Well-differentiated thyroid cancer

WELL-DIFFERENTIATED CANCER

THYROID

Much progress has been made in our understanding of the epidemiologic factors, biologic behavior, diagnosis, treatment, and molecular biology of well-differentiated thyroid carcinoma since the study by Thompson and colleagues in 1978.l The development of fineneedle aspiration (FNA) has allowed us to separate patients who will benefit from thyroidectomy from those whose conditions can be managed nonoperatively. The development of risk groups using preoperative, intraoperative, and postoperative clinical data helps us determine the aggressiveness of tumors and the requirement of extensive treatment and who will do well with lesser treatment. Improved understanding of the efficacy of thyroid suppression therapy and radioactive iodine therapy has given us useful adjuncts to surgical treatment. In the future, as the principles of thyroid oncogenesis are elucidated at the molecular level and applied at the clinical level, we will be better able to diagnose and treat patients with differentiated thyroid malignancies. CLINICAL

INCIDENCE

Thyroid carcinoma accounts for approximately 1.5% of all malignancies and approximately 0.5% of all deaths from cancer.2’3 In the United States approximately 12,000 patients, or 40 persons per million population, are diagnosed with thyroid carcinoma each year.‘j4 The mortality rate of six persons per million population per year ’ coupled with the low incidence suggests a favorable prognosis. However, because cancer occurs in approximately 15% of patients with clinically solitary thyroid nodules and clinically silent thyroid carcinoma t-Cl.0 cm) occur in up to 35% of thyroid glands removed at autopsy or surgery,5,6 a selective approach must be used to identify patients where thyroid nodules should be removed. Thyroid carcinoma was documented in 24 cases per million population in 1947, in 39 cases per million population in 1971, and in 41 844

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FIG. 1. The dorsal surface of the tongue contains many discrete flat-topped papules (arrow). Aggregation of cutaneous lesions around the right angle of the mouth gives the impression of a small wart. (Reprinted with permission from Thyresson HN, Doyle JA. Mayo Clinic Proc 1981;56:179-184.) cases per million population in 19NL1” The increase from 1947 to 1971 may be related to radiation exposure. During a three-decade period from the late 1940s to the late 197Os, more than one million people received radiation to the thyroid for treatment of benign head and neck and chest disorders such as acne, thymus hyperplasia, scalp hemangiomas, tonsil enlargement, keloids, and external otitis.lJ7

FACTORS

PREDISPOSING

TO THYROID

CARCINOMA

Exposure to low-dose (0.06 to 20 Gy) external radiation and a solitary thyroid nodule are the most common and extensively studied risk factors for the development of thyroid carcinoma. Familial factors also increase the risk of thyroid carcinoma. Patients with defined Curr

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FIG. 2. A typical distribution of discrete and confluent papules (arrows) is found around the mouth and nose in patients with Cowden’s disease. (Reprinted with permission from Thyresson HN, Doyle JA. Mayo Clinic Proc 1981;56;179-84.)

genetic syndromes such as Gardner’s syndrome (familial polyposis) and Cowden’s disease (multiple hamartoma syndrome) have a higher risk of thyroid malignancy. Gardner’s syndrome is associated with multiple polyps of the gastrointestinal tract and colon cancer and carries an increased risk of developing papillary thyroid carcinoma.8’s Cowden’s disease is an autosomal dominant disorder characterized by mucocutaneous lesions (Figs. 1 and 2) and internal malignancy. Patients with Cowden’s disease are prone to the development of breast cancer, colon cancer, and benign and malignant thyroid con94s

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ditions.“” Cowden’s disease is associated with goiter in 40% of patients and with thyroid carcinoma in 10% of patients.lO’ll Some patients also have familial papillary or follicular thyroid carcinoma without other tumors.” Medullary thyroid carcinoma, although not discussed specifically in this monograph, is often familial and may occur in association with the multiple endocrine neoplasia syndromes (MEN) type 2A and 2B or without other endocrinopathies. Living in an iodine-deficient or endemic goiter area increases the frequency of follicular and anaplastic thyroid carcinoma.1’13-15 During the 192Os, when endemic goiter was common, follicular and anaplastic carcinoma were diagnosed more frequently. Today, however, 64% of thyroid carcinomas are papillary, including patients with mixed papillary-follicular tumors and with follicular variants of papillary thyroid carcinoma: Living in an area of high dietary iodine intake appears to increase the incidence of papillary carcinoma.‘4 It is unknown whether iodine intake influences tumor aggressiveness although the mortality rates from thyroid carcinoma are higher in areas of endemic goiter. Higher circulating levels of estrogens may minimally increase the risk of breast and thyroid carcinoma. In one study, women with a history of breast carcinoma were almost three times more likely to experience the development of thyroid carcinoma, and women who weighed 60 kg or more had a 2.5-fold elevation in risk.16 Other factors that appear to increase the frequency of thyroid carcinoma are a history of thyroid pathologv,l’ exposure to carcinogens18’1g resiand possibly alcohol ingestion.21 Functional dence near volcanoes” thyroid disorders and smoking are not associated with thyroid carStudies in humans22 and animals15’23 that have been excinoma.‘l posed to irradiation suggest that treatment with thyroid hormone decreases the risk of developing thyroid carcinoma. A recent study by Linos and co11eagues24 suggests that drinking coffee may decrease the frequency of thyroid carcinoma in persons who have not undergone irradiation. THE THYROID

NODULE

Thyroid nodules are common and come to medical attention in three forms. The solitary thyroid nodule is a clinically discrete nodule in a normal-sized thyroid gland or in a diffusely enlarged thyroid gland, as occurs in patients with Hashimoto’s thyroiditis or Graves’ disease. A dominant nodule is a large nodule in a thyroid gland with smaller nodules. Multiple palpable nodules are usually described as multinodular goiter. Although clinically solitary thyroid nodules on physical examination are more likely to be cancerous, approximately two-thirds of patients with thyroid malignancy actually have multiple nodules by imaging or by histologic examination after thyroidecCurr

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tomy.Z5 Thus the distinction between the solitary thyroid nodule and the multinodular thyroid may be a function of the sensitivity of the detection technique being used. In one study, the incidence of malignancy was the same for patients with a solitary nodule (4.7%) or for patients with nontoxic multinodular goiter (4.1% )p6 In general, however, a solitary nodule or a dominant nodule is of more concern and warrants further evaluation. Thyroid nodules are clinically apparent in 4% to 7% (15 million people) of the adult US population and are more common in women than men.26-30 Based on ultrasonoadults, the graphic studies31 and autopsy series3’ of asymptomatic prevalence of thyroid nodules is 30% to 50% (100 million people). New nodules develop at a rate of approximately 0.1% per year (250,000 annually), yet only 5% of these nodules harbor cancer.33 The obvious dilemma for the clinician is how to select the 5% of patients with thyroid carcinoma from the large number of patients with benign thyroid nodules. The differential diagnosis of thyroid nodules includes colloid (adenomatousl nodules, follicular adenomas, thyroid cysts, adenomatous nodule in a multinodular colloid goiter and carcinoma. Approximately 84% of malignant thyroid nodules are papillary, 6% are follicular, 4% are medullary, 3% are Hurthle cell, 1% are anaplastic, 1% are lymphoma, and 1% are other rare tumors. Cysts found to be without solid components by ultrasonography that are less than 4 cm in diameter are rarely cancerous. Complex cysts, however, have a 15% risk of being cancerous.25’34 Although most thyroid nodules are asymptomatic, several clinical features help to identify patients with thyroid nodules that are more likely to be carcinoma (Table 11. Most patients have an asymptomatic nodule that either they or their physician detected. Pain or tenderness occurs in nodules that expand rapidly and may indicate malignancy. These symptoms and signs also occur in patients with thyroiditis or those who bleed into their nodules. Rapid enlargement of a thyroid nodule suggests carcinoma, and such malignancies are often more aggressive or anaplastic.25’35 Nodules that enlarge while the patient is receiving thyroid suppression therapy are also more likely to be malignant. A thyroid nodule in a male is more likely to be malignant, although both benign and malignant lesions are more common in females. Although the peak age for developing papillary carcinoma is 30 years of age and for follicular carcinoma is 45 years of age, a thyroid nodule occurring at the extremes of age is more likely to be malignant. For example, among thyroid nodules in patients under 14 years of age or over 70 years of age, 50% are maIignant.25’35 Most patients with thyroid carcinoma are euthyroid. Patients with Graves’ disease or thyroiditis may have a slightly increased risk of thyroid carcinoma.36 Most of these carcinomas are small or microscopic papillary thyroid carcinomas that are found incidentally in the re94s

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TABLE 1.

Characteristics

of benign

and

malignant

thyroid

nodules

Benign

Malignant

History

Family history of benign goiter Long duration without growth Mulinodular goiter Diffuse goiter without discrete nodule Decreasing size with thyroid hormone replacement

Previous thyroid cancer Family history of thyroid cancer, Cowden’s disease, Gardner’s syndrome, familial medullary thyroid cancer, MEN type 2 Enlarging nodule on thyroid suppressive therapy Exposure to low-dose therapeutic radiation in the neck Rapidly gmwing or painful thyroid nodule Development of nodule at under 14 years of age or over 65 years Hoarseness

Physical and laboratory findings

Soft, mobile nodule Benign by FNA Simple cystic thyroid nodule with less than 4 cm diameter by sonography Hypetfunctioning “hot” nodule on radioiodine scan High serum level of antithymid antibodies Decreasing size with thyroid hormone replacement

Hard, fixed, solitary nodule Ipsilateral cervical adenopathy Ipsilateral vocal cord paralysis Suspicious or malignant cytology by FNA Hypofunctioning “cold” nodule on radioiodine scan Solitary solid nodules and cysts > 4 cm and complex cysts on ultrasonography Increasing serum thyroglobulin in a patient with a history of papillary or follicular thyroid cancer

*

sected thyroid, and many are multifocal. These occult, incidental papillary carcinomas are of minimal clinical consequence. A family history of medullaxy or papillary thyroid carcinoma increases the likelihood that a thyroid nodule is malignant.25 A history of exposure to low-dose (0.06 to 20 Gy) therapeutic radiation to the thyroid increases the risk of the development of thyroid carcinoma.37-41 Patients with a history of exposure to radiation have Curr

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949

a 7% chance of the development of thyroid carcinoma; patients with a thyroid nodule and exposure to radiation have a 40% chance of the development of thyroid carcinoma.42 Patients with a history of thyroid carcinoma are at the highest risk of the development of recurrent carcinoma because of the failure to resect all of the tumor that may be multifocal or because of metastatic disease.35 On physical examination, solitary thyroid nodules or dominant nodules in a multinodular gland have an approximately 15% chance of being malignant. Nodules in patients with multinodular goiters have a 1% chance of harboring malignancy,35 but patients with multiple nodules on palpation have been reported to have a similar frequency of malignancy as patients with solitary palpable nodules.25 When imaging studies are performed, as many as two-thirds of the patients with clinically evident solitary nodules actually have multiple nodules.43’44 Lesions that are hard, gritty, or fixed to the surrounding tissue are more likely to be malignant. Malignancy is also more common if the patient has hoarseness or is documented to have unilateral vocal cord paralysis. Cervical adenopathy is found in 15% of adults with a malignant thyroid nodule and in up to 85% of children with thyroid carcinomaT5 Patients with metastatic thyroid carcinoma in cervical lymph nodes sometimes have no palpable thyroid lesion despite careful clinical or ultrasound examination. At operation, however, the ipsilateral thyroid lobe virtually always contains a papillary carcinoma, although in many cases it is microscopic. LABORATORY TESTS

Determining the serum TSH concentration is usually the only biochemical test needed in a patient who has no clinical manifestations of hyper- or hypothyroidism. In selected patients, a T4 index or free T3 may be helpful. Serum calcitonin levels should only be determined when medullary thyroid carcinoma is suspected.25 FINE-NEEDLE

ASPIRATION

The diagnostic test of choice for evaluating thyroid nodules is FNA biopsy. This procedure is easily accomplished in the office. It is safe, cost effective, and usually causes no more discomfort than a venipuncture. The use of FNA biopsy has increased the yield of carcinoma in excised thyroid nodules to 50% and decreased the need for surgery by 50% .25 In addition, FNA biopsy has decreased the need for ultrasonography and radioiodine scanning and, thereby, has reduced the cost of care. The accuracy and clinical utility of FNA has been well documented in numerous series and summarized in several m~ews*2526,33.45 950

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Solitary

or dominant

I nodule No ionizing radiation

I

\ Ionizing radiation

Thyroid hormone treatment. sonogram thyroglobulin

I-123 scan Hot or warm

thyroid

I Repeat FNA

Cold I Probable thyroidectomy

I Observe

I Nodule regresses-observe Nodule same size-repeat FNA Nodule enlarges-thyroidectomy

FIG. 3. An algorithm is presented for the evaluation and treatment of patients with solitary or dominant thyroid nodules Fifteen percent of FNA specimens are inadequate, and 85% are diagnostic (5% cancer, 20% suspicious or follicular, and 75% benign).

The

technique

FNA is described in detail in previous Briefly, the patient is placed in a supine position, and the nodule is carefully palpated and identified. The skin is prepared with alcohol. A 23gauge, 5/8-cm needle on a plastic syringe attached to a syringe pistol is inserted into the nodule. The aspirate is obtained by applying suction to the syringe while moving the needle within the nodule. The suction is released, and the needle is withdrawn. The aspirate is ejected onto glass slides and immediately placed in 95% alcohol or kept dry. The slides placed in alcohol are stained with a modified Papanicolaou technique, and the air dried slides are stained with Wright’s solution. Patients often experience minor discomfort, and rarely a hematoma may develop. For this test to be of value, it is essential that the slides be reviewed by an experienced cytopathologist. Cytologic findings are satisfactory (diagnostic) in approximately 85% of specimens and unsatisfactory (nondiagnostic) in 15% of specimens.33,51 Results of FNA are classified cytologically as benign (75% 1, suspicious or indeterminate (20% 1, and malignant (5% ).33151J53 Biopsies considered to be benign have a false-negative rate (not diagnosing thyroid carcinoma when it is on sampling errors and present) of approximately 4%33 depending misdiagnosis. EITOI-S can be reduced by an experienced clinician and cytopathologist. Aspiration biopsy should not be performed in patients with nodules who have received low-dose irradiation because

pUbliCations.Z6,28,ZS,45-S2

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thyroid carcinoma is present in 40% of these patients and because of the multicentric nature of these tumors the carcinoma is often missed by aspiration3’ (Fig. 3). Patients with benign cytologic evidence can be safely followed. However, if the lesion continues to enlarge in patients receiving thyroid hormone or if it exhibits other worrisome features, another aspiration biopsy should be performed or the lesion should be removed. Sampling errors occur most frequently with very small (Cl cm) or very large (>4 cm) nodules, hemorrhagic nodules, or multinodular glands. These errors can be minimized by obtaining multiple specimens or by using ultrasound guided needle biopsy. 25S33We use ultrasonography for small or occasionally questionable thyroid nodules, especially if the initial FNA specimen is indeterminate. An inadequate biopsy specimen occurs in up to 20% of FNA specimens, and, when repeated, one half of these will be diagnostic.“Of cytologic specimens interpreted as suspicious or indeterminate, most are follicular and Hiirthle cell neoplasms. Distinguishing between a follicular or Hiirthle cell carcinoma and a follicular or Htirthle cell adenoma is dependent on seeing capsular or vascular invasion on permanent histologic section or on documenting metastatic disease. This distinction cannot be made on cytologic specimens. Approximately 20% of follicular neoplasms and Hiirthle cell neoplasms by FNA are malignant . 33,53 Approximately 60% of suspicious papillary lesions are malignant.33 Of the cytologic specimens labeled malignant, approximately 1% of these are false positives, and this confusion is often attributed to Hashimoto’s thyroiditis.25 When a cyst is encountered in the course of performing FNA, it should be completely drained because 70% of simple cysts are adequately treated by aspiration alone.54 Although the findings are less accurate because of cellular degeneration, the cyst fluid should still be sent for cytologic examination. Cysts greater than 4 cm in diameter and complex cysts (that is, those that contain both solid and cystic components) have a greater chance of being malignant.3 When a cyst is complex, the solid component should be biopsied percutaneously after the fluid component has been aspirated.35 ULTRASONOGRAPHY Ultrasound examination of the thyroid is useful in several settings. It is superior to FNA in diagnosing nodular goiter.” For patients with a history of therapeutic radiation to the head and neck, ultrasonography can detect nodules that palpation cannot. Although no ultrasound features are pathognomonic for malignancy, some features are more helpful for differentiating benign from malignant lesions. Benign lesion are more likely to have a halo and to be isoechoic, homogeneous, well defined, and noncalcified. Malignant lesions are more 952

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FIG. 4. Radioiodine

scan demonstrates a “hot” nodule before receiving TSH (right) and after receiving TSH (left). Stimulation with TSH proves a normal thyroid gland is suppressed by the “hot” nodule.

likely to be hypoechoic and nonhaloed, and they may have a cystic component or calcification.55 We primarily use ultrasonography for follow-up of patients whose cysts have been treated by FNA and for determining whether a solid or complex nodule in a patient receiving thyroid suppressive therapy is changing in size.35 Ultrasonography can also be used to identify nonpalpable, regional lymph node metastases. RALIIOIODINE

THYROID

SCAN

When thyroid nodules are classified as suspicious or as follicular neoplasms on cytologic examination, a thyroid scan using lz31 or Tc 99 can be useful in determining the functional status of the nodule. Iodine isotopes are preferred because their uptake reflects the ability of a nodule to transport and organify iodine, whereas the uptake of technetium reflects only the ability to transport the radionuclide.56 Functional nodules take up more radioiodine than the surrounding normal thyroid tissue and are termed warm or hot (Fig. 41. The lack of uptake in the tissue surrounding the hot nodule can represent either suppressed thyroid tissue, thyroid agenesis (usually on the left), previous thyroid resection, or a giant cold nodule. Physical examination and sonography can document the presence of normal thyroid Curr

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953

FIG.

5. A radioiodine

scan

demonstrates

a “cold”

nodule

in the right

lobe

of the thyroid.

tissue surrounding the hot nodule as well as an lz31 scan after TSH stimulation (Fig. 4). Overall, approximately 5% of solitary thyroid nodules are warm or hot, and less than 1% are malignant. Among follicular neoplasms by cytologic examination, the percentage of nodules that are hot and malignant is higher. These lesions can therefore be followed safely.“36 However, if a hot nodule causes hyperthyroidism or continues to grow, thyroidectomy is indicated. We do not think it is cost effective to scan all patients with thyroid nodules. We primarily use preoperative scans in patients with follicular neoplasms by FNA. Most cytologically suspicious lesions are cold or nonfunctioning (that is, taking up less radioiodine than normal thyroid tissue), and approximately 20% of these lesions are malignant lS3’ (Fig. 5). Diagnostic lobectomy is indicated for most patients with solitary, cold nodules.

THYROID SUPPRESSION THERAPY Debate continues over the therapeutic thyroid hormone to suppress the growth 964

effectiveness of the use of of benign thyroid nodules Curr

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1994

or to prevent the recurrence of thyroid carcinoma.34 The exogenous synthetic thyroid hormone suppresses the release of TSH from the pituitary and thereby decreases the growth stimulation of normal and neoplastic thyroid cells. The goal of suppression therapy is to reduce the size of a benign nodule or to arrest its growth. Methods for following the effectiveness of this therapy in nodules that are benign by cytologic examination include physical examination, documentation of nodule size with ultrasonography, and suppression of serum TSH and thyroglobulin levels5’ Numerous, but not all, studies support the use of thyroid hormone to suppress serum TSH levels in patients with benign thyroid lesions. Nearly 100 years ago Brunss8 treated 370 patients with goiters using thyroid hormone and documented that approximately two-thirds of the nodules decreased in size and that onethird either continued to grow or failed to regress. The best results were obtained in young patients with diffuse goiters. Many of the nodules that decreased in size recurred when the thyroid hormone was discontinued. Greer and Astwood5’ were the first to compare alterations in goiter size with a control group. Again, they found that nearly two-thirds of the patients receiving thyroid hormone had objective evidence of regression of the thyroid nodules. Morita and colleaguess reported that thyroid nodule size decreased and serum thyroglobulin levels also decreased in 18 (38% 1 of 47 patients treated with thyroxine at a dose of 0.1 mgday. In nonresponders, the nodules did not decrease in size, and serum thyroglobulin”levels did not fall (Fig. 61. Other studies confirm these results.34’60 In 1987, Gharib and col1eagueP challenged these findings when they reported results of a double-blind, placebo-controlled clinical trial of suppressive therapy. High-resolution (10 MHz) sonography was used to document the size of colloid nodules before and after 6 months of treatment with either levothyroxine (n = 281 or placebo (n = 2.5). Although more nodules decreased in size in the thyroxine-treated patients, some nodules in patients receiving placebo also decreased in size so that no significant difference was noted between the two groups. These results have been confirmed up to 3 years in other randomized controlled studies.62.63

These data conflict with the older, noncontrolled trials34,57-“0 that suggest that many benign thyroid nodules are responsive to thyroid suppressive therapy. Obviously, patients with large thyroid nodules are less likely to respond,34’61 whereas patients with increased serum TSH levels, those with Hashimoto’s thyroiditis, multinodular goiters, diffuse goiters, and small solitary nodules are more likely to respond.34,57-61 For many patients with small thyroid nodules, prevention of further growth is also important and avoids unnecessary operations. Nodule growth during therapy is a strong indication for operationW Risks associated with thyroid suppression therapy include subclinical thyrotoxicosis, clinically overt thyrotoxicosis in paCurt- Probl

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1994

ass

Logarithmic Scale

Tg p/L

** I

n.8. r

*

n.s.

I

I

I

1

1600 1000

100

10

before

altar

before

non-respondarr

FIG. 6. or failed difference ference (Reprinted al. J Clin

after rorponders

Serum thyroglobulin levels in patients with thyroid nodules that decreased in size to decrease in size in response to treatment with thyroid hormone. *Significant 0, < 0.05) between initial and final serum thyroglobulin levels. **Significant dif(p < 0.05) of final serum thyroglobulin levels in responders versus nonresponders. with permission from The Endocrine Society. Morita T, Tamai H, Ohshima A, et Endocrinol Metab 1989;69:227-30.)

Curr

Probl Surg, December

1994

tients who have received an overdose, cardiovascular side effects, and possibly osteoporosis with long-term thyroid suppression.z5 For patients we plan to follow because of a benign cytologic examination, including those at low risk for cancer (family history of benign goiter, multinodular thyroid glands, Hashimoto’s thyroiditis, hot nodules, or thyroid cysts), we perform a lo-MHz real-time ultrasound examination. This documents the precise size of the nodule in three dimensions and whether the nodule is solid or cystic and solitary or multiple. We also order a serum TSH (to be sure the patient is euthyroid) and a serum thyroglobulin level. We then treat the patient with enough thyroid hormone to suppress the serum TSH level but keep the serum T4 level at the upper limit of normal. This dose of thyroxine is usually between 0.125 and 0.15 mg/day depending on the patient’s size. Three months later, we examine the patient and repeat the sonography and serum TSH and thyroglobulin levels. If the nodule decreases in size and the serum thyroglobulin levels fall, the lesion is most likely at little risk for cancer and can be followed safely. If the nodule has not changed in size, the patient should either be examined in another 3 months, or a repeat biopsy should be performed. When the nodule enlarges or new nodules develop during TSH suppressive therapy, thyroidectomy is usually recommended. OTHER

DIAGNOSTIC

STUDIES

Chest radiographs are helpful for identifying tracheal deviation from a large lesion or pulmonary metastases and for detecting other coexistent pathologv. A finely speckled pattern of calcification within the thyroid on chest radiography or ultrasonography suggests the presence of psammoma bodies, suggesting a papillary carcinoma. Psammoma bodies are present in approximately two-thirds of papillary thyroid carcinomas. The appearance of a rim or eggshell calcification suggests a benign lesion. Bilateral calcification at the upper lateral portion of the thyroid suggests medullary thyroid carcinoma, whereas heavy irregular calcification suggests a nultinodular goiter. Laryngoscopy to ascertain the function of the recurrent laryngeal nerves is indicated for all patients with any change in their voice or hoarseness and for all patients who have had previous neck surgery because these patients may have an asymptomatic recurrent laryngeal nerve injury. CT or MRI of the neck is useful for determining the extent of local invasion, regional metastases, and substernal extension of the tumor in patients with large tumors when the limits of the tumor cannot be delineated. These studies are usually unnecessary but can be helpful for patients with large, invasive thyroid tumors and occasionally before reoperations. MRI is somewhat better Curr

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than CT for differentiating between recurrent scarring due to the previous procedure(s).65

INDICATIONS

or persistent

tumor

and

FOR OPERATION

Thyroidectomy is indicated whenever a patient with a thyroid nodule has a reasonable likelihood of having cancer. The most obvious indication for surgery is a cytologic diagnosis of carcinoma on FNA biopsy, Most patients with a cytologic diagnosis of “suspicious” on FNA should also undergo thyroidectomy. A cytologic diagnosis of follicular neoplasm in a patient with a cold nodule by lz31 scanning or a Htirthle cell neoplasm is also an indication for thyroidectomy. Another indication for surgery is a nodular thyroid in a patient with a history of low-dose radiation to the neck. These patients have a 40% chance of having cancer in the thyroid gland and therefore should undergo thyroidectomy.42 Cystic lesions of the thyroid are usually benign, but one should consider resecting complex cysticsolid lesions, cysts larger than 4 cm in diameter, and cystic lesions of the thyroid that continue to recur after at least three attempts at aspiration because cancer is more likely to be present in the thyroid gland of these patients.“’ Some patients who have recurrent pure cysts without solid components by ultrasound examination can be treated effectively by sclerotherapy with an injection of tetracycline and lidocaine into the cyst.67,68 One should be aware that some cancers, especially those larger than 4 cm in diameter, may necrose and have cystic components.6s Thyroidectomy is usually indicated in patients with hard or gritty solitary thyroid nodules, clinical symptoms of pressure, hoarseness, dysphagia, adjacent cervical adenopathy, vocal cord paralysis, or recent rapid painless growth of a nodule. A patient who has a family history of medullary carcinoma or MEN type 2 and who has an elevated basal or stimulated calcitonin level, even in the absence of a palpable mass, should have a total thyroid resection.70 Patients whose thyroid nodule enlarges despite TSH-suppressive therapy with thyroxine also warrant thyroidectomy. Most clinicians agree on the indications for surgery for patients with thyroid nodules and on the need to perform a diagnostic lobectomy for any nodule that is suspicious for cancer; however, considerable debate concerns the extent of thyroidectomy in patients with thyroid carcinoma. We believe that virtually all thyroid nodules that might be cancer should be removed by lobectomy because a subsequent completion total thyroidectomy, if necessary, can be performed with a minimally increased risk of morbidity. Thyroid nodules in the isthmus should be removed by wedge resection. 958

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Thyroid carcinomas arise from follicular cells (papillary, follicular, Hiirthle, anaplastic), parafollicular cells (medullary, anaplastic), and stroma (lymphoma, sarcoma). Thyroid carcinomas vary considerably in their clinical behavior, with occult papillary and minimally invasive follicular cancer rarely causing death, whereas virtually all patients with anaplastic thyroid carcinoma die of the tumor.

BENIGN TUMORS OF THE THYROID GLAND Adenomatous and colloid goiter are the most common forms of thyroid enlargement and are characterized by multiple nodules of varying size and consistency. The nodules are demarcated but not encapsulated. They often have a gelatinous consistency with areas of degeneration or calcification. Microscopically, they contain nodules of various sizes with flattened follicular epithelium. A variant of adenomatous goiter is the adenomatous nodule that is a solitary dominant mass that mimics adenoma. Patients with these nodules often have a nonregressing solitary nodule. Such nodules may be difficult to distinguish cytologically from a true adenoma. They are demarcated but not encapsulated, and occasionally other small nodules exist in the thyroid gland.The most common benign thyroid neoplasm is the adenoma. These often present as a solitary thyroid nodule or a dominant nodule in a goiterous gland. Hemorrhage may lead to rapid enlargement. Grossly, they are distinguished from goiterous nodules by their capsule. They appear different from the surrounding thyroid tissue, and they compress the adjacent tissue.4 Microscopic patterns of growth include follicular, microfollicular, Htirthle cell, and embryonal. Malignancy usually cannot be determined by cytologic or microscopic patterns but only by capsular invasion, blood vessel invasion, or rarely by the presence of metastatic diseasee4 Papillary adenomas have been described. These are very rare, and all may in fact be low-grade papillary cancer: Papillary nodules have been described in nodular goiters, Hashimoto’s thyroiditis, and Graves’ disease.’

MALIGNANT

TUMORS OF THE THYROID GLAND

The classification and relative frequency of the malignant tumors of the thyroid gland are shown in Table 2. Differentiated thyroid carcinomas of follicular cell origin include papillary, follicular, and Htirthle cell tumors. Cur-r Probl

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TABLE 2.

Classification frequency of malignant thyroid gland Classification

Papillary Pure Mixed papillaryfollicular Follicular variant Follicular Hiirthle cell’ Medullary Anaplastic Others Lymphoma Metastatic carcinoma Teratoma Carcinosarcoma Sarcoma Squamous cell

and tumors

relative of the Incidence(%

1

80

10 3 5 1 1

‘Hiirtble cell carcinoma is not classitkd as a distinct entity by the American Thyroid Association and World Health Organization, but we believe it should be classilied separately (see text).

PAPILLARYcARcINoMA Grossly, papillary carcinoma is a firm and unencapsulated neoplasm sharply circumscribed by the surrounding thyroid tissue. It may be multicentric in up to 80% of cases’l and frequently involves both lobes? The occult sclerosing carcinoma (Crile-Hazard tumor) appears as an irregular white scar within a normal or goiterous gland. Histologically, these carcinomas can be divided into pure papillary, mixed papillary-follicular, and the follicular variant of papillary carcinoma. Mixed papillary-follicular patterns are most common, with pure papillary being rare. If any papillary components are seen, the tumor is considered to be a papillary carcinoma. The papillary component is characterized by a fibrous stalk with a periphery of follicular epithelium (Fig. 7). Laminated calcifications called psammoma bodies are often, found in the stalk region; however, their absence does not rule out malignancy (Fig. 8). The nuclei are often optically clear (ground glass, “orphan-Annie,” water clearI (Fig. 9). The follicular variant of papillary thyroid carcinoma forms only follicles without papillary structures, yet the cells have the optical clearing of papillary tumors4 (Fig. 7). The prognosis and biologic behavior is the same for all three types.7’ Occult papillary carcinomas are less than 1.5 cm in diameter, and minimal papillary carcinomas am less than 1.0 cm in diameter.’ 960

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1994

FIG. 7. Photomicrographs demonstrate papillary cancer of the thyroid: mixed papillarytype (A) demonstrating a fibrous stalk with a periphery of follicular epithelium and variant of papillary cancer (B) demonstrating only follicles without papillary struc-

follicular follicular tures yet tion: A,

the nuclei have the optical ~500~; B, x1002.)

Cur-r Probl

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1994

clearing

seen

in papillary

tumors.

(Original

magnifica-

961

FIG. 8. A photomicrograph bodies

with

laminated

of a specimen of papillary cancer demonstrates calcifications. (Original magnification x250.)

psammoma

These lesions are often incidental findings on sonography or in thyroid glands that have been removed for non-neoplastic conditions. Intrathyroidal cancers are larger than 1.5 cm but confined to the thyroid gland, whereas extrathyroidal carcinomas invade the soft tissues of the neck or metastasize to regional nodes or distant sites.l Papillary thyroid carcinoma frequently spreads intrathyroidally via lymphatics and also to regional cervical lymph nodes. Cervical and upper mediastinal lymph node metastases are common, and in prophylactic lymph node dissections, positive nodes are found in up to 90% of patients.73 Distant metastases occur most frequently in the lung and bone. In the lung, metastases often create a ditfuse pattern of involvement rather than a single mass lesion4 (Fig. 10). MINIMAL

AND

OCCULT

PAPILLARY

CARCINOMA

Minimal (1.0 cm diameter1 and occult (Cl.5 cm diameter1 papillary carcinomas are of interest because their incidence far exceeds that of papillary carcinomas greater than 1.5 cm, and the prognosis of patients with small tumors is so good it mandates a more conservative surgical approach than for lesions greater than 1.5 cm. The reported prevalence of occult carcinomas is related to the method of pathologic examination of thyroid specimens removed at operations or at autopsies. The rates vary from 0.45% to 13% of Caucasian individuals 962

Curr

Probl

Surg,

December

1994

FIG. 9. A photomicrograph nuclei.

(Original

magnification

of a specimen x250.)

of papillary

cancer

demonstrates

ground-glass

in Michigan, 28% of Japanese individuals in Japan,74 and 36% of autopsy s ecimens in Fin1and.l Higher rates occur in more meticulous studies ? and in older patients. In a study of autopsies in patients under 40 years of age, only 1 of 147 thyroid glands was found to have a papillary carcin0ma.l These occult tumors are usually smaller than 5 mm, multifocal (32%), and occur with equal frequency in both thyroid 1obes.l In one autopsy study,74 16% of patients with occult thyroid tumors had metastases to cervical lymph nodes. No enlarged lymph nodes were found, and no patients died of thyroid carcinoma. The increase in prevalence of occult thyroid carcinoma over large, clinically detectable thyroid carcinoma is not well understood. The effect of environmental carcinogens and exposure to radiation may explain the high prevalence of occult tumors and individual differences in tumor surveillance, or immunomodulation may explain why larger, clinically significant cancers develop in some patients. Radiation, genetic predisposition, and other factors can induce thyroid carcinomas; iodine deficiency and growth factors can promote the growth of these tumors and perhaps lead to metastafic disease.75 In patients who have been treated surgically by less than total thyroidectomy for occult papillary carcinomas, Mazzaferri and colleagues76 reported a recurrence rate of 7.5% and no deaths. However, deaths do occur and are estimated at 0.4 per 100,000 men and 0.8 per 100,000 women per year.‘S77,78 Curr

Probl

Surg,

December

1994

963

FIG. 10. A

chest

radiograph

demonstrates

diffuse

pulmonary

metastases

For occult carcinomas, the prognosis is so good that resections more extensive than lobectomy with isthmusectomy confer no additional advantage.7s’80 However, those patients with invasive tumors or distant metastases should be considered for total thyroidectomy. We also recommend total thyroidectomy for patients with nodal metastases because,, even though these patients have an excellent prognosis, some recurrences develop and a few patients die of the tumor. Once the thyroid gland has been removed, one can scan for, detect, and treat other metastases with radioiodine in approximately twothirds of patients.81 RADIATZON-ASSOCLQTED

THYZ3OZD CARCINOMA

Exposure of the neck, head, or chest to low-dose therapeutic radiation increases the risk of the development of both thyroid carcinoma and benign thyroid conditions such as nodular goiter and Hashimoto’s thyroiditis.82 Low-dose therapeutic irradiation has been used for treating patients with scrofula (tuberculous adenitis of the 964

Curr

Probl

Surg,

December

1994

FIG. patient

11. A photomicrograph with

a benign

thyroid

demonstrates a microscopic nodule. (Original magnification

focus of papillary x250.)

cancer

in a

neck), enlarged thymus gland, tonsillar enlargement, external otitis, ringworm of the scalp, acne, and other conditions. In 1950, Duify and Fitzgeralds3 first reported an association between radiation therapy and thyroid carcinoma in 3 of 28 children with a history of radiation exposure to the head and neck. Radiation is more tumorigenic in children, and it is dose dependent. Several studies’7J41,84*85 document that age at radiation exposure is inversely correlated with risk. The highest risk appears to be in children under 7 years of age, but an increased risk exists for the development of thyroid carcinoma in patients up to 50 years of age at the time of irradiation.86 Nearly a linear increase has been found in both benign thyroid nodules and thyroid carcinoma with increasing radiation exposure from approximately 0.06 to 20 GY.~‘,‘~ The frequency of thyroid carcinoma decreases in patients after exposure to more than 20 Gy to the thyroid gland, but exposure of up to 60 Gy to the head and neck is associated with a slightly higher risk of thyroid carcinoma.88 At over 60 Gy, there is no higher frequency of thyroid carcinoma in man, but hypothyroidism usually develops. Patients exposed to low doses of therapeutic radiation have a 1% to 7% chance of thyroid carcinoma developing, with an increasing risk for at least three decades after radiation exposure.37’8s However, when a patient has a thyroid nodule and has a history of thyroid irradiation, a 40% chance exists of having thyroid carcinoma.42’8s’s0 In 60% of patients, the cancer is in the index Curr

Probl

Surg,

December

1994

966

nodule that draws attention to the thyroid gland; and in 40% of patients, it issituated elsewhere in the thyroid gland.42’8g’s0 This is important in the cytologic findings of FNA because a benign nodule in these patients may be associated with carcinoma elsewhere in the gland (Fig. 11). A higher frequency of hyperparathyroidism and parathyroid tumors, salivary gland tumors, and breast carcinoma is found in patients who have a history of exposure to low-dose therapeutic irradiation to the head, neck, and chest.84’s1-g4 Despite the higher frequency of multifocal tumors and mixtures of benign and malignant tumors, the prognosis of patients with radiation-induced thyroid carcinomas in general is similar to that for patients with sporadic tumors. In several reports, no increased risk of thyroid carcinoma has been found in persons treated with radioactive iodine for Graves’ disease, but an increased risk of developing benign thyroid nodules has been foundY5 The cancers that do develop in these patients may be more aggressive. The usual dose of radiation the thyroid gland receives when a patient is treated with radioactive iodine for Graves’ disease is approximately 90 GY.~~The lack of effect of high-dose exposure is best explained by the thyroid cellular destruction after such treatment. Serum levels of thyrotropin (TSH), triiodothyronine (T,), or thyroxine (T,) are helpful for determining that the patient is euthyroid. Most patients with thyroid carcinoma, however, have normal thyroid function. Serum thyroglobulin levels can help define an individual’s risk for the development of thyroid neoplasms. Thyroid nodules are more likely to develop in patients with elevated blood thyroglobulin levels than in those patients whose serum thyroglobulin level is normal. Progressively increasing serum thyroglobulin levels may indicate that a nodule has developed.41 Familial factors may be important in determining who is at risk for radiation-associated thyroid carcinoma. Perkel and colleagues,g6 by comparing siblings with radiation exposure, noted that some sibling pairs appeared to have a higher risk of thyroid carcinoma after radiation exposure. The distribution of different histologic types of thyroid carcinoma after radiation exposure appears to be the same as the distribution of thyroid tumors in general. Thus more patients after radiation exposure have papillary cancers, but this is also the most frequent sporadic tumor. TREATMENT

OF PAPZLLARY

THYROID

CARCINOMA

Considerable controversy exists in the literature and among experienced thyroid surgeons as to whether total thyroidectomy or less than total thyroidectomy is the preferable operation for patients with 966

Curr

Probl

Surg,

December

1994

papillary thyroid carcinoma.s7~ss The three factors fueling the controversy are the fact that approximately 80% of these patients do well regardless of the operation, a higher morbidity rate is associated with more extensive thyroid resections, and no prospective studies compare different methods of treatment. Several retrospective reviews have, however, touted a selective surgical approach for patients with papillary thyroid carcinoma based on the separation of patients into low-risk and high-risk groups. Other investigators recommend total or near total thyroidectomy for virtually all patients with papillary thyroid carcinomas greater than 1.5 cm when these operations can be performed safely. With the exception of thyroid nodules situated on the isthmus, the minimum operation that should be performed for any patient with a documented or suspected carcinoma is an ipsilateral (diagnostic) lobectomy. The main reason for this is that one does not have to reoperate in the area of scarring and it avoids cutting through thyroid carcinoma and possibly seeding the tumor. For tumors in the isthmus, excisional biopsy and wedge resection of the isthmus with a l-cm margin of normal thyroid tissue is acceptable. Partial lobectomy or lumpectomy is inadequate therapy for unilateral tumors because such treatment is associated with a higher recurrence rate and a belower survival rate.7s’100 Total lobectomy is also recommended cause pathologists sometimes change a benign diagnosis by frozen section to a malignant diagnosis on permanent section. In such cases, one does not have to reoperate on the side where the parathyroid glands and recurrent laryngeal nerve have been exposed. Isthmusectomy and removal of the pyramidal lobe, if present, are also recommended because these add little time or risk to the operation and prevent possible recurrent disease in the isthmus leading to tracheal invasion. Also they avoid an unsightly bulge in the central neck in patients in whom compensatory thyroid hypertmphy develops after thyroid resection. For patients with multinodular goiters and a dominant nodule, total lobectomy is performed on the side of the dominant nodule, and subtotal lobectomy is performed on the contralateral side if it is also goitemus. If a question arises whether the dominant nodule may be malignant, frozen section examination is recommended. Although total thyroidectomy has been advocated for patients with benign goiter,“’ we disagree with this approach unless the patient has a history of irradiation, no normal thyroid tissue is found, or other specific reasons exist for total thymidectomy. Even though total thyroidectomy can be performed with minimal risk, a unilateral procedure is always safer.‘02 For encapsulated papillary carcinomas less than 1.5 cm in diameter with clear histologic margins that are removed incidentally during thymidectomy for another tumor or for Graves’ disease, no furCurr

Probl

Surg,

December

1994

967

TABLE Total

3.

Rationale

for total

thvroidectomv

thymidectomy

Radioactive iodine can be used to detect and treat residual normal thyroid or local or distant metastases. Serum thymglobulin is a more sensitive marker of recurrence when all normal thymid is removed. The microscopic foci of cancer present in up to 85% of patients are eliminated as sites of recurrence. Recurrent cancer develops in the remaining contralateral lobe in approximately 7% of patients, and one half of these patients die of thyroid cancer. Recurrence is lower in patients who have undergone total thymidectomy. Eliminates the 1% risk of a differentiated thyroid cancer changing to an undifferentiated cancer.

versus

less than

Less than

total

total

thvmidectomv

thymidectomy

Fewer complications develop. One half of local recurrences can be cured with surgery. Less than 5% of recurrences occur in the thyroid bed. Little clinical significance is given to multicentricity. Prognosis is good with lesser procedures.

ther thyroid surgery is required because the prognosis for these patients is excellent. An ultrasonographic examination of the remaining thyroid gland is useful for identifying coexistent residual tumors, and a baseline serum thyroglobulin level may be useful. A repeat serum thyroglobulin level determination can be performed in 6 months to be sure it is not increasing. For papillary tumors greater than 1.5 cm in diameter, we102’ lo3 and others” g80“, lo4-lo6 recommend total thyroidectomy when this operation can be performed safely. Others’, 107-111recommend less than total thyroidectomy. The rationale for both these recommendations are listed in Table 3. The most important rationale for total thyroidectomy is that it allows one to use radioactive iodine to both identify and treat residual normal thyroid tissue or local or distant metastases.81 In patients who have had a total thyroidectomy, two-thirds of papillary and follicular metastases take up radioactive iodine; but in patients with remaining normal thyroid tissue this is markedly decreased because normal thyroid tissue has a loo-fold greater affinity for iodine than most differentiated thyroid tumors and the presence of thyroid tissue decreases the elevation in TSH that occurs after thyroid hormone treatment is discontinued. Serum thyroglobulin levels are more sensitive for detecting residual and recurrent thyroid tumor in patients after total thyroidectomy than in patients undergoing less than total thyroidectomy because of the ability of thyroid remnant to produce thyroglobulin.81 After total thyroidectomy, the serum thyroglobulin level should be less than 99s

Curr

Probl

SW..

December

1994

60 50 2

5 Years After

10 lnitii

Thempy

FIG. 12. Cumulative recurrence rates are depicted for patients with either a primary tumor 1.5 cm or larger or multiple primary lesions, local tumor invasion, or cervical metastases. Recurrence following no adjunctive therapy (m), thyroid hormone (0) or 13’I‘and thyroid hormone a). P values refer to treatment modalities directly above and below. (Reprinted with permission from Mazzaferri, EL. Seminars in Oncology 1987;14:314-32.)

3 rig/ml; if it is measurable, residual tumor should be suspected, and a radioactive iodine scan should be performed to diagnose and treat any tumor. The serum thyroglobulin level is most sensitive when a patient is hypothyroid in preparation for a radioiodine scan because the TSH stimulus for thyroglobulin is maximal at this time.“’ Histologic studies of the contralateral thyroid lobe in patients with papillary carcinoma have shown microscopic foci of cancer in up to 85% of patients113, and total thyroidectomy eliminates these foci as potential sites of recurrence. Patients undergoing lobectomy have a recurrence rate in the contralateral lobe of 5% to 2596, with a mean of 7%.‘13 Mazzaferri and colleagues7sS1oo reported a recurrence rate of 11% after total thyroidectomy compared to 22% for subtotal thyroidectomy. In addition, the lowest recurrence rates occurred in those patients who also received radioactive iodine ablation and TSHsuppressive therapy (Fig. 12).7s,‘oo Massin and colleagues114 and Schlumberger and colleaguesS1 have documented similar results. The results of these retrospective studies probably underestimate the benefits of these treatments, because patients with more extensive tumors were more likely to be treated aggressively and more of these patients were probably included in the group receiving more extensive therapy. Recurrent cancer is of concern because approximately Cur-r Probl

Surg,

December

1994

969

TABLE

4. Correlation

between

Uptake W in pm-ablation scan

pre-

and

post-

ablation

uptake Proportion of patients with 5 1% uptake on post-ablation scan

No. of patients

l-10 >lO-20

= 100%

34

34134

15

13/15 = 87% 415 = 80%

>20-30 >30-40

11

9111 = 82%

>40-50

2

2/z = 100%

IReprinted

5

with permission

from Leung SF, Law MW, Ho SK. Br J Radio1 1992;65:905-9.)

one half of the patients in whom recurrent thyroid carcinoma develops eventually die of thyroid carcinoma, and some of these patients initially were in a low-risk gro~p.~~~“~ Additionally, because recurrence is lower in patients who have undergone total thyruidectomy, these patients require fewer reoperations. Total thyroidectomy also dramatically decreases the 1% risk of a differentiated thyroid carcinoma changing to an undifferentiated cancer with its attendant grim prognosis.1’5 The rationale for less than total thyroidectomy is summarized in Table 3. Most surgeons who recommend thyroid lobectomy rather than total thyroidectomy cite the higher complication rate after total thyroidectorny.7,‘0~,l~~-~~~,~~~,~~6 However, numerous studies have documented that in the hands of an experienced surgeon, total thyroidectomy can be performed with minimal morbidity.7~s8’ss~‘02-10fi Thomas’17 recommended near-total thyroidectomy to maximize the resection of cancer, yet minimize the chance of causing permanent hypoparathyroidism. We recommend near-total thyroidectomy when it is necessary to avoid injury to the recurrent laryngeal nerve or parathyroid glands. When the parathyroid glands are situated off the thyroid gland and the recurrent nerve can be safely dissected from the thyroid, we see no advantage of near-total thyroidectomy. Postoperative radioiodine ablation of the thyroid remnant should be performed in high-risk patients who underwent a near-total thyroid lobectomy. The smaller the thyroid remnant, the easier it is to ablate with radioiodine (Table 4). In those patients who are noncompliant and will not take thyroid medications, a thyroid lobectomy is probabl:’ the safest operation. Although total thyroidectomy does not address micrometastasis to lymph nodes directly, this operation does facilitate radioactive iodine ablation of those micrometastases. LYMPH

NODE

DISSECTION

Cervical lymph node metastases in patients with papillary thyroid carcinoma are clinically evident or are found microscopically in up to 80% of patients, yet their impact on prognosis is controversial.71 970

Curr

Probl

Surg,

December

1994

GROUPS8V AM

FIG. 13. Graphs depict recurrences (A) and deaths (8) caused by differentiated thyroid cancer in 100 patients. (Reprinted with permission from Harwood J, Clark OH, Dunphy JE. Am J Surg 1978;136:107-12.)

Less than 10% of patients with follicular thyroid carcinoma have cerSeveral studies suggest a minor adverse vical lymphadenopathy.l18 influence on prognosis.11y-122 Tennvall and colleagues”’ reported that patients with matted lymph nodes had an appreciably worse prognosis. Harwood and colleagues121 reported that when patients with and without lymph node metastases were matched by age and gender, lymph node metastases had an adverse effect on recurrence and survival (Fig. 13). These results were confirmed more recently by Sellers and colleagues123 and Coburn and colleagues124 who point out that node-positive patients with tumor invasion who are over 45 years of age and who have positive mediastinaf nodes have more aggressive disease. Some studies 34,7s~125-127 suggest that the presence of positive lymph nodes does not affect survival and Cady and colleagues”’ suggested that patients with lymph node metastases may have a better prognosis. The confounding variable in these studies may be age. Almost 80% of patients under 20 years of age have palpable nodal metastases at presentation, whereas in older patients, only 20% have clinically palpable nodes. The adverse effect of having palpable nodal metastases may be mitigated by the improved prognosis related to youth. lzl Lymph-node metastases at the time of presentation probably do increase the risk of recurrence in the neck but have only a slight detrimental impact on survival. We recommend the following surgical approach to patients with lymph-node metastases. During the thyroid resection, surgeons Curr

Probl

Surg,

December

1994

971

FIG. 14. Anterior (left) and lateral (right) views of the neck illustrate the pattern of lymph node involvement in thyroid cancer. (Reprinted with permission from Frankenthaler RA, Sellin RV, Cangir A, Goepfert H. Am J Surg 1990;160:341-3.)

should remove all lymph nodes adjacent to the tumor and medial to the carotid sheath, including the Delphian node located in the cricothyroid membrane. Prophylactic lymph-node dissection (that is, removing nonpalpable lymph nodes lateral to the carotid sheath) is not recommended because, despite the fact that microscopic cancer is present in nodes in at least 80% of these patients, a recurrence develops in only 8% of patients.121’1zg Hutter and colleaguesl” reported that prophylactic lymph-node dissection was probably unnecessary even though it decreased the recurrence rate. Fewer deaths also occurred in patients treated by prophylactic dissection (3 versus 61, but no significant change was noted in survival. We advocate a modified radical neck dissection for patients with clinically palpable cervical metastases (therapeutic dissection) because radioactive iodine and external radiation therapy are often ineffective in eliminating palpable nodes, the jugular nodal metastases.‘lg The ipsilateral paratracheal vein chain of nodes, and the spinal accessory nerve chain of nodes are excised (Fig. 14). This operation can be performed by lateral extension (MacFee) of the Kocher transverse collar incision. Occasionally a higher parallel horizontal incision is necessary in patients with extensive adenopathy. To minimize morbidity, we preserve the spinal accessory nerve, jugular vein, and sternocleidomastoid muscle unless they are invaded by tumor. Removing only the individual enlarged nodes (“berry picking”) is not advisable because for all patients with palpable nodes there is cancer in the smaller lymphatics, so that 972

Curr

Probl

Surg

December

1%~

recurrent disease is common.130’131 Because only 10% of patients have involvement of the contralateral cervical nodes, contralateral neck dissection is usually not recommended except fo< patients with extensive bilateral disease. Suprahyoid dissections are seldom necessary because metastases only occur in 1% of patients. The superior mediastinal nodes may be involved in up to 6% of cases and should be removed if palpably enlarged.13’

DISTANT

METASTASES

Thyroid carcinomas metastasize most frequently to lymph nodes, but also to lung and bone and, less frequently, to the brain, liver, and skin. Follicular cancers metastasize to distant sites more frequently than papillary cancers. Recurrent disease usually is seen as metastatic disease in patients who have undergone a total thyroidectomy and usually occurs during the first 6 months after thyroidectomy but may occur as long as 41 years after thyroidectomy.‘33 Follow-up should therefore be most intensive during the first years after thyroidectomy. In most studies, recurrence occurs in approximately 20% to 30% of patients and the S-year survival is approximately 80%. Early detection and treatment of recurrent disease including pulmonary metastases may improve this signiticantly.81 Patients with metastatic thyroid carcinoma can be treated with some success with radioiodine or reoperation especially when the recurrent disease is focal or the metastatic deposits are small. Serum thyroglobulin level determination is a sensitive method of documenting recurrent disease after total thyroidectomy. Serum thyroglobulin levels are present in up to 95% of patients with metastatic papillary, follicular, or Hiirthle cell cancer. Radioiodine uptake is present in approximately 75% of patients with papillary and follicular thyroid carcinoma. A negative total body scan therefore does not exclude the presence of metastatic disease, especially in a patient with an elevated thyroglobulin level. Other diagnostic tests include neck ultrasonography, neck and thoracic CT or MRI scans, and other radioisotopes such as thallium or sestamibi. In patients who have an elevated serum thyroglobulin level, the administration of 100 mCi of radioactive iodine with a total body scan 5 days later documents tumor in approximately 35% of patients and serum thyroglobulin levels decrease to undetectable levels in approximately 35% of such patients.‘l Bone metastases are sometimes solitary and often painful. Focal lesions should be removed surgically, and the patient should receive a large dose of radioactive iodine. These patients are at very high risk of dying within 5 years. Another dose of radioactive iodine (approximately 100 mCi) is therefore given in an attempt to sterilize the site.133 Curr

Probl

Surg

December

1994

973

External irradiation is recommended for treatment of large metastases that do not take up radioactive iodine in support bones, because this often relieves bone pain and can prevent further destruction and fracture. Chemotherapy including doxorubicin (Adriamycin) unfortunately is helpful in only an occasional patient.

RECURRENT

THYROID CARCINOMA

Recurrent thyroid carcinoma occurs in approximately 2.5% of patients with differentiated thyroid carcinoma.1’s7’100’134 It is somewhat surprising that recurrence does not develop in more patients because about 80% of patients have at least micrometastases to cervical lymph nodes at the time of operation. Recurrence occurs most frequently in the cetical lymph nodes or in the remaining thyroid tissue after a less than total thyroidectomy. Most recurrences occur within several years after thyroidectomy, but they may occur at any time later. The mortality rate in patients in whom recurrent disease develops ranges from 36% to 50% within 15 years of initial treatment.s7’135’1 6 Virtually every study suggests that incompletely resected tumors; invasive tumors; tumors larger than 5 cm; recurrent tumors; poorly differentiated tumors; aneuploid tumors; tumors that have metastasized to lung, bone, and other sites; tumors that fail to take up radioactive iodine; and tumors in older patients behave in a more aggressive manner. Tumors that metastasize regionally to the cervical lymph nodes (especially when nodes are matted), multifocal tumors, tumors with extensive angioinvasion, tumors that have a low adenylate cyclase response to TSH, tumors in patients from iodine-deficient areas, and tumors with p53 tumor suppressor gene mutations or combined and ras oncogene mutations are also more aggressive. 13eE9 Thus patients after thyroidectomy can be separated into low- and high-risk groups for tumor recurrence and death based on clinical data or laboratory studies. Early detection of recurrence is optimized by the following protocol. After total or near total thyroidectomy, patients are treated with triiodothyronine (Cytomel, T,) (25 kg two or three times daily) for 6 to 12 weeks rather than with L-thyroxine (T,) because of the shorter half-life of T, (1 day versus 1 week for T4). A low-iodine diet is given for 3 weeks before the radioiodine scan, and the T, is discontinued 2 weeks before the scan. A sensitive serum TSH and thyroglobulin level is determined when the patient is hypothyroid in preparation for the scan. Patients with increased (>lO rig/ml) thyroglobulin levels almost always have residual normal thyroid tissue or metastatic disease. When the thyroglobulin level after the total thyroidectomv is more than 40 rig/ml, most patients have distant metastases.81,102 Falsepositive increases in serum thyroglobulin levels usually caused by 974

Curr Probl Surg, December 1994

FIG. 15. A CT scan of the anterior tastases

in a patient

with

papillary

mediastinum thyroid cancer.

and

chest

demonstrates

pulmonary

me-

antithyroglobulin antibodies can occur but are very rare. For virtually all patients with thyroid carcinoma of follicular cell origin, except those with minimally invasive follicular tumors or occult papillary thyroid carcinomas, we recommend scanning with 2 mCi of lz31. For patients with radioactive iodine uptake, we recommend ablative treatment with 30 mCi for low-risk patients and 100 to 150 mCi for high-risk patients with no appreciable serum thyroglobulin level and no radioiodine uptake. An MRI or CT scan should be performed of the neck and anterior mediastinum in patients with elevated thyroglobulin levels, especially in high-risk patients (Fig. 151. Such scanning can detect an early recurrence that may be amenable to resection or external radiation therapy. Before reoperation, the previous operative and pathology reports should be reviewed for additional information about any remaining thyroid tissue, site of nodal metastases, position of the parathyroid glands, and the recurrent laryngeal nerve(s).The best means of minimizing recurrence and improving survival is adequate initial thyroidectomy combined with postoperative treatment with radioactive iodine ablation and TSH suppressive therapy.81~100~102~‘03~114~134 In paCurr

Probl

Surg,

December

1994

975

tients in whom less than total thyroidectomy has been performed for either benign or malignant thyroid lesions, the potential exists for residual or recurrent thyroid disease; the potential exists for cervical lymph-node metastases in the patients who have had malignant disease. Patients with prior thyroid operations are frequently denied repeat thyroid operations because of the fear of an increased risk of rate in patients undercomplications.134 Although the complication going reoperation is higher compared to initial operation, in the hands of experienced surgeons it is still low (less than 2% ).134,140,141 A complete lobectomy without dissection of the contralateral lobe at the initial operation facilitates reoperation because reexploration is usually not required on the side of previous dissection and the recurrent nerve and parath id lands on the opposite side are not obscured by scar tissue. PgBefore reoperation, vocal cord function should be evaluated by direct or indirect laryngoscopy to document any vocal cord dysfunction.

FOLLICLJLAR

CARCINOMAS

Pure follicular thyroid carcinoma is an uncommon tumor, occurring in 10% of thyroid carcinomas.11s The incidence appears to be decreasing in formerly endemic goiter areas where iodine intake has increased.’ Patients with follicular carcinoma are generally 10 to 15 years older than patients with papillary thyroid carcinoma. Most patients with follicular carcinoma are in their fifth or sixth decade of life. As with other thyroid tumors, follicular carcinomas are more common in women. Approximately 60% of patients with follicular carcinoma have an asymptomatic thyroid nodule.“’ Follicular carcinoma differs from papillary carcinomas in several ways. Follicular carcinomas are more often solitary as opposed to the multicentric nature of papillary carcinomas. Many follicular carcinomas are discovered in association with benign thyroid nodules and multinodular goiter and in areas of iodine deficien;?. Papillary carcinomas tend to occur in areas of high iodine intake. Follicular carcinomas tend to invade blood vessels and metastasize via hematogenous routes to distant sites, most commonly bone, lung, and the brain. Patients &th papillary carcinoma may have nodal metastases without a palpable primary tumor, and patients with follicular carcinoma may have distant metastases before the primary tumor becomes clinically evident.’ The incidence of distant metastases in follicular carcinoma is as high as 33%.141 Cervical lymph node involvement in follicular carcinoma occurs in approximately 10% of patients, and when it does, it often appears to occur by direct invasion. 142-144Follicular carcinoma is less frequently associated with previous radiation exposure. Finally, although occult papillary carcinoma is common, occult follicular car976

Cur-r

Probl

Surg.

December

1994

FIG. 16. A photomicrograph nal magnification

demonstrates

follicular

cancer

with capsular

invasion.

(Origi-

x250.)

cinema is rare. This suggests that follicular carcinomas may begin as follicular adenomas. Interestingly, follicular adenomas are common and account for approximately 20% of thyroid nodules, whereas papillary adenomas are rare.14’ Histologically, the diagnoses of pure follicular carcinoma is difflcult .72 It is a carcinoma composed of follicles with no papillary structures (Fig. 16). Unlike papillary carcinomas, follicular carcinomas are well-encapsulated tumors, the cells of which contain non-vesicular nuclei compared to the ground-glass nuclei of papillary tumors. No psammoma bodies occur in follicular carcinomas, Some patients have a follicular variant of papillary carcinoma, and as many as 20% of patients with thyroid carcinomas classified as follicular carcinomas actually have this variant. The follicular variant of papillary carcinoma is composed primarily of follicles, but the cells contain ground-glass nuclei, and the biologic behavior is similar to papillary carcinomas1 (Fig. 7). Although follicular neoplasms can be identified on cytologic specimens from FNA biopsies, it is generally not possible to distinguish between a follicular adenoma (no capsular or vascular invasion) and a follicular carcinoma without examining the removed specimen. Several studies have examined the risk factors influencing the prognosis of patients with follicular cancer.72,142-144 The most consistently cited independent predictive variable for postoperative distant metastases and survival is the degree of tumor invaCurr

Probl

Surg,

December

1994

977

sion into blood vessels and, to a lesser degree, tumor capsule at the time of ~agnosis.53,64,142,146 Angioinvasion in particular appears to be a strong independent predictor of outcome.141,144 Two other important factors adversely affecting prognosis include older atient age and the presence of distant metastases at diagnosis.53,64,14 r j146Lymph node involvement,53”46 extrathyroidal invasion,120’146 local recuruptake of radioiodine, adenylate cyclase rerence,53 aneuploidy, sponse to TSH,147 and expression of epidermal growth factor (EGF) receptors also provide useful information for predicting tumor aggressiveness. Our recommendation for surgical treatment of follicular thyroid neoplasms is the following. A cytologic result of follicular neoplasm on a FNA biopsy of a thyroid nodule in a euthyroid patient is usually an indication for a diagnostic thyroid lobectomy and isthmusectomy. If the serum TSH level is suppressed, an 1311 scan is indicated because hot nodules are almost never cancer; thus the patient can be followed. Unfortunately, frozen section diagnosis is often unreliable for follicular and Hiirthle cell neoplasms. In patients found to have follicular carcinomas over 1.0 cm in size with angioinvasion or more than minimal capsular invasion, a completion thyroidectomy is performed. Radioactive iodine scanning and ablation of any remaining areas of uptake are also performed. If permanent section reveals a folbcular carcinoma less than 1.0 cm or a tumor with minimal invasion, no further therapy is needed. The rationale for total thyroidectomy in patients with follicular carcinoma is essentially the same as for papillary carcinoma. The key difference is that, although follicular carcinoma is solitary, unlike the multicentric nature of papillary carcinoma it has a higher incidence of distant metastases especially to the lung and bone. Total thyroidectomy facilitates radioactive iodine ablation of any distant metastases especially when small metastases occur in the 1ung.14’ After surgery, patients are treated with sufficient thyroid hormone to suppress TSH production because this appears to lower the recurrence rate~34.143,14s,149 Monitoring of serum thyroglobulin levels, as in patients with papillary carcinoma, is a sensitive and specific method for detecting persistent or recurrent disease.15’ Again, the best time to determine the serum thyroglobulin level is when serum TSH levels are elevated when patients are hypothyroid in preparation for scanning or ablation therapy.

HijRTHLE

CELL NEOPLASMS

Considerable logic diagnosis 976

OF THE THYROID

controversy has surrounded the cytologic and pathoof Hiirthle cell adenomas and carcinomas since the Curr

Probl

Surg,

December

1994

last CURRENT PROBLEMS IN SURGERY in 1978. At that time, Thompson and colleagues1 recommended total thyroidectomy for any Hiirthle cell neoplasm larger than 2 cm in diameter because of the difficulty in distinguishing benign from malignant tumors by histologic criteria. Several reviews in the past decade have further elucidated the histologic criteria that can help to distinguish benign from malignant Hiirthle cell neoplasms and have thus shown hemithymidectomy to be curative for the vast majority of patients with benign neoplasms on permanent section.151’152 Most patients with Hiirthle cell neoplasms are seen during the fifth and sixth decades of life with a range from 2 months to over 80 years of %e.151,153 More than 60% of these patients have a thyroid The nodules are usually nonfunctioning on radionumass. 152~154-156 elide scan, single in 86% of patients, and multiple in 14% of patients.l’l A history of previous head and neck irradiation is given in 1.5% to 39%.lS2 156J57 These patients appear to have an increased incidence of Hiirthle cell neoplasms and up to a 40% incidence of synchronous follicular or papillary carcinoma.157’158 At presentation, 70% of patients have disease confined to the thyroid; 20% of patients have lymph node involvement; and 10% of patients have distant metastases.153 The most common metastatic sites, in order of frequency, are cervical lymph nodes, lung, bone, the central nervous system, and mediastinal lymph ,nodes.156 Survival is shorter for women. Capsular invasion and solid pattern of growth predict a more aggressive tumor.156 Tumor size does not help to differentiate benign from malignant neoplasms or predict tumor aggressiveness and s~rvival.~~~~~~~ The histogenesis of the Hurthle cell tumors is confusing because they have characteristics that suggest they may originate from follicular or parafollicular cells. The confusion began in 1894 when Hiirthle described the parafollicular C cell in the dog, acknowledging that Baber had described this cell in the thyroid gland of several laboratory animals in 1877.15s”60 In 1919, Ewing incorrectly described a thyroid tumor as a “Hiirthle cell tumor” based on Hiirthle’s description.16’ However, Langhans had already described this tumor in 1907 as “wuchernde Struma” and noted the distinct cell it contained was originally described by Askanazy in 1898.‘61-163 A variety of names have since developed for Hiirthle cell tumors, including oncocytoma, oxyphil tumor, mitochondrioma, and Askanazy cell tumor, but Hiirthle cell tumor is used most frequently. By light microscopy the Hurthle cell is a round, frequently polygonal cell with eosinophilic, finely granular cytoplasm representing abundant mitochondria by electron microscopy.164 Hiirthle cells have distinct cytoplasmic membranes and round, hyperchromatic eccentrically placed nuclei with irregular chromatin.164’165 Electron microscopic examination reveals Cum

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1994

979

FIG. (Original

17.

A photomicrograph magnification x250.)

demonstrates

a Hijrthle

cell

cancer

with

vascular

invasion.

the cytoplasm is almost completely filled with mitochondria, a large number of lysosome-like dense bodies, and dilated Golgi zones confined to the apical portion of the cytoplasm.165J166 Nodules of nonencapsulated, hyperplastic Hiirthle cells are found in thyroid glands with Hashimoto’s thyroiditis, Graves’ disease, and nodular goiter. These represent metaplasia and have no malignant potential.ls3 Hiirthle cells involved in neoplastic lesions are usually solitary and encapsulated. The Hiirthle cell is generally accepted to be a variant of the follicular cell, yet some former data suggested that they may arise from parafollicular C cells.167,168 Similarities between Hiirthle cells and follicular cells include the inability to distinguish adenoma from carcinoma by cytologic examination and the need for evidence .of angioinvasion (Fig. 171, capsular invasion, or metastatic disease for the diagnosis of malignancy. Unlike parafollicular cells, most Hiirthle cell and follicular neoplasms have TSH receptors and respond to TSH stimulation with an increase in adenylate cyclase activity?” Most Hiirthle cell and follicular neoplasms produce thyroglobulin, whereas C cell or arafollicular cells make thyrocalcitonin and not thyroglobulin.f6s~17 B Aas oncogene activation has also been documented in both follicular and Hiirthle cell tumors but is uncommon or rare in medullary thyroid carcinomas.170-17z Despite these similarities between Hiirthle cell neoplasms and follicular neoplasms, several differences are clinically important. Follicular tumors take up 980

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Sur5

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1994

radioiodine frequently, and Hiirthle cell tumors rarely take up radioiodine; however, Bondeson and colleagues16s reported two patients with Hiirthle cell carcinoma lung metastases that did accumulate radioactive iodine, and we have had a patient with radioactive iodine uptake in a breast metastasis. Hiirthle cell carcinomas are sometimes bilateral and multiple, like papillary and medullary thyroid carcinoma, whereas these characteristics are infrequent in follicular carcinoma.152 Cervical lymph-node metastases are common in patients with Hurthle cell, papillary, and medullary thyroid carcinoma but uncommon in patients with follicular carcinoma. ‘la DNA ploidy is useful to predict the aggressiveness of Hiirthle cell, papillary, and medullary thyroid carcinoma but less predictive for follicular cancer.118J173 Clearly most studies document that the Hiirthle cell is a variant of the follicular cell, yet its malignant characteristics distinguish it from the follicular cell. The ability to separate a Hurthle cell adenoma from a Hiirthle cell carcinoma with morphologic criteria has been a controversial issue since Langhans described the tumor in 1907. Frazell and D~ffyl~~ in 1951 and Horn17’ in 1954 were the first to attempt to distinguish benign from malignant tumors using defined microscopic criteria. They both identified a few false negatives in the benign group and concluded that microscopic criteria were inadequate to distinguish benign from malignant. In 1974, Thompson and colleagues176 supported these conclusions by showing that three of *four patients with Hurthle cell tumors classified as benign died of Hurthle cell carcinoma. Based on this high rate of false negatives in the benign group (75%) and a correlation between increasing tumor size and malignancy, the authors recommended total or completion thyroidectomy for all Hiirthle cell neoplasms larger than 2 cm.17” These conclusions have prompted several reviews over the past 10 years including more than 800 patients with Hiirthle cell neoplasms.151J156 With strict microscopic criteria, these studies have shown that, based on no invasion of the veins or capsule, cancer will develop in fewer than 1% of patients classified as having Hiirthle cell adenomas. Carcangiu and criteria benign, indeterco11eagues156 defined the strict microscopic minate, or malignant tumors as follows: “Malignant lesions exhibited obvious capsular invasion, obvious blood vessel invasion, or (for the nonencapsulated tumors) invasion of the surrounding thyroid or extrathyroid tissues. Tumors were designated as indeterminate when they lacked the above features but exhibited one or more of the following: minimal capsular invasion, questionable blood vessel invasion, predominantly solid pattern of growth, marked nuclear atypia, or extensive necrosis. Tumors were designated as benign when they lacked the histologic features that defined the malignant and the indeterminate categories. For the process to qualify as obvious capsular invasion, interruption of the capCurr

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December

1994

981

sule had to be full thickness. Penetration by the tumor of the inner aspect of the capsule or presence of tumor island embedded within the capsule was defined as minimal capsular invasion and not regarded by itself as a definite sign of malignancy. To qualify as obvious blood vessel invasion, the vessel had to be of venous caliber, be located in or immediately outside the capsule (rather than within the tumor mass), and contain a cluster of tumor cells attached to the wall and protruding into the lumen. Tumor cells located in spaces within the capsule were considered to represent questionable vascular invasion when a similar change was observed but not all of the above criteria were met.” Carcangiu and colleagues156 and Grant and colleagues151 concluded that histologic criteria alone can accurately distinguish between benign and malignant neoplasms and that routine total thyroidectomy for benign neoplasms is not justified. In a third review by McLeod and colleagues153 in 1990, two explanations are offered for the disparate data Iiom his studies compared with the others. It is possible that the referral pattern to the University of Michigan is highly selective for Hiirthle cell tumors with more aggressive biologic behavior, and the improvement in histopathologic definition for these tumors over the past 15 years has led to more reliable classification. Because of the anxiety created due to the occasional inaccuracy of the histologic findings, investigators have tried using DNA analysis to predict whether a Hiirthle cell neoplasm will behave in a benign or a malignant manner. Most studies suggest that nuclear DNA content or ploidy alone does not distinguish between benign and malignant Hiirthle cell neoplasms. Hiirthle cell carcinomas with a diploid DNA pattern, however, usually behave in a benign fashion, whereas aneuploid tumors are more likely to be lethal.‘73’177-‘81 Ultrastructural studies,16431SZ immunohistochemical studies,164,170 presence of the r-as oncogene p21 antigen, and the adenylate cyclase response to TSH118,13s have unfortunately been unable to differentiate benign from malignant Hiirthle cell neoplasms. FNA is useful for diagnosing the presence of Hiirthle cells but is not useful in distinguishing between benign and malignant neoplasms. Physical examination, radioisotope scans using thallium or sestamibi, or more accurately, 10 mHz ultrasonography can identify bilateral or multifocal lesions and can occasionally identify regionally involved lymphadenopathy.151J183 Radioisotope scans are unfortunately not helpful in distinguishing between benign and malignant Hiirthle cell neoplasms unless metastatic disease is identified. The general agreement now is that a patient with a Hiirthle cell neoplasm by FNA should have this tumor removed because 15% to 20% will be cancerous. We recommend treating patients with Hiirthle cell neoplasms in the same manner as patients with follicular neoplasms. All patients with a suspicious thyroid nodule and patients who are found to have Hiirthle 9.92

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December

1~4

cells on FNA cytology should undergo an initial total lobectomy and isthmusectomy. If the lesion appears to be benign by frozen section examination and no adjacent ipsilateral adenopathy is found, the treatment is complete. This is adequate treatment if the final pathologic evidence reveals a benign Hurthle cell adenoma. If the final pathologic evidence reveals a carcinoma, a completion total thyroidectomy should be performed. Total thyroidectomy should also be performed for patients with Hurthle cell carcinomas on frozen section. Because of the 10% to 40% incidence of lymph node involvement, we recommend a routine ipsilateral central neck dissection. A modified lateral neck dissection is recommended for patients with clinically enlarged nodes. We also recommend total thyroidectomy for patients with a Hurthle cell neoplasm on FNA and a history of head and neck irradiation. Nearly 40% of these patients have cancer, and knowing where the cancer is situated within the thyroid gland is difficult. We recommend postoperative thyroid suppressive therapy for all patients with Hurthle cell carcinoma because many of these tumors have TSH receptors and usually make thyroglobulin.‘58 Although most Hurthle cell carcinomas fail to take up radioiodine, approximately 10% do, and some metastatic lesions have been treated successfully with radioiodine ablation.‘84 Radioiodine ablation has the additional benefit of destroying any thyroid& remnant. Sestamibi or thallium scans also appear useful for detecting residual or metastatic disease.“’ An MRI or CT scan is performed when there is no radioiodine uptake. To date, no successful results have been obtained with chemotherapy.‘80”84.‘85 External radiation is palliative and is recommended for patients whose tumor cannot be completely excised and for patients with bone metastases.1559*74J184 In conclusion, benign Hurthle cell neoplasms can almost always be distinguished from malignant neoplasms with a set of well-defined microscopic criteria. Patients with a thyroid nodule and Hiirthle cells on aspiration cytology should undergo a diagnostic total lobectomy and isthmusectomy. For a benign neoplasm on final pathologic examination, no further operation is necessary; but for a malignant lesion, total thyroidectomy with central neck dissection should be performed. TECHNIQUE

OF THYROIDECTOMY

Several surgical procedures have been used in the treatment of thyroid tumors, and their indications have been discussed. We propose the following definitions: Lumpectomy-removal rounding thyroid Curr

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December

of the nodule tissue. 1994

alone with minimal

sur983

Partial thyroidectomy-removal of the nodule with a larger margin of surrounding thyroid tissue. Subtotal thyroidectomy-bilateral removal of more than one half of the thyroid gland on each side plus the isthmus. Lobectomy or hemithytoidectomycomplete removal of one thyroid lobe and the isthmus. Near total thyroidectomytotal lobectomy and isthmusectomy, leaving less than 10% of the posterior lateral portion of the contralateral lobe. Total thyroidectomy-removal of both thyroid lobes and isthmus. All thyroid nodules that are diagnostic of cancer by FNA, all discrete thyroid nodules in patients with a history of exposure to lowdose therapeutic radiation, and thyroid nodules in patients who have a family history of medullary carcinoma of the thyroid should be removed by total or near-total thyroidectomy. Near-total thyroidectomy is preferable to total thyroidectomy when protection of the parathyroid glands or the recurrent laryngeal nerve is necessary. Indirect laryngoscopy should be performed on patients who have had previous thyroid or parathyroid operations or who have hoarseness or a change in the quality of their voices. Indirect laryngoscopy is performed because a patient may have vocal cord paralysis with a normal voice. This is important because it is occasionally necessary to sacrifice a recurrent laryngeal nerve, and one would be extremely reluctant to do this if the opposite recurrent nerve were not functioning because the patient would need a permanent tracheostomy. All patients should be euthyroid at the time of operation and otherwise prepared as for any procedure requiring general anesthesia. After the induction of general anesthesia, the patient is placed in a low Fowler position with the neck hyperextended by a sandbag placed under the shoulders and upper back. This hyperextension of the neck moves the thyroid gland anteriorly and out of the mediastinum. The head must be well supported or severe posterior neck pain may occur. Approximately 20 degrees of reverse Trendelenburg should be obtained. The skin is prepared with 1% iodine. A Kocher transverse incision paralleling the normal skin lines of the neck is made 1 cm caudad to the cricoid cartilage because this places it precisely over the isthmus of the thyroid gland. In general, the incision extends from the anterior border of one sternocleidomastoid muscle to the other and through the platysma muscle. The upper flap is mobilized by placing five straight Kelly clamps on the dermis and platysma muscle and subcutaneous tissues and dissecting to the level of the thyroid cartilage. In a similar fashion, the lower flap is mobilized in a caudal direction to the level of the suprasternal notch. The thyroid gland is then exposed by a midline incision 984

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December

1994

through the superficial layer of deep cervical fascia between the strap muscles extending from the suprasternal notch to the thyroid cartilage. On the side of the thyroid nodule, the more superficial sternohyoid muscle is separated from the underlying sternothyroid muscle. This dissection can be performed by blunt dissection and should be carried laterally until one sees the ansa hypoglossal nerve situated on the lateral edge of the sternothyroid muscle and on the medial side of the internal jugular vein. Dividing these strap muscles is usually not necessary, but if they are adherent to the underlying thyroid tumor, the portion of the adherent muscle attached to the tumor should be sacrificed and allowed to remain attached to the thyroid. The sternothyroid muscle is then dissected free from the thyroid and prethyroidal fascia by blunt dissection until the middle thyroid vein or veins are encountered. This dissection is facilitated by retracting the thyroid lobe medially with a moist gauze, and the strap muscles and carotid sheath are retracted laterally. The middle thyroid vein is divided, and a silk suture is placed deeply through the thyroid gland for retraction. The suture should never be placed through the tumor, nor should the tumor be clamped. The upper pole is mobilized by continuing cephalad until the superior thyroid artery and veins are identified. These vessels should be individually identified, skeletonized, triple-clamped, ligated, and divided. The superior thyroid artery is doubly ligated because, if the clamp slips or the suture breaks or becomes dislodged, the retracted vessel is often difficult to identify and ligate. It is best to ligate the superior pole vessels individually on the capsule of the upper pole of the thyroid gland rather than higher to avoid injury to the external laryngeal nerve that usually runs on the middle of the cricothyroid muscle. The tissues posterior to the superior pole can now be easily swept from the thyroid gland by blunt dissection. One must remember that the upper parathyroid gland is usually situated at the level where the recurrent laryngeal nerve enters the cricothyroid muscle. The area cephalad to the cricoid cartilage is a relatively safe area because the recurrent laryngeal nerve enters the cricothyroid muscle below the cricoid cartilage. The external laryngeal nerve (“high-note” nerve) is the motor branch of the superior laryngeal nerve and is responsible for tensing the vocal cords. Injury to this nerve occurs in up to 10% of patients, and because it is usually about the size of a single strand of spider web, it is usually best to avoid it. In most patients the external laryngeal nerve runs in the fascia of the cricothyroid muscle, but in about 15% of patients it may loop down with the superior pole vessels. The best way to avoid injury to the external laryngeal nerve is to provide gentle traction on the thyroid gland in a caudal and lateral direction and to ligate the superior pole vessels individually rather than cross clamp the entire superior pole pedicle. The fascia between the thyroid gland medially Curr

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December

1994

986

and the cricothyroid muscle (anterior superior suspensory ligament) can be divided; and the pyramidal lobe, if present, can be removed. The right and left recurrent nerves must be preserved during every thyroid operation. Both netves enter at the posterior medial position of the larynx in the cricothyroid muscle just above the cricoid cartilage, but the course of the two nerves varies considerably. The right recurrent laryngeal nerve takes a more oblique course than the left recurrent laryngeal nerve and may pass anterior or posterior to the inferior thyroid artery. In approximately 1% of persons, the right recurrent nerve is nonrecurrent and may enter the thyroid from a superior or lateral direction. Both recurrent laryngeal nerves may branch before entering the larynx; this occurs more frequently on the left side. This is important to recognize because all of the motor fibers of the recurrent laryngeal nerve almost always run in the tracheoesophageal groove because of its deeper origin from within‘the thorax. To identify the recurrent laryngeal nerves, one must remember that they are supplied by a small vascular plexus, and a tiny vessel runs parallel with the nerve directly on it. In young persons, distinguishing between an artery and the recurrent laryngeal nerve is usually easy; but in older persons with arteriosclerosis, the “white” artery may be mistaken for a nerve, and the nerve may be injured because it was presumed to be identified in a different position. It is usually safest to identity the recurrent laryngeal nerve low in the neck and then follow it to where it enters the cricothyroid muscle through the ligament of Berry. The recurrent laryngeal nerves can usually be palpated through the surrounding tissue in the neck before they can be seen. Another technique is to dissect carefully along the edge of the thyroid. No tissue should be divided until one is sure it is not the recurrent nerve. In patients with extensive thyroid tumors or in patients requiring reoperation, extensive scarring is often present, and it is best to identify the recurrent laryngeal nerve from a medial approach by dividing the isthmus with colodny clamps and ligating and dividing the superior thyroid vessels, By carefully dissecting the thyroid off the trachea, one can identify the recurrent laryngeal nerve where it enters the cricothyroid muscle. The most difficult part of the dissection during a thyroidectomy involves the ligament of Berry (posterior suspensory ligament). This ligament is situated at the posterior lateral portion of the thyroid gland just caudal to the cricoid cartilage. A small branch of the inferior thyroid artery traverses the ligament, as do one or more veins from the thyroid gland. If bleeding occurs during this part of the dissection, it should be controlled by pressure with a gauze pad. Nothing should be clamped in this area until the recurrent laryngeal nerve is identified. 986

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December

19%

Most individuals have four parathyroid glands situated on the posterior lateral capsule of the thyroid. The upper and lower parathyroid glands are supplied by both the inferior and the superior thyroid arteries. The upper parathyroid glands are usually lateral to the recurrent laryngeal nerve at the level of the ligament of Berry and are the glands that are usually the easiest to preserve during thyroidectomy because of their more lateral and posterior position. The lower parathyroid glands are almost always situated anterior to the recurrent laryngeal nerves and caudal to where the recurrent laryngeal nerve crosses the inferior thyroid artery. The parathyroid glands should not be mobilized extensively or they will be devascularized during the dissection. When a parathyroid gland cannot be safely dissected free of the thyroid gland, it should be removed, confirmed by frozen section, and then autotransplanted into the contralateral sternocleidomastoid muscle. There is no reason to perform a biopsy on normal appearing parathyroid glands during thyroid surgery because this obviously subjects them to injury. Rarely, thyroid carcinomas may invade the trachea or esophagus (Fig. 18). Up to 5 cm of trachea can be resected safely. If the invasion is anterior and small, a tracheostomy may be placed at the site of resection. When the invasion is lateral or posterior, one or two Penrose drains can be left near the resection site to serve as an exit for air. The Penrose drains are removed after several days when no more evidence of air leakage exists. Occasionally, it isnecessary to resect several centimeters of trachea. In these cases, the recurrent laryngeal nerves should be mobilized from the trachea, and the myelohyoid fascia and muscles should be divided above the thyroid cartilage. Care must be taken to avoid injury to the internal laryngeal nerves. The trachea is resected and re-approximated with 3-O Maxon (Davis and Geck, Wayne, NJ.) sutures. When lymph nodes are enlarged in the lateral neck and subsequently prove to be cancer on frozen section, a modified neck dissection is performed through a lateral extension to the anterior margin of the trapezius muscle (MacFee extension). The jugular vein, spinal accessory nerve, and sternocleidomastoid muscle are preserved unless they are directly adherent to or invaded by tumor. A median sternotomy is rarely necessary for removal of the thyroid gland because the blood supply to the thyroid gland and thymus is primarily through the inferior thyroid arteries in the neck. Metastatic lymph nodes frequently extend inferiorly in the tracheoesophageal groove into the superior mediastinum. These nodes can almost always be removed through a cervical incision without a sternotomy. Rarely, metastatic nodes may spread to the aortic pulmonary windows. When a median sternotomy is necessary, one should divide the sternum to the level of the third intercostal space and then laterally on one side at the space between the third and fourth ribs. Curt- Probl

Surg,

December

1994

987

FIG. 18. A papillary

988

CT scan of the neck (A) and a photomicrograph (B) in a patient cancer demonstrate invasion into the trachea. (Original magnification

Curr

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Surg,

with recurrent x2.50.)

December

1994

On completion of a thyroid operation, the sternothyroid muscles are approximated, leaving a small opening in the midline at the suprasternal notch to allow for the egress of blood and to make bleeding more evident. The sternohyoid muscles and the platysma muscle are similarly approximated. The skin is then closed with butterfly clips. A sterile pressure dressing is applied. Complications include seroma, hemorrhage, keloid formation, ischemic or’traumatic injury or removal of the parathyroid glands, injury to the external laryngeal nerve with inability to sing high notes, and injury to the recurrent laryngeal nerve with transient or permanent hoarseness. After the operation, the patient is kept in a low Fowler position with the head and shoulders elevated 10 to 20 degrees for 6 to 12 hours to keep a negative pressure in the veins. The patient may resume eating within 3 to 4 hours, and an antiemetic such as prochlorperzine maleate is ordered as needed because many patients experience postoperative nausea and emesis. The serum calcium level is measured approximately 5 to 8 hours after the operation and again on the first and, if still hospitalized, second mornings after thyroidectomy. Patients are given oral calcium supplements if the serum calcium is below 7.5 mgdl or if they experience perioral numbness or tingling. The serum phosphate level is also determined; if it is low there is less concern about hypoparathyroidism, whereas if it is high (>4.5 mgdl) one must be concerned about permanent hypoparathyroidism. Patients are discharged with a presc;ption for L-thyroxine (0.1 mg to 0.2 mg/day orally) and told to take calcium tablets for any tingling or muscle cramps.186”87 PROGNOSTIC

FACTORS

To better predict survival, several prognostic factors for differentiated thyroid cancer have been studied, including age, gender, histopathologic features, extent of primary tumor, lymph node status, and the presence of metastases. Although some of these factors are identifiable before the operation (age and gender), others are identifiable at operation or after the operation (extent of primary tumor, nodal status, and distant metastasesl. The clinical importance of identifying significant risk factors is to use this information to select the extent of operation required and to select appropriate postoperative radioactive iodine therapy for optimal outcome. The concept of prognostic factors in thyroid cancer was first described in 1954, by Sloanl” and McDermott and colleaguesl” when they identified age as a prognostic factor. In 1979, Byar and the European Organization for Research on Treatment of Cancer (EORTC) Thyroid Cancer Cooperative Gro~p’~~ developed a prognostic index based on a multivariate analysis of 507 patients with thyroid cancer. Curr

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1994

989

Also in 1979, Cady and co11eagues135 reviewed 600 patients with primary differentiated thyroid cancer and confirmed previous studies documenting that the recurrence rate and death rate were different in risk groups, based on age and gender. In 1987, Hay and colscoring system based on patient leagues1so described a prognostic age, tumor grade, extent, and size (AGES). In 1988, Cady and colsuggested a classification similar to that proposed by Hay leagues”’ and colleagues.1so They suggested the acronym AMES for age, metastases, extent, and size. An even simpler classification was defined by Degroot and colleagues’ (class I-tumor confined to the thyroid; class II-nodal involvement; class III-local invasion; and class IVdistant metastases). The EORTC multicenter experience in 507 patients with all histologic types of thyroid cancer, including medullary and anaplastic, identified the following important prognostic factors: age, gender, principal cell type, extrathyroidal invasion, and the presence of distant metastases. Based on the regression coefficients from the model, the following scoring system was devised for assigning patients to prognostic risk groups: Age at diagnosis +12 if male i-10 if medullary or if poorly differentiated follicular +45 if principal cell type is anaplastic +lO if T-category in TNM classification is T, +15 if there is at least one distant metastatic site +15 in addition to the above if multiple distant metastatic exist.

sites

The prognostic index (PI) was the sum of these points. Based on the PI, five risk groups were formed and correlated with 5-year survival. A total score less than 50 was associated with 95% five-year survival, whereas only 3% of patients with a score greater than 109 survived 5 years. Intermediate scores were associated with intermediate survival rates. One marked finding of this study was that 94% of patients in the risk group with a score greater than 109 had anaplastic tumors. Most investigators would exclude medullary and anaplastic thyroid cancers from their classification because medullary thyroid cancers are of different cell origin and virtually all patients with anaplastic tumor die of this tumor. In 1985, Tennvall and colleagues11s questioned the validity of the EORTC study for having a short median follow-up of 3.3 years and including all histologic types of thyroid carcinoma. These authors studied the clinical validity and reproducibility of the EORTC prognostic index by using multivariate analysis on 226 patients with differentiated thyroid carcinomas, with a median follow-up of 11 years. 990

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December

1%k1

Age at diagnosis, locally advanced disease, and distant metastases were reproducible as important prognostic factors, but gender was not found to influence sutvival. This, however, was probably because of the relatively small number of patients; numerous other studies suggest that thyroid cancer is more aggressive in men.7s~100~107~1so Cady and colleagues135 in 1979 reviewed the cases of 600 patients treated for primary differentiated tfollicular and papillary) thyroid carcinoma between 1931 and 1970 with a minimum follow-up of 15 years. They found that age and gender outweighed the effect of pathologic type, local disease extension, type of treatment, and site of recurrence or metastasis. These risk groups (age and gender) were used to define low-risk (male, <40 years; female, <50 years) and high-risk (all older patients) groups. Recurrence and death rates in patients at low risk were 11% and 4%, respectively; in patients at high risk, the recurrence and death rates were 33% and 27%. These results improved among a group of 309 patients studied from 1961 to 1980,1s1 such that the recurrence and death rates were 4.2% and 1% in the low-risk group and 19.7% and 15.4% in the high-risk groups, respectively. The surgical philosophy included less than total thyroidectomy with thyroid suppressive therapy, but minimal use of radiotherapy.135 These authors also reviewed 97 patients with surgically incurable well-differentiated carcinoma and found survival correlated better to risk group (age, gender) classification than to any details of disease presentation or management.1sz In 1988, Cady and colleagues,l ’ prompted by publication of the AGES classification (Hay), reanalyzed 821 patients treated for papillary and follicular thyroid cancer from 1941 to 1980. Included in the low-risk group were younger patients without distant metastases (men, 140 years of age; women, 150 years of age) and older patients with primary cancers less than 5 cm in diameter confined to the thyroid gland if papillary and displaying only minor tumor capsular invasion if follicular cancer. The high-risk group included all patients with distant metastases, primary cancers 5 cm in diameter or larger regardless of extent of disease and all older patients with extrathyroidal extension of papillary cancer or follicular thyroid cancer with major capsular invasion.lo7 In the last 20 years of the study, 89% of the patients were in the low-risk group, and 22% of these patients were treated by thyroid lobectomy, with a death rate (1.6%) nearly identical to that of patients who underwent bilateral operations (1.8%). Among the 11% of patients in the high-risk group, 46% died of thyroid cancer. The ratio of death rates was 26 : 1. These authors advocated a unilateral operation without postoperative radioiodine ablation in low-risk patients because of the decreased surgical morbidity and because of the lack of improved survival with more extensive procedures. In addition, recurrences developed in only 5% of these patients, and most could again be treated with surgical therapy.lo7 Curt- Probl

Surg,

December

1994

991

McConahey and colleagues1Y3 retrospectively analyzed the survival of 859 patients with papillary cancer diagnosed between 1946 and 1970 and suggested the AGES classification.‘g0 The scoring for the AGES classification is as follows: 0.05 X patient age if 40 or older + 1 if grade 2, + 3 if grade 3 or 4, + 1 if extrathyxoidal (direct invasion only, not metastatic cervical nodes), + 3 if distant metastases + 0.2 X maximum tumor diameter in centimeters. In 1990, Hay and colleagueslg4 applied this scoring system to a total of 1500 patients diagnosed with papillary cancer between 1945 and 1985. The patients were divided into four groups, and patients with an AGES score less than 3.99 group 1) had a 20-year mortality from papillary thyroid cancer of only 1%. Mortality rates rose with the AGES score such that those patients with a score of 4 to 4.99, 5 to 5.99, and 6 or greater had mortality rates of 20%, 67%, and 87%, respectively. Hay and colleagues1g5 revised this classification in 1993 by adding the completeness of tumor resection at primary operation. This study group comprised 1779 patients with papillary thyroid cancer (followed for >26,000 patient-years), divided by treatment dates into 1940 to 1964 (n = 764) and 1965 to 1989 (n = 1015). The new prognostic model was derived from the training set (1940 to 1964) and validated externally with the later (1965 to 1989) ‘test’ data set. The final model included five variables abbreviated by metastasis, age, completeness of resection, invasion, and size (MACIS). The final prognostic score was defined as: MACIS = 3.1 (if age <39 years) or 0.08 X age (if >40 years of age), + 0.3 X tumor size (in centimeters), + 1 (if incompletely resected), + I (if locally invasive), + 3 (if distant metastases present). Wenty-year cause-specific survival rates for patients with MACIS less than 6, 6 to 6.99, 7 to 7.99, and 8+ were SS%, 89%, 56%, and 24%, respectively (p < 0.0001). The TNM staging system “‘J’~ describes the anatomic extent of disease based on the extent of the primary tumor (Tl, the absence or presence and extent of regional lymph-node metastases (Nl, and the absence or presence of distant metastases (M).*s6 This staging system also incorporates both the histologic diagnosis and the age of the patient using age 45 years for both men and women to help separate low- and high-risk groups. Three variables, common to all the risk groups except the Degroot classification (EORTC, AGES, MACIS, AMES, TNM), include the patient’s age, local invasion, and distant metastasis. Tumor size is common to all the risk groups except the EORTC and Degroot schemes, Only the EORTC and the AMES classifications include gender as a significant predictive variable. The AGES score is the only scheme that includes histologic grade, and this was replaced by completeness of resection in the MACIS score. Hay and colleagues ls4 reported a comparison of the EORTC, TNM, AGES, and AMES scores on the Mayo cohort of 1500 patients. These authors separated the 992

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1994

1500 patients into low- and high-risk groups based on each scheme. High-risk patients were defined as having an EORTC score of more than 66, TNM stage III and IV, AGES score of more than 4, or AMES high risk and amounted to 22%, 18%, 14%, and 12% of the 1500 patients, respectively. Cady’s mortality-rate ratio between high- and low-risk groups was then applied with the cause-specific mortality rate at 20 years. The ratios were 21: 1 for the EORTC scheme, 18: 1 for the TNM classification, 37: 1 for the AMES scheme, and 40: 1 for the AGES classification. Clearly, the separation of low- and high-risk groups is accomplished more effectively by the AMES and AGES classifications. The 20-year mortality rate for the low-risk groups were 1.0% (AGES) and 1.1% (AMES) and for the high-risk groups 40.3% however, that (AGES) and 40.8% (AMES).lg4 It should be mentioned, these are retrospective studies and placement in these groups depends on intraoperative and postoperative information in addition to preoperative information. Mazzaferri and colleagues76’7g’100 have reported a retrospective analysis of a cohort of 693 patients with papillary thyroid cancer diagnosed between 1958 and 1972 with a median follow-up of 10 years. Factors associated with recurrence included age (<20 and >701, size greater than 1.5 cm, local tumor invasion, regional lymph node involvement, and distant metastases. Regarding survival, males had a worse survival; no patients with tumors less than 1.5 cm in diameter died; and local tumor invasion, regional lymph node involvement, and distant metastases decreased survival. These observations and the results of several other I,eviews111~1zo~125~1s7~1s8 support the findings from Hay at the Mayo Clinic and Cady at the Lahey Clinic regarding the significance of prognostic factors for differentiated carcinoma of the thyroid gland. Other reports have identified other prognostic indicators that may help define patients at particular risk for aggressive thyroid cancer behavior. These include DNA ploidy as determined by flow adenylate cyclase response of the tumor to cytometry, 180~1s4~1gs-204 TSH stimulation, 13’ EGF receptor status,75,205 multifocal tumors, and the presence of oncogenes and tumor suppressor gene mutationS.137,138 DNA aneuploidy has been identified as a poor prognostic indicator by several investigators. 180~1g4~1sg-204 HayIs correlated DNA ploidy with the EORTC score, TNM stage, AGES score, and AMES risk group and found that patients with nondiploid DNA had a significantly increased cancer-related death rate. Our group has studied the importance of adenylate cyclase response to TSH in patients with thyroid cancers of different stages. The ratio of TSH stimulated to basal adenylate cyclase activity in thyroid cancers diminishes with advancing stage13’ (Fig. 191. This may reflect a degree of deditferentiation. Certain patients with stage I have a low TSH stimulated to basal adenylate cyclase ratio, which may represent a subset of patients with Curr

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SW-~, December

1994

993

‘IIT1

CEcimm stags

1

+ SEM

I

I

CEdlDlMlstage 2

l-e25

p<.oaM

mean

I

-

stags 3,4

rd

p<.w6

I.1

Crrdma-

I ( hldlllary

Cfmima

hll

PC.02

Id

I

FIG. 19. A graph

illustrates adenyfate cyclase responsiveness to TSH of patients with benign and malignant thyroid neoplasms. Patients with benign nodules showed a marked increase in “cyclase responsiveness” over normal tissue, and a progressive decline is seen in cyctase responsiveness with increasing stage and aggressiveness of the neoplasms. Analysis of variance reveals a significant trend with the staged carcinomas (p < 0 02) Medullary carcinomas that lack TSH receptors, as expected, show no response to TSH (TSH/basal cyclase = 1.05 + 0.04). (Reprinted with permission from Siperstein AE, Zeng QH, Gum ET, Levin KE, Clark OH World J Surg 1988;12:528-33 )

a poor prognosis. The status of epidermal growth factor receptors may also reflect tumor aggressiveness.75’205 Despite the excellent prognosis of patients included in the low-risk groups, total thyroidectomy with postoperative radioiodine ablative therapy is associated with the fewest recurrences and best prognosis 76J 7g,100 Studies by Massin and colleagues,114 Schlumberger and colleagues,‘l Lennquist,” Grant and colleaguesg7 and others document fewer recurrences and improved survival with more extensive initial treatment. It is difficult to argue against total or near-total thyroidectomy when this operation is performed safely.* TREATMENT

WITH

RADIOACTIVE

IODINE

Considerable controversy surrounds the use of radioactive iodine to scan for and ablate residual normal thyroid tissue or metastatic disease in patients with papillary and follicular thyroid cancer. Some ‘Refs. 394

3, 15, 76, 79, 81, 97, 98, 100,

102,

103,

114 Curr

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&n-g,

December

1994

of this controversy relates to whether one believes that total or neartotal thyroidectomy is necessary for the treatment of patients with papillary, follicular, and Hiirthle cell thyroid cancer. Although one can ablate normal thyroid tissue with radioactive iodine, our belief is that one should remove as much thyroid as possible so that smaller’ doses of radioactive iodine can be used to ablate the remnant tissue .lo3 This is especially important for patients who have metastatic disease where subsequent repetitive and often large doses of radioactive iodine are required to ablate the metastatic tumor~40~81~20” In 1937, Dr. Robley Evans at MIT, at the suggestion of Dr. J. Howard Means at the Massachusetts General Hospital, produced a radioactive isotope of iodine. Dr. Joseph Hamilton and colleagues at the University of California at Berkeley were the first to use radioiodine in patients. Hertz and Roberts”’ in 1946 treated 29 hyperthyroid patients with increasing doses of 13’I. Six of these patients required urgent thyroidectomy after treatment so that the therapeutic effectiveness was questioned. 1311, with a half-life of 8 days, was made available by the United States Atomic Energy Commission and was first used in a patient with thyroid cancer in St. Louis in 1946. Several factors influence the uptake of radioactive iodine within metastatic thyroid tumors. These include the amount of residual normal thyroid, serum TSH level, ambient serum iodine concentration, tumor type and differentiation, and patient age. Uptake within the thyroid tumors can be enhanced by limiting the amount of normal thyroid tissue, increasing TSH, giving more isotope, eating an iodine deficient diet, and perhaps by increasing the duration of elevated TSH. Schlumberger and colleagues81 documented that, in approximately two-thirds of patients with thyroid cancer, the metastatic thyroid cancer takes up sufficient radioactive iodine to be amenable to ablative therapy with 1311. Radioactive iodine is more effective at eradicating small foci of neoplastic thyroid tissue than ablating macrometastases. This suggests that, whenever possible, radioactive iodine should be used prophylactically (after total thyroidectomy when clinical cancer is not apparent) rather than therapeutically (when metastatic tumor is clinically documented]. Studies have shown that approximately 80% of patients with differentiated thyroid cancer have micrometastases in their lymph nodes at the time of thyroidectomy and approximately 10% to 15% have occult pulmonary metastases, despite no clinical evidence of tumor. 130,203 Although no prospective studies have concerned the merits of treating patients with differentiated thyroid cancer with radioactive iodine, numerous retrospective studies support its use. Mazzaferri and colleagues79’209 studied 576 patients with papillary thyroid cancer and found that, for lesions greater than 1.5 cm, the recurrence Cur-r

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996

rate was 13.1% when patients were not treated with postoperative radioactive iodine and 6.4% when they received 1311 (p < 0.001 by cox regression analysis). Leepe?’ reported a 5-year survival rate of 100% for patients with follicular cancer treated with radioactive iodine, whereas the survival rate was 33.3% in untreated patients. DeGroot and colleagues’ reported that patients with papillary thyroid cancers larger than 1 cm had fewer recurrences (p < 0.01) and fewer deaths (p < 0.05 by chi-square analysis) when treated with radioactive iometastases dine. Massin and colleagues114 reported that pulmonary developed in fewer patients and that fewer patients died when they were treated by total thyroidectomy and 1311. Schlumberger and colleagues” noted that patients whose pulmonary metastases were detected only by radioiodine scanning were likely to be successfully treated; whereas when macrometastases were identified on chest radiograph or CT scan, however, few patients could be cured. Thus when micronodular disease was present, the relative risk of death tripled; when macronodular disease was present, the relative risk of death increased six-fold. Further data supporting the prophylactic use of 13’ I for patients with differentiated thyroid cancer is provided by Wong and colleagues?11 Radioactive iodine reduced recurrence rates by 54%. The change in life expectancy gained by the ablation of thyroid remnants was approximately equal to that gained by lowering serum cholesterol levels to less than 200 mg/dl in 35-year-old adults or by coronary artery bypass in patients with two vessel coronary artery disease. Thus although Crilezl’ stated that postoperative thyroid suppression is equal in outcome to radioactive iodine for the treatment of patients with papillary thyroid carcinoma and Cady and colleagueP3 question its use, most data suggest that prophylactic treatment is therapeutically efficacious. Radioactive iodine is, unfortunately, less effective when metastatic thyroid cancer is clinically evident. For example, radioactive iodine is effective in treating nonpalpable cervical lymph node metastases, 7s~20sbut Wilson and Block214 reported that it is rarely effective in patients with palpable nodes. Maxon and colleagues~06S215 in contrast, reported a 74% success rate in treating nodal disease with 1311 when treating with relatively large doses. Maxon states that, when the projected radiation dose to the tumor is less than 300 Gy, he prefers surgical excision, but he does not state how often this occurs. Maxon and colleagueszo” analyzed the 5-year mortality in patients with pulmonary metastases as reported in the literature. The mortality rate was 38% in patients whose metastases concentrated radioactive iodine and 69% in those who did not (p < 0.001). Patients with skeletal metastases have an even poorer response to treatment with radioactive iodine, and the presence of bony metastases predicts an ominous prognosis. Only 7% of patients with bony metastases can be cured with radioactive iodine, but an additional 36% of patients 996

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1%~

will show some improvement after radioactive iodine treatment. Treatment with external radiation therapy or orthopedic surgery is often required.@ We recommend that when patients have cetical lymph nodes or pulmonary or skeletal metastases that can be completely removed surgically, the metastatic disease should be removed surgically. The patient should then receive a large ablative dose of radioactive iodine (approximately equal to 150 mCi). Serum thyroglobulin levels, especially when patients are hypothyroid in preparation for a radioiodine scan, are very useful in determining when a patient has persistent disease. Most nuclear medicine physicians with updated equipment use 2 mCi of lz31 to scan for metastatic disease after a patient has been off thyroxine (T& for at least 6 weeks and off triiodothyronine (T,) for at least 2 weeks. Preparation with a low-iodine diet for several weeks is also recommended. Diagnostic scans with 5 mCi of 1311 can cause thyroid stunning.~ Kung et a12’ reported that 40% of patients had a stunned thyroid after a scanning dose of 3 mCi; this increased to 67% after receiving 5 mCi and 89% after receiving 10 mCi. One half of the patients with such stunning of thyroid remnants failed to respond to 1311 subsequently. We and others generally recommend outpatient treatment with 30 mCi of 1311 for low-risk patients (young age; small, well-differentiated, localized tumors). For high-risk patients, we recommend hospitalization and treatment with 100 to 150 mCi of 1311. Maxon and colleagues215 noted successful treatment using up to 30 mCi in only 104 of 195 (53%) of cases. When they empirically gave 100 mCi, 248 of 287 (86%) of the patients were successfully ablated. They also reported a significant (p < 0.01) relationship between the completeness of the initial thyroidectomy and successful outcome. These physicians currently estimate the amount of 1311 that is delivered to the thyroid remnant and have documented that delivering approximately 300 Gy to residual thyroid or metastatic deposits is usually effective and there is little to no benefit of using larger doses4’ The salivary glands, bladder, parietal cells of the stomach, bone marrow, breast, and the thyroid are all exposed to significant radiation during radioactive iodine ablation. Several studies, but not all, have suggested a slight increase in leukemia and cancers of the stomach, salivary glands, kidney, and gonads.216 Such problems in a worstcase scenario would occur in approximately 4% of patients receiving 300 mCi and in approximately 10% of patients receiving 800 mCi or more .40 In summary, radioactive iodine is most effective given prophylactically (before a tumor is clinically apparent) but is fortunately sometimes effective therapeutically. Palpable cervical nodal metastases should be removed by a modified radical neck dissection, and isolated pulmonary and bone metastases should also be removed surgically. Radioactive iodine should then be given to ablate any remaining micrometastases. Serum thyroglobulin levels are useful (esCurr

Probl Surg, December

1994

997

pecially when the patient is hypothyroid) for documenting ence of persistent disease and suggests that scanning doses of 131I may be efficacious?17 SIGNAL TRANSDUCTION

the preswith large

AND ONCOGENES

Growth of the normal thyroid follicular cell is regulated by extracellular growth factors and inhibitors via cell surface receptors and intracellular signal transduction pathways. Each step in this pathway is regulated by certain genes and their products. Thus cell proliferation is regulated by growth-promoting proto-oncogenes (genes that are either overproduced or whose mutation results in an unregulated protein product), counterbalanced by growth-constraining tumor suppressor genes. Mutations in either of these may lead to unregulated cell growth. TSH released by the pituitary gland is the predominant stimulator of thyroid growth. Several other stimulators and inhibitors of thyroid growth exist (Table 5). Some of these growth factors, such as TSH, thyroid-stimulating immunoglobulin, and vasoactive intestinal polypeptide (VIP) work via the adenylate-cyclase protein kinase A signal transduction system. Others work via the phosphoinositide-protein kinase C system and still others work via tyrosine kinase (Fig. 20). The binding of TSH to its cell surface receptor induces a conformational change that results in the activation of the stimulator guanyl nucleotide protein (Gs). Activation of Gs in turn causes activation of adenylate cyclase, an enzyme that converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (CAMP). Cyclic AMP then acts as a second messenger to activate protein kinase A, which regulates a number of intracellular proteins via phosphorylation. There are inhibiting G proteins (Gil that, when stimulated, can cause decreased activation of adenylate cyclase. Investigation into the relationship between thyroid neoplasia and CAMP levels has shown that the growth of thyroid neoplasms may be driven by increased intracellular CAMP levels. This phenomenon has been well documented in thyroid cell membranes derived from patients undergoing thyroid surgery where basal levels of CAMP production have been shown to be increased in thyroid neoplasms.13’ In normal thyroid cell membranes, stimulation of the TSH receptor adenylate cyclase pathway by maximally stimulating concentrations of TSH results in a 2.5-fold increase in CAMP production. This is in contrast to thyroid neoplasms that may show as much as a IO- to 15-fold increase in CAMP production with TSH stimulation as compared to the basal state. When thyroid cancers are stratified by their stage, a progressive decrease occurs in cyclase responsiveness with increasing tumor aggressiveness; however, the absolute and relative levels of CAMP production in even the most aggressive cancers are 998

Cur-r Probl

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1994

TABLE

5. Thymid

gmwth

factors

Stimulators

Inhibitors

Thyroid-stimulating hormone WSHI Thyroid-stimulating bnmunoglobulins Epidermal gmwth factor (EGF) Insulin-like growth factors 1 & 2 (IGF) Fibrublast growth factor IFGF) Human chorionlc gonadotropin (HCG) Growth hormone (GH) Iodine deficiency Interleukin-1 (IL-11 Platelet-derived gmwth factor (PDGF) Pmstaglandin E, NE,) Vasoactive intestinal peptide (VIP) Vitamin C

(TSI)

Iodine Somatostatin Adenosine Lithium Alpha-adrenergib Transforming Vitamin

agents gmwth factor

beta

CTGF-p)

A

greater than that observed in normal thyroid tissue (Fig. 19). To date, four sites in the signal transduction pathway have been identified that may cause increased intracellular CAMP: overexpression of TSH receptors, mutation in the third intracytoplasmic loop of the TSH receptor, overexpression of the alpha subunit of the Gs protein, and a mutation of the Gs protein @p oncogene). Duh and colleaguesz18 showed a correlationbetween TSH receptor number and CAMP production in a large number of thyroid membrane preparations derived from human neoplastic thyroid tissues and a subset of patients had very high TSH receptor number and a marked increased CAMP production. Recently, a point mutation in the third intracytoplasmic loop of the TSH receptor was found in 3 of 11 follicular adenomas (hot nodules), and these point mutations were associated with high cAh4P production.21g However, no TSH receptors mutations have been found in thyroid carcinomas. Overexpression of the alpha subunit of the Gs protein was identified in a group of thyroid neoplasms that demonstrated the most marked increases in CAMP production with TSH stimulation.220 Point mutations in the alpha subunit of the Gs protein (gsp) have been identified in thyroid hot nodules221 and subsequently in papillary thyroid cancers with high basal cyclase levels.222 These mutations occur in the alpha subunit of the Gs protein at codon 201 or 227 and result in decreased GTPase activity, which traps the G protein in a state of constitutive activation and results in increased activation of adenylate cyclase. Although the above mechanisms that result in increased CAMP production may accelerate the growth of thyroid tissues, it is likely that abnormal expression of other signal proteins as a consequence of somatic mutations are also needed for thyroid tumorigenesis to occur. Four growth-stimulatory proteins (ras, gsp, ret and trk) and one inCurr

Probl

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1994

939

TSH

EGF

Protein Phqsphorylation / Nuclear

hernbrane c DNA

1

FIG. 20. A schematic diagram illustrates the TSH-adenylate cyclase (AC)-protein kinase A (PKA), TSH-phospholipase C (NC)-protein kinase C (PKC), and EGF-tyrosine kinase signal transduction pathways in a thyroid cell. ATP, Adenosine triphosphate; PIP,, phosphatidylinositol-4, 5-biphosphate; If3, inositol-1 , 4, 5-triphosphate; DAG, diacylglycerol; Ca, calcium. (Reprinted with permission from Clark OH, Duh QY. Thyroid growth factors and oncogenes. In: Benz CC, Edison TL, ed. Oncogenes and tumor suppressor genes in human malignancies. Boston: Kluwer Academic Publishers, 1993: 87-104).

hibitory protein (~53) have been identified as primary targets for mutation in human thyroid tumorszz3 The ras gene product is similar to the gsp gene product in that it acts as a signal transducing G protein. Similar to gsp, point mutations at codons 12, 13, or 61 constitutively activate the G protein.224 These ras mutations are found in benign and malignant tumors and occur in approximately 50% of follicular and anaplastic tumors.222~225 Evidence suggesting that the ras oncogene is capable of initiating oncogenesis include its presence in early benign lesions and its ability to induce a proliferative response while retaining differentiated function in normal thyroid follicular cells in culturezZ3 and the increased presence of K-ras oncogenes in radiation associated thyroid cancer.“(j The ret and trk oncogenes are rearrangements in which the signal transducing tyrosine kinase domain is fused to a new upstream region resulting in the replacement of an upstream negative-regulatory 1ooo

Curr

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1~~94

domain with a neutral domain and thus constitutive activation of tyhave been described to rosine kinase.227’228 Three ret chimeras date.2”7,22%230 These appear to be specific to thyroid tumors and the ret reearrangement is predominantly found in papillary thyroid cancer with an incidence of 17% ? The tumor suppressor gene ~53 has an incidence of 42% in anaplastic thyroid cancer but is rarely found in well-differentiated cancers.223 Further studies are obviously necessary to document whether the presence of specific oncogenes OI tumor suppressor genes will predict tumor behavior. The authors topathology manuscript

thank Howard Epstein, MD, for assistance in reviewing and Tonie Grimes and James Osborn for assistance preparation.

the hiswith the

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