Surgery for Thyroid Disease

Symposium on Thyroid Disease

Surgery for Thyroid Disease Carlos A. Weber, M.D.,* MD.,* and Grlo H. Clark, M.D.t MD.t

The thyroid is the most frequently operated upon endocrine gland. Although hyperthyroidism and thyroid malignancy are only the second and third most common indications for thyroidectomy (after nontoxic goiter), these are the areas in which controversies have arisen over questions of patient selection and choices of operation. This article will cover the indications for surgery and extent of operation in patients with thyrotoxicosis and with thyroid nodules and cancers, and will conclude with a brief discussion of some technical aspects of thyroid surgery. HYPERTHYROIDISM

At the beginning of this century, it has been estimated, patients with 20 per cent chance of succumbing acutely to thyroid hyperthyroidism had a 20 storm. Another 40 per cent would follow a course of exacerbations and remissions, leading ultimately to thyrocardiac disability. Of the remaining 40 per cent who spontaneously became euthyroid, about half would remain so, the others progressing to hypothyroidism. 74 The most impressive result of disability current therapy has been the virtual elimination of death and disal)ility caused by hyperthyroidism; our ability to render patients euthyroid ha~ imexpen'iC of proved only modestly. These gains have been achieved at the eXperiS{~ making more patients hypothyroid. These observations reflect our limited understanding of the pelt hogenesis of hyperthyroidism, especially of Graves' disease, its most cornrnon CUEl mon form. Unable to influence the underlying course of the disease, we ernemSurpl i..,ing pirically to combat its more crippling manifestations. It is not surpri.sing that several strategies for achieving these limited aims have evolved;, ;·ach evolved,ach with distinct advantages and disadvantages (Table 1). The singular advantage of the antithyroid medications is their ability to control thyrotoxicosis without permanent injury to the thyroid gland. They are thus uniquely applicable when the thyrotoxic state may be self*Instructor in Surgety, University of California, San Francisco, and '!eterans '.1eterans Administration Hospital, San Francisco, California tProfessor of Surgery, University of California, San Francisco, and Veterans Administration Hospital, San Francisco, California

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Table 1. TREATMENT

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Comparison of Treatments for Thyrotoxicosis ADVANTAGES

DISADVANTAGES

Antithyroid drugs

Nonablative N onablative

Permanent remission rare Complications: low white cell count Prolonged dosing required

Radioiodine

Outpatient Inexpensive Safe

Ablative Hypothyroidism frequent Delayed control Possible carcinogenesis

Surgery

Prompt control Few remissions Less hypothyroidism Treats local symptoms

Ablative Costly. requires hospital stay Costly, Complications: nerve injury, hypoparathyroidism

Outpatient Useful if diagnosis in doubt

limited, or its cause is unclear, for example, in"Hashitoxicosis." Treatment is relatively inexpensive and can be conducted on an outpatient basis. Serious side effects (granulocytopenia and agranulocytosis) are rare. On the other hand, permanent remission after cessation of therapy occurs less than 47,109 half the time, perhaps as rarely as 11.4 per cent. centY· 109 The alternative of long-term maintenance therapy is costly and presupposes a high degree of patient compliance. A remission is especially unlikely in the presence of a 95. 102, 102. 109 or one that fails to shrink during treatment;47, 95 more large goiter47 ., 95, than moderate chemical or clinical hyperthyroidism;102 a high titer of thyroid-stimulating immunoglobulins;27 or the HLA-B8 antigen. 59 Radioiodine acts by interfering with thyroid follicular cell replication, causing an irreversible and progressive decline in thyroid function. Its adcausing. vantages are efficacy, safety, and avoidance of hospitalization and operation. A potential disadvantage in some situations may be the delay in controlling the thyrotoxic state: as many as one fourth of patients may still be hyperthyroid after 2 years. 94 Of more concern is the potential for carcinogenesis in the thyroid gland or elsewhere. Though no increase in thyroid malignancies after 1311 therapy was documented by the Cooperative Thyrotoxicosis Therapy Follow-up Study,28 their follow-up interval was short compared with the intervals known to elapse between exposure to other forms of ionizing radiation and the apperance of thyroid tumors. Benign neoplasms were more frequent after 1311 therapy, especially in young patients, and those malignancies that did occur were of high grade. The biggest single drawback of 131 1 therapy is that almost all patients will eventually become hypothyroid. The incidence of hypothyroidism is large in the first three years after treatment, and thereafter increases at a fixed rate of about 3 per cent per year, independent of the dose of radiation received. 2,2. 44 Attempts to curtail the development of hypothyroidism after 131 1 by limiting the dose have resulted only in more frequent recurrences 131I 12.01 in place of 131 1 resulted of hyperthyroidism. 16, 94 Neither has the use of 12.51 in any advantage. Subtotal thyroidectomy offers prompt control of thyrotoxicosis, the gaiters, and the greatest chance to alleviate local symptoms caused by large goiters,

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probability of rendering a patient euthyroid. On the other hand, it is costly and requires hospitalization. Further, it is the only treatment that exposes the patient to any risk, however small, of permanent hypoparathyroidism or nerve injury. In summary, we have no ideal treatment for hyperthyroidism. Radioiodine is the most common therapy in the United States for adults with Graves' disease, but subtotal thyroidectomy may be advantageous or indicated in certain situations: 1. When a large goiter or a multinodular goiter is present, or when uptake of radioactive iodine is low. In these instances, large doses of radioiodine would be required and would treat only the hyperthyroidism, leaving the patient with the goiter.

2. When local symptoms, such as pain or dysphagia, are present, only removal of the thyroid can reasonably guarantee relief. 3. When a cold nodule is present within a toxic gland. These nodules prove to be malignant at least as often as cold nodules in euthyroid glands. 65 Appropriate surgical excision allows both the hyperthyroidism and the nodule to be definitively addressed. 4. When a patient is noncompliant, or when follow-up is likely to be difficult. The risk of subsequent hypothyroidism is considerably less with subtotal thyroidectomy than with radioactive iodine, an advantage if the patient's ability or willingness to take replacement therapy is in doubt. Also, most patients who will become hypothyroid after subtotal thyroidectomy will do so within 2 years of their operation. 82 Beyond this time the risk is much lower than after radioactive iodine treatment. Surgery may thus be preferred if prolonged follow-up is unlikely,. unlikely. 5. When a pregnant woman cannot be controlled with low doses of antithyroid medications.' medications. Hyperthyroidism develops or is present in roughly 2 of every 1000 pregnancies. HH , 107 If untreated it can lead to abortion, premature labor, or neonatal hyperthyroidism. 107 Although the thionamides cross the placenta, their use in pregnancy appears to be safe as long as the dose can be minimized. If enough drug reaches the fetal thyroid to inhibit it, fetal TSH increases and neonatal goiter results. This is unusual when the dose of propylthiouracil can be kept below 100 to 200 mg per day. 10, H When larger amounts are required to keep the mother euthyroid, a subtotal thyroidectomy should be performed during the second trimester, with thyroxine replacement until delivery to eliminate any possibility of maternal hypothyroidism. In the preparation of the pregnant patient for surgery, beta blockers should be avoided, if possible, as they can cause fetal growth retardation, hypoglycemia, and bradycardia. 107 Iodides, although they cross the placenta and can cause neonatal goiter,29 may be used for 10 to 14 days in the immediate preoperative period to decrease gland friability and vascularity. It is agreed that radioiodine should not be used in pregnancy. H, H. 29, 29. 107 6. When a thyrotoxic woman wishes to become pregnant as quickly as possible after completing therapy, subtotal thyroidectomy is the preferred

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form of treatment, since euthyroidism is achieved more rapidly than with radioactive iodine, and since most physicians advise delaying pregnancy for one year after radioactive iodine treatment.

7. When the patient is a child or adolescent. Evidence exists that younger persons are more susceptible to radiation-induced thyroid neoplasia than are adults. 28, 28. 41 Reports of thyroid cancer following radioactive io64,• 93 have prompted most clidine treatment for Graves' disease in children64 nicians to avoid this form of treatment. Antithyroid medications and surgery have both been used with satisfactory results. 64, 90, 104 8. When hyperthyroidism is due to a solitary toxic nodule or to a multinodular goiter, several considerations argue in favor of surgical treatment for most patients. In the case of a toxic nodular goiter, surgery is favored because it removes the goiter, and because radioactive iodine uptake is 1311 theoretically patients, For solitary toxic nodules, 131 generally low in these patients. has the ability to ablate only the functioning nodule while sparing the adjacent normal but suppressed thyroid tissue. tissue, However, this tissue is thereby exposed to radiation doses that are potentially cancer-promoting (Figs. 1 and 2).41 Thyroid cancer following such exposure has been reported, albeit rarely. 49 Furthermore, when doses of radioactive iodine adequate to ablate these generally large toxic nodules are used, hypothyroidism is no less 1311 therapy for Graves' disease. 4o 4O Attempting to common than following 131 limit hypothyroidism by administering smaller doses results in failure to 32 suppress many nodules. 32 On the other hand, surgical ablation of a toxic nodule requires only excision of the nodule, or at most a lobectomy. This reduces the risk of vocal cord palsy, and hypoparathyroidism should not occur. In one series of 60 patients treated surgically for toxic adenomas, there was no permanent nerve injury or hypocalcemia, and no recurrent thyrotoxicosis. Four patients developed hypothyroidism. 32

cm

1. Diagram of spatial Figure 1. relation between an adenoma and the thyroid gland. The size of the thyroid and the location of the nodule are assumed to be such that the nodule center is 6 cm from the tip of the opposite lobe. Concentric circles are used to indicate dose in rads at various distances from the center of a 4-cm diameter nodule receiving 30,000 rads from 1311. (From Corman, C. A., and Robertson, J. S.: Radiation 13l 1 I or surdose in the selection of 131 gical treatment for toxic thyroid adenoma. Ann. Intern. Med., 89:85-90, 1978; with permission.) 89:85--90,

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Figure 2. Radiation dose at points 1 cm to 6 cm from center of nodules receiving 30,000 rads from 1311. Nodule radius is indicated by size of shaded area. Radioactivity in nodule, ex131 1, is shown in oval boxes, and gamma radiation dose in rads at pressed as millicuries of 131 points progressively more distant from nodule center is shown in rectangular boxes. (From 131 0[1 31 1 or surgical treatCorman, C. A., and Robertson, J. S.: Radiation dose in the selection of ment for toxic thyroid adenoma. Ann. Intern. Med., 89:85-90, 1978; with permission.)

The question arises whether solitary functioning but nontoxic ("warm") nodules should be excised, since approximately 10 per cent of these will become toxic if followed 6 years. 50 Hamburger suggests that impending toxicity can be predicted by finding a large nodule (3 cm or greater), a high normal serum T3 concentration, a blunted response to thyrotropin-releasing hormone, or complete suppression of extranodular tissue on thyroid scanning. 51 Patients without these findings can safely be followed.

Preparation of the Thyrotoxic Patient for Surgery No patient should currently be expected to die as a result of thyroid surgery. Adequate preoperative preparation of thyrotoxic patients contributes to maintenance of this standard by eliminating the risk of thyroid storm perioperatively. Additionally, the gland is easier to handle intraoperatively, minimizing complications. More than one acceptable method of achieving preoperative euthyroidism exists. The most widely accepted employs the thionamide antithyroid medications (usually propylthiouracil in the United States) with the addition of Lugol's iodine or SSKI (potassium iodide), three drops twice daily, for 10 to 14 days prior to surgery, in order to decrease gland friability and vascularity. In the last decade, the beta-adrenergic blocking drugs have been used increasingly, either alone or in combination with other agents, to prepare thyrotoxic patients for surgery. Results comparable to those obtained with thionamides have been achieved. 100 Reported advantages of propranolol include reduction in the time required before surgery,36 decreased blood loss, 100, 115 10ss,1°O, U5 and decreased gland friability.u5 However, several problems have emerged. Since propranolol has no effect on thyroid function, hypermetabolism persists in thyrotoxic patients even while tachycardia, tremor, and restlessness are ameliorated. Thyroid storm can thus occur in patients treated solely with propranolol. 31 Care must be taken to administer propranolol immediately before operation and for several days postoperatively, since its half-life is short (2 to 4 hours) compared with that of thyroxine.

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When postoperative doses are omitted, thyrotoxic crises can occur. 100 Propranolol may fail to control perioperative tachycardia and hyperthermia in severely thyrotoxic patients unless unusually large doses are employed. 36 Some of these difficulties may be overcome if propranolol is given in combination with potassium iodide for the 10 days preceding operation. 35 reported that this regimen resulted in clinical and chemical Feek35 euthyroidism in 10 patients, with no evidence of the "escape" phenomenon 30 in patients treated with iodide alone. observed by Emerson30 In summary, all hyperthyroid patients should be rendered euthyroid before either surgery or radioiodine radio iodine treatment is undertaken. The combination of a thionamide plus iodide is safe and effective and is the preferred method under most circumstances. If a patient is noncompliant or develops intolerance to the thionamides, or if it is impractical to delay surgery for more than a few weeks while the euthyroid state is reached, then the combinatin of iodide and propranolol should be employed.

Surgical Treatment Subtotal thyroidectomy offers the hyperthyroid patient the greatest chance of achieving euthyroidism, and the least delay in achieving this state. In addition to the complications of hypoparathyroidism and recurrent nerve injury which can occur with all forms of thyroid surgery, the surgeon treating the thyrotoxic patient must also be concerned with the interrelated issues of postoperative hypothyroidism and recurrent or persistent hyperthyroidism. A number of factors have been observed to influence thyroid function after subtotal thyroidectomy (Table 2). Without any apparent influence on outcome are the type, dose, and duration of preoperative therapy, and the 72 The principal factor the surgeon can control is the size of the goiter. 72 size of the thyroid remnant. Obviously a total thyroidectomy (remnant weight == 0) prevents recurrent disease but renders all patients hypothyroid. This approach has been advocated by some authors;15, 84, 103 their rationale is that prevention of hyper- not hypothyroidism, should be the main concern of therapy, since the former is the cause of morbidity (cardiac disability) and mortality (thyroid storm) in thyrotoxic patients. 55 Also, it is argued, by rendering all patients hypothyroid initially, one obviates the necessity for long-term follow-up. A more moderate view is that total thyroidectomy should be considered in thyrotoxicosis when preventing a recurrence is paramount, as in young children, in whom one wishes to avoid treating a

Table 2.

Postoperative Thyroid Function

INFLUENCE ON THYROID FUNCTION

NO INFLUENCE ON THYROID FUNCTION

Remnant size Antibody titers Age of patient Type of goiter Lymphocytic infiltration in gland Timing of follow-up

Size of gland Type of antithyroid medication Dose of antithyroid medication Duration of antithyroid medication

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100 100 80

•

-u

\J

0 l.... '>-. ~ ..c ...c

60

~ >-. ...c ..c

40

0a a.. 0..

•

2i' ~2 20 0

a

• •

•

•

b

~

<.,

ry/~) ,.," t»~ :;: ~~ "," <,)~ IQ" 'O~ 1'\." A\.~ Q)~ ~~ ," ,~ Cb" o:.~ 0:.." r::j" r-,.{ >/ ~ <.{ ~ '{ "."I Qj 0( 0( c::f' r:::f' ~"--.:'

7Y ry 'Y

"- ""Weight of thyroid remnant (g)

Figure 3. Hypothyroidism in relation to size of thyroid remnant. a, 2-7.5 gm; slope, 9.6 per cent per gm. b, &-16.5 gm; slope, 2.1 per cent per gm. (From Michie, W.: Whither thyrotoxicosis? Br. J. Surg., 62:673-682, 62:673--682, 1975; with permission.) 99 Total thyroidectomy postoperative recurrence with radioactive iodine. 99 may also benefit patients with severe exophthalmos. 15, 84 If a euthyroid patient is the goal, however, some functioning thyroid tissue must be preserved. In the range from 2 to 8 gm, increasing the remnant size by 1 gm decreases the rate of postoperative hypothyroidism by about 10 per cent;72 increasing the remnant size above 10 gm does not, however, lead to further appreciable decreases in hypothyroidism, but rather to more recurrences (Fig. 3).63 The fact that some 15 to 20 per cent of patients seem to progress to hypothyroidism even if a large remnant is left is in accord with what is known about the natural history of untreated 74 and about progression to hypothyroidism in some pathyrotoxic patients 74 tients treated only with antithyroid drugs. 114 The fact that hypothyroidism may be the destiny of some irreducible minimum number of thyrotoxic patients helps to explain the time course of its appearance after subtotal thyroidectomy. Although the vast majority of postoperative hypothyroidism occurs in the first 6 months to 2 years followsurgery, 82 there remains a small annual increment of risk (0.7 per cent ing surgery,82 96 These patients may well be those who would per year or less) thereafter,2, 96 have become hypothyroid with any therapy, or with none at all. Most thyroid surgeons try to preserve a thyroid remnant of between 4 and 10 gm. 7, 8, 72, 98 98 The remnant may be tailored to try to account for other factors that may increase the likelihood or the hazard of an adverse result in either direction. Thus, children, who recur frequently and in whom radioactive iodine therapy is undesirable, may be left with smaller remnants. A larger remnant may be advisable if any of the other factors thought to increase the risk of postoperative hypothyroidism are present, such as ex-

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gland, 44, 82 82 high titers of antithyroid tensive lymphocytic infiltration of the gland,44, antibodies,44, 59, 59, 72 72 or a toxic nodular goiter. 54, 54, 85 85 One must not assume that selecting a "proper" remnant size for each patient guarantees euthyroidism. Even when the remnant is precisely sized by comparing it with a portion of resected tissue trimmed to the desired weight, the remaining mass of functional gland tissue is not thereby fixed, since this depends upon the proportion of thyroid epithelium in the remnant. Wilkin et al. estimated, on the basis of volume hlstometric studies, that a 10 gm thyroid remnant could contain from 1.1 to 7.1 gm offunctionof functionIII Further, as already noted, many other factors being thyroid epithelium. HI sides remnant size appear to influence postoperative thyroid function. It is not therefore surprising that manipulating any single variable should produce less than uniform results. Noguchj18 Noguchi 78 found that hypothyroidism could occur with remnants from 3.5 to 14 gm, and hyperthyroidism with remoffrom from 6 to 14 gm. nants of Despite these multiple uncertainties, good results can be achieved. In recent reports, 88 to 92 per cent of patients have been euthyroid, with a follow-up.8,8, 67 67 Remnants of about 10 gm were preminimum of 2 years of follow-up. served. Overall, reported incidences of hypothyroidism following subtotal thyroidectomy have ranged from 2 to 42.8 per cent, and of recurrent hyperthyroidism, from 0 to 15 per cent. 96 In interpreting such figures one must take into consideration the definition of hyper- and hypothyroidism, 100 noted that Toft!oo including the timing of follow-up. Thus, for example, Toft transient hypothyroidism may be detected in up to 20 per cent of postoperative patients who ultimately will become euthyroid. Six months seems an ideal time for initial assessment of thyroid function after surgery: transient hypothyroidism will have resolved, and the bulk of permanent postoperative hypothyroidism will have appeared. 82 Long-term follow-up is still necessary, however, especially since the risk of recurrent hyperthyroidism 63 does not decrase dramatically with time. 63 Surgery for thyrotoxicosis today is gratifyingly safe. Mortality in 69.·By By Kocher's time was 40 per cent, from thyroid storm and hemorrhage. 69 the middle of this century this figure had declined to 0.2 to 0.32 per cent cent!'1, 14 14 and is now essentially nil. Complications also have become infrequent: 29 per cent of Billroth's patients suffered vocal cord paralysis after thyroid surgery; today this complication is seen in 0.5 to 2 per cent of pa96 Complications tients. Permanent hypocalcemia has a similar incidence. 96 are at least three times as frequent, however, in reoperations for recurrent hyperthyroidism. 54, recurrences are usually best 54, 82, 99 99 For this reason, treated with radioactive iodine. Conclusion

Most patients with hyperthyroidism will eventually require some form 131 1 is effective and of ablative therapy. Either subtotal thyroidectomy or 131 safe. The unique advantages of surgery are its ability to deal with local complications, the rapidity with which control of thyrotoxicosis can be euthyroidism is more likely to result achieved, and the fact that permanent euthyrOidism from surgery than from any other method of therapy.

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THYROID NODULES AND CANCER Although carcinoma of the thyroid is the most common endocrine can111000 of the 4 per cent of adults cer, its incidence is only 40 per million, or 1/1000 46 ,, 75, 106 106 The process of selecting those patients with palpable thyroid nodules 46 who need thyroidectomy has been rendered more efficient and precise by the use of aspiration biopsy cytology, which returns a diagnosis in about 80 per cent of cases, with few false positives and negatives. negatives,5,5, 66, 66, 75, 106 106 The reliability of aspiration biopsy cytology depends upon the availability of a skilled, experienced cytologist, cytologist. If none is available, a combination of other 18,,46 tests and clinical criteria18 46 can be used to select patients for surgery. Even with adequate sampling and experienced cytologists, an unequivocal diagnosis is not always possible; 15 to 30 per cent of patients are classified as "indeterminate" or "suspicious. "suspicious."5, 66, 106 Much of this uncertainty results "5,66,106 from the inability of aspiration biopsy cytology to distinguish follicular adenomas from well-differentiated follicular carcinomas. 75 Since about 20 per cent of this group will ultimately prove to have cancer,5, 66, 75 they must be strongly considered for thyroidectomy. Also, in persons with a thyroid nodule and a history of low-dose external irradiation to the head and neck region biopsy results may be misleading. 87 Roughly 7 to 9 per cent of persons 45 of external radiation will exposed to appropriate doses (6.5 to 2000 rads 45 develop thyroid cancer,34, 86 86 lesions are frequency multicentric (50 to 70 per cent) and bilateral (35 to 50 per cent),34, 86, 87, 112 and the palpable nodule is frequently not the site of the malignancy. In one study the palpable nodule was in the lobe containing the cancer only about half the time. 92 Thus, although a nodule in an irradiated gland is a marker for cancer 35 to 50 per cent of the time, it is not a reliable guide for diagnostic sampling. To reiterate, thyroidectomy is indicated whenever a patient with a thyroid nodule (or without one) has a reasonable likelihood of having cancer. This criterion can be met by (1) an unequivocal cytologic diagnosis of malignancy in a nodule, (2) a cytologic diagnosis of "suspicious" or "follicular neoplasm" in a "cold" nodule, (3) any nodule in a patient with a history of neoplasm" childhood irradiation to the head and neck, or (4) an elevated serum calcitonin in a relative of a patient known to have multiple endocrine neoplasia, type;2 type ~ (MEN 2). Even when cancer is not an issue, surgery may be recommended for nodules causing symptoms or cosmetic deformities.

Preoperative Preparation In addition to establishing that the patient's general health is satisfactory, a few specific measures are necessary. First, the surgeon must enlist the aid of a skilled anesthesiologist, since the anesthesia itself is the major risk to the patient. Second, a thyroid pathologist with capability for frozen section diagnosis must be available. Third, the patient must be euthyroid. Fourth, in any patient with a thyroid nodule and hypertension or autonomic symptoms, the diagnosis of pheochromocytoma must be excluded or established prior to induction of anesthesia. Finally, in patients with previous operations on the neck or with any complaint of hoarseness or change in voice, vocal cord function should be evaluated.

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Extent of Surgery for Well-Differentiated Thyroid Cancer Thyroid cancer is a relatively uncommon condition with a generally favorable prognosis. Many factors appear to influence the outcome: age, sex, tumor type, stage of disease, and use of adjunctive therapies such as thyroxine and radioiodine radio iodine all play a role. The specific contribution of the degree of completeness of thyroidectomy to improved survival, though real, is small and difficult to document. More important than settling the issue of whether most or all of the thyroid gland should be removed for well-differentiated cancer, is emphasizing that the minimum operation for any thyroid nodule suspected of being cancer should be a lobectomy with isthmectomy.5,5, 98 The reasons for concluding this are as follows: (1) partial isthmectomy. lobectomy or nodulectomy leads to unacceptably high recurrence and mortality rates;83 (2) if the nodule is benign or a small well-differentiated carcinoma, no further resection is necessary; and (3) if reoperation is required, only the originally undisturbed side need be explored, and fewer complications ensue. The isthmus should be removed along with the suspicious lobe, both to prevent tracheal invasion in case of recurrence of cancer and to prevent a cosmetic defect should compensatory growth of the remaining thyroid tissue occur. Despite universal agreement on this point among thyroid surgeons, lesser operations are still performed as much as 42 per cent of the time for thyroid cancer in community hospitals. 112 112 For differentiated cancers less than 1.5 cm in diameter, the prognosis is so good that resections more extensive than lobectomy with isthmectomy 71 At the Mayo Clinic, only one death was confer no additional advantage. 57, 71 attributable to thyroid cancer in 137 patients with such minimal lesions followed for an average of 25 years after conservative operative management. For larger differentiated cancers, and for all cancers in irradiated glands, we favor total thyroidectomy if this can be accomplished safely for the patient. Multicentricity is a characteristic of up to 80 per cent of thyroid S8 Thus, although the biologic behavior of these often microscopic cancers. 88 foci of cancer, if left behind, is not universally malignant, studies haye shown fewer recurrences,71 longer disease-free intervals,89 fewer late pulmonary metastases,68 and trends towards improved survival after total thylTIOnary roidectomy.68, 70, 71 Furthermore, removal of essentially all thyroid tissue permits the use of thyroglobulin and radioiodine in the postoperative period to search for and treat micrometastases. 22, 22. 10,t) 10~ Surgeons who differ with this conclusion cite the low documented incidence of recurrences in the remnant gland 25 , 60, 60, 70 as evidence that the ubiquity of tumor microdeposits need not have clinical significance. They point out that in many studies there is no survival difference between patients 17, 26, 33 They also retreated with total and less than total thyroidectomies. 13, 17,26,33 port prohibitively high complication rates (for example, permanent hypoparathyroidism in 24 per cent) after total thyroidectomy. 26, 33, 108 It is indisputable that the overall risk of parathyroid or nerve injury from total thyroidectomy is greater than if part of the thyroid is preserved. 37 reviewed the results of 24,108 thyroi.d Foster37 thyroid operations performed at 1154 hospitals throughout the United States in 1970. In 1853 operations for malignant neoplasms, the rates of hypoparathyroidism and vocal cord paral-

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ysis were 8 per cent and 1 per cent after total thyroidectomy versus 2 per cent and 0.5 per cent after subtotal thyroidectomy. Patient selection influences these results, however: In centers where less than total thyroidectomy is the standard operation for differentiated cancer, total thyroidectomy will be performed in precisely those patients with more extensive disease and a greater likelihood of complications. These patients might be expected to have poorer survival if the two treatments were equivalent. When total thyroidectomy is performed routinely for differentiated thyroid cancer, the risk of permanent hypoparathyroidism or recurrent laryngeal 24 ,, 62 nerve injury can be 1 per cent or less. 24 62 It must be re-emphasized that provided all gross tumor is removed, the added benefit of complete thyroidectomy is small. Permanent hypoparathyroidism is probably a greater threat to the patient's long-term wellbeing. Therefore, any operation for a suspected thyroid malignancy should commence on the side of greater involvement. If the disease involves the nerve or the parathyroid glands and these are sacrificed, a rim of thyroid tissue including the posterolateral capsule can be preserved on the opposite side, protecting the remaining nerve and parathyroids. The remnant can subsequently be ablated with radioactive iodine. Surgery for Nodal Metastases Up to 80 per cent of adults and children with differentiated thyroid cancer have at least microscopic tumor deposits in regional cervical lymph 52, 58, 58, 79 79 Although some nodes, though palpable metastases are less frequent. 52, have suggested that nodal metastases might have no influence or even a favorable influence on survival,13 survival, 13 this is probably not the case if age is taken into account: patients between ages 7 and 40 have more frequent metastases, but also a better overall prognosis. 13, 13, 70, 70, 89 89 If patients with similar age groups are compared, those with nodal metastases have more recurrences and deaths due to thyroid cancer in every age range. 53 53 Although elective node dissections will, as mentioned, disclose micrometastases in 50 to 90 per cent of patients, survival is not adversely influenced by waiting until nodes are palpable before performing neck dissec58,, 80 tion. 58 80 Radioiodine can successfully ablate nonpalpable neck metastases detected by scintiscan. If palpable nodal disease is detected either at initial presentation or subsequently, the nodes should be removed with a formal neck dissection. Simply removing the enlarged nodes ("berry-picking") Cberry-picking") is inadequate, since the presence of disease in large nodes invariably signals the presence of tu79 On the other hand, a classic mor in subpalpable nodes and in lymphatics. 79 radical neck dissection, unless required to extirpate palpable disease, confers no advantage over a modified neck dissection that spares the sternomastoid muscle, the internal jugular vein, and (usually) the accessory nerve. 113 113 This can almost always be accomplished by extending laterally the standard transverse collar incision used for thyroidectomy. Similarly, superior mediastinal nodes, if present, can be excised from the neck without a separate sternotomy incision. Suprahyoid dissections are seldom necessary, since thyroid cancer metastasizes to this location only about 1 per cent of 39 the time. 39

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Advanced Differentiated Thyroid Cancer Between 10 and 20 per cent of differentiated thyroid tumors will be found at operation to have invaded adjacent structures such as the trachea, larynx, recurrent nerves, blood vessels, or muscles. 9,9, 25 The goal of the surgeon should still be to eradicate all gross tumor. This can usually be accomplished without sacrific of important functional structures. In particular, when vocal cord function is intact preoperatively, it should be possible to "shave" the tumor off the nerve without damaging it. Microscopic residua of cancer can be treated with radioactive iodine. The majority of patients can be cured. 25

Postoperative Adjunctive Therapy Surgery is only one part of a coordinated program of therapy for differentiated thyroid carcinoma. Postoperative scanning for nonpalpable metas1311 improve survival and reduce the tases and appropriate treatment with 131 number of recurrences. 68,70 So, in the experience of most investigators,22, 70 does suppression of TSH with thyroid hormone. A theoreticarbasis for this finding is provided by the presence of functional TSH receptors in thyroid tumor tissue. 22

Hiirthle Cell Tumors These lesions are considered separately from other well-differentiated tumors because of their somewhat puzzling behavior. In the experience of some investigators,6, 101 101 the malignant potential of Hiirthle cell neoplasms is equal to or less than that of other differentiated tumors, and good results 38,• 48, 97 emphasize the agare obtained with limited resections. Other reports 38 gressive, invasive behavior of Hiirthle cell tumors and the inability of histocharacter, Gundry et al. 48 recommended total logic criteria to predict their character. Hiirthle thyroidectomy for all H iirthle cell lesions larger than 2 cm. In contrast, experience at the University of California, San Francisco, with 75 Hiirthle cell neoplasms encountered in 39 years, suggests that tu42 mor histology is a reliable predictor of malignant or benign behavior: 42 None of the 71 lesions histologically classified as adenomas recurred or contributed to the death of any patient. Our current policy is to perform a total lobectomy and isthmectomy for any solitary lesion interpreted as a Hiirthle cell adenoma on frozen section. If permanent section discloses features of malignancy, the total thyroidectomy is completed.

Medullary Thyroid Carcinoma This fascinating tumor arises from the parafollicular C cells of the thyroid gland, has a sporadic and an hereditary form, is associated with secretion of elevated levels of calcitonin, either basally or in response to provocative testing, and ha~ a prognosis intermediate between that of differentiated and anaplastic thyroid cancers. The hereditary form (MEN 2a and 2b) is almost universally bilateral, occurs in the upper central portion of both lobes, and is accompanied by C-cell hyperplasia. This premalignant lesion can be seen in isolation in members of MEN 2 kindreds without palpable thyroid' abormalities. The sporadic form is usually unilateral; C-cell hyperplasia does not occur. In both forms, when palpable disease is present

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in the thyroid, metastases to regional lymph nodes have usually occurred. For these reasons and because these tumors do not take up radioactive iodine, the standard operative approach is more aggressive than for welldifferentiated thyroid cancers. A total thyroidectomy is usually performed, even for sporadic medullary thyroid carcinoma, because of the difficulty of excluding the presence of the hereditary form. As well, lymph nodes in the central neck and superior mediastinum, are removed, and an ipsilateral modified neck dissection is usually performed. In estabished MEN 2 kindreds, semiannual or annual screening with basal and stimulated calcitonin levels can identify individuals with microscopic medullary thyroid carcinoma or with only C-cell hyperplasia. In these patients a total thyroidectomy alone usually results in complete eradication of disease, as evidenced by normalization qf postoperative calcitonin levels. If macroscopic medullary thyroid carcinoma was present at the time of the original operation, it is common for calcitonin levels to remain elevated even without evidence of clinical recurrence. Appropriate modified neck dissections, if not already done, may result in normalization of calcitonin levels. If disease was originally bilateral, simultaneous catheterization of the cervical and hepatic veins may localize clinically inapparent disease. Some patients may do well without evidence of recurrent tumor despite persistent elevations of calcitonin levels. 2 patients who are discovered by screening Excluding those MEN 2 before their tumors become palpable, the longest survivals occur in the sporadic form of the disease. Overall 5-year survival is about 50 per cent. 5, 20, 43, 63, 81 Undifferentiated Carcinoma Undifferentiated or anaplastic thyroid carcinoma is fortunately rare. It typically occurs in older persons and may be signaled by the abrupt enlargement of a goiter with development of local symptoms. Disease is usually advanced at the time of discovery, with local, nodal, and distant metastases. Seldom can surgical removal of the entire tumor be effected. The goals of operation are then to provide tissue for definitive diagnosis and to debulk the central neck region to prevent later asphyxiation. 55, 23 A recent report suggests that an agressive multimodal approach to anaplastic giant cell carcinoma, consisting of radiotherapy and chemotherapy both before and after surgical removal of the tumor, may produce some long-term surHo vivors. Ho

TECHNICAL ASPECTS OF THYROID SURGERY Thyroid surgery can and should be conducted with slight morbidity mortality, Removal of the thyroid gland from its subcutaand essentially no mortality. neous position requires division of one muscle, the platysma. Patients experience only minor discomfort; most leave the hospital 2 or 3 days after surgery. Most complications in thyroid surgery are the result of injury to small but important structures in proximity to the thyroid gland. Optimal exposure, required for the safe conduct of thyroid surgery, is achieved only on~y by attending to numerous details: proper positioning of the

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patient with the neck hyperextended; proper placement of the incision directly over the isthmus of the gland; and, above all, meticulous hemostasis throughout the course of the operation. Blood-staining of the tissues in the operative field greatly increases the difficulty of identifying tiny entities such as parathyroid glands. Whenever the operative plan calls for total removal of one or both lobes of the thyroid, the corresponding recurrent laryngeal nerve and parathyroid glands must be identified. The recurrent nerve is most readily located where it crosses (usually under) the inferior thyroid artery. The artery is placed under tension (retracting the thyroid medially and the carotid sheath laterally) to facilitate this. The commonest site of injury to the nerve, however, is further cephalad and medial, at the point where it enters the cricothyroid muscle. Here the thyroid gland lies directly on the nerve, just anterior to it. Indeed, thyroid tissue may extend posterior to the nerve at this point, and a small artery and vein usually lie adjacent. Clamping without good exposure may result in injury to the recurrent nerve as the thyroid is detached from the trachea. The parathyroid glands can usually be sought and located in relation to the recurrent nerve and inferior thyroid artery. The inferior gland is customarily anterior and caudad to these structures; the superior gland lies in a posterior and cephalad position. The thyroid surgeon must be familiar with the spectrum of variants of parathyroid anatomy. Once identified, the glands must be dissected from the thyroid gland without handling them directly, if possible, and without compromising their blood supply. This is accomplished by dissecting directly on the thyroid capsule, elevating the parathyroids on laterally based vascular pedicles. Small branches rather than the main trunk of the inferior thyroid artery are ligated, since the latter is usually the blood supply of both parathyroid glands. If a parathyroid gland is devascularized during operation, it should be removed, biopsied to confirm that it is parathyroid, and reimplanted in the sternomastoid muscle on the least involved side. With these precautions, permanent hypoparathyroidism should occ.ur infrequently. Transient hypoparathyroidism, manifested by symptoms and signs (numbness, paresthesias, Chvostek's sign, Trousseau's sign), precipitous decline in serum calcium levels to the 7.0 mg per dl range, and rise in serum phosphorus levels, may occur more frequently (usually within 24 to 48 hours of surgery) and can virtually always be managed with oral calcium replacement. The mild decline in serum calcium (approximately 1 mg per dl) seen in almost all patients after thyroidectomy does not portend parathyroid dysfunction. 24 A A complication of thyroid surgery whose frequency is probably impossible to assess is injury to the external laryngeal nerve. This motor nerve, it a branch of the superior laryngeal nerve, innervates the cricothyroid muscle (a tensor of the vocal fold). Paralysis of the cricothyroid muscle results in subtle voice changes: easy fatigability, inability to project the voice, and decreased range of pitch or volume. On laryngoscopy the cord is seen to lllove move normally but may have an irregular or wavy outline. Injury to this nerve may be inconsequential or catastrophic, depending on the patient's circumstances. The most famous victim of external laryngeal nerve injury

nn 1111

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was Amelita Calli-Curci, Galli-Curci, a great lyric soprano of the 1920s, who underwent thyroidectomy for relief of airway obstruction from a large goiter. Her postoperative return to the stage as Mimi in Puccini's La Boheme was described in Time: 3400 who No audience ever wanted to applaud a singer's voice more than did the 3400 bought out the Chicago Civic Opera House last week to hear Galli-Curci sing Mimi in La Boheme. When the garret door opened upon Puccini's heroine, frail and pathetic in a grey ruffled ruffied gown, they shouted and clapped for a full minute. But the applause they gave her later was less shattering and was more for her nerve than for her singing. Veterans grieved that her upper voice had crumbled, found her middle register competent but a little breathless. The passages when she caught her old fluency and full tone were too rare to give much hope ... critics returned to their desks to write the obituaries of a great voice.

No larger than a spider web, the external laryngeal nerve normally descends medial to the superior thyroid vessels and runs within the fascial envelope of the cricothyroid muscle. It can be avoided by staying lateral to the muscle when dissecting the superior pole vessels. In about 15 per cent of patients, however, the nerve runs with the superior thyroid artery or 76 If it is absolutely essential to avoid injury to the among its branches. 76 "high-note nerve," as in public speakers or professional singers, the superior pole vessels should be divided individually on the capsule of the thy21 roid gland rather than higher. 21 CONCLUSION Complications in thyroid surgery come about not as a result of major insults to a patient's metabolism or physiology, but through inattention to technical details. There is thus undoubtedly a "learning curve" in thyroid surgery; the availability of a surgeon with the requisite experience may influence the choice of therapy or the extent of operation. Conversly, seldom should a patient be denied a needed thyroid operation because of general debility. Most importantly, thyroid surgery, even for malignant conditions, usually results in significant and lasting improvements in well-being for properly selected patients. REFERENCES 1. Beahrs, O. H., Ryan, R. F., and White, R. A.: Complications of thyroid surgery. J. Clin. Endocrinol., 16:1456-1469, 1956. iodine 2. Becker, D. V., McConahey, W. M., Dobyns, B. M., et al.: The results of radio radioiodine treatment of hyperthyroidism: A preliminary report of the Thyrotoxicosis Therapy Follow-up Study. In Fellinger, K., and Hofer, C. (eds.): Further Advances in Thyroid Research. Vienna, Verlag der Wiener Medizinischen Akademie, 1974. C. E., and Robb, J. A.: ThyrOid Thyroid nodules indeterminate by needle 3. Block, M. A., Dailey, G. biopsy. Am. J. Surg., 146:72-78, 1983. 4. Block M. A., and Miller, J. M.: Modified neck dissection for thyroid carcinoma. Am. J. Surg., 101 101:34~354, :349-354, 1961. 5. Block, M. A.: Surgery of thyroid nodules and malignancy. Curr. Probl. Surg., 20:113203, 1983.

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6. Bondeson, L., Bondeson, A. A.-G., -G., Ljungberg, 0., et al.: Oxyphil tumors of the thyroid. Ann. Surg., 194:677-680, 1981. suhtotal thyroidectomy 7. Bradley, E. 1., Ill, DiGirolamo, M., and Tarcan, Y.: Modified subtotal in the management of Graves' disease. Surgery, 87:623--629, 87:623-629, 1980. 8. Bradley, E. L.,III, L.,IlI, and Liechty, R. D.: Modified subtotal thyroidectomy for Graves' disease: A two-institution study. Surgery, 94:955-958, 1983. oflocally 9. Breaux, E. P., and Guillamondegue, O. M.: Treatment of locally invasive carcinoma of the thyrOid: thyroid: How radical? Am. J. Surg., 140:514-517, 1980. 10. Burrow, G. N.: Maternal-fetal considerations in hyperthyroidism. Clin. Endocrinol. Metab., 7:115-125, 1978. 11. Burrow, G. N.: The thyroid thyrOid in pregnancy. Med. Clin. North Am., 59:1089-1098. 12. Cady, B., Cohn, K., Rossi, R. L., et al.: The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery, 94:978-983, 1983. B., Sedgwick, C. E., Meissner, 13. Cady, B.,Sedgwick, Meissnei, W. A., et al.: Risk factor analysis in differentiated 43:810-820, 1979. thyroid cancer. Cancer, 43:81{}-820, 14. Cattell, R. B.: Surgical treatment of hyperthyroidism. J.Clin. Endocrinol., 9:999-1006, 1949. 15. Catz, B., and Perzik, S. L.: Total thyroidectomy in the management of thyrotoxic and euthyroid Graves' disease. Am. J. Surg., 118:434-439, 1969. I31I1 therapy of ofthyrotoxicothyrotoxico16. Cevallos, J. L., Hagen, G. A., Maloof, F., et al.: Low-dosage 131 sis (diffuse goiters). N. Engl. J. Med., 290:141-143, 1974. 17. Christensen, S. B., Ljungberg, 0., and Tibblin, S.: Surgical treatment of thyroid carcinoma in a defined population: 1960 to 1977. Am. J. J. Surg., 146:349-354, 1983. thyroid nodules in the elderly. Am. J. 18. Clark, O. H., and Demling, R.: Management of thyrOid Surg., 132:615-619, 1976. 19. Clark, O. H.: Hyperthyroidism. In Clark, O. H. (ed.): Surgical Endocrinology of the Thyroid and Parathyroid. St. Louis, C. V. Mosby Co., in press. 20. Clark, O. H.: Medullary thyroid carcinoma. In Clark, O. H. (ed.): Surgical Endocrinology of the Thyroid and Parathyroid. St. Louis, C. V. Mosby Co., in press. 21. Clark, O. H.: Surgical treatment. In Clark, O. H. (ed): Surgical Endocrinology of the Thyroid and Parathyroid. St. Louis, C. V. Mosby Co., in press. 22. Clark, O. H.: TSH suppression in the management of thyroid nodules and thyroid can5:39-47, 1981. cer. World J. Surg., 5:39--47, 23. Clark, O. H.: Thyroid nodules and thyrOid thyroid cancer. In Clark, O. H. (ed.): Surgical Endocrinology of the Thyroid and Parathyroid. St. Louis, C. V. Mosby Co., in press. 24. Clark, O. H.: Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann. Surg., 196:361-370, 1982. Cody, H. S., III, Ill, and Shah, J. P.: Locally invasive, well-differentiated thyroid cancer. 25. eody, Am. J. Surg., 142:480-483, 1981. 26. Crile, G., Jr.: The treatment of papillary carcinoma of the thyroid occurring after irradiation. Surg. Gynecol. Obstet., 150:850-852, 150:85{}-852, 1980. 27. Davies, T. F., Yeo, P. P. B., Evered, D. C., et al.: Value of thyroid-stimulating antibody determinations in predicting short-term relapse in Graves' disease. Lancet, 1:1181-1182, 1977. 28. Dobyns, B. M., Sheline, G. E., Workman, J. B., et al.: Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: A report of the Cooperative Thyrotoxicosis Therapy Follow-up Study. J. Clin. Endocrinol. Metab., 38:976998, 1974. 29. Editorial: ThyrOid Thyroid disease and pregnancy. Br. Med. J., 2:977-978, 1978. 30. Emerson, C., Anderson, A., and Howard, W.: Serum thyroxine and triiodothyronine concentrations during iodine treatment of hyperthyroidism. J. Clin. Endocrinol. Metab., 40:33-36, 1978. Rubenfield, S., Garher, Garber, A. J., et al.: Propranolol does not prevent thyroid 31. Eriksson, M., Ruhenfield, storm. N. Engl. J. Med., 296:263-264, 1977. Talbot, C. H.: The treatment of autonomous functioning thyroid 32. Eyre-Brook, I. A., and Talhot, nodules. Br. J. Surg., 69:577-579, 1982. 33. Farrar, W. B., Cooperman, M., and James, A. G.: Surgical management of papillary and follocular carcinoma of the thyroid. Ann. Surg., 192:701-704, 1980. 34. Favus, M. J., Schneider, A. B., Stachura, M. E., et al.: Thyroid cancer occurring as

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35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.

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a late consequence of head-and-neck irradiation. N. Engl. J. Med., 294:1019-1025, 1976. Feek, C. M., Sawers, J. S. A., Irvine, W. J., et al.: Combination of potassium iodide and propranolol in preparation of patients with Graves' disease for thyroid surgery. N. Engl. J. ~led., Med., 302:883-885, 1980. Feely, J., Crooks, J., Forrest, A. L., et al.: Propranolol in the surgical treatment of 68:865--869, hyperthyroidism, including severely thyrotoxic patients. Br. J. Surg., 68:865-869, 1981. Foster, R R. S., Jr.: Morbidity and mortality after thyroidectomy. Surg. Gynecol. Obstet., 146:423-429, 1978. Frazell, E. L., and Duffy, B. J.: Hiirthle cell cancer of the thyroid. Cancer, 4:952-956, 1951. Frazell, E. L., and Foote, F. W., Jr.: Papillary thyroid carcinoma: Pathologic findings in cases with and without clinical evidence of cervical node involvement. Cancer 8:1164-1166, 1955. thyroid nodules treated Goldstein, R, R., and Hart, I. R: R.: Follow-up of solitary autonomous thyrOid 1311. N. Engl. J. Med., 309:l473-1476, with 1311. 309:1473-1476, 1983. 131 ofl31I Gorman, C. A., and Robertson, J. S.: Radiation dose in the selection of 1 or surgical treatment for toxic thyroid adenoma. Ann. Intern. Med., 89:85--90, 89:85-90, 1978. 119:515--519, Gosain, A. K., and Clark, O. H.: Hiirthle cell neoplasms. Arch. Surg., 119:515-519, 1984. Graze, K., Spiler, 1. I. J., Tashjian, A. H., et al.: Natural history of familial medullary thyroid carcinoma. N. Engl. J. Med., 299:980-985, 1978. Green, M., and Wilson, G. M., Thyrotoxicosis treated by surgery or lodine-131: Iodine-131: With J., 1:1005-1010, 1:1005--1010, 1964. special reference reference,to to development of hypothyroidism. Br. Med. J., Greenspan, F. S.: Radiation exposure and thyroid thyrOid cancer. J. J. A. M. A., 237:2089-2091, 1977. Greenspan, F. S.: Thyroid nodules and thyroid cancer. West J. Med., 121:359-365, 1974. Greer, M. A., Kammer, H., and Bouma, D. J.: J.: Short-term antithyroid drug therapy for J. Med., 297:173-176, 297:173-176,1977. the thyrotoxicosis of Graves' disease. N. Engl. J. 1977. Gundry, S. R, R., Burney, R R. E., Thompson, N. W., et al.: Total thyroidectomy for Hiir198:1. thle cell neoplasm of the thyroid. Arch. Surg., 118:529-532, 198;t Hamburger, J. J. I., 1., and Meier, D. A.: Cancer following treatment of an autonomously functioning thyroid nodule with sodium iodide 1-131. Arch. Surg., 103:762-764, 1971. Hamburger, J. 1.: I.: Evolution of toxicity in solitary nontoxic autonomously functioning thyroid nodules. J. J. Clin. Endocrinol. Metab., 40:1089-1093, 1980. Hamburger, J.: J. Med., J.: The autonomously functioning thyroid adenoma. N. Engl. J. 309: 1512-1513, 1983. 309:1512-1513, Harness, J. K., Thompson, N. W., and Nishiyama, R R. H.: Childhood thyroid carcinoma. Arch. Surg., 102:278-284, 1971. Harwood, J., Clark, O. H., and Dunphy, J. E.: Significance of lymph node metastasis J. Surg., 136:107-112, 1978. in differentiated thyroid cancer. Am. J. Heimann, P., and Martinson, J.: Surgical treatment of thyrotoxicosis: Results of 272 operations with special reference to preoperative treatment with antithyroid drugs and L-thyroxine. Br. J. Surg., 62:683-688, 1975. J. Surg., 2:314-315, 1978. Heimann, P.: Commentary. World J. Holm, L.-E., Dahlqvist, 1., I., Israelsson, A., et al.: Malignant thyroid tumors after iodine131 therapy. N. Engl. J. Med., 303:188-191, 1980. Hubert, J. P., Kiernan, P. D., Beahrs, O. H., et al.: Occult papillary carcinoma of the thyroid. Arch. Surg., 115:394-398, 1980. R V. P., Frazell, E. L., and Foote, F. W., Jr.: Elective radical neck dissection: Hutter, R. an assessment of its use in the management of papillary thyroid cancer. CA, 20:8793, 1971. Irvine, W. J., Gray, R R. S., Morris, P. J., et al.: Correlation ofHLA and thyroid antibodies with clinical course of thyrotoxicosis treated with antithyroid drugs. Lancet, 2:898900,1977. 900, 1977. Ito, J., Noguchi, S., Murakami, N., et al.: Factors affecting the prognosis of patients with carcinoma of the thyroid. Surg. Gynecol. Obstet., 150:539-544, 1980. Jackson, C. E., Talpos, G. B., Kambouris, A., et al.: The clinical course after definitive

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operation for medullary thyroid carcinoma. Surgery, 94:955-1001, 94:955--1001, 1983. J. W., and Ballinger, J.J. F.: Total thyroidectomy. Ann. Surg., 62. Jacobs, J. K., Aland, J. 197:542-549, 1983. K;alk, W. J., J., Durbach, D., Kantor, S., et al.: Post-thyroidectomy thyrotoxicosis. Lancet, 63. ~alk, ',. 1:291-293, 1978. 64. Kogut, M. D., Kaplan, S. A., Collipp, P. J., et al.: Treatment of hyperthyroidism in EngL J. J. Med., 272:217-221, 1965. children. N. Engl. 65. Lividas, D., Psarras, A., and Koutras, D. A.: Malignnt cold thyroid nodules in hyperJ. Surg., 63:726-728, 1976. thyroidism. Br. J. 66. Lowhagen, T., Granberg, P. 0., and Lundell, G.: Aspiration biopsy cytology (ABC) in nodules of the thyroid gland suspected to be malignant. Surg. Clin. North Am., 59:318, 1979. 67. Makiuchi, M., Miyakawa, M., Sugenoya, A., et al.: An evaluation of several prognostic GynecoL Obstet., 152:639factors in the surgical treatment for thyrotoxicosis. Surg. Gynecol. 641, 1981. 68. Massin, J.-P., Savoie, J.-C., Gamier, Garnier, H., et al.: Pulmonary metastases in differentiated thyroid carcinoma. Cancer, 53:982-992, 1984. 69. Mayo, C. H.: Treatment of the posterior capsules of the thyroid gland in thyroidectomy based on 375 operations for goitre. Trans. Am. Surg. Assoc., 25:52-60, 1907. 70. Mazzaferri, E. L., Young, R. L., Oertel, J. E., et al.: Papillary thyroid carcinoma: The impact of therapy in 576 patients. Medicine, 56:171-196, 56:171-196,1977. 1977. Mazzaferri, 71. M azzaferri, E. L., and Young, R. L.: Papillary thyroid carcinoma: A 10-year follow-up report of the impact of therapy in 576 patients. Am. J. Med., 70:511-517, 1981. 72. Michie, W., Beck, J. J. S., and Pollet, J. E.: Prevention and management of hypothyroidism after thyroidectomy for thyrotoxicosis. World J. Surg., 2:307-319, 1978. 73. Michie, W., Pegg, C. A. S., and Bewsher, P. D.: Prediction of hypothyroidism after partial thyroidectomy for thyrotoxicosis. Br. Med. J., 1:13-17, 1972. 74. Michie, W.: Whither thyrotoxicosis? Br. J. Surg., 62:673-682, 1975. T. R., Abele, J. J. S., and Greenspan, F. S.: Fine-needle aspiration biopsy in the 75. Miller, T: management of thyroid nodules. West. J. Med., 134:198-205, 1981. 76. Moosman, D. A., and DeWeese, M. S.: The external laryngeal nerve as related to thyGynecoL Obstet., 127:1011-1016, 1968. roidectomy. Surg. Gynecol. 77. Mukhtar, E. D., Smith, B. R., Pyle, G. A., et al.: Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine, and antithyroid drugs. Lancet, 1:713-715. 78. Noguchi, S., Murakami, N., and Noguchi, A.: Surgical treatment for Graves's disease: A long-term follow-up of 325 patients. Br. J. J. Surg., 68:105--108, 68: 105--108, 1981. 79. Noguchi, S., Noguchi, A., and Murakami, N.: Papillary carcinoma of the thyroid. I. Developing pattern of metastasis. Cancer, 26:1053-1060, 1970. 80. Noguchi, S., Noguchi, A., and Murakami, N.: Papillary carcinoma of the thyroid. n. II. Value of prophylactic lymph node excision. Cancer, 26:10~1-1064, 26:1061-1064, 1970. 81. Norton, J. J. A., Doppmann, J. L., and Brennan, M. F.: Localization and resection of clinically inapparent medullary carcinoma of the thyroid. Surgery, 87:616-622, 1980. 82. Olson, W. R., Nishiyama, R. H., and Graber, L. W.: Thyroidectomy for Hyperthyroidism. Arch. Surg., 101 :175--180, 1970. 101:175--180, 83. Ozaki, 0., Notsu, T., Hirai, K., et al.: Differentiated carcinoma of the thyroid gland. World J. Surg., 7:181-185, 1983. 84. Perzik, S. L.: The place of total thyroidectomy in the management of 909 patients with J. Surg., 132:480-483, 1976. thyroid disease. Am. J. 85. Reeve, T. S.: Invited commentary. World J. J. Surg., 2:316-317, 1978. J., Karanfilske, B. T., et al.: Continuing occurrence of thyroid 86. Refetoff, S., Harrison, J., carcinoma after irradiation to the neck in infancy and childhood. N. Engl. J. J. Med., 292:171-175, 1975. 87. Rosen, I. B., Palmer, J. A., Bain, J., et al.: Efficacy of needle biopsy in postradiation thyroid disease. Surgery, 94:1002-1007, 1983. 88. Russell, W. 0., Ibanez, M. L., Clark, R. L., et al.: Thyroid carcinoma: Classification, intraglandular dissemination, and clinicopathological study based upon whole organ 11:1425--1460,1963. sections of 80 glands. Cancer, 11:1425-1460, 1963. 89. Samaan, N. A., Maheshwari, Y. K., Nader, -S., et al.: Impact of therapy for differentiNader,S., ated carcinoma of the thyroid: An analysis of 706 cases. J. Clin. Endocrinol. Metab., 56:1131-1138, 1983.

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J. D., and Talbot, N. B.: Childhood thyrotoxicosis: A long90. Saxena, K. M., Crawford, J. 2:1153-1158, 1964. term perspective. Br. Med. J., 2:115~1158, 91. Schneider, A. E., B., Favus, M. J., J., Stachura, M. E., et al.: Incidence, prevalence, and characteristics of radiation-induced thyroid tumors. Am. J. J. Med., 64:24~252, 64:243-252, 1978. 92. Schneider, A. B., Pinsky, S., Bekerman, C., et al.: Characteristics of 108 thyroid can~ cancers detected by screening in a population with a history of head and neck irradiation. Cancer, 46:1218-1227, 1980. 93. Sheline, G. E., Lindsay, S., et al.: Thyroid nodules occurring after treatment of thyrotoxicosis with radioiodine. J. Clin. Endocrinol., 22:8-18, 1962. 1311 I in treatment 94. Smith, R. N., and Wilson, G. M.: Clinical trials of different doses of 131 of thyrotoxicosis. Br. Med. J., 1:129-132, 1967. 95. Solomon, D. H., Beck, J. J. C., VanderLaan, W. P., et al.: Prognosis of hyperthyroidism treated by antithyroid drugs. J. A. M. A., 152:201-205, 1953. 96. Sugrue, D. D., Drury, M. I., McEvoy, M., et al.: a!.: Long-term follow-up of hyperthyroid J. Surg., 70:408-411, 1983. patients treated by subtotal thyroidectomy. Br. J. 97. Thompson, N. W., Dunn, E. L., Batsakis, J. G., et al.: Hiirthle cell lesions of the thyroid gland. Surg. Gynecol. Obstet., 139:555--560, 139:555-560, 1974. 98. Thompson, N. W., Nishiyama, R. H., and Harness, J. K.: Thyroid ThyrOid carcinoma: Current controversies. Curr. Probl. Surg., 15:1-67, 1978. 99. Thompson, N. W.: Invited commentary. World J. J. Surg., 2:317-319, 1978. J., Sinclair, 1., Thyroid function after surgical treatment 100. Toft, A. D., Irvine, W. J., I., et al.: ThyrOid of thyrotoxicosis. N~ N. Engl. J. Med., 298:643--647, 298:643-647, 1978. 101. Tollefsen, H. R., Shah, J. P., and Huvos, A. G.: Hiirthle cell carcinoma of the thyrOid. thyroid. Am. J. J. Surg., 130:390-394, 130:39