The thyroid is a butterfly-shaped endocrine gland that regulates a variety of hormone interactions, including the pace at which the body burns energy, manufactures proteins, and maintains heart function. One cause of a solid thyroid nodule is thyroid cancer, which is diagnosed in less than 10% of all patients presenting with this type of lump.
In addition to thyroid cancer, there are several additional types of benign solid thyroid nodules. A thyroid nodule may be diagnosed after the patient or physician notices a lump in the front of the patient's neck. Regardless of the results, the physician will also usually order a thyroid ultrasound to determine if the nodule is a solid thyroid nodule or is cystic. Figure 18-1B) The central area of a microfollicular adenoma displays regular nuclei and some interfollicular edema. Figure 18-1C) Hurthle (oxyphile) cell tumor, lower half of photomicrograph, with well circumscribed margin established by an intact delicate fibrous capsule. Figure 18-1D) High power view of a Hurthle cell tumor made up of microfollicles lined by large acidophilic cells, the cytoplasm of which is granular and filled with mitochondria. Thyroid nodules are not expression of a single disease but are the clinical manifestation of a wide range of different diseases.
Benign neoplastic nodules are divided into embryonal, fetal, follicular, Hurthle, and possibly papillary adenomas on the basis of their characteristic pattern 12.
Whether papillary adenoma is a real entity is debatable; most observers believe that all papillary tumors should be considered as carcinomas. Nearly half of all single nodules have on gross inspection a gelatinous appearance, are composed of large colloid-filled follicles, and are not completely surrounded by a well-defined fibrous capsule. When the patient was first examined, enlargement of the thyroid had been known for at least 6 years. During the subsequent 3 days the pain in the neck gradually diminished, but the size of the mass remained more or less the same. Usually hemorrhage occurs without known provocation, but occasionally is seen after trauma to the neck. In certain areas such as Switzerland, up to one-third of all thyrotoxic patients have hyperfunctioning adenomas (10), largely in multinodular glands. Factors that must be considered in reaching a decision for management include the history of the lesion, age, sex, and family history of the patient, physical characteristics of the gland, local symptoms, and laboratory evaluation.
A most important piece of information regarding a nodule is a history of prior neck irradiation.
The adenoma is typically felt as a discrete lump in an otherwise normal gland, and it moves with the thyroid.
The presence of a diffusely multinodular gland, ascertained on the basis of palpation, US, or scanning, has in past years been interpreted as a sign of safety.
Occasionally the gland has, in addition to a nodule, the diffuse enlargement and firm consistency of chronic thyroiditis, a palpable pyramidal lobe, and antibody test results that may be positive. The patient is usually euthyroid, and this impression is supported by normal values for the serum FTI and T3 levels. The serum TG concentration may be elevated, as in all other goitrous conditions, and therefore is not a valuable tool in differential diagnosis. Although MTC constitutes a small fraction of thyroid malignancies, and an even smaller proportion of thyroid nodules, several reports suggest that routine screening of nodular goiters by CT assay is an appropriate approach (34-37). For many years core needle biopsy of the thyroid was employed successfully in some clinics to provide a histologic diagnosis on which to base therapy (38).
Figure 18-1B Epithelial cells in a follicular arrangement suggesting adenoma, but which could be from a follicular carcinoma. Significant complications such as bleeding, infection, induced necrosis, or cyst formation are rare. A particular problem is posed when cytology discloses a follicular proliferation or a Hurthle celll proliferation.
Thanks to great technological advances, our understanding of the genomics of thyroid cancer has dramatically improved in last years.
Published studies have clearly demonstrated that the most important driver genetic events of papillary and follicular thyroid cancer, respectively, occur in the MAPK and PI3K–AKT pathways. Diagnosis by determining expression of relevant genes using gene microarray technology logically should be informative, since expression profiles of hundreds of genes can be analyzed at one time. Several studies (51a-51g) addressed the issue whether the search of miRNAs in cytological material can refine FNAC diagnosis specially in indeterminate lesions since miRNAs can be easily extracted from fresh FNAC sample or from residual cells left within the needle cup. It is accepted practice to perform ultrasound examination of all thyroid nodules as the first study, or in conjunction with FNA.
Figure 18-2.Ultrasooigraphic examination by transverse image of the thyroid containing a solid nodule in the left lobe and a homogeneous appearance of the right lobe. A current problem is the proper way to manage thyroid nodules found incidentally on ultrasounds or CAT scans done for other purposes.
The scintiscan received much attention in the past as an aid in the differential diagnosis of thyroid lesions (Chapter 6). Several alternative isotopes, such as selenomethionine, radioactive phosphate, gallium, and technetium-labeled bleomycin, have been introduced for scanning, but none has proven to give clear cut evidence of malignancy or to be diagnostically superior to FNA.
While FNA clearly has reduced the initial incidence of surgery in the management of nodules, the long term effect is less clear. All thyroid nodules once discovered should undergo a complete diagnostic evaluation, regardless of the presenting manifestation or size. Figure 18-4.Diagnostic sequence and therapeutic decisions in managing a patient with an apparent single nodule of the thyroid. Three therapeutic options are available for toxic nodules: surgery, 131-I therapy and ethanol injection. Surgery is indicated for large nodules, particularly when they have a large cystic component, in very young patients (although rare) and in those refusing radioiodine therapy. The third option for the treatment of toxic or pre-toxic nodules, ethanol injections, has been proposed by Italian authors (66, 67). It is not appropriate to maintain postmenopausal women, on doses of hormone that produce even mild hyperthyroidism for a long period, in view of the potential induction of osteoporosis and arrhythmias.
Patients receiving thyroxin therapy, or not, are followed indefinitely at 6- to 12-month intervals, and future management varies with the patient’s course. The most important requirement for surgery is the selection of an experienced surgeon in an institution with an adequate Department of Pathology.
After operation many thyroidologists favor treating patients with long-term replacement therapy with thyroid hormone.
Occasionally, when the patient is recuperating from lobectomy for a presumed benign lesion, the permanent tissue sections indicate to the pathologist that the diagnosis is actually carcinoma of the follicular or papillary type. Bennedbaek and Hegedus have carefully evaluated percutaneous ethanol injection therapy in benign solitary solid cold thyroid nodules. Dossing et al treated 78 euthyroid outpatients  with a benign solitary solid and scintigraphically cold thyroid nodule causing local discomfort, with Interstitial Laser Photocoagulation (ILP).
In areas of iodide deficiency diffuse thyroid enlargement is found during pre-teen years, and multi-nodularity commonly occurs by teenage.
Nodules in children are infrequently cystic, perhaps because cystic nodules represent an end stage in some long standing benign growths. If there is rapid growth, if possibly related nodes are present or if there is any other suggestion of malignancy, or if the nodule is the apparent cause of hyperthyroidism, resection is inevitable.
Wide spread use of ultrasound for exam of any neck pathology has resulted in frequent recognition of thyroid nodules that are too small to be palpated on clinical examination. If the lesion can be palpated it is appropriate to offer FNA cytological exam and proceed as for management of larger lesions.
2.Namba, H, Matsuo, K, Fagin, J 1990 Clonal composition of benign and malignant human thyroid tumors. Hypothyroidism refers to a common thyroid condition caused due to low levels of thyroid hormone in the body. Hypothyroidism may be caused due to certain thyroid gland conditions, or due to pituitary gland abnormalities which lead to decreased production of TSH or the thyroid stimulating hormone.
Hypothyroidism in women is commonly caused due to dysfunction of the thyroid gland after surgical removal of the gland as treatment for hyperthyroidism, or for thyroid cancer, an enlarged thyroid gland, or thyroid nodules which are malignant or overactive. Pregnant women require increased levels of the thyroid hormone to cope up with the bodily changes. Radioactive iodine therapy for hyperthyroidism can also destroy the thyroid gland and cause hypothyroidism. In rare cases, hypothalamus and pituitary gland abnormalities can also increase the susceptibility to developing hypothyroidism. Other causes of hypothyroidism in women include radiation therapy, deficiency of iodine, bacterial and viral infections which cause short-term thyroid gland damage, certain drugs that inhibit the functions of the gland, Hashimoto’s thyroiditis and similar autoimmune diseases, etc. It is important to seek medical attention whenever women experience the symptoms of an underactive thyroid gland. As hypothyroidism in women is generally caused due to decreased levels of thyroid hormone, the disease is primarily treated via varied thyroid hormone replacement drugs prescribed by a doctor. In case hypothyroidism in women is caused due to diseases or infection of the thyroid gland, then it is resolved by treating the underling illness. It is vital to treat instances of hypothyroidism during pregnancy, promptly and efficiently. Eating healthy is the most essential part of pregnancy for the mother as well as the child. Tinea versicolor is a type of fungal skin infection caused by a yeast species that naturally occurs on the human skin.
Hiccups are a natural function of the human body and everyone experiences it time to time but these are most common in babies, especially among the ones under a year old. Medically referred to as dysgeusia, a taste of metal in mouth is an indication of an acidic, metallic, or sour flavor in the mouth.
Hypertensive retinopathy is the damage to the retina and retinal circulation due to high blood pressure. HIV causes a breakdown of your body’s immune system, all areas of the body are susceptible to infection, including the eye. Inflammatory disease that damages nerve coverings, causing weakness, coordination and speech disorders. It is comprised of a right lobe and a left lobe, and is located at the base of the throat — below the thyroid cartilage — also known as the Adam's apple. An inflammatory nodule, caused by chronic inflammation of the thyroid, is one common type of nodule.
Sometimes, however, the nodule is incidentally detected during an imaging test for another reason.
A fine needle biopsy of the thyroid, an in-office procedure to remove cells from the nodule, is also typically performed.
Its clinical importance, by contrast, is out of all proportion to its incidence, because cancers of the thyroid must be differentiated from the much more frequent benign adenomas and multinodular goiters.
The one we currently follow groups the lesions on the basis of histologic findings (Table 18-1).
The nodule shows microfollicles, is sharply circumscribed by a delicate even fibrous capsule, and there is no invasion of the capsule or blood vessels by the tumor. Non-neoplastic nodules are the result of glandular hyperplasia arising spontaneously or following partial thyroidectomy; rarely, thyroid hemiagenesia may present as hyperplasia of the existing lobe, mimicking a thyroid nodule.
This is presumably related to the fact that adult thyroid cells normally divide once in eight years. One-half hour after leaving the clinic, the patient’s neck gradually began to enlarge, and she developed pain in the area of the thyroid and a rasping hoarseness. At the practical level, thyroid adenomas appear to be benign from the start and most thyroid carcinomas are likewise malignant from their inception, and do not appear on pathological examination to originate in an adenoma. These mutations generally involve the extracellular loops of the transmembrane domain and the transmembrane segments, and are proven to induce hyperfunction by transfection studies.
Slices of cold nodules incubated in vitro were unable to accumulate iodide against a concentration gradient, although peroxidase and iodide organification activities were present (13). They include adenoma, cyst, multinodular goiter, a prominent area of thyroiditis, an irregular regrowth of tissue if surgery has been performed, thyroid hemiagenesis, and of course, thyroid cancer. The age of the patient is an important consideration since the ratio of malignant to benign nodules is higher in youth and lower in older age. Patients with the hereditable multiple endocrine neoplasia syndrome (MEN), type I, may have thyroid adenomas, parathyroid adenomas, islet cell tumors, and adrenal tumors, whereas patients with MEN types II and III, have pheochromocytomas, medullary thyroid carcinomas, hyperparathyroidism, and mucosal neuromas (22-24) (vi).
Any irradiation above 50 rads (50 cGrays) to the thyroid during childhood should be viewed with concern.
Recent onset, growth, hoarseness, pain, nodes in the supraclavicular fossae, symptoms of brachial plexus irritation, and local tenderness all suggest malignancy, but of course do not prove it. Enlarged lymph nodes should be carefully sought, particularly in the area above the isthmus, in the cervical chains, and in the supra- clavicular areas. Multinodular goiters coming to surgery have a significant prevalence of carcinoma (4-17%), but this finding was believed to be due largely to selection of patients for surgery, and not to be typical of multinodular goiters in the general population (31,32). These findings strongly suggest thyroiditis but do not disclose the nature of the nodule, which must be evaluated independently. Calcitonin assay is indicated in the presence of a suggestive family history or of coincident features of the MEN-II syndromes.
Such screening offers the possibility of finding tumors before they have metastasized, and MTC is rarely found on FNA. Difficulties in acceptance of the procedure by surgeons, patients, and pathologists prevented its widespread application. Surprisingly the release of thyroglobulin into the blood stream appears to induce development of anti-thyroxine antibodies, of IgG or IgM class, in some (2-20%) patients, especially those with prior evidence of autoimmune thyroid disease (42). FNA cannot differentiate follicular adenoma from follicular carcinoma, since this distinction can only be based on the presence of capsular or vascular invasion, which cannot be detected on a cytologic smear.
A number of mutations have been demonstrated in differentiated thyroid cancers and some of them are considered driver mutations for a specific cancer histotypes, often configuring a genotype-phenotype relationship. Studies using the methodology on samples derived from FNA are currently being reported, although none has as yet reached practical clinical utility. This group also concluded that  there is “insufficient evidence to recommend use of gene expression classifiers (GECs) for decisions on cytologically indeterminate nodules”, that with the exception of mutations such as BRAFV600E, molecular evidence is insufficient to determine the extent of surgery , and that patients with nodules that are nega­tive on mutation testing should still be monitored by close follow-up.
Good technique demonstrates nodules if more than 3 mm in size, indicates cystic areas, may demonstrate a capsule around the nodule, and the size of the lobes. As noted above, US-detectable nodules are present in a large proportion of all adults- perhaps 20 % as an average figure. The scan can provide evidence for a diagnosis in a multinodular goiter, in Hashimoto’s thyroiditis, and rarely in thyroid cancer when functioning cervical metastases are seen. The same is true for other imaging techniques such as thyroid thermography, CT scan or MRI.
Over three years of follow-up, at least 30% of our patients, who are believed to have a benign nodule, eventually undergo surgery.
This allows the selection of patients with nodules that are malignant or suspicious of malignancy and therefore eligible for surgery. The majority are papillary or mixed papillary-follicular tumors, with fewer pure follicular and rare solid or anaplastic carcinomas. Antithyroid drugs can be used if necessary prior to definitive therapy, for example during pregnancy.
Surgery consists of a total lobectomy and must be performed after restoration of a normal thyroid function by antithyroid drugs.
The procedure consists in percutaneous intra-nodular ethanol injection, which induces cellular dehydration followed by coagulative necrosis and vascular thrombosis and occlusion. Possibly long-term replacement with thyroid hormone tends to prevent recurrence, although this outcome is uncertain (70). There is no unanimity on the value of this treatment, and many endocrinologists do not believe thyroid therapy is useful.
The patient is occasionally pretreated for several weeks with of thyroid hormone to suppress the normal thyroid and thereby better delineate the nodule from the normal gland. Although a surgeon with limited experience in neck surgery can remove a thyroid nodule, an adequate near-total thyroidectomy and modified radical neck dissection requires experience, if damage to the recurrent laryngeal nerves or induction of hypoparathyroidism is to be avoided. The incidence of death, recurrent laryngeal nerve paralysis, or permanent hypoparathyrodism should be zero.
Occasionally the difficulty of interpreting frozen sections will lead to thyroidectomy for a tumor that is ultimately classified as benign. If the lesion is over 1 cm in size, there is a history of irradiation, or the lesion is follicular, completion of the thyroidectomy is advisable, as discussed below, since up to 30% of such re-operations disclose residual tumor. Ninety-eight percent ethanol (25 – 50% of nodule volume) was injected under ultrasound guidance intending to achieve uniform spread throughout the nodule.


In contrast, in an iodide-replete country, discovery of a nodule in the thyroid of a child is (fortunately) uncommon, and always raises alarm because of the risk of neoplasia.
For the remaining patients, a question is whether to do a fine needle aspiration cytological exam, or offer resection without this examination.
If the nodule is definitively benign at surgical pathological exam and the remainder of the thyroid is normal, lobectomy or more limited resection is performed.
Usually such nodules are < 1cm in largest diameter, typically they are asymptomatic, and are not associated with lymph nodes or other suggestions of malignancy.
The probability of malignancy is lower than in larger lesions, although exactly how much so is uncertain. It is clear that shrinkage can be anticipated in only a small fraction of lesions, but this treatment may help reduce future growth, provides a reason for the patient to remain under medical observation, and may, by shrinking the normal tissue, make the nodule palpable and thus more easily examined.
1998 Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma.
Hamburger, J I 1980; Evolution of toxicity in solitary nontoxic autonomously functioning thyroid nodules.
The disorder can result in some severe complications in women, particularly those in the age group between 35 and 60 years.
TSH activates the thyroid gland to secrete the triiodothyronine or T3 and thyroxine or T4 hormones.
Women with minor hypothyroidism may not experience any symptoms, especially in the initial stages.
Hypothyroidism and its resultant complications are completely treatable with medications, effective regulation of thyroid hormone levels, and certain lifestyle changes. The symptoms of hypothyroidism usually show improvement within the first week of treatment itself. Patients must however consult a doctor before commencing the intake of thyroid hormone supplements so as to prevent any unwanted pregnancy complications. Especially because of the morning sickness one has to be more conscious while choosing what to eat. The skin disease, identified by an abnormal rash on skin, is caused due to uncontrolled growth of the yeast.
They experience the same in the womb, as young as 6 months or 6 weeks after the conception. Ebola is undoubtedly the most deadly of all diseases, causing deaths of almost 25 to 90 percent of the patients with an average of more than 50 percent. Initial symptoms can include vision fluctuations as blood sugar levels fluctuate, change in prescription in your spectacles (myopic shift).
AIDS related eye problems include retinal ischemia causing cotton wool spots, and more seriously CMV retinitis. When a cystic or solid thyroid nodule occurs, it is often located at the edge of the thyroid. Colloid nodules are another kind of nodule that may be seen in patients presenting with this type of thyroid mass. Once the nodule is discovered, a doctor will often order a blood test to check the thyroid hormone level. A pathologist analyzes the collected cells, and if they are suspicious for cancer, the biopsy may be repeated or the nodule may be surgically removed to make a final diagnosis. The latter, depending on the criteria employed, occur in up to 4% of the population, and thyroid nodules may be present in 20% or more of adults subjected to routine thyroid echography.
The frequently encountered papillary tumors can be subdivided into the small proportion that have only papillary histologic characteristics and the larger group having, in addition, follicular elements.
This practice is imprecise because adenoma implies a specific benign new tissue growth with a glandlike cellular structure, whereas a nodule could as well be a cyst, carcinoma, lobule of normal tissue, or other focal lesion different from the normal gland. Non-neoplastic thyroid diseases, such as Hashimoto’s thyroiditis or subacute thyroiditis may appear as thyroid lumps which are not true nodules but just the expression of the underlying thyroid disease. The adenomas usually exhibit a uniform orderly architecture and few mitoses, and show no lymphatic or blood vessel invasion. It is our impression that papillary tumors are best thought of as carcinomatous, although the degree of invasive potential may be very slight in some instances.
Many pathologists report these as colloid nodules, and suggest that each is a focal process perhaps related to multinodular goiter rather than a true adenoma.
One clue to their origin is that they are four times more frequent in women than in men, although no definitive relation of estrogen to cell growth has been demonstrated. Perhaps this has to do with the specific discrete mutational event causing their development. Although hyperfunctioning nodules may remain unchanged for years, some gradually develop into toxic nodules, especially if their diameter exceeds 3 cm (7). Mutations of the stimulatory GTP binding protein subunit are also present in some patients with hyperfunctioning thyroid adenomas (12). Hashimoto’s thyroiditis offten presents with a lumpy gland on physical exam, and a nodular or pseudo-nodular appearance on ultrasound is frequent.
Further, we have observed that 6% of our patients with thyroid carcinoma have a history of malignant thyroid neoplasm in other family members, and familial medullary cancer (without MEN) is well known.
Exposure to 100-700 rads during the first 3 or 4 years of life has been associated with a 1-7% incidence of thyroid cancer occurring 10-30 years later (25-30).
The usual cause of sudden swelling and tenderness in a nodule is hemorrhage into a benign lesion. Their presence suggests malignant disease unless a good alternative diagnosis is apparent, such as recent oro-pharyngeal sepsis or viral infection. However, in an era of generalized iodine sufficiency, when multinodular goiters are less common, this opinion needs re-evaluation. It should be remembered that 14 – 20% (30, 33) of thyroid cancer specimens contain diffuse or focal thyroiditis.
Low free thyroid hormones or elevated TSH results should raise the question of thyroiditis. A chest x-ray should be taken if a normal film has not been reported in the prior 6 months. As an alternative technique, thin needle aspiration cytologic examination has been widely adopted after favorable reports by Walfish et al (39) and Gershengorn et al (40). In these cases, the histological verification of the lesion is common, even though only 10-20% of nodules with follicular histology are proven to be malignant. The MUC1 gene, and telomerase activity, are highly expressed in carcinomas rather than in adenomas in operative specimens (49, 49a). The main effect was due to determination of BRAF V600E mutation, which is present in 50-80% of papillary cancers. Durand et al analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon microarrays.
Future prospective and retrospective research are recommended on a large cohort of indeterminate lesions to validate the diagnostic value of miRNA in FNAC.Basically, we still wait a proven genetic diagnostic technique that can be applied to FNA samples with near-perfect reliability and accuracy. If the scan demonstrates a hyperfunctioning nodule suppressing the remainder of the gland, and the patient is thyrotoxic as demonstrated by an elevated serum FT4 or FT3 level, or suppressed sTSH, the chance of malignancy is very low. This occurs because they, or their physicians, remain concerned about the nodule, or the nodule is painful or grows, or is cosmetically unsatisfactory.
In addition, surgical treatment may be needed for some benign nodules, either single or associated with multinodular goiter, when they are large or associated with signs and symptoms of compression, discomfort, or for cosmetic concerns.
Radioiodine is a very effective therapy and is becoming the treatment of choice in most patients over 21 years of age and particularly in older patients and those with coincident serious illness, because of its ease and convenience, slightly lower expense, avoidance of a scar, and avoidance of hospitalization. Also after surgery, late hypothyroidism is common (30-40% in our experience), while the occurrence of surgical complications is nearly absent in the hands of experienced surgeons. However solid evidence for the value (modest) of the treatment, and lack of problems, is gradually accumulating. In all patients under age 25, all men, and those with a history of neck irradiation, any change usually constitutes grounds for resection. The surgeon should be prepared to do a lobectomy if the lesion is benign, or a more extensive operation and appropriate lymph node removal if, from the operative findings and examination of frozen sections, it is malignant. In this day of specialization, patients deserve a surgeon who has more than a casual interest in the field.
Performance of an occasional unnecessary thyroidectomy is not a serious problem in the hands of a surgeon who has few operative complications. Many thyroidologists caring for pediatric patients would suggest resection directly, but the alternative position is to do an FNA, be guided by the results, and to follow the patient closely with resection in mind if any unfavorable sign occurs (90).
If the lesion is a hypercellular follicular adenoma or if there is uncertainly in the exam, or if other nodules are found, a lobectomy and contra-lateral sub-total resection is often performed. Often incidentally found, such nodules produce a problem because of the difficulty in achieving a specific diagnosis, which is desired by the patient.
Ultrasound guided FNA is possible for lesions closer to 1 cm in size, and in patients who clearly want every diagnostic assurance available. Growth under observation and in the absence of cytological diagnosis, or development of nodes or local symptoms, indicate the need for resection.
Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Although exercise constitutes the most important part of losing weight, one makes considerate amount of changes in the eating habits and lifestyle as a whole. Women who hear the heart beats of their baby for the first time will find the experience to be exhilarating and fascinating.
These overgrowths of tissue may become large, but do not grow past the area of the thyroid. A thyroid scan, a test that uses radioactive iodine to help determine if the nodule is malignant or benign, may also be used in the diagnostic process. My neck was numb and my radiologist very competent, but not something I ever want to experience again, unless it's like in the tough part of my heel where there aren't as many nerve endings.
The differential diagnosis of thyroid nodules is now easily accomplished by fine needle aspiration cytology in 60-90% of the cases, allowing a significant reduction in the number of thyroid surgeries performed for thyroid nodules.
There is no agreement that these groups differ functionally, and current terminology treats them as one. In the following section, the term nodule appears frequently when there is need for a nonspecific term. They are characteristically enveloped by a discrete fibrous capsule or a thin zone of compressed surrounding thyroid tissue. These tumors are usually not surrounded by a capsule of compressed normal tissue, and often show degeneration of parenchyma, hemosiderosis, and colloid phagocytosis (Fig.
Thyroid radiation, chronic TSH stimulation, and oncogenes believed to be related to the origin of these lesions are discussed below in the section on thyroid cancer. An adenoma may first come to attention because the patient accidentally finds a lump in the neck or because a physician discovers it upon routine examination. There was on exam a normal right thyroid lobe, and a 4 x 5 cm soft mass occupying the position of the left lobe.
The pain was significant enough to keep her awake that night, and she returned to the hospital the next day. However, in animals chronically given 131-I and antithyroid drugs, a gradual progression of types of lesions from adenomas to carcinomas is seen. Others undergo spontaneous necrosis with a return of function in the formerly suppressed normal gland. Others have also observed this phenomenon and have shown that TSH can bind to the membranes of the cells and activate adenyl cyclase as usual, but that subsequent metabolic steps are not induced (14). In some patients Hurthle cell rich nodular areas develop, and of course some patients have coexistent but (presumably) etiologically distinct adenomas or cancers.
Radiation exposure during adolescence or early adulthood for acne or for other reasons has also been identified as a cause of this disease. Although the presence of a nodule for many years suggests a benign process, some cancers grow slowly. Soft tissue x-ray films of the neck may disclose indentation or deviation of the trachea if the tumor is more than 3 or 4 cm in diameter. Routine screening has been adopted as a standard procedure for evaluation of nodules in many clinics in Europe, but not in the USA. The procedure is technically simple and acceptable to patients, but requires an experienced operator and collaboration with a skilled cytopathologist (Figure 18-1). False-negative and false-positive diagnoses do of course occur, but are each under 5% with experienced hands. An additional indication for FNA is the diagnostic evaluation of extra-thyroidal neck masses, especially lymph nodes, both at presentation and when the diagnosis of thyroid carcinoma has already been established. Overexpression of cyclin D1 and underexpression of p27 predict metastatic behavior in papillary nodules (49b). However cytologic diagnosis of papillary cancer is itself very accurate and BRAF identification would primarily help in a few uncertain cases. Expression patterns of a series of 19 genes allowed discrimination between follicular adenomas+normal tissue, from follicular thyroid and papillary thyroid carcinomas.
It uses parallel “next  generation sequencing”  targeted multiple portions of the genome in parallel searching for gene mutations  in PIK3CA,  PTEN, TP53, TSHR, CTNNB1, RET, AKT1, and TERT, as well as  gene fusions involving RET, BRAF, NTRK1, NTRK3, AKT, PPARc, and THADA.
The technique is more sensitive than scintiscanning, is noninvasive, involves less time, allows serial exams, and is usually less expensive.
Whether to do US guided FNA on all non-palpable nodules, those generally smaller than 1cm and often as small as 3-5mm, is a question not clearly answered. Tumors that accumulate RAI in a concentration equal to or greater than that of the surrounding normal thyroid tissue, but that do not produce thyrotoxicosis, are also typically benign (54, 55).
Interestingly, fluorodeoxyglucose-PET scanning for other purposes occasionally turns up a hot spot in the thyroid.. But in most cases operation probably occurs because the patient cannot be entirely reassured by the physician that the lesion is safe.
All the other nodules are candidates either for medical therapy or simply follow-up with no therapy. The activity of 131-I to be administered will depend on the size of the nodule and usually ranges between 185 and 740 MBq (5-20 mCi). Cytologic examination of the aspirated fluid should be done, but the specimens are often not satisfactory for diagnosis. Suppression of TG to a normal level by T4 therapy is a gratifying and reassuring response, and is correlated with nodule shrinkage (86).
In women 25 years of age and up, the situation should be carefully reviewed and reaspiration performed. If the lesion is described as a hypercellular follicular adenoma, we feel it is best to do a lobectomy and contralateral subtotal lobectomy. Indeed, in the absence of such surgical skill, medical therapy may offer significantly fewer problems for certain patients with nodules than those arising out of inadequate surgery.
Only 1-2 days are required in the hospital, and currently some surgeons do thyroid lobectomy as an “outpatient” proceedure.. On the other hand, reoperation at a later date for cancer erroneously diagnosed at initial surgery as benign is all too often required, and does not offer the patient the best chance of operative cure and freedom from operative complications.
We note that thyroxin treatment has been shown to decrease recurrence of nodules in patients operated for thyroid disease induced by childhood irradiation (88). An alternative approach is to ablate the residual lobe with 30 mCi of RAI, which is effective in eliminating most of the tissue. While the majority of patients benefited from reduction in nodule size, significant side effects included transient thyrotoxicosis, permanent facial dysesthesia, paranodular fibrosis, pain, and tenderness. This high incidence raises the issue whether all such nodules should be immediately resected, or if it is legitimate to employ the available diagnostic tests to select those for whom surgery should be advised? The majority are inactive on isotope scanning, solid on ultrasound, do not produce hyperthyroidism, and are painless. Our attitude is to perform FNA in virtually all cases, the reason being not only the selection of therapy, but, even if surgery is already planned, to provide the surgeon with the most likely diagnosis, thus allowing better planning of the surgical procedure.
Presence of neck adenopathy, local symptoms such as pain or dysphonia, growth under observation, or a history of external radiation to the neck, signal concern and suggest that resection is the proper course. The smaller lesions are difficult to aspirate with certainty even under ultrasonic guidance. Depending on the size of the patient and the lump, the nodule may be visible in the front of the neck. Hashimoto's disease, a condition characterized by chronic inflammation of the thyroid, may also result in a nodule. Still another type of solid thyroid nodule, the hyper-functioning thyroid nodule, produces hormones and may contribute to the onset of hyperthyroidism. This chapter is concerned with the clinical and pathological description of benign and malignant thyroid nodules and with the diagnostic and therapeutic approach to them.


All types of nodules may become partially cystic, presumably through necrosis of a portion  of the growth.
Many pathologists consider all of these tumors as low-grade carcinomas in view of their frequent late recurrences. Of specific interest in relation to benign nodules is the remarkable observation by Vassart and colleagues that activating mutations of the TSH receptor are the specific cause of most autonomously functioning thyroid nodules (3) including those found in the context of a mulitnodular goiter (4).
Rarely, symptoms such as dysphagia, dysphonia, or stridor may develop, but it is unusual for these tumors to attain sufficient size to cause significant symptoms in the neck.
The patient was very anxious, and there was a 10 x 12-cm tender fluctuant swelling occupying the area of the thyroid. Pathologic examination occasionally gives evidence for conversion of an adenoma to a carcinoma. Patients with functioning autonomous nodules may be overtly thyrotoxic; more commonly, however, the nodule functions enough to suppress the remainder of the gland, but not enough to produce clinical hyperthyroidism (8). Activity of the sodium-potassium-activated ATPase, thought to be related to iodide transport, is intact, and ATP levels are normal, even though iodide transport is inoperative. Although this association was known by 1950, patients were still being seen with radiation-related tumors who received x-ray treatment as late as 1959. In our series, the average time from recognition of a nodule to diagnosis of cancer was 3 years. Characteristically a benign thyroid adenoma is part of the thyroid and moves with deglutition, but can be moved in relation to strap muscles and within the gland substance to some extent. Fine, stippled calcifications through the tumor (psammoma bodies) are virtually pathognomonic of papillary cancer. While calcitonin levels above 60 typically signal the presence of Medullary cancer, abnormal levels between 10 and 60 may be present with C-cell hyperplasia or no objective abnormality, and may spontaneously normalize(37.1). Two to four aspirations of the nodule, in different areas of the nodule, are recommended by many expert cytologists, particularly when the nodule is large enough (41). Willems and Lowhagen (43), in reviewing a collected series of nearly 4,000 surgically proven fine needle aspiration studies, found that 11.8% were considered to be malignant lesions.
In these cases FNA may be integrated with the measurement of thyroglobulin content in the liquid recovered after washing the needle. Expression of c-MET, galectin, VEGF, cathepsin B, thymosin, and HMG1 has been correlated with increased probability of malignancy. The procedure is believed applicable to the material collected by FNAB, but needs testing in a prospective study (51).
In fact, some observers insist that functioning nodules cannot be malignant (55), in spite of reports of malignant change in occasional warm or hot nodules (55-59). A simple and practical flow-chart for the management of thyroid nodules, based on the results of the diagnostic evaluation is offered in Fig.18-4.
Transient, sometimes severe, local pain is the most frequent side effect, followed by transient fever, and occasionally transient dysphonia.
If the changes can be explained in the context of a benign process and the reaspirate is benign, continued careful medical follow-up is acceptable, but operation will often be preferred by the patient or physician. Many of these lesions turn out on final pathology to be malignant, and reoperation is then avoided.
Post-operative morbidity is slight and transient, and the cosmetic appearance is almost always satisfactory.
Although easy for the patient, and certainly free of surgical complications, whether this provides the same protection as re-operation is not known. They conclude that the optimum strategy is yet uncertain and that the procedure is limited, especially by local pain and the significant number of side effects, so that caution is advisable in routine use (89). Also, this approach is taken in view of the occasional false positive or false negative diagnosis by intra-operative pathological examination. What will be said applies also to nodules found within a multinodular goiter, although as a separate entity this disease is discussed in Chapter 17. Transformation of hyperplastic thyroid tissue into invasive cancer occurs in occasional patients with congenital goitrous hypothyroidism, and occasionally cancers are seen inside an adenoma or in a gland that was known to have harbored a nodule for many years. In such patients, T3 levels may be slightly elevated, serum TSH below normal, and the pituitary response to TRH is typically suppressed (9). Radiation therapy for other benign or malignant lesions in the neck is still in use in selected patients; such exposure will thus continue to be a relevant part of the history. A history of residence in an endemic goiter zone during the first decades of life is also relevant and must raise the possibility of multinodular goiter as the true diagnosis.
Pain, tenderness, or sudden swelling of the nodule usually indicates hemorrhage into the nodule but can also indicate an invasive malignancy.
Male sex, non-cystic nature, hypo-echogenicity, and stippled calcifications were associated with increased risk of malignancy per nodule. One common technique for sampling the whole nodule, is to introduce the needle in the center of the nodule, aspirate and then move the needle in another direction and aspirate again. If the lesion is metastatic from a differentiated thyroid cancer, thyroglobulin concentrations are very high (45). The authors conclude that nondiagnostic FNAs should not be considered benign, and that reaspiration, if uninformative, should be followed by selective surgical treatment (46).
Dipeptidyl aminopeptidase IV activity is almost universally present in follicular carcinomas, and usually negative in adenomas (49c).
A more comprehensive analysis is offered by the next-generation sequencing (NGS) approach which is able to interrogate multiple genes simultaneously in a cost-effective way with high sensitivity and working with low input of  starting material (50d-50h). Purely cystic lesions are reported to have a lower incidence of malignancy than solid tumors (3% versus 10%), and diagnosis of a cyst raises the possibility of aspiration therapy (52).
Some studies have indicated that the incidence of carcinoma in these clinically non-detectable nodules is effectively the same as in larger nodules. Malignant tumors usually fail to accumulate iodide to a degree equal to that of the normal gland. Although no controlled series is available, it seems obvious that some carcinomas that occur first as nodules will cause death.
Long term follow-up studies have shown that the rate of recurrence is limited to a few patients, and almost no patient developed hypothyroidism (68).
The desired course in follow-up is for a gradual reduction and disappearance of the offending lesion.
Complications increase if a carcinoma is discovered, and thyroidectomy and node dissection are required.
Since the natural history of such nodules is to enlarge, many will ultimately come to operation. Fortunately, a thyroid nodule does not automatically mean cancer, and even then, 99 percent of thyroid cancer is very treatable, with nearly a 100 percent cure rate. Pathologists usually grade them on the probability of being malignant, based on factors such as invasion of the thyroid tumor capsule or blood vessels, without differentiation into benign and malignant. Occasionally there is bleeding into the tumor, causing a sudden increase in size and local pain and tenderness.
Occasionally a patient develops metastatic cancer years after resection of an embryonal or Hurthle cell adenoma. If the nodule is resected, the gland resumes normal function, and serum TSH and the TRH response is normalized (see also Chapter 13). Because of the high prevalence (20-40%) of carcinoma in nodules resected from irradiated glands, the finding of one or more clear-cut nodules in a radiated gland, or a cold area on scan, must be viewed with alarm and requires consideration for removal, as indicated below. Hoarseness may arise from pressure or by infiltration of a recurrent laryngeal nerve by a neoplasm.
Mixed solid and cystic lesions allegedly have a higher frequency of malignant change than either pure cysts or solid lesions. At present our operational approach is to attempt biopsy in nodules 5-10 mm in size, and base treatment on the results. About all that can be stated with certainty is that some patients do die from thyroid carcinoma, and that if the surgeon removes a nodule that is really an invasive tumor before it has metastasized, or while it is still under the control of the defense mechanisms of the body, a cure is effected.
With time, hypothyroidism may develop in up to 30-40% of the patients, since the remainder of the gland receives 1,000-8,000 rads (64). However, in our opinion, this therapeutic option should be limited to highly selected cases, such as small nodules, well accessible to palpation, in patients at surgical risk or refusing radioiodine. 18-5, below) It is recognized that the efficacy of this treatment to shrink nodules is modest, but it does appear to reduce the size of 10-20% of the lesions (75-79), may prevent further growth, and keeps patients under obseervation..
Although this result occasionally is seen, most often the lump remains the same or a bit smaller and persists year after year. Hurthle cell tumors are found on electron microscopy to be packed with mitochondria, which accounts for their special eosinophilic staining quality.
After bleeding into an adenoma, transient symptoms of thyrotoxicosis may appear with elevated serum T4 levels, and suppression of thyroidal RAIU.
Microscopic examination showed a microfollicular thyroid adenoma with recent hemorrhage and necrosis.
Rearrangement of the RET gene, the genetic abnormality responsible for a subset of papillary thyroid carcinoma, is frequently found in microcarcinoma, suggesting that this lesion is malignant from the beginning without the need for accumulating several genetic lesions (6).
The adenyl cyclase system in the plasma membrane of some hyperfunctioning nodules has been found to be hyper-responsive to TSH in some studies (17) but not in others (18).
Obviously the presence of a firm, fixed lesion, associated with pain, hoarseness, or any one of these features, should signal some degree of alarm. Frates et al recommend that for exclusion of malignancy in a thyroid with multiple nodules larger than 10mm, up to four nodules should be considered for FNA, and that the risk factors noted above may guide selection of nodules for biopsy. Gharib and co-workers recently analyzed data on 10,000 FNAs, and found the procedure to be the preferred first step in diagnosis (44).
In smaller nodules or those judged very difficult to sample, the patient is advised to have repeated follow-up by exam and US at 6-12 month intervals. Hypothyroidism is more frequent in patients with positive anti-thyroid autoantibodies prior to therapy (59a). Small autonomous functioning thyroid nodules, without thyrotoxicosis, can be left untreated and followed. Sclerotherapy by ethanol injection is an other promising method of treatment for thyroid cysts. Meta-analyses of studies on thyroid hormone suppressive therapy for solitary thyroid nodules were presented by Castro et al (80) and Zelmanovitz et al (81). These authors found in a study of 78 euthyroid children with benign nodules, that T4 threatment reduced size up to 50%, while untreated nodules typically enlarged. As noted above, most hyperfunctional nodules are associated with- presumably caused by- activating mutations of the TSH receptor.
In contrast, prior exposure to internal radiation from 131-I for diagnostic or therapeutic purposes has not to date been associated with an increased risk of developing thyroid carcinoma. The converse situation, the absence of such characteristics, suggests but does not prove benignity. The diagnostic accuracy was nearly 98%, with under two percent false positives and false negatives. It is uncertain whether ultrasound guided fine needle aspiration biopsy is appropriate in these individuals. Schlumberger and coworkers found that cystic appearance, hyperechoic punctuations, loss of hilum, and peripheral vascularization were major ultrasound criteria of lymph node malignancy. In a study of this problem by Papini et al 7% of nodules under 1 cm in size were found to harbor carcinomas. Tumors smaller than 1 cm in size are below the discriminating power of most of the available scanning devices. Nearly 30-40% will eventually evolve into toxic nodules (69), but many may stay as they are or even undergo spontaneous cystic degeneration. A major reduction in cyst volume, with very low rate of recurrence has been reported in two publications (72, 73). A 50% reduction in nodule volume was found in 17% more of T4-treated patients than those left untreated, and nodule volume increased more than 50% in a larger proportion of untreated patients.
All of these points suggest that transformation of an adenoma into a carcinoma occurs occasionally, but it appears to be an unusual sequence of events. Miller et al.52 compared fine needle aspiration, large needle aspiration, and cutting needle biopsy. However, considering that 4% are reported to be papillary cancers when diagnosed under ultrasound guidance, probably most careful physicians will elect to do such a biopsy, if possible (47). These authors believe that FNA is generally indicated, and especially if the nodule is solid and hypo-echogenic, has irregular margins, intranodular vascular spots, or microcalcifications. Thus, a nodule 1 cm or less in diameter that fails to collect RAI (cold nodule) might not be delineated at all on the scintiscan. Although, in theory, this radiation could induce cancer formation, this has not been reported. Large cysts (over 40 ml volume) can also be treated by ethanol injection in several sessions with > 50% reduction in size in most cases (74). Nodules which are recent, small, colloid or showing degenerative changes at cytology are those more prone to respond to thyroxin treatment (82,83). NIS expression is increased, with respect to normal thyroid tissue, in hyperfunctioning nodules and low or absent in cold nodules both benign and malignant (20). They found fine needle aspiration cytologic examination was able to detect almost all carcinomas, but believe that cutting needle biopsy is a useful additional procedure, especially in larger (over 2-3 cm) nodules. Further, many nodules turn out to be neither cold nor hot (preferential isotope accumulation); rather, they accumulate RAI in approximately the same concentration as the surrounding thyroid tissue. An almost identical result (84) was found in a randomized, double-blind, placebo controlled study done by a group of French clinicians, who also noted that thyroxin treatment dramatically reduced the number of newly recognized nodules during follow-up. We, as others, tend to operate on patients with suspicious FNA histology, since about 25% prove at surgery to be malignant. Normal tissue in front of or behind the nodule may also accumulate isotope and in this way obscure a deficit in collection within the lesion itself.
Round shape, hypoechogenicity, and the loss of hilum taken as single criteria are not specific enough to suspect malignancy (52.1). For all of these reasons, it is our impression that the thyroid scintiscan has value, but except for the clearly toxic nodule, does not form an absolute predictor as to whether a palpable nodule is malignant or benign. However studies with follow-up after thyroxine withdrawal demonstrate rapid increase in thyroid nodule and goiter volumes, and these authors did not advise routine use  for benign nodules. Patients who are not operated are seen at 6 or 12 month intervals, and examined for any sign such as pain, growth, hoarseness, or nodes that might indicate a change in the character of the tumor. Ultrasound gives also valuable information on the extranodular thyroid tissue, that may be useful for the differential diagnosis: a typical pattern of diffuse hypoechogeneity is almost synonymous with autoimmune thyroiditis (53). Usually pertechnetate scanning provides the same information as RAI scanning, but exceptions occur. Patients are usually re-biopsied after 2-3 years and possibly again after 5-8 years to document the benign nature of the lesion.
The outcome of reaspiration of benign nodular thyroid disease was investigated by Erdogan et al in studies on more than 200 patients (48). Thyroid scan is applied to autonomously functioning nodules and FNA to all the other nodules either cystic or solid or mixed. In older patients therapy must be considered on an individual basis, after excluding other underlying chronic diseases, such as heart problems.
Three of 216 patients had a diagnosis changed from benign to papillary carcinoma at the time of the second biopsy.
If a patient is already on L-T4 and has a good compliance with no side effects, treatment may be continued after 60 years, slightly reducing the daily dose. The authors conclude that a second aspiration of clinically suspicious nodules can correct some initial false negative results, but routine reaspiration was not useful in clinically stable disease.
In case of multinodular goiter, a condition frequently associated with intra-glandular areas of functional autonomy, particular attention should be paid to the TSH pre-treatment level.
A variety of techniques have been applied to improve accuracy of interpretation of FNA cytology or histology. The appropriate dose should be checked by measuring FT3 and TSH, 3-4 months after its institution.
Normal free T3 values exclude significant over-treatment, even when FT4 is in the upper limit of normal.



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