Multinodular Goiter: Diagnosis and Management

DISEASES OF THE THYROID Pathophysiology and management

Edited by

Malcolm H. Wheeler MD (Wales), FRCS (Eng)

Consultant Surgeon University Hospital of Wales and Cardiff Royal Infirmary Cardiff Wales UK and

John H. Lazarus MA, MD (Cantab) FRCP (Lond and Glas)

Senior Lecturer and Consultant Physician University of Wales College of Medicine Cardiff Wales UK

CHAPMAN & HALL London • Glasgow • Weinheim • New York • Tokyo • Melbourne • Madras Published by Chapman & Hall, 2-6 Boundary Row, London SEI 8HN, UK

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First edition 1994

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(05? Printed on acid-free text paper, manufactured in accordance with ANSI/NISO Z39.48-1992 (Permanence of Paper). CONTENTS

List of contributors ix

Foreword by Sir Richard I. S. Bayliss, KCVO, MD, FRCP xiii

Preface xv

1 The Evolution of Treatment of Thyroid Disease 1 (a) Medical aspects 3 Reg Hall

(b) History of thyroid surgery 11 Barnard j. Harrison and Richard B. Welbourn

2 Thyroid Physiology 19 (a) Thyroid hormone production, transport and metabolism 21 Georg Hennemann, RoelofDocter and Eric P. Krenning

(b) Thyroid hormone action 29 Jayne A. Franklyn

3 Etiology of Benign Thyroid Disease 51 (a) Epidemiology 53 Gordon Caldwell and Michael Tunbridge

(b) Genetic factors 61 David I. W. Phillips

(d) Immunological factors 85 Philip S. Barnett and Alan M. McGregor

4 Diagnostic Tests of Thyroid Function and Structure 105 (a) Hormone measurements 107 Rhys John and John H. Lazarus VI Contents

(b) Thyroid antibodies 117 Jadwiga Furmaniak and Bernard Rees Smith

(d) Fine needle aspiration cytology 153 Ronald H. Nishiyama, S. Thomas Bigos and Daniel S. Oppenheim

5 Hyperthyroidism 163 (a) Clinical features 165 John H. Lazarus

(b) Graves' disease 171 Anthony P. Weetman

(d) Other causes of hyperthyroidism 201 John H. Lazarus

(e) Surgery for hyperthyroidism 207 Malcolm H. Wheeler

6 Multinodular Goiter: Diagnosis and Management 219 C. Renate Pickardt and Peter C. Scriba

7 The Solitary Thyroid Nodule 231 Malcolm H. Wheeler

8 Hypothyroidism: Etiology and Management 245 Nobuyuki Amino and Junko Tachi

9 Thyroid Disease and Pregnancy 269 John H. Lazarus

10 Etiology of Thyroid Cancer 281 (a) Molecular genetics 283 Raj V. Thakker

(b) Growth factors and oncogenes 299 David Wynford-Thomas

11 Pathology of Thyroid Cancer 343 H. Ruben Harach and Sir E. Dillwyn Williams 12 Clinical Features and Management of Thyroid Cancer (a) Differentiated thyroid carcinoma Norman W. Thompson

(b) Anaplastic giant cell thyroid carcinoma Martin Bäckdahl, Bertil Hamberger, Torsten Löwhagen and Göran Lundell

(d) Medullary thyroid carcinoma Jon A. van Heerden and Ian D. Hay

(e) Management of metastatic thyroid cancer Martin Schlumberger

(f) Prognostic factors and DNA ploidy determination in differentiated thyroid carcinoma lan D. Hay

Index MULTINODULAR GOITER: DIAGNOSIS AND MANAGEMENT 6

C. Renate Pickardt and Peter C. Scriba

Multinodular thyroid enlargement is a iodine deficiency and endemic goiter are symptom of different thyroid diseases with found all over the world, particularly in varying underlying pathogenetic principles mountainous areas and continental regions, (Table 6.1). From the epidemiological point where iodine prophylaxis is not used [1,3]. of view, endemic and sporadic goiters have The known data concerning the severity and to be distinguished. Goiter endemia is degree of iodine deficiency and goiter preva• assumed by definition in regions with a lence in Europe are shown in Figures 6.1, prevalence of more than 10% among the 6.2. USA, Canada and Japan and the coastal population under investigation [1]. areas of all continents are free of iodine In most endemic areas, iodine deficiency deficiency diseases. In iodine deficient re• is the main cause of goiter development. gions, iodine insufficiency is the most prob• Another cause of goiter endemia is the able cause of goiter. But neither morpholo• intake of goitrogens via the drinking water gical nor functional criteria can discriminate as in Columbia and the Himalayas specifically between endemic and sporadic (Chapter 3(c)). In other regions iodine de• goiter in an affected individual. ficiency and dietary goitrogens from veget• Sporadic goiter can be divided into cases able foodstuffs are together responsible for with a genetic background, including indi• this kind of endemic disease [2], which is viduals with congenital goiters in non- best documented for Zaire. Vegetables with endemic areas, and other cases induced by goitrogenic effect contain thioglycosides or goitrogenic drugs. Spontaneous cases may cyanogenic glycosides. In this context also arise from thyroiditis or growth stimu• cigarette smoking is thought to be a cofactor lating globulins, especially when thyroid for goitrogenesis, since it increases serum enlargement occurs suddenly. The different thiocyanate concentration. Regions with genetic defects of thyroid hormone synthesis

Table 6.1 Causes of multinodular goiter

Endemic Sporadic

Iodine deficiency Genetic defects of thyroid hormone synthesis Dietary goitrogens Genetic defects of thyroid hormone action Environmental goitrogens Goitrogenic drugs Thyroiditis syndromes Acromegaly TSH producing pituitary adenoma

Diseases of the Thyroid. Edited by Malcolm H. Wheeler and John H. Lazarus. Published in 1994 by Chapman & Hall, London. ISBN 0 412 43030 4. 220 Multinodular goiter

or thyroid hormone action (T4 receptor defect) are rare causes of goiter formation, which can however result in multinodular goiter in affected families. In the minor forms of these defects there may be compensation of thyr• oid function so that the individual remains euthyroid, whereas the major forms will be detected by evidence of hypothyroidism and goiter or even cretinism early in the child• hood. Sporadic goiter induced by drugs interfer• ing with thyroid hormone synthesis or re• lease is now a rare event. This is due to the fact that indications for antithyroid drug treatment are established, dosage for hyper• thyroidism is easy to control, and side effects of substances such as lithium, carbu- tamide, fluoride and aminoglutethimide are well recognized in medical practice. Iodine induced goiters are observed main• Figure 6.1 Urinary iodine excretion (^tg/g creati• ly in limited areas in Japan, where excessive nine); updated map of the original publication intake of seaweed is thought to be responsi• [4]. (Regional values are denoted in brackets.) ble for a defect of the escape from the Wolff-Chaikoff effect. This population may develop hypothyroidism. An acute development of multinodular goiter gives rise to the suspicion of in• flammatory thyroid disease, which is painful in the case of acute thyroiditis and the subacute thyroiditis of De Quervain, or pain• less in the case of granulomatous diseases such as sarcoidosis or tuberculosis. In general, nodular transformation of the enlarged thyroid is the consequence of ear• lier diffuse thyroid enlargement under the continuing influence of the goitrogenic prin• ciple [5,6]. Therefore, patients with multi• nodular goiter usually are older than those with diffuse thyroid enlargement [5,7]. It has been shown for sporadic goiter that there is a linear relationship between age and thyr• oid volume and nodularity, respectively, with an average yearly increase of 4.5% of goiter volume, as calculated by Berghout, et al. [5,8]. During nodular transformation Figure 6.2 Goiter prevalence (%); updated map of the original publication [4]. (Regional values hypo-, normal, and hyperfunctioning are denoted in brackets.) nodules may develop within the same Clinical picture 221 gland. Also, multiple autonomously func• Table 6.2 Clinical symptoms of tioning nodules can be observed in multi• multinodular goiter nodular goiters with associated euthyroid- Feeling of tightness ism. This so-called multifocal functional Feeling of a foreign body autonomy is a disease with a relatively high Dysphagia frequency in regions with endemic goiter, Urge to cough but little attention has been paid to this final Hoarseness consequence of chronic iodine deficiency. As Dyspnea, stridor long as iodine deficiency persists, these pa• Upper venous obstruction tients often remain frequently euthyroid or develop borderline hyperthyroidism. Only of hypothyroidism. In the more complete when the amount of autonomously function• forms of these genetically determined dis• ing tissue is high does spontaneous hyper• eases the affected individuals are overtly thyroidism occur. However, this group of hypothyroid. Patients with sporadic goiter patients bears an unknown risk of iodine due to drugs are also usually euthyroid. In induced hyperthyroidism when there is a lithium treated individuals, however, brisk and/or prolonged increase of iodine hypothyroidism has been observed. The rare intake (Chapter 5(d)). In our hospital, this condition of TSH-producing pituitary tumor disease is twice as often the cause of hyper• has already been discussed. Patients with thyroidism as immunogenic thyroid disease. acromegaly and goiter are euthyroid. Symptoms from nodular goiter are summarized in Table 6.2. A feeling of tight• 6.1 CLINICAL PICTURE ness or of a foreign body may be non• In endemic goitrous areas, the medical his• specific and independent of the actual thyr• tory of multinodular goiter reveals a long• oid volume or nodules; these complaints standing thyroid enlargement in most cases may draw the attention of the patient and [9,10]. As long as the patient has no signs or his medical attendant to the thus incidental• symptoms of thyroid dysfunction and no ly detected disease. Dysphagia and an urge local complications, the disease is often un• to cough may result also from retrotracheal noticed and may be detected just by chance. thyroid tissue which may be detected only In other cases, increasing growth of the by the surgeon. Hoarseness can be a sign of whole organ, or of one or more nodules, is functional impairment of the recurrent responsible for local symptoms (Table 6.2) laryngeal nerve; this functional impairment and brings the patient to medical attention. can also be induced spontaneously in rare This history is typical of endemic goiter in cases by benign thyroid nodules. Dyspnea iodine deficient regions as well as for ende• and stridor may be due to tracheal com• mic goiter in areas with a significant intake pression or dislocation by episternal or in• of goitrogens. Depending on the degree of trathoracic goiters. Both true and false en- iodine deficiency or dietary intake of goit• dothoracic goiter can cause compression of rogens, patients may be euthyroid or have the upper venous system, accompanied by a more or less pronounced signs of hypothyr• more or less pronounced venous bypass of oidism. In European countries with mild the ventral thoracic wall (Figure 6.3). So- iodine deficiency, the goitrous population is called downhill varicosis of the esophagus euthyroid with few exceptions [3,11]. Other usually remains symptomless (Figure 6.4). causes of multinodular goiter, such as defec• Patients with acute and subacute thyroidi• tive thyroid hormone synthesis or hormone tis present with a painful enlarged goiter; action, induce gradual and differing degrees pain usually disseminates over the neck to 222 Multinodular goiter

the ears or teeth. Palpation of the nodules differ from those of endemic goiter. With intensifies the pain. In chronic inflammatory respect to the usually short history of these diseases, such as sarcoidosis, the nodules nodular goiters, thyroid malignancy also has are painless and local symptoms do not to be considered.

6.2 DIAGNOSTIC PROCEDURES

6.2.1 PALPATION AND INVESTIGATION BY ULTRASOUND

Diagnostic procedures are summarized in Table 6.3. Conventionally, the multinodular thyroid is detected by simple palpation [7- 9,12]. We perform palpation standing be• hind the sitting patient. In this way, thyroid tissue can be defined by the movement induced by swallowing a gulp of water. Nodularity can be detected and described separately for each lobe and for the thyroid isthmus, while also noticing the consistency. It is of importance to state whether the lower pole can be defined clearly in the episternal part of the neck, thus generally excluding endothoracic parts of the thyroid. Historically, goiter size is estimated according to the WHO classification (Table 6.4) which was originally proposed for Figure 6.4 So-called downhill varicosis of the epidemiological purposes. Today, individual esophagus in a patient with recurrent goiter. goiter size can be estimated with greater Diagnostic procedures 223

Table 6.3 Diagnostic procedure

Palpation High resolution ultrasonography

Adequate evaluation of thyroid function (basal TSH, FT4/ FT3) Radioisotopic scintiscan (with quantitative evaluation of Tc uptake; in special situations, radioiodine scan) Cytologic evaluation of fine needle biopsy Appropriate evaluation of local complications

Table 6.4 Estimation of thyroid size, WHO classification

Stage Clinical findings

0-A No goiter 0-B Goiter detectable only by palpation and not visible even when the neck is fully extended I Goiter palpable, but visible only when the neck is fully extended; this stage also includes nodular glands, even if not goitrous II Goiter visible with the neck in normal position; palpation is not needed for diagnosis III Very large goiter which can be recognized at a considerable distance

accuracy and reproducibility by ultrasound oids on palpation, multinodularity was investigation [6,11-15]. Thickness, width documented with a four times higher sensi• and length of both thyroid lobes have to be tivity as shown by Hay and co-workers [14]. measured. The thyroid volume can then be Moreover, by this method, sonomorpholo- calculated by the formula for an ellipsoid gical criteria can be used to differentiate using an empirical correction factor of 0.479 between solid, cystic and mixed solid and or 11/6, respectively [6]. The formula is: cystic nodules. Among the solid nodules, those of high or normal echogeneity can be volume = a . b . c . 11/6 distinguished from those with reduced where a is the maximal length, b the maxim• echogeneity by comparison with the normal al width and c the maximal thickness. thyroid and the neighboring muscular tis• If the investigator has some expertise, the sue. This may be helpful in determining the reproducibility is sufficient for clinical pur• nodule(s) to be investigated further by fine poses. The deviation of the results is ±10%. needle aspiration to exclude or confirm This method has limitations in large nodular malignancy [18], but it has to be emphasized goiters, where coupling of the transducer to that the sonomorphological appearance of a the neck surface may not be feasible, and in nodule per se never definitely excludes patients with endothoracic thyroid tissue. malignancy. Evaluation of nodularity in a thyroid with In patients with thyroiditis, all thyroid normal or enlarged volume [5,9,11,14,16,17] nodules appear hypo-echogenic. When in• can be performed with a much higher sensi• flammatory thyroid disease is assumed, tivity by high resolution ultrasonography white blood cell count and determination of when compared with palpation. By this the ESR can be helpful. In patients with method, in patients with uninodular thyr• acute thyroiditis due to bacterial infection, or 224 Multinodular goiter in those with suspicion of a granulomatous agnostic use of radioisotopic imaging of the inflammation, general investigations have to thyroid world-wide. In euthyroid patients be performed because disseminated man• with a sonographically solitary nodule, ifestations have to be excluded. radioisotopic investigation may be omitted when malignancy can be excluded cytologi- cally. Also, in solitary pure thyroid cysts the 6.2.2 EVALUATION OF THYROID FUNCTION confirmation of the lack of isotope uptake is The diagnosis comprises appropriate evalua• not needed. In all other conditions of uni- or tion of thyroid function. For practical pur• multinodular goiter, the impact of isotopic poses, a normal basal TSH level, when imaging is high with respect to further determined by a sensitive assay system, diagnostic and therapeutic decisions and provides the information that the patient is should therefore be recommended. euthyroid. An elevated basal TSH has to be In endemic goitrous regions, the multino- expected in a patient with decreased thyroid dularity may be caused by cold and hot hormone effect or with impaired thyroid nodules within the same gland. Patients hormone synthesis, whereas completely or with this thyroid disease are at risk of partially suppressed TSH will indicate ele• hyperthyroidism in the future. Moreover, vated thyroid hormone synthesis and action. there is no reasonable form of medical treat• When the TSH levels are completely sup• ment for this situation. In patients with pressed (below the limit of detection) precli• sporadic goiter without defects of thyroid nical or overt hyperthyroidism has to be hormone synthesis or action, if multinodu- excluded by determination of free thyroid larity is present, scintiscan has to be recom• hormone levels (FT4 and/or FT3). Preclinical mended for the same reasons. Especially in and overt hyperthyroidism has a relatively non-endemic areas, metastases of non- high incidence in patients with multinodular thyroidal malignancy (bronchial, renal and goiter in iodine deficient areas. breast carcinomas), parasitic infections and granulomatous diseases have to be consi• dered as the causes of these nodules. 6.2.3 RADIOISOTOPIC IMAGING

Visualization of intrathyroidal functional 6.2.4 CYTOLOGICAL INVESTIGATION BY heterogeneities and calculation of regional FINE NEEDLE ASPIRATION differences of functional activities in the thyroid can only be achieved by radioisotope Cytological investigation of smears of fine scintiscan [13] and calculation of the uptake needle aspiration (FNA) material has its [19,20]. In nodular goiters, the technetium- main significance in patients with solitary 99m pertechnetate scintiscan can detect nodules [9,10]. In multinodular goiters, this hypo- and non-functioning nodules as well investigation should be used when one of as hyperfunctioning hot nodules. Under ex• the nodules shows recent growth or has a ogenous or spontaneous TSH-suppressive hypo-echogenic structure in comparison conditions, quantitative determination/ with the normal thyroid tissue. It can also be calculation of the regional technetium up• used simply to exclude malignancy in all take represents a measure of the auton• nodules, when surgical treatment is refused. omous functional activity of hot nodules In inflammatory thyroid diseases, FNA pro• [19,20]. In contrast, the documentation of vides the material for the microbiological hypofunctioning so-called 'cold' nodules is identification of any bacterial infection. independent of the TSH secretion. The validity of cytological investigation There is considerable variation in the di• depends on the experience of the person Treatment 225 performing FN A as well as on the cytologist. patients. Hoarseness or vocal fatigue re• It may reach approximately 90% sensitivity quires a laryngeal inspection. During preop• in the documentation of malignancy in solit• erative preparation of every patient this ary cold nodules. The result should include latter investigation is recommended for a clear description of thyroid cell morpholo• medico-legal reasons. gy, and of any visible infiltration by lympho- In patients with a nodular goiter and an or granulocytes or cells of foreign origin. intrathoracic mass, identification of the mass Classification according to Papanicolaou as thyroid tissue requires radioiodine imag• criteria is not helpful because it does not ing and is part of the preoperative investiga• refer to the thyroid morphology and the tion. Computerized tomography is also re• possible different morphological types of quired; this allows the exact visualization of thyroid cancer. the anatomical relationship between the in• The result of cytological investigation can trathoracic thyroid tissue and the surround• show clearly benign or unequivocally malig• ing structures and the distinction between a nant cells, but there can also be a suspicious false or true endothoracic goiter. The use of zone. Moreover, the investigation can indi• iodine containing contrast media must be cate a follicular adenoma of high cellularity. avoided, otherwise an unexpected malignant The consequences of the latter two findings thyroid tumor cannot be subsequently trea• are discussed controversially in the Anglo- ted by radioiodine. If available, MRI may be American literature [10,21]. In the case of a used in cases with difficult anatomical inter• suspicious result, biopsy can be repeated but relationships between the endothoracic goi• for follicular adenoma, cytological measures ter and thoracic structures (Figure 6.5). are unsuitable to exclude a low grade follicu• However, in uncomplicated situations, the lar carcinoma. Therefore, we prefer surgical use of the latter two methods seems to be removal of the nodular lobe with histological inappropriate. classification of the tumor.

6.3 TREATMENT 6.2.5 APPROPRIATE EVALUATION OF LOCAL COMPLICATIONS 6.3.1 MEDICAL TREATMENT

In most patients with multinodular goiter The treatment of nodular thyroid disease by clinical investigation gives sufficient in• TSH suppressing doses of T4 is controversial formation to exclude major local complica• [10,12,13,21-24]. It is, however, thought to tions, but, if surgical treatment is consi• be appropriate in order to select patients dered, more intensive exploration of tracheal who respond to this treatment sufficiently and vocal cord function has to be performed from those who do not respond, assuming [9,13]. Dislocation and compression of the that the latter group clearly should be oper• trachea can be excluded by standard X-ray ated upon for their resistant nodular goiter investigation of the thorax. Varicosis of the [10]. Reported results of T4 medication range esophagus (Figure 6.4) may be diagnosed by from a response rate of 55.7% [22] to approx• contrast studies. This complication can be imately zero [21] in solitary nodular disease. expected mainly in patients with large re• In our own investigation of patients with currences. Tracheal compression with func• diffuse endemic goiters [23] reduction of the tional impairment should be investigated by total thyroid volume reached 30%. These measuring the inspiratory and expiratory data were confirmed by others [12], but airway resistance, which can exclude bronc• there is no study in which normalization of hial obstruction immediately in dyspnoeic the thyroid volume and the disappearance of 226 Multinodular goiter

Figure 6.5 (a) Computerized tomography, axial slice orientation, without contrast agent. The figure demonstrates a huge mass in the upper mediastinum. The trachea is laterally displaced and can be identified as a hypodense structure. Note the calcification in the central portions of the tumor.

nodules is documented convincingly. Thus, hormonal suppressive treatment cannot be accepted as a reasonable long term treatment for euthyroid nodular disease. In patients with nodular disease due to dyshormogene- sis or reduced thyroid hormone action, thyr• oid hormone supplementation is indicated in order to optimize the metabolic status. In this group thyroid hormone treatment may induce a limited reduction in thyroid volume, and may be used to avoid surgery. In all other situations, thyroid surgery is indicated and necessary if mechanical com• plications are to be prevented or have to be treated, and if the possibility of malignant neoplasia has to be excluded. Figure 6.5 (b) MRI, T2 weighted sequence, coron• More recently, treatment with stable al slice orientation: demonstrates a huge mass iodine has had a renaissance, at least in with high signal intensity, and some irregular• Germany, a country with endemic goiter ities. The mass displaces the trachea to the right [12,15,25]. This method of treatment is suc• side and additionally leads to an enormous com• cessfully used after exclusion of autonomy in pression of the brachiocephalic trunk. No infiltra• hypothyroid neonates [25] in peripubertal tion is shown and histology proved this to be a children [15] and in younger adults [12] with multinodular goiter without any malignant inva• sion. (We thank our colleagues of the Klinik and diffuse goiters due to iodine deficiency. Poliklinik für Radiologie of the University of However, in these groups of patients, with Munich for these two figures: 6.5(a)(b).) the exception of the neonates, normalization Treatment 227 of thyroid volume was rarely reached. Thus, The unequivocal indication for thyroid iodine supplementation in iodine deficiency surgery is the suspicion of malignancy. In induced goiters is not a promising concept patients with one or more so-called 'cold' with respect to nodular shrinking. It may nodules, especially those with recent however be a reasonable way to prevent growth, malignancy has to be considered further growth of pre-existent goiters after even before the classical signs of a malignant exclusion of functional and morphological tumor can be recognized clinically. The dis• complications. cussion concerning the minimal volume of a nodular lesion which gives rise to the suspi• cion of a malignant tumor seems nowadays 6.3.2 RADIOIODINE TREATMENT to be senseless with regard to our know• In patients with recurrent goiter or elderly ledge of papillary thyroid cancers (Chapter patients, radioiodine treatment is a useful 11). Suspicion of malignancy in small alternative to reduce goiter volume signi• nodules arises from the cytological findings ficantly [26]. The precondition is that the only. The reported prevalence of malignant mechanically effective parts of the enlarged tumors of the thyroid depends mainly on gland consist of functionally active thyroid the preselection of patients undergoing the tissue with sufficient radioiodine uptake. evaluation. For patients below 20 years or This treatment is safe and the reduction of above 60 years of age, and for males, the risk the thyroid volume is sufficient to improve of malignancy in thyroid nodules is believed respiratory obstructive symptoms and dys• to be increased when cold nodules can be phagia. Hypothyroidism may result during diagnosed. Other authors [10] do not see an long term follow-up. increased probability of malignancy with age, but differentiated carcinomas are more often observed below the age of 40 years, 6.3.3 SURGICAL TREATMENT whereas the prevalence of undifferentiated Mechanical complications are the reason for carcinomas increases thereafter. surgical treatment of multinodular goiter in The possibility of malignancy is increased more than 60% of patients in Germany; in hypofunctioning solitary thyroid nodules, among these, tracheal compression is the especially in those with reduced echogeneity main complication. In some cases, parts of when compared with the surrounding thyr• thyroid tissue may be inserted between oid tissue [18], but it has to be pointed out esophagus and trachea, thus impressing the that most of these data refer to solitary pars membranacea of the trachea from be• nodules. Since comparable investigations for hind, resulting in dry cough and dyspnea. multinodular goiters are lacking, we propose The situation is difficult to diagnose before that during the initial investigation of these surgical intervention. Patients with dyspha• conditions ultrasound investigation, tech• gia and Horner's syndrome should be oper• netium scintiscan, and, in cases of cold ated on for both diagnostic and treatment nodules, FNA with cytological investigation, purposes. should be combined to exclude or confirm a In general, intrathoracic goiters, with or malignant tumor with the greatest possible without mechanical complications, should accuracy. If cytological investigation leads to be removed surgically because of the risk of the suspicion of a follicular adenoma, surgic• significant, perhaps even life threatening, al treatment and histological exclusion of a pressure effects developing in the future and highly differentiated follicular carcinoma is because malignancy cannot be excluded with mandatory. When malignancy has thereby certainty. become unlikely, the decision for surgical 228 Multinodular goiter treatment depends on the local symptoms 2. Delange, F. (1974) Endemic goitre and thyr• and sometimes also on cosmetic reasons. oid function in Central Africa. Monographs in In multinodular goiters, bilateral resection Paediatrics. 2: 1-171. 3. Gutekunst, R. and Scriba, P.C. (1989) Goiter usually has to be performed because of and iodine deficiency in Europe: The ETA bilateral nodular degeneration. In order to report as updated in 1988. Journal of Endocrino• avoid recurrence, it is recommended that all logical Investigation. 12: 209-15. nodules be resected completely [27]. In large 4. Subcommittee for the Study of Endemic goiters with pronounced multinodularity, it Goitre and Iodine Deficiency of the European may be difficult to define normal thyroid Thyroid Association. (1985) Goitre and iodine tissue intraoperatively, so that a near total deficiency in Europe. Lancet, i: 1290. thyroidectomy has to be performed. 5. Berghout, A., Wiersinga, W.M., Smits, N.J., et al. (1990) Interrelationships between age, The functional result depends on the thyroid volume, thyroid nodularity, and thyr• volume of residual functionally intact thyr• oid function in patients with sporadic nontox• oid tissue. If the remnant has a volume of a ic goitre. American Journal of Medicine. 89: normal sized thyroid gland, euthyroidism is 602-8. a possible result, whereas for smaller rem• 6. Brunn, J., Block, U., Ruf, G., et al. (1981) nants hypothyroidism has to be expected. Volumetrie der Schilddrüsenlappen mittels Real-time-Sonographie. Deutsche Medizinische The classical permanent complications of Wochenschrift. 41: 1338-40. surgical treatment of all thyroid diseases are 7. Meng, W., Meng, S., Hampel, R., et al. (1982) palsy of the recurrent laryngeal nerve and Ergebnisse der Schilddrüsenhormontherapie hypoparathyroidism. The frequency of these bei blander Struma. Zeitschrift fur die Gesamte complications depends strongly on the ex• Innere Medizin und Ihre Grenzgebiete. 37: 540-2. perience of the surgeon. These complica• 8. Berghout, A., Wiersinga, W.M., Smits, N.J., tions are seen less often after surgery for et al. (1988) The value of thyroid volume multinodular goiter compared with Graves' measured by ultrasonography in the diagno• sis of goitre. Clinical Endocrinology. 28: disease [28] and increase significantly in 409-14. operations for recurrent goiter [29]. 9. Ashcraft, M.W. and van Herle, A.J. 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