic autoregulatory mechanisms. These mechanisms are principally seen in response to alterations in iodide availability. For example, an excess of dietary iodide leads to autoregulated inhibition of iodide uptake into the follicular cells, whereas iodide deficiency results in increased iodide transport and uptake. Large doses of iodide have more complex effects, including an initial increase followed by a decrease in...

B

As a result, the serum TSH level increases, stimulating thyroid growth.17 The increase must be relatively short lived and intermittent because most patients have normal serum TSH levels. Other growth factors are obviously involved since the sizes of various nodules vary considerably in the same patient. Furthermore, goiters may grow despite administration of T4 in doses that reduce the serum TSH level to a subnormal level or in patients with toxic nodular goiter....

Background

Medullary thyroid carcinoma (MTC) occurs in sporadic and hereditary clinical settings and displays a variety of clinical behaviors ranging from moderately aggressive to extremely indolent. The discovery of the gene responsible for hereditary MTC has shed light on the biologic basis for this range of clinical presentations. MTC was described in 1959 by Hazard, Hawk, and Crile.1 MTC is a tumor of the thyroid C cells, also known as the parafollicular cells (Fig. 15-1). These cells are of neural...

Bone Disease

Although historically most patients with normocalcemic hyperparathyroidism were identified because of renal calculi, an increasing number of patients have recently been identified by screening patients for osteoporosis with dual-energy x-ray absorptiometry (DEXA) scans. Traditionally, hyperparathyroidism was associated with overt bone disease in a significant number of patients. This traditional bone disease was frequently symptomatic and associated with radiologic findings such as bone cysts,...

Causes of Goiter

Several mechanisms, including the interplay of intrinsic and extrinsic factors in the thyroid, cause goiter. The goitrogenic process involves genetic, environmental, dietary, endocrine, and other factors. The most common worldwide cause of endemic nontoxic goiter, as mentioned earlier, is iodine deficiency. In patients with sporadic goiter, the cause is usually unknown. Sporadic goiter is a result of environmental or genetic factors that do not affect the general population. The various types...

Childhood Thyroid Carcinoma

The nuclear accident at Chernobyl in 1986 refocused interest on radiation as a factor in the development of thyroid carcinoma.113122 Prior to 1950, irradiation was frequently used to treat acne, enlarged tonsils and adenoids, chronic sinusitis, and other benign conditions.115 External radiation was commonly used to irradiate enlarged thymuses in infants and young children. The latent period, the interval from exposure to the appearance of thyroid cancer, was assumed to be 10 years and increased...

Clinical Characteristics

Graves Disease Flame Figures Fna Thyroid

Hurthle cells are large polygonal, eosinophilic cells with pleomorphic, hyperchromatic nuclei and fine granular, acidophilic cytoplasm, representing an abundance of mitochondria (Fig. 14-1). The individual cells are 10 to 15 pm in diameter and can vary in shape and size from small dumbbells to bizarre giant cells. Hurthle cell neoplasms are encapsulated collections of Hurthle cells (Fig. 14-2). Therefore, the presence of nonencapsulated Hurthle cells does not signify a neoplastic process,...

Clinical Evaluation

Careful clinical assessment with particular attention to clinical risk factors (Table 9-1) gives important indicators for the diagnosis and requirements for surgery. Most thyroid nodules are asymptomatic, presenting as a chance finding by the patient or during a medical examination. Pain is uncommon, but a malignant lesion may occasionally cause discomfort in the neck. With respect to single and multiple nodules, current evidence suggests that when a dominant nodule appears in a multinodular...

Clinical Features

The clinical manifestations of Cushing's syndrome usually begin gradually (Table 70-1). Patients frequently report increasingly severe asthenia, enhanced appetite, and weight gain. In premenopausal women, oligomenorrhea is common and may occur before any other apparent clinical change. Typically, these patients have centripetal obesity with moon face, fullness of the supraclavicular fat pads, and a buffalo hump. The limbs look thin in relation to the rest of the body, and muscular hypotrophy...

Clinical Manifestations

Most patients diagnosed with primary hyperparathyroidism today do not have the classic or historical clinical manifestations of this disorder such as osteitis fibrosa cystica, nephrolithiasis, nephrocalcinosis, peptic ulcer disease, gout, or pseudogout. The pentad of symptoms painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones is more common, although most patients have few dramatic symptoms. The symptoms and other associated complications of primary...

Clinical Presentation

The clinical presentation of childhood thyroid carcinoma has changed in several ways over the past several decades. The 1992 report on the University of Michigan experience demonstrated important changes in history and clinical presentation.4 The study compared patients treated from 1936 to 1970 with those treated from 1971 to 1990. The Michigan surgeons found that 50 of the former group reported a history of head and neck irradiation compared with only 3 in the latter group. Similarly, the...

Clinical Presentation and Diagnosis

Goiter is classified according to the size of the thyroid gland on inspection and palpation, and the following grading system was proposed by WHO in I96032 Stage 0 no goiter Stage la goiter detectable only by palpation and not visible even when the neck is fully extended Stabe lb goiter palpable but visible only when the neck is fully extended Stage II goiter visible with the neck in the normal position palpation is not needed for diagnosis FIGURE 3-2. Classification of goiter size. 1, Stage la...

Complications of Neck Dissection

Hematoma Following Neck Dissection

More extensive neck dissections, especially in the central neck compartment, are associated with a higher risk of hypoparathyroidism and other complications.34-69 With complete resection of all fatty and lymph node tissue from the central neck, the recurrent laryngeal nerves and the vascular supply to the parathyroid glands are at risk, especially when combined with total thyroidectomy.14-47-62'69-94-96 Awareness of these potential problems emphasizes the importance of meticulous dissection and...

Conclusion

In conclusion, new findings concerning thyroid oncogenes and tumor suppressor genes, as well as studies of growth factors, are starting to explain why patients acquire specific thyroid tumors with different behaviors. 1. Brabant G, Hoang-Vu C, Cetin Y, et al. A differentiation marker in thyroid malignancies. Cancer Res 1993 53 4987. 2. Dremier S, Goldstein J, Mosselmann R, et al. Apoptosis in dog thyroid cells. Biochem Biophys Res Commun 1994 200 52. 3. Coclet J, Fourean F, Ketelbant P, et al....

Conclusions

Fewer patients now undergo classic open bilateral neck exploration for PHPT because of the desire for smaller scars, shorter postoperative stay, and less postoperative distress. Better preoperative localization studies now allow for patient selection for targeted parathyroidectomies with low rates of persistent disease.23 Endoscopic parathyroidectomy offers thorough exploration of the neck, unilaterally23 or even bilaterally.1024 The use of qPTHa reduces the possibility of missing a second...

Contraindications

Not all patients presenting with PHPT are candidates for this surgery. Contraindications are mainly due to a larger goiter, FIGURE 51-1. Endoscopic parathyroidectomy by a lateral approach trocar positions. Laparoscope being inserted into trocar A previous surgery in the parathyroid vicinity, suspicious multiglandular disease, and equivocal preoperative localization studies. Depending upon the operator's experience and according to the specific technique utilized, these contraindications can...

Desensitization of Signal Transduction

Continuous agonist stimulation of receptors usually leads to a decrease in receptor-mediated AC activity and cAMP levels. This process is termed desensitization. Desensitization, or a decreased response to the same or repetitive stimuli, is an important physiologic process and a well-described mechanism of receptor-signaling modulation that occurs in a variety of cell systems. There are two types of desensitization homologous and heterologous. Homologous desensitization is agonist specific,...

Diagnosis

In 1974, Thompson and colleagues reported a series of 25 patients with Hurthle cell neoplasms in which 75 of these whose lesions were initially described as benign (i.e. adenomas) subsequently died of Hurthle cell carcinoma.12 This led to the suggestion that gross and histopathologic examination of Hurthle cell neoplasms could not reliably predict clinical behavior and that all lesions should be treated as malignant or potentially malignant. Since then, however, several studies have shown that...

Embryology

The thyroid, the parathyroid glands, and the thymus originate from the embryonic pharyngeal region. The pharynx itself is initially an endodermally lined cul-de-sac that forms the cephalic extremity of the foregut. This is derived from a part of the yolk sac. The foregut diverticulum is divided into a more cranial pharynx and a more caudal proper foregut with the appearance of the primordium of the pulmonary apparatus as a small ventral outgrowth. When the embryo is approximately 26 days old,...

Embryology and Anatomy of Parathyroid Gland

Normal parathyroid glands originate from the third and fourth pharyngeal pouches and are of endodermal origin.4 The inferior parathyroid glands and the thymus are derived from the third pharyngeal pouch, whereas the superior parathyroid glands arise from the fourth pharyngeal pouch.5 Because third pharyngeal pouch derivatives (i.e., the inferior parathyroid glands and thymus) migrate farther, these parathyroid glands are more likely to be in ectopic or aberrant positions than are the superior...

Embryology of Parathyroid Glands

The parathyroid glands develop from the third and fourth pharyngeal pouches.2 The upper parathyroid glands originate from the dorsal tips of pharyngeal pouch IV.3 The ventral portion of pharyngeal pouch IV consists of the ultimobranchial body, which is incorporated into the lateral part of the developing thyroid and eventually supplies the parafollicular or C cells. The common embryologic origin of the lateral part of the thyroid and the upper parathyroids accounts for the occasional...

Epidemiology

Epidemiologic data on the prevalence of primary HPT are sparse for most countries. An autopsy study of a Swedish population revealed parathyroid adenoma in 2.4 and subclinical disease represented by micronodular chief cell hyperplasia in another 7 , with an apparent continuum of abnormality ranging from hyperplastic micronodular lesions to the adenomas.7 Borderline hypercalcemia could be clinically detected in occasional patients with hyperplastic glands containing larger, predominant nodules...

Etiology of Hyperplasia

The development of hyperplastic parathyroid glands in patients with renal failure is primarily due to hypocalcemia, although other factors, including low calcitriol or 1,25-hydroxy-vitamin D3, high phosphate levels, and local growth factors, are involved. The decrease in serum calcium levels results from a decrease in the enzyme la-hydroxylase in the kidney that converts 25-dihydroxy vitamin D3 to 1,25-dihydroxyvitamin D. Hyperphosphatemia in patients with renal failure decreases the activity...

Flank Approach

Like the posterior approach, the flank approach is extraperitoneal. It is most useful for obese patients in whom exposure offered by other approaches would be compromised. In these patients, the flank approach uses gravity to assist with retraction by allowing the patient's adipose tissue to fall away from the incision. The flank approach is also useful in the presence of a large adrenal mass in a patient with scarring and adhesions in the abdomen from previous surgeries. Finally, the flank...

Follicular Adenoma

Pathologic Features of Follicular Adenoma Follicular adenomas are benign tumors of the thyroid gland that grow in glandular or follicular patterns. They can occur in any portion of the thyroid and in any age group they are more common in young adults. Adenomas are usually solitary and less than 3 cm in size, although significant numbers of exceptions to these rules exist.6 The lesions tend to grow slowly within a capsule of surrounding compressed thyroid glandular tissue. Over time, they...

Follicular Neoplasms of the Thyroid

In the normal thyroid gland, the basic functional unit is the follicle. Follicles are single-layer spheres of follicular cells surrounding a lake of viscous colloid that primarily stores thyroglobulin. Other cell types that are present in the thyroid gland are interposed between these follicular spheres. These cells include perifollicular cells, also called C cells, which secrete calcitonin, as well as some supportive fibrous tissue, vascular structures, and nerves. The most common tumors of...

Follicular Thyroid Tumor

Thyroid tumors of follicular cell origin serve as a good model for studying possible genetic events regarding tumor origin, transformation, and progression. Multiple genetic events appear to be responsible for the progression from adenoma to carcinoma in some tumors (see Fig. 36-1).1,2,22,23 Follicular adenomas have close cytologic and morphologic similarity to follicular carcinomas the defining difference is the presence of capsular invasion and or vascular invasion in carcinomas. Because of...

General Principles

The following principles apply to all thyroid operations 1. Good exposure of the thyroid gland is essential for good results. 2. No operation should be performed on the thyroid gland without proper identification of the anatomic structures. 3. Bleeding can and should be kept to a minimum. 4. Diathermy (even bipolar) should be avoided in the area around the laryngeal nerves. As in all operations, optimal access to the entire operative field is one of the keys to success. It is a misconception,...

Genes Protooncogenes and Thyroid Cancers

Thyroid carcinomas and familial adenomatous polyposis (FAP) Thyroid carcinoma and Cowden's disease RET protooncogene encodes a transmembrane receptor that is a member of the receptors of the tyrosine kinase family and is found on chromosome 10 (lOql 1.2).31123 The gene is expressed normally in thyroid gland, adrenal gland, nerve tissue, and developing kidney and pathologically in neuroendocrine tumors (MTC, pheochromocytomas) and hyperplasia and neoplasia of parathyroid glands. The RET gene...

Genetic Factors

The thyroid gland contains a series of enzymes that are essential for the biosynthesis and secretion of thyroid hormones. A defect in any of these hormones can result in diminished hormone synthesis and a condition of goiter formation known as dyshormonogene sis. Because the defects are inherited disorders, dyshormonogenesis is also known as familial goiter. These enzyme defects may be partial or complete. Patients with a more severe enzymatic defect may develop goiter and cretinism early in...

Goiter Growth

Goiters result from focal follicular cell hyperplasia at one or multiple sites within the thyroid gland. Iodine deficiency works synergistically with other causes of goiter but does not appear to change the basic mechanisms of goitrogenesis. There is a positive correlation between the total DNA content of the goiter and goiter weight. The increased amount of interstitial tissue and colloid formation usually contributes little to the total goiter growth. An intrinsically abnormal growth pattern...

Hiirthle Cell Thyroid Tumor

Hurthle cell thyroid tumors comprise 1 to 5 of all thyroid neoplasms and have been classified as variants of follicular thyroid tumors. They differ from follicular thyroid carcinomas by their inability to trap radioiodine and by FIGURE 36-6. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 15 Hiirthle cell adenomas and 13 Hiirthle cell carcinomas. the accumulation of mitochondria and eosinophilic cytoplasm on histology. They are also more likely to be...

Historical Aspects

The striking clinical malady of exophthalmic goiter, with its distinctive protruding eyes, tachycardia, nervousness, and enlarged thyroid, has been known for more than 150 years. Thyrotoxicosis was first described in 1786 by Parry, a physician in England, but was not reported until after his death in 1825. It was also noted by von Basedow and a handful of others.1 To this day, on the continent of Europe, it is known as Basedow's disease. In the English-speaking world it is named for Robert...

Historical Considerations

Most endocrine tumors are solitary, occurring in single organs without concomitant disease in other endocrine tissues. The first known report of neoplasia arising in multiple endocrine organs in the same individual appeared in 1903, when Erdheim described an acromegalic patient noted on autopsy to have tumors of both the pituitary and parathyroid glands.1 Thereafter, only similar sporadic reports of multiple endocrine tumors appeared in the literature until 1954, when Wermer first described a...

Historical Introduction

In 1869, Paul Langerhans showed that islands of characteristic cells are distributed throughout the pancreas and that these islands are richly innervated.1 After the demonstration that diabetes evolves after pancreatectomy,2 it was suggested in 1901 that the disease is caused by lack of a factor produced by these islets of Langerhans.3 Although several researchers were close to the discovery of insulin, the critical pieces of work in this area were performed by Banting, Best, MacLeod, and...

Hyperplasia

It is common knowledge that nodules develop in normal thyroid glands with aging.67 In growing thyroids, the development of the goiter is almost invariably accompanied by the development of multiple nodules of varying size.68 The nodules are generally softer than normal tissue. The surface of a sectioned hyperplastic gland appears granular, and the histopathologic picture shows a dysplastic arrangement with wide variation of follicle size and areas with increased cell density (Fig. 28-3)....

Hypoparathyroidism Postsurgical

Surgical destruction of the parathyroid glands is the most common cause of hypoparathyroidism. Hypoparathyroidism can occur after any surgical procedure that involves the anterior neck but is most commonly seen as a complication of parathyroid surgery or thyroid surgery, or after extensive resection for head and neck cancer. Trauma to the parathyroid vascular pedicles or inadvertent removal of the glands leads to either transient or permanent hypoparathyroidism. Estimates of the incidence of...

Imaging Consequences

Because of the central location within the abdominal cavity and the vicinity of numerous viscera, plain films are rarely informative. Occasionally, a large adrenal mass may be suggested by the downward displacement of the kidney, but this appearance is rarely seen, and differentiation from renal, splenic, pancreatic, gastric, and retroperitoneal tumors requires further investigation. Calcification may be seen in the adrenal glands and can be idiopathic or result from neonatal causes...

Importance of LThyroxine Suppressive Therapy

Both the function and the growth of some metastatic thyroid tumors are under TSH control. It is a common observation that bone or lung metastases increase in size and take up radioiodine during periods of T4 withdrawal, whereas a reduction in size and lack of uptake are observed during periods of T4 therapy. Serum Tg, a marker of cell function, increases dramatically during hypothyroidism (see Fig. 17-1), whereas Tg levels return to low values during treatment with T4. In the classic article by...

Incidence

Pheochromocytoma has an incidence of 2 to 8 cases per million persons annually,6 7 which constitutes a curable form of hypertension in 0.1 to 1 of hypertensive patients,8 and as many as 800 persons may die annually in this country from associated complications.9 Of patients with pheochromocytomas discovered only at the time of autopsy, 75 died suddenly from either myocardial infarction or a cerebrovascular catastrophe. Moreover, one third of the sudden deaths occurred during or immediately...

Indications for Operative Treatment

As discussed earlier, the clinical profile of primary hyperparathyroidism has undergone a distinct change over the past few decades, particularly with the introduction of automated blood chemistry panels. The 1990 National Institutes of Health Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism was convened to set forth evidence-based diagnosis and management guidelines for this group of patients. The panel recognized surgery as the only definitive...

Interaction Cross Talk of the Different Signal Transduction Systems

Cellular responses to external stimuli involve an integration of inputs from hormones, neurotransmitters, and growth factors. This integration is able to interact with distinct second messengers. The effect of one signal transduction system may alter the response of another, as already mentioned. This is called cross-talk. Although TSH stimulates both the AC system and the phosphoinositide turnover-calcium systems in animal cell cultures and human neoplastic membranes,43'106 the response...

Intranuclear Oncogenes

Nuclear protooncogenes involved in thyroid growth are c-myc, c-jurt, and c-fos. They were characterized by their similarity to viral oncogenes. Unlike most oncogenes encoding cell surface receptors or signal-transducing proteins, nuclear protooncogenes function by means of gene amplification. Because external stimulation of cells by growth factors activates cellular receptors, signal-transducing proteins, second messengers, and nuclear protooncogenes by means of increased gene expression, it is...

Invasive Preoperative Methods

Invasive localization studies are indicated when the combined results of the noninvasive tests are negative, equivocal, or conflicting. FIGURE 46-8. Sestamibi scan with thymic parathyroid adenoma. FIGURE 46-8. Sestamibi scan with thymic parathyroid adenoma. I TABLE 46-2. Characteristics of the Most Common Noninvasive Localization Studies Tl-TC thaHium-technetium US ultrasonography CT computed tomography MRI Fine-needle aspiration (FNA) of the parathyroid tumor performed under sonographic...

Islet Function

A key role for the pancreatic islets is to deliver an optimal amount of peptide hormones into the bloodstream to optimize carbohydrate metabolism. Of most importance in this respect is insulin, which facilitates the transport of glucose into insulin-dependent cells for storage as glycogen and fat with a concomitant reduction in blood glucose and free fatty acid levels as a consequence. One of the most important target organs for insulin action is the liver, in which at least 50 of the insulin...

Laparoscopic Ultrasound

We used laparoscopic ultrasonography in 15 selected cases. In 1 patient it showed the location of a 0.7-cm aldosteronoma in an adrenal gland after open surgery failed to find the organ. In 2 patients, no adenoma was found, necessitating only biopsy and closure rather than adrenalectomy. In 2 patients with large masses (10 and 12 cm), no extra-adrenal or lymph node involvement was found. The masses were completely removed laparoscopically and proved to be histologically benign. In 1 patient,...

Localization

Whereas 3 decades ago bolus nephrotomography or angiography might have provided the mainstay of localization, three excellent localization modalities are currently available. Soon after the development of CT scanning, the adrenal was noted to be exceptionally well depicted,19 and CT is now considered the most reliable, efficient, precise, and widely available localization technique (Fig. 71-2). Because 90 of tumors are located in the adrenal glands, a high-quality CT scan is likely to identify...

Localization of Persistent or Recurrent Medullary Thyroid Carcinoma

Computed Tomography and Ultrasonography A number of methods have been used to localize residual or recurrent disease in patients with persistent or recurrent calcitonin elevation after surgery for MTC. Careful physical examination may reveal adenopathy in the jugular and para-tracheal regions. Patients with advanced metastatic disease may acquire subcutaneous tumors of the trunk and extremities. Imaging studies that have been reported to be successful in localization include ultrasonography...

Localizing Procedures

The adrenal imaging techniques used as localizing procedures are adrenal scintigraphy, computed tomography (CT), FIGURE 70-2. Different clinical appearances of patients with Cushing's syndrome in relation to early diagnosis. A to C, The faces of some patients observed in 1982, 1987, and 1995, respectively. FIGURE 70-2. Different clinical appearances of patients with Cushing's syndrome in relation to early diagnosis. A to C, The faces of some patients observed in 1982, 1987, and 1995,...

Location of Distant Metastases

The lungs are the most common site of distant metastases in differentiated thyroid cancer, followed by the skeleton. Both lung and bone metastases also occur in about one third of patients with distant metastases. Other less common sites of metastases are the brain, the liver, the skin, and, rarely, the omentum and adrenal glands.9 These rare sites of metastatic disease are found more frequently in patients with lung and bone metastases. The pattern of metastatic lung involvement may vary from...

Lymphatic Drainage of the Thyroid

The thyroid has an extensive lymphatic drainage, which may flow in a variety of directions.2-3 Thyroid follicles are enveloped with lymphatic vessels. The intraglandular lymphatic connections are extensive and enable lymphatic drainage from one lobe to the other through a complex of intrathyroidal and pericapsular nodes.4 The major lymph vessels running efferently follow the branches of the thyroid arteries and veins in three main directions superiorly, laterally, and inferiorly. The upper...

Management

Patients presenting with Hiirthle cell neoplasms usually have had a solitary thyroid nodule evaluated by FNA. In our experience, 35 of these lesion ultimately prove to be malignant, although in some series, up to 60 have been reported to be cancers.8 25 Accordingly, we recommend surgical exploration for patients in whom the FNA demonstrates a Hiirthle cell neoplasm. A careful exploration is always undertaken to detect the presence of obvious malignant disease i.e., tumor invasion into adjacent...

Medical Treatment

Although thyroid hormone administration may be beneficial suppressive therapy for diffuse colloid goiter, once nodule formation has developed, patients are unlikely to benefit.67-68 TSH suppression with exogenous T4 may also reduce the size of some malignant nodules.69 This clearly underscores the problem of potential misdiagnosis for the unwary when using this therapy as a nonoperative management of thyroid nodular disease. Toxic nodular goiter (Plummer's disease) may identify a toxic nodule...

Medullary Thyroid Carcinoma

Apart from the RET protooncogene (RET) point mutation of chromosome 10, no other genes have been found to be involved in the original growth of medullary thyroid carcinomas. Germline RET mutations have been identified in about 98 of patients with familial medullary thyroid carcinoma, and somatic RET mutations have been frequently detected in sporadic medullary thyroid carcinomas.51 In sporadic medullary thyroid carcinomas, the RET gene is mutated in codon 918, where a methionine is substituted...

Molecular Characterization of the NIS Gene

The molecular characterization of NIS was accomplished in 1996 when Dai and colleagues cloned the transporter3 from Xenopus laevis oocytes, using the complementary DNA (cDNA) libraries derived from FRTL-5 cells (functional rat thyroid-derived cell line). The cDNA encoding the human NIS (hNIS) gene was identified on the expectation that hNIS would be highly homologous to rat NIS.7 The hNIS gene is located on chromosome 19pl2-13.2. It comprises 1929 base pairs encoding a 643-amino acid...

Multiple Endocrine Neoplasia

MEN 2 syndrome is an autosomal dominant inherited disease, affecting approximately 500 to 1000 kindreds.23 Medullary thyroid cancer (MTC), pheochromocytomas, and parathyroid hyperplasia are the typical association for patients with MEN 2A. MEN 2B patients present with tumors from the adrenal medulla, intestinal and mucosal ganglioneuromatosis, and a characteristic marfanoid habitus. Other less frequent variants include familial medullary thyroid carcinoma (FMTC), MEN 2A with cutaneous lichen...

Natural History

The natural history of nontoxic goiter varies. Children in endemic areas generally have diffuse goiters, whereas sporadic goiters tend to develop at an older age and tend to be nodular. Patients with multinodular goiter are usually older and have larger goiters than do patients with diffuse or uninodular goiters. The growth rate of thyroid nodules is usually slow, but some goiters increase up to 20 yearly.28 Rapid growth of a nodule is usually caused by hemorrhage or cyst formation. One must...

Natural History of Treated Primary Hyperparathyroidism

In 1925, Mandl of Austria performed the first operation for primary hyperparathyroidism (PHPT).1 His patient had sustained a spontaneous thigh bone fracture and was immobilized. Three months after a parathyroid adenoma had been excised, the patient could walk with crutches. The effect of the operation was conspicuous. During the next 4 decades, most patients with PHPT continued to have obvious symptoms relieved by surgery. In the mid-1960s, the number of operations for PHPT started to increase...

Neoplasia

Early neoplastic lesions are generally monoclonal and arise from a single mutation (or several) in a cell,74 which results in a greater propensity of these cells to multiply more rapidly or to die more slowly than surrounding cells. With the new knowledge of the monoclonal origin of nodules in hyperplastic disease, the dichotomy between hyperplastic and neoplastic transformation has become less distinct. In a hypothetical overlapping gray zone (Fig. 28-5), the growth of both hyperplastic and...

Nodule Formation

With increasing age, most thyroid glands and goiters become nodular. Initially, many goiters are diffuse however, with intermittent stimulation, some diffuse goiters outgrow their blood supply and become nodular (Fig. 4-2).20,21 Some thyroid cells are more sensitive to growth factors and become larger nodules. If these nodules trap and organify iodine, the nodule may be hot or autonomous rather than cold. Hot nodules are associated with TSHR and gsp mutations. In general, formation of thyroid...

Nontoxic Multinodular Goiter Theories of Pathogenesis and Thyrocyte Regulation

The pathogenesis and hence the treatment of multinodular goiter are debatable. If a goiter were simply induced by uninhibited TSH stimulation, one might expect it to be a diffuse goiter. Early studies by Taylor suggested a natural progression from diffuse toward multinodular.104 Indeed, TSH levels are in general not elevated in sporadic goiters. Studer and Ramelli105 suggested that newly generated follicles involve thyrocyte clones that may retain the ability to concentrate iodine (hot nodules)...

Operative Approach

The incision is deepened down through the platysma, and superior and inferior sub-platysmal flaps are developed. The median raphe is divided and the strap muscles are retracted laterally without division. The thyroid lobes are sequentially elevated, and all four parathyroid glands and any supernumerary glands are exposed. Most supernumerary glands are located in proximity to the other glands or less often in ectopic locations. Transcervical thymectomy should be...

Operative Technique

The lymph nodes in the central neck compartment are usually resected in continuity with the thyroid itself. The strap muscles are retracted laterally during the dissection. When the strap muscles inhibit exposure, they can be divided superiorly, since they are innervated from below. The technique of the total thyroidectomy has been described in previous chapters. As mentioned earlier, the central neck dissection puts the recurrent laryngeal nerve and the blood supply to the parathyroids at...

Other Sporadic Islet Cell Tumors

Most other functional islet cell tumors such as glucagonomas, vasoactive intestinal polypeptide tumors (VIPomas), and somatostatinomas are too large at diagnosis to be amenable to enucleation and require resection when feasible.2123 More than half of these tumors are malignant with either local invasion or hepatic metastases at the time of diagnosis. Whenever feasible, debulking of tumors is desirable short of Whipple's procedure even when hepatic metastases are present. When local invasion of...

Pancreas

The introduction of insulin therapy for the management of diabetes mellitus is one of the greatest milestones in the history of medicine. Beta-cell replacement therapy is the only treatment that reestablishes and maintains long-term physiologic normoglycemia,81 because intensive subcutaneous insulin regimens cannot completely mimic the physiologic fluctuations of in vivo insulin secretion.82 The two options for replacement of beta-cell function in patients are whole-organ pancreas...

Pancreastatin

Another peptide that is produced by the islet B cells is pancreastatin, which is a carboxyterminal amidated TABLE 78-1. Endocrine Peptides and Neuropeptides in the Istet Cells and Gastrointestinal Peptide Hormones Affecting Islet Cell Hormone Secretion Effect on Insulin Effect on Glucagon TABLE 78-1. Endocrine Peptides and Neuropeptides in the Istet Cells and Gastrointestinal Peptide Hormones Affecting Islet Cell Hormone Secretion Effect on Insulin Effect on Glucagon 49-amino acid peptide...

Papillary Carcinoma

Papillary carcinomas are the most common malignant neoplasms of the thyroid gland.6 They are rarely composed solely of papillae, with the most common form containing both follicles and papillae. Such tumors were classified as mixed papillary and follicular carcinomas. Follow-up studies have convincingly demonstrated that mixed and purely papillary tumors are associated with similar outcomes, so the separation of mixed papillary and follicular from the purely papillary form is not warranted.7...

Papillary Thyroid Carcinoma

DNA copy number changes are uncommon in papillary thyroid carcinomas as compared with other poorly differentiated and well-differentiated thyroid carcinomas. Papillary thyroid carcinomas in CGH studies have variable rates of genetic aberrations and specific sites of aberrations. Nonetheless, several common aberrations have been identified, including gains on chromosomes lq, 5q, 6q 9q 13q, 19q, 21q, 4 and 7, and losses on chromosomes lp, 9q, 16q, 17, 19, and 22.911 Hemmer and associates10 found...

Parathyroid

The treatment of surgically acquired and idiopathic hypoparathyroidism requires life-long treatment with vitamin D and oral calcium supplementation. This is not, however, a perfect physiologic replacement because, although it sufficiently regulates blood calcium and phosphate levels, it does not reverse the lowered urinary calcium reabsorption and excessive urinary calcium excretion, which may result in renal stones.25 Owing to the complexity of parathyroid hormone's metabolic interactions,...

Parathyroid Calcium Sensor Proteins

A calcium sensor protein on the parathyroid cell surface was identified by monoclonal antibodies generated by immunization with human adenoma cells.49 Such a monoclonal antibody abolished the calcium-regulated Ca2+ and PTH release of normal and pathologic parathyroid cells.50 51 The antibody blocked the calcium-induced Ca2+, transient intracellular calcium mobilization as well as the steady-state elevation resulting from calcium influx. Because the antibodies also competed with calcium binding...

Parathyroid Embryology and Developmental Abnormalities

The inferior parathyroid glands arise from the dorsal part of the P III. The thymus arises from the ventral portion of the same pouch. This common origin justifies labeling P III and thymus as parathymus. The dorsal part of the PIV gives rise to the superior parathyroids. The fate of the ventral portion of the P IV is little understood in humans. Gilmour4 regarded it as the origin of the thymus IV (rudimentary thymus IV), which rapidly undergoes involution. The fatty lobules sometimes found at...

Pathogenesis

The patterns of organ involvement and familial clustering of the MEN syndromes suggest an autosomal dominant mode of inherited transmission in each, with essentially complete penetrance but a varying degree of expression. In the 1960s, the observation that both thyroid parafollicular C cells (the cells of origin of medullary thyroid carcinoma) and cells of the adrenal medulla (which give rise to pheochromocytomas) derive from the embryonic neural crest and are of the amine precursor uptake and...

Pathologic Features

Aldosterone-producing adenomas are usually solitary tumors involving only one adrenal gland (Fig. 68-1). Most adenomas are smaller than 2 cm in diameter. The mean diameter in 210 patients with surgically proven aldosterone-producing adenomas in our series was 1.8 cm, which is consistent with previous reports.12 The cut surface usually has a characteristic golden yellow appearance. Microscopically, the typical tumor is mostly composed of large lipid-laden clear cells. In contrast, idiopathic...

Pathology of Tumors of the Thyroid Gland

Tumors of the thyroid gland can be problems for endocrinologists, surgeons, and pathologists. Carcinomas of the thyroid gland range from the innocuous occult papillary carcinoma to the extremely lethal anaplastic form. Approximately 12,000 new cases of thyroid cancers are discovered each year in the United States however, fewer than 1 of deaths caused by cancers are due to thyroid cancers.1 Because only 9 of patients affected by the disease die from it, malignant tumors of the thyroid gland are...

Pathophysiology of Endemic Goiter

Endemic goiter is the end result of the physiologic and morphologic changes in the thyroid gland as an adaptation to an insufficient supply of dietary iodine. When iodine intake is low, thyroid hormone synthesis is impaired. This impairment leads to an increased thyroidal clearance of iodide from the plasma and decreased urinary excretion of iodide, an adaptation toward iodine conservation. T3, being three to four times more potent than T4 but containing only three fourths as much iodine as T4,...

Peripheral Action of Thyroid Hormones

The major effects of thyroid hormone action occur through the intranuclear action of T3, with T4 being largely a prohormone.29 It remains controversial as to whether T4 might also regulate non-nuclear biologic responses in some contexts, for instance, the activation of certain mitochondrial or cellmembrane enzymes.29 In the 1960s, Tata and associates observed that T3 treatment resulted in the rapid synthesis of nuclear RNA, which preceded increases in protein synthesis and mitochondrial oxygen...

Peripheral Transport and Metabolism of Thyroid Hormones

More than 99 of circulating thyroid hormones are bound to serum proteins, including thyroxine-binding globulin (TBG), transthyretin, and albumin.27 TBG is a glycoprotein that contains only one binding site per molecule. TBG is responsible for the transport of more than three fourths of thyroid hormone in the blood, and its levels are significantly increased by elevated levels of estrogens, as occurs in pregnancy. Dissociation of the free hormone from its binding proteins is rapid and efficient....

Physical Examination

In general, the size of a smaller goiter is overestimated, whereas the size of larger goiters is underestimated. Thyroid enlargement is often best observed when the patient swallows. A visible goiter has usually reached a size of 30 to 40 mL ( 1.5- to 2-fold increase in the size of a normal thyroid gland). One should determine whether the thyroid gland is symmetrical or a solitary nodule, a multinodular goiter, or a dominant nodule in a multinodular goiter. Does the goiter move with swallowing,...

Pituitary Tumors

In MEN 1 kindreds, pituitary tumors are found less frequently than primary HPT or PETs.40 Signs and symptoms related to a pituitary adenoma are the initial clinical presentation of MEN 1 in up to 25 of first in the kindred cases but in less than 10 of familial cases that are TABLE 76-2. Indications for Genetic Screening At-risk family members in known MEN t kindreds Young patients (< 50 years) with multigland or recurrent HPT (normal renal function) Patients with prolactinomas 14 MEN 1)...

Poorly Differentiated Small Cell and Anaplastic Carcinomas

Poorly differentiated carcinomas purportedly are carcinomas that have clinical outcomes midway between those of well-differentiated and anaplastic carcinomas.8486 Insular carcinomas and poorly differentiated carcinomas, as they occur in papillary and follicular carcinomas, are the two major forms. The category of poorly differentiated carcinomas is compromised by the inclusion of tall cell, columnar cell, and mixed tall and columnar carcinoma variants of papillary carcinomas.33 87 88 As noted...

Postoperative Adjuvant Therapy

Because of the excellent prognosis of most patients with low-risk papillary thyroid carcinoma, it has been difficult to demonstrate any benefit from adjuvant therapy in the form of radioiodine or TSH suppression therapy. Vickery,39 Cady,1'38 and their associates concluded that the usual course of low-risk papillary carcinoma treated by conservative surgery is generally so benign that further beneficial effects of radioiodine, thyroid suppressive treatment, or total thyroidectomy have never been...

PPoma and Nonfunctioning Neuroendocrine Tumor

PPomas secrete pancreatic polypeptide, but this hormone does not appear to cause symptoms in men and this tumor is considered nonfunctional. PPomas and nonfunctioning pancreatic neuroendocrine tumors are tumors that have no functional syndrome. Dopamine agonists have been shown to decrease circulating levels of PP and chromogranin A in patients with large unresectable islet cell tumors.75 PPomas produce symptoms by tumor mass effects. This tumor is diagnosed because the patient has cachexia,...

Predictors of Thyroid Tumor Aggressiveness

The antecedents of attempts to predict thyroid cancer behavior date back to the 1930s, when the concept of lateral aberrant thyroid12 was established, because thyroid tissue appearing in lymph nodes in the neck was known to be associated with an innocent clinical behavior pattern in a vast majority of cases. As a result, these cases were considered to be not cancer but an arrested embryonic migration phenomenon, until Crile convincingly demonstrated small primary papillary cancers in such...

Preoperative Localization

Without preoperative localization, the chance of exploring the correct side in which the parathyroid adenoma is located is 50 .6 If the adenoma is not found on the initial side, the contralateral side has to be explored, which increases operative time and possibly morbidity. The accuracy of available imaging studies for parathyroid localization depends on the size and position of the adenoma, the degree of parathyroid hyperfunc-tion, and other unknown factors. In patients with mild PHPT and a...

Preventive Surgery for Multiple Endocrine Neoplasia Type 2 Gene Carriers

Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually before age 30 years). Therefore, at-risk family members who are found to have inherited the RET gene mutation are candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET mutation carriers often harbor foci of MTC in the thyroid gland even when stimulated calcitonin levels are normal.14'18-33'34'4547 In a series from Washington...