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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 5th edition.

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Chapter 83Neoplasms of the Thyroid

, MD and , MD.

It was estimated that in 1999, more than 17,000 individuals would be diagnosed with carcinoma of the thyroid gland, and about 1,200 patients would die due to complications of these diseases or their treatments.1,2 Of these patients, 80% and 14% respectively, would have papillary and follicular carcinomas, which are the differentiated carcinomas that derive from the thyroid hormone producing follicular epithelial cells. Another 4% would have medullary carcinoma, which is a neuroendocrine malignancy, and the remaining 2% would have the highly aggressive anaplastic carcinoma. Rates of disease recurrence and cancer-specific mortality are increased in patients with metastases, especially those with extracervical spread. In the SEER report of 15,700 patients, the overall 10-year-age and gender-corrected survival rates were 98% for papillary, 92% for follicular, 80% for medullary, and 13% for anaplastic carcinoma.3 Older age at diagnosis and wider spread of disease are associated with a worse prognosis, independent of the type of cancer. Although differentiated carcinomas have a 2:1 female predominance, gender does not appear to affect prognosis.

Due to lack of randomized comparative trials and generalized consensus, decisions regarding the selection of treatments for these diseases are based on retrospective analyses. Therapy can involve multiple modalities, including surgery, radioiodine, biological response modifiers, thyroid hormone, external radiation, and chemotherapy. Nonetheless, increasing numbers of patients die annually from thyroid cancer, mandating newer therapeutic strategies.

Diagnostic Evaluation of the Solitary Thyroid Nodule

The most common clinical presentation of a patient with thyroid carcinoma is with a solitary thyroid nodule (Table 83.1).4 In the setting of an unsuppressed serum thyroid stimulating hormone (TSH) concentration, cytologic examination of a fine-needle aspirate (FNA) of the nodule is the most appropriate diagnostic procedure.5 Papillary, medullary, and anaplastic carcinomas can be readily diagnosed on the basis of cytologic criteria. Similarly, benign diagnoses, such as hyperplastic lesions, colloid nodules, and autoimmune thyroid disease, can be established cytologically. However, the distinction between follicular carcinoma and benign follicular adenoma requires histologic demonstration of either invasion through the tumor capsule or vascular invasion. Hence, follicular adenomas and carcinomas are grouped together cytologically as indeterminate or suspicious follicular neoplasms. Up to 15% of aspirations are inadequate or nondiagnostic, largely due to aspiration of cystic, hemorrhagic, or hypocellular colloid nodules, but ultrasound-guided repeat aspiration reduces this frequency in half.6 The false-positive and false-negative rates for nodules characterized as “malignant” and “benign,” respectively, are less than 5%.7 For suspicious follicular lesions, the overall rate of carcinoma is about 20%, with higher rates associated with larger nodule size, older age, and male gender.8,9

Table 83.1. Differential Diagnosis of a Thyroid Nodule.

Table 83.1

Differential Diagnosis of a Thyroid Nodule.

By radionuclide scanning, malignant thyroid lesions are usually hypofunctioning or “cold,” but this finding is both nonspecific and nondiagnostic. In contrast, a “hot” hyperfunctioning nodule causing thyrotoxicosis is highly likely to be a benign follicular adenoma. When a follicular neoplasm is found, an 123I scan should be obtained to rule out a hyperfunctioning nodule. Patients who are > 50 years old, who have larger nodules, or who are male should have surgery performed. As an alternative to immediate surgery, younger patients with smaller nodules may be treated with levothyroxine to suppress serum TSH levels to less than 0.1 mU/L for 6 to 12 months. A nodule that does not completely resolve in this interval should then be excised.

Ultrasonography is capable of finding solitary nodules in about 25 to 50% of asymptomatic individuals, but occult lesions < 1 cm in diameter are rarely malignant.10 Most patients with asymptomatic occult nodules can be followed up conservatively without intervention.11 Other imaging procedures, such as computed tomography (CT) and magnetic resonance imaging (MRI) have no role in the routine diagnostic evaluation of thyroid nodules.

Differentiated Thyroid Carcinoma


The only well-established risk factor for differentiated thyroid cancer is radiation exposure, especially during infancy. External radiation, delivered therapeutically decades ago for benign conditions, such as thymic and tonsillar enlargement, and currently for malignant diseases, such as Hodgkin’s lymphoma, is associated with an excess relative risk for thyroid malignancy of 3 to 9 per Gy.12 Exposure to internal sources of radiation after the Chernobyl nuclear accident led to a 3 to 75-fold increase in the incidence of papillary carcinoma, the highest risks seen in younger children.13 Although nuclear testing and other sources of fallout have affected large areas of the United States, follow-up studies have yet to identify definite evidence of increased rates of thyroid cancer.14.15

Differentiated carcinoma is a component of several inherited syndromes, including familial adenomatous polyposis, Gardner’s syndrome, Cowden’s disease, Turcot’s syndrome, and Carney complex. Familial nonmedullary carcinoma, described in families with at least two first-degree relatives with the disease, has been reported in 5% of all papillary carcinoma patients.16

Papillary carcinomas are frequently associated with rearrangements of two different genes coding for transmembrane neurotrophic tyrosine kinase receptors, ret and trk.17 In transgenic mice, an activated ret in thyroid epithelial cells causes papillary carcinoma.18 About 40% of papillary carcinomas in adults and 60% in children have these two genetic alterations, with ret rearrangements being about three times more common. Activating rearrangements of ret may be one of the end results of exposure to ionizing radiation, as in the Chernobyl accident.19 Other genes that may contribute to oncogenesis of papillary carcinoma include met (a tyrosine kinase receptor hepatocyte growth factor) and ras (leading to constitutive activation of the MAP kinase cascade). For follicular neoplasms, activation of ras appears to be a common early step in oncogenesis but is not sufficient to cause malignancy.

Pathologic Features (Figure 83.1)

Papillary carcinomas are characterized by the presence of papillae consisting of a well-defined fibrovascular core surrounded by one or two layers of tumor cells. Follicles and colloid are typically absent. Nuclei tend to be large, oval, and appear crowded and overlapping on microscopic sections. The nuclei contain hypodense powdery chromatin, cytoplasmic pseudoinclusions due to a redundant nuclear membrane, and nuclear grooves. Individually, these features are not pathognomonic of papillary carcinoma, but in combination they define the disease. About one-half of papillary carcinomas contain calcified psammoma bodies, which are the scarred remnants of tumor papillae that presumably infarcted.

Of the several histologic subtypes, the follicular variant accounts for about 10% of all papillary carcinomas.20 The cells are organized into follicles rather than papillae, but cytologically, they display the typical nuclear features of papillary carcinomas. Rates of recurrence and survival with the follicular variant are very similar to those of patients with common-type papillary carcinomas. The tall cell variant of papillary carcinoma is a more aggressive tumor, characterized by tumor cells with eosinophilic cytoplasm that are twice as tall as they are wide.21 The primary tumors tend to be large, are often invasive, and frequently have both local and distant metastases at the time of diagnosis. The 5-year survival rate is 75% to 85%. The columnar variant is also generally more aggressive.

Follicular carcinomas are distinguished from benign follicular lesions on the basis of invasiveness. These tumors are commonly encapsulated, and invasion can commonly be demonstrated in one or more foci along the capsule or across vascular endothelial walls. Semiquantitative assessment of the magnitude of invasion can separate follicular carcinomas into minimally invasive and widely invasive lesions; a minimally invasive follicular carcinoma has only scattered foci of capsular or vascular invasion. Cytologic features do not reliably distinguish benign from malignant follicular lesions.

Hürthle cell neoplasms are formed by cells containing numerous mitochondria, which impact a granular, eosinophilic appearance to their cytoplasm. Most have a follicular architecture and are diagnosed as adenomas or carcinomas by the same criteria applied to other follicular neoplasms. A Hürthle cell variant of papillary carcinoma is much less common and tends to be more aggressive than typical papillary carcinomas.

Insular carcinomas are often placed in the category of poorly differentiated thyroid carcinomas, which implies a status between that of differentiated and anaplastic carcinomas. Insular carcinoma generally concentrate radioiodine and are therefore treated as differentiated cancers. They are formed by small cells with variable mitotic activity, arranged in nests, with foci of necrosis.

Clinicopathologic Staging

Multiple staging schemes exist for thyroid carcinoma, each characterized by assignment of stage on the basis of parameters such as patient age, tumor size, tumor grade or differentiation, presence of local invasion, and regional or distant metastases (Table 83.2). The most commonly used classifications include [AMES, AJCC-TNM, AGES, MACIS], Clinical Class, Ohio State, and NTCTCS (National Thyroid Cancer Treatment Cooperative Study).22–28 Making a selection from these various approaches to risk stratification remains a significant clinical challenge. Using multiple cohorts of patients with differentiated carcinoma, the NTCTCS and TNM staging approaches had superior predictive value, compared with the University of Chicago, Ohio State, MACIS, and AMES strategies.28,29 The prognostic importance of histologic features, such as tumor size and extrathyroidal invasion, underscores the need for pathologists to determine and report these data on each thyroidectomy specimen examined for differentiated thyroid carcinoma.30

Table 83.2. TNM-AJCC Staging Scheme for Thyroid Carcinomas.

Table 83.2

TNM-AJCC Staging Scheme for Thyroid Carcinomas.

Primary Surgical Management

Total thyroidectomy is the preferred initial surgical procedure for most patients with differentiated thyroid carcinoma. The use of total thyroidectomy is supported by the following arguments: (1) the foci of papillary carcinoma are found in both thyroid lobes in 60 to 85% of patients;31 (2) 50 to 10% of recurrences of papillary carcinoma after unilateral surgery occur in the contralateral lobe, with subsequent high risk of disease-related death;32 and (3) the efficacy of therapy with radioiodine and the sensitivity of serum thyroglobulin levels as a tumor marker are maximized by resection of as much thyroid tissue as possible. In a retrospective analysis of the outcomes of papillary carcinoma patients who underwent definitive primary surgical therapy at the Mayo Clinic, 1,685 AMES low-risk patients had 20- and 40-year cause-specific mortality rates of 1% and 3%, respectively, and recurrence rates of 10% and 13%, respectively.33 Although there was no difference in the cause-specific mortality rates, the 20-year recurrence rate after lobectomy was 22%, compared with 8% for patients treated with total thyroidectomy. Other retrospective studies reported similar results of reduced recurrence, although with minimal improvement in survival.27,34,35

In contrast, the arguments put forth to support a unilateral procedure include (1) lack of a major survival benefit with more extensive surgery; and (2) fewer complications following unilateral surgery, including hypoparathyroidism and recurrent laryngeal nerve paralysis.36 A report from the Memorial Sloan-Kettering Cancer Center analyzed a series of 465 patients with differentiated carcinoma who met the following criteria; age < 45 years, tumor < 4 cm in size, low-grade histology, absence of distant metastasis, and absence of extrathroidal extension.37 With a median follow-up of 20 years, the overall regional and distant recurrence rates were 9% and 2%, respectively. There was no significant difference in the local recurrence rates (4% versus 1%) or overall failure rates (13% versus 8%) for the 276 patients treated with unilateral lobectomy, compared with the 90 treated with total thyroidectomy.

Resolution of the controversy concerning the extent of thyroidectomy might be achieved through a randomized trial comparing total thyroidectomy with ipsilateral lobectomy. However, using data from published series, 3,100 patients and at least 6 years of follow-up would be necessary to detect an improvement in cause-specific mortality rates from 1.5 to 0.4%;38 four times as many patients would be required for a comparison of complication rates. In the absence of prospective trials, a total thyroidectomy should be performed by an experienced thyroid surgeon if the primary papillary carcinoma is at least 1 cm in diameter, if there is extrathyroidal extension of tumor, or if there are metastases. This operation should also be performed in patients with a history of exposure to ionizing radiation of the head and neck, given the high rate of tumor recurrence with lesser operations.39 If an experienced thyroid surgeon is unavailable, then the slightly more conservative “near-total” procedure should be performed, or the patient should be referred to an appropriate surgeon.40 In selected patients whose papillary tumor is < 1 cm in diameter and confined to one lobe of the gland, a unilateral lobectomy should be sufficient.27 For patients with a cytologically suspicious follicular neoplasm, unilateral lobectomy and isthmusectomy should be performed; a complete thyroidectomy is done if there is a diagnosis of malignancy.

Microscopic regional nodal metastasis of papillary carcinoma occurs in up to 80% of patients. However, only about 35% have cervical or mediastinal node metastasis grossly detectable at the time of surgery. Unlike most other malignancies, the presence of lymph node metastasis is only a minor risk factor for mortality. A meta-analysis of nine studies demonstrated no relationship between the lymph node status at presentation and survival, although several studies did show an increased risk of tumor recurrence. As a surrogate outcome measure, however, disease recurrence after nodal metastasis of papillary carcinoma portends a markedly increased risk for mortality.41 Two of five studies that examined follicular carcinoma demonstrated decreased survival rates in patients with initial nodal disease, although this is an uncommon presentation.42

Given that the presence of regional nodal metastasis influences recurrence rates, neck dissection should be performed at the time of thyroidectomy, if node involvement is identified. In a retrospective analysis of 141 papillary carcinoma patients, 51% who were treated with thyroidectomy alone developed regional recurrence, compared with 18% who also had lateral and central neck dissection.43 These results suggest that neck dissections at the time of initial thyroidectomy may decrease the incidence of regional recurrence and support the practice of routine preoperative ultrasonography to evaluate regional lymphatics. In the presence of invasion of aerodigestive tract structures, similar survival rates are achieved from either complete surgical resection or shave excision leaving only microscopic residual disease.44 In the presence of frank cartilage destruction or intraluminal involvement of the aerodigestive tract structures, a shave excision cannot be performed without leaving gross tumor behind, leading to a 50% death rate within 4 years. Surgery in patients with extensively invasive thyroid carcinoma should, therefore, aim to remove all gross tumor, attempting to retain as much airway, vocal, and digestive function as possible. However, only if the tumor is unresectable or the patient does not agree to a radical resection should gross tumor be left behind in the neck.

Postoperative Adjuvant Therapy


Adjuvant ablation of residual thyroid tissue following primary surgery has three rationales (1) to destroy any residual microscopic foci of disease, (2) to increase the sensitivity of subsequent 131I scanning for detection of recurrent or metastatic disease by eliminating uptake by residual normal tissue, and (3) to improve the value of measurements of serum thyroglobulin as a tumor marker. Combining retrospective data from multiple studies, radioiodine ablation is associated with a 50% reduction in loco-regional relapse, and long-term disease-specific mortality is probably reduced in patients with primary tumors that are at least 1 to 1.5 cm in diameter, are multicentric, or have soft tissue invasion at presentation.24,27,45,46 Despite the common perception that adjuvant radioiodine is uniformly administered,47 treatment has been given to only one-third of patients with differentiated carcinoma.1 Nonetheless, adjuvant radioiodine should probably be administered to all patients with differentiated carcinoma who are at least 45 years old at diagnosis, whose primary tumor is at least 1 cm in diameter, or who have evidence of extrathyroidal disease, either by direct invasion outside of the gland or loco-regional metastases. For patients with residual disease following optimal surgery, including extracervical metastases, radioiodine therapy is also recommended.

The efficacy of radioiodine depends on patient preparation, tumor-specific characteristics, sites of disease, and administered radioiodine activity. Iodide uptake by thyroid tissue is stimulated by TSH and is suppressed by increased endogenous iodide stores. Following thyroidectomy, the patient’s thyroid hormone levels must decline sufficiently to allow the TSH concentration to rise to above 25 to 30 mU/L.48 This period of hormone withdrawal typically lasts 4 to 5 weeks. To minimize the resulting symptoms of hypothyroidism, the shorter-acting hormone liothyronine (T3) is often administered at doses of 25 μg two times per day.49 Lower doses are administered to elderly patients and those with ischemic heart disease. Liothyronine is stopped at least 2 weeks prior to dosing for a radioiodine scan. Patients should avoid foods with high iodine content for at least 2 weeks prior to the scanning.50

Radioiodine scans for localization of uptake prior to ablation or therapy are usually performed with a diagnostic activity of 2 to 5 mCi of 131I. Between 24 and 96 hours after the diagnostic dosing, whole body scans and spot images of the neck and other areas of uptake are performed with a gamma-scintillation camera with a large field of view. Most patients demonstrate significant uptake of radioiodine within the thyroid bed following thyroidectomy, presumably from normal residual thyroid. Quantitative dosimetry can be performed to determine lesion uptake and to predict effective tumor radiation dose; however this requires specialized equipment and software.51 Greater sensitivity for the detection of residual or metastatic tumor can be attained with the use of higher amounts of 131I. But, larger radioisotope activities can lead to “stunning,” in which reduced uptake of the subsequent ablative or therapeutic dose occurs due to radiation delivered by the diagnostic dose.52,53 Use of 123-I, with a lower radiation dose to thyroid tissue, may prevent stunning of therapeutic uptake after a diagnostic scan.54

With postoperative radioiodine uptake in the thyroid bed, an empirically selected activity of 131I is administered for adjuvant ablation, typically 100 mCi. Lower activities of radioiodine have also been used, permitting treatment that does not require hospitalization for radiation safety precautions. Assuming that the 24 hour radioiodine uptake is less than 5%, this lower activity has a similar efficacy of successful ablation and could be considered for patients with disease entirely confined to the thyroid gland.55,56 Nonetheless, there is scant information about long-term outcomes, and considerably more study is required before such low doses can be generally recommended.27 Alternatively, quantitative dosimetry can be applied to estimate the radioiodine activity necessary to deliver an effective radiation dose to the tissue of at least 30,000 cGy.57 When substantial yet unsuspected loco-regional disease is detected, strong consideration is given to additional surgery before radioiodine administration.

A post-treatment scan is performed several days after administration of the radioiodine dose, although the diagnostic utility of such scans immediately after ablative treatments is maximal in patients whose thyroid bed activity was previously ablated.52,58

Thyroid Hormone

Patients require lifelong thyroid hormone treatment to prevent hypothyroidism and to minimize TSH stimulation to tumor growth. With TSH-suppressive thyroid hormone therapy, disease-free survival may be improved 2 to 3-fold, particularly in TNM or NTCTCS stage III and IV patients.59,60 However, potential morbidity from overly aggressive thyroid hormone suppression therapy includes acceleration of osteopenia61,62 and provocation of atrial fibrillation.63 Whereas some studies have also suggested that TSH-suppressive therapy leads to induction of cardiac hypertrophy and dysfunction,64,65 these findings have also been disputed.66,67

It seems reasonable, therefore, to treat patients with L-thyroxine, the degree of TSH suppression being dependent on the patient’s initial clinicopathologic features.60 For patients with primary tumors > 1 cm in diameter, the TSH should be maintained between 0.05 and 0.5 mU/L; in those patients with extrathyroidal invasion or extracervical metastases, the TSH should be suppressed below 0.05 mU/L. Patients who remain disease-free for 5 to 10 years may have their degree of TSH suppression reduced by lowering their doses of thyroid hormone; other mitigating factors, such as concurrent cardiac disease, may also dictate a need for reduced hormone dosing.

External Beam Radiation

External beam radiotherapy (EBRT) may be an effective adjuvant therapy to prevent loco-regional recurrence in older patients with locally invasive papillary carcinoma.68,69 A review of 282 patients found that postoperative EBRT did not significantly affect the loco-regional control of disease-specific survival rates. However, in a subgroup of 155 patients with papillary histology and microscopic residual disease (evidence of disease at or within 2 mm of the resection margin, or tumor that was shaved off cervical structures), EBRT produced a significant improvement in 10-year rates of loco-regional control (93% versus 78%) and disease-specific survival (100% versus 95%).69 Increased freedom from loco-regional and distant relapse has been reported in patients over 40 years with extrathyroidal extension and lymph node involvement from papillary carcinoma, when treated with adjuvant EBRT in addition to total thyroidectomy, two courses of 131I and TSH suppression.68 In neither study was a benefit of adjuvant EBRT demonstratetd for patients with follicular carcinoma. The recommended dosages for adjuvant EBRT are in the range of 40 to 50 Gy.70 Efforts to initiate a definitive randomized study of adjuvant EBRT are ongoing, although the study will require a large number of patients and long follow-up to obtain sufficient power to determine the benefit of adjuvant therapy.

Long-Term Follow-Up

Diagnostic Imaging

After initial ablation, radioiodine scanning following thyroid hormone withdrawal should be repeated annually until at least two negative whole body scans are obtained. The predictive value for 10-year relapse-free survival of one negative radioiodine scan is about 90%, whereas two consecutive negative scans have a predictive value greater than 95%.71

Ultrasonography of the thyroid bed and cervical node compartments can accurately identify loco-regional metastases and recurrence measuring several millimeters in diameter and facilitate FNA of such lesions.72 Ultrasonography should be considered in the routine follow-up of patients with extrathyroidal invasion or loco-regional nodal metastases. As many as half the patients with loco-regional disease diagnosed by high-resolution ultrasonography may have false-negative radioiodine scans or undetectable serum thyroglobulin.72 CT is not as sensitive for detecting such small lesions, but the technique is more readily standardized and less operator dependent. Routine chest radiographs are of limited sensitivity, particularly in the setting of micronodular metastases but may identify macronodular metastases that do not concentrate radioiodine.

Serum Thyroglobulin Monitoring

The synthesis and secretion of thyroglobulin (Tg) is a differentiated characteristic of thyroid follicular cells.74 In the long-term follow-up of patients, measurement of the serum Tg concentration aids the detection of residual, recurrent, or metastatic disease, particularly given the rough correlation between tumor size and Tg level. After thyroid resection and ablation, serum Tg concentrations should approach the limits of assay detectability. The Tg level may take 1 or more years to decline to an undetectable nadir following primary therapy.75 An important factor in the interpretation of Tg concentrations is the concurrent level of TSH, given the dependence on TSH for Tg production. Like radioiodine scanning, the sensitivity for detection of residual cancer is enhanced by elevation of the serum TSH during thyroid hormone withdrawal. The sensitivity of detecting disease by measurement of Tg during thyroid hormone withdrawal is 85 to 95% but may be as low as 50% during TSH suppression or with dedifferentiated tumors.76 Thyroid hormone withdrawal and symptomatic hypothyroidism to obtain TSH stimulation of both radioiodine uptake and Tg levels may be avoided by the use of thyrotropin-α (recombinant human TSH). The maximum sensitivity for detecting residual thyroid tissue or disease following two injections of thyrotropin-α stimulation depends on simultaneous measurement of serum Tg and performance of a whole-body radioiodine scan, with a diagnostic accuracy approaching that of diagnostic studies done after thyroid hormone withdrawal. A patient who is identified as requiring radioiodine therapy can then undergo thyroid hormone withdrawal and treatment 1 month later, as thyrotropin-α has not been formally studied for stimulating therapeutic uptake of radioiodine. Similarly, the utility of stimulated Tg measurements in the absence of scanning remains to be determined.

Despite the sensitivity of Tg immunoassays, problems remain in their clinical application. In immunometric assays, reported Tg concentrations can be falsely lowered by autoantibodies that bind Tg and prevent antigen interaction with assay’s antibodies.78 For the 25% of the thyroid cancer population with anti-Tg autoantibodies, serum Tg levels must be interpreted with caution. The persistence of anti-Tg autoantibodies following thyroidectomy and radioiodine ablation may in itself indicate the presence of residual thyroid tissue and an increased risk for recurrence.79 Use of sensitive polymerase chain reaction ((PCR) methods allows the detection of Tg messenger RNA circulating in the peripheral blood of patients with thyroid cancer, presumably contained within circulating tumor cells.80 Besides permitting assessment of disease status in the presence of anti-Tg autoantibodies, such assays may also be more sensitive in patients whose TSH levels are suppressed due to thyroid hormone therapy.

Therapy of Metastatic Disease


Function-preserving node dissection is preferred, if possible, for patients with nodes > 1cm in diameter.42 For extracervical metastases, surgical resection can lead to improved survival in selected patients. In one report, nearly 30% of patients who underwent complete resection of their skeletal, pulmonary or intra-abdominal metastases remained disease free after an average follow-up of 8 years.81 Among patients with one or more brain metastases, surgical removal significantly improved median survival from 4 to 22 months.82 Symptom palliation can also result from surgical treatment, particularly for lesions causing pain or spinal cord compression.


131I treatment of regional nodal metastases yields a complete response in 80% of patients when at least 8,000 to 10,000 cGy is delivered but can be suboptimal in patients with bulky disease.57 Patients with residual postoperative disease in the thyroid bed or in the regional lymph nodes are treated with high activities of 131I. Efficacy has been reported with 150 mCi as an average dose, either as a result of empiric therapy or as determined by dosimetry.

Patients treated for iodine-concentrating pulmonary metastases, which occur in about 5% of cases of differentiated cancer, have a 5-year survival rate of 60%, compared with 30% for those whose tumors do not take up iodine.83,84 Long-term survival is highest in those patients with pulmonary metastases seen on 131I scanning but not seen on chest radiography or CT. Nevertheless, only a minority of patients with such micronodular disease have a complete remission, perhaps because the delivery of tumoricidal radiation doses is minimized for metastases < 1 mm in size.85 Patients with macronodular pulmonary metastases seen on chest radiography but not detected by 131I scanning have the worst prognosis, and only rarely respond to large doses of 131I. Radioiodine activities of 150 to 175 mCi are recommended for empiric treatment of pulmonary metastases. Advocates of dosimetry suggest treatment of distant metastases with the maximum tolerable doses, that is, that dose which delivers no more than 200 cGy to the red marrow and 80 to 120 mCi whole body retention.86 Such activities may exceed 300 to 400 mCi but are calculated to allow the greatest degree of tumor kill without dose-limiting toxicity. Skeletal metastases often do not concentrate 131I; complete resolution of disease occurs in fewer than 10% of treated patients, and partial remission in only 35%.83 Patients with follicular carcinoma may be more likely to respond (Figure 83.2). Empiric doses of 200 mCi are generally suggested for distant metastases outside the lungs. Following surgical debulking, radioiodine therapy can also be administered to patients with iodine-concentrating intracerebral metastases.82

Figure 83.2. Anterior and posterior views of whole body 131I imaging in a patient with metastatic follicular thyroid carcinoma.

Figure 83.2

Anterior and posterior views of whole body 131I imaging in a patient with metastatic follicular thyroid carcinoma. Two years after a thyroidectomy and radioiodine ablation, the patient developed back and extremity pains. Following thyroid hormone withdrawal, (more...)

Regimens to deplete body stores of iodine, such as loop diuretics, mannitol, or very-low-iodine diets, may increase uptake by lesions, but with a concomitant increase of total body irradiation. Acute and chronic complications of 131I can limit the usefulness of this treatment. In the short term, radiation thyroiditis, painless neck edema, sialoadenitis, and tumor hemorrhage or edema occur in 10 to 20% of patients, particulary when higher doses are given. The radioprotectant amifostine may prevent symptomatic reduction in long-term salivary gland function as a result of 131I but the potential impact to reduce the therapeutic benefit of the radioiodine in thyroid tissue precludes its routine use at this time.87 Over the long term, 131I therapy may be associated with development of secondary malignancies, such as acute myelocytic leukemia, usually occurring between 2 and 10 years after therapy. The risk is considerably lower when the total blood dose per treatment is less than 2 Gy and when repeat treatments are given no more frequently than annually. Increased prevalence of cancers of the bladder, salivary gland, colon, and female breast has also been reported in patients, but with little agreement on the degree of absolute risk.88,89 Oligospermia and transient ovarian failure also occur, but subsequent infertility is rare except after high doses. Patients who receive repeated high radiation doses to the lung parenchyma from radioiodine treatment of diffuse pulmonary metastases rarely develop pulmonary fibrosis.

As production of Tg and incorporation of radioiodine represent distinct differentiated functions of follicular cells, metastatic disease can be suspected by the presence of a detectable serum Tg in the absence of radioiodine uptake. Such “false-negative” results occur in up to 15% of diagnostic radioiodine scans in patients with detectable Tg levels following thyroid ablation. Because a high frequency of post-therapy scans demonstrate foci of radioiodine uptake combined with a subsequent decrease in the serum Tg level, it has been proposed that patients with elevated serum Tg and negative diagnostic radioiodine scans should receive empiric 131I therapy with 100 to 300 mCi.90,91 But, the underlying risk for disease-related morbidity or mortality in patients with scan-negative, Tg-positive disease is not well-defined, particularly for patients without evidence of tumor mass by other imaging modalities. At present, there is no evidence that either partial reductions in serum Tg levels or elimination of radioiodine uptake visible only on post-therapy scans is associated with improved patient outcome. Fewer than 20% of patients achieve undetectable Tg levels and complete ablation of radioiodine uptake on post-therapy scans in extracervical sites; so, “cure” is uncommon. The potential risks of repeated high-dose empiric therapy must be considered as well, as described above. With these concerns in mind, it seems reasonable to consider empiric radioiodine therapy for Tg-positive, scan-negative disease as experimental, of unproven benefit, and requiring a prospective clinical trial. Diagnostic imaging should be performed to identify foci of disease that could be surgically resected or treated by other means (Figure 83.3), such as scintigraphy with 111-indium-DTPA-Phe-octreotide, 99mtechnetium-tetrofosmin, or 201thallium, positron emission tomography (PET), CT, or MRI.92,93 Given the propensity of follicular thyroid carcinoma to metastasize to bone skeletal imaging with 99mtechnetium pyrophosphate may also be of value. In the absence of surgically resectable disease, only patients with evidence of progressive metastases or who are at high risk for disease-related mortality might receive a therapeutic trial of radioiodine before embarking on other systemic treatment modalities. However, for younger patients with stable elevated Tg levels and no radiographic evidence of disease, evidence of benefit is insufficient to warrant empiric radioiodine.

Figure 83.3. Contrast-enchanced CT of the neck in a patient with recurrent papillary thyroid carcinoma.

Figure 83.3

Contrast-enchanced CT of the neck in a patient with recurrent papillary thyroid carcinoma. Patient had previously undergone thyroidectomy and radioiodine ablation. Although a diagnostic radioiodine scan performed 1 week previously had shown no pathologic (more...)

Biologic Modifiers of Radioiodine Responsiveness

Poor up-take and diminished retention of radioiodine are associated with tumor dedifferentiation and poor response to treatment. Certain histologic subtypes, such as Hürthle cell carcinoma and the tall cell variant of papillary carcinoma, concentrate131I less effectively. Older patients and women may also be less likely to have adequate uptake in metastases. Restoration of responsiveness to radioiodine therapy has, therefore, been a major goal of investigation during the past several years. Because lithium can increase iodine retention by thyroid tissue, a recent study examined patients who had diagnostic131I scans before and after receiving lithium for 1 to 2 days.94 131I retention was higher and more prolonger during lithium administration, and the estimated radiation dose to the metastases was 2.3 times higher. This increase was proportionally higher in tumors with lower baseline iodine retention, suggesting a potential approach to poorly responsive metastases. Whether these findings will result in improved eradication of metastases remains to be determined.

Isotretinoin has been reported to reverse the loss of radioiodine concentrating ability associated with tumor dedifferentiation. In vitro studies in follicular carcinoma cell lines have shown that incubation with isotretinoin can cause decreased cellular proliferation, decreased 3-H-thymidine incorporation, and increased uptake of radioiodine.95,96 Several clinical reports suggested that increased radioiodine uptake could be induced in metastatic poorly responsive lesions.97,98 In a larger trial, 20 patients with inoperable metastatic disease and absent radioiodine uptake were treated with isotretinoin, 1 to 1.5 mg/kg daily for up to 5 weeks.99 Of the 16 patients studied, radioiodine uptake was increased in 8 after their course of retinoid therapy, permitting radioiodine treatment in 6. Tg levels, detectable in all patients before retinoid treatment, rose in 12 patients and decreased in 6, but there was no correlation between the Tg change and radioiodine response. Unfortunately, tumor size increased in 60% of patients and decreased in only 1 patient, suggesting minimal clinical benefit.

Loss of iodide uptake may be related to decreased expression of the sodium–iodide symporter in the tumor cells. On the basis of the hypothesis that hypermethylation of the promoter region of the symporter gene leads to decreased expression and loss of iodide uptake, it could be presumed that demethylation might restore iodide uptake. In vitro, a 15-fold increase in iodide uptake was demonstrated in one dedifferentiated papillary thyroid cancer cell line treated with the demethylating agent 5-azacytidine.100 Further clinical trials are now under way in patients with iodide-unresponsive thyroid cancers.

External Beam Radiation

Patients with unresectable gross locally invasive or metastatic disease in the neck may also benefit from the addition of EBRT. Of 33 patients with gross residual disease who received postoperative EBRT, the 5-year local control and disease-specific survival rates were about 65%.69 EBRT can also benefit patients with painful skeletal metastases. When surgical resection is not feasible, palliative radiation should be offered to patients with bone lesions that either cause pain or pose a risk for pathologic fracture. Radiation doses of 50 Gy in 25 fractions may be given for solitary lesions, but reduced doses should be administered for vertebral foci.70


Although 10 to 15% of patients with differentiated thyroid cancer die from their disease, and an even higher proprotion suffer morbidity from recurrence, two recent authoritative texts devoted to thyroid cancer apportioned only 1% of their content to discussion of chemotherapy for these diseases.101,102 This reflects the dearth of substantial research in this area. Little progress has been made since the original reports of partial responses to doxorubicin in about one-third of patients. The best responses occur in patients with pulmonary metastases and high performance status. Combining the results of 10 published reports, doxorubicin yields a nearly 40% response rate for progressive differentiated cancers unresponsive to radioiodine, including Hürthle cell carcinoma103 The recommended dose is 60 to 75 mg/m2 every 3 weeks, administered as a continuous intravenous infusion for 48 to 72 hours to minimize the risk of cardiac toxicity. Cumulative doses of up to 600 mg/m2 can be administered in responsive patients. Other single chemotherapeutic agents that have been attempted include bleomycin, cisplatin, carboplatin, methotrexate, melphalan, mitoxantrone, etoposide, and aclarubicin, without suggestion of improved response rates. In one comparative trial, the combination of doxorubicin, 60 mg/m2, and cisplatin, 40 mg/m2, induced complete or partial response in 16%, whereas doxorubicin alone yielded a 31% response rate.104 Of another 11 patients treated with the combination of doxorubicin, bleomycin, vincristine, and melphalan, 36% had partial or complete response, with 1 patient experiencing a complete remission lasting at least 5 years.105 Toxicities, including pancytopenia and gastrointestinal side effects, are markedly more common and severe, however, during these combination therapies, without clear evidence of greater benefit. The future of chemotherapy for metastatic thyroid cancer lies in the advent of routine in vitro testing of new chemotherapeutic agents against thyroid cancers, and patients with advanced thyroid cancer should be included in phase I trials that might provide preliminary evidence of activity. Other agents that may have in vitro activity against thyroid cancer cells include tamoxifen, octreotide, TNP-470, and paclitaxel. However, human trials are either lacking or have failed to demonstrate clinical benefit.103

Management of Differentiated Carcinoma in Special Populations

Thyroid carcinoma in children and adolescents is uncommon, and few large series have evaluated the long-term prognosis and appropriate therapy for young patients with these malignancies. A recent series described the extended follow-up of 112 young patients with differentiated thyroid carcinoma treated at the M.D. Anderson Cancer Center.106 One-fourth of the 99 living patients had developed recurrent disease, and 6 patients died of thyroid cancer at a mean of 26 years after initial diagnosis. One patient who had lung metastases at the time of diagnosis died of progressive pulmonary disease after 36 years. The other 5 patients developed lung and bone metastases and died after a 2- to 20- year disease-free interval. Three more patients died from complications of radiation therapy, 1 due to tracheal necrosis 26 years after diagnosis and 2 due to cervical sarcomas over 20 years after diagnosis. Two died from subsequent breast cancer, although it remains unclear if this was a complication of thyroid cancer therapy.89 In another series of 61 young patients treated for thyroid cancer, the 20-year survival rate was 97%.107 Two patients died of progressive metastatic thyroid cancer within 10 years of the initial operations. Three of the 10 patients who had lobectomy or subtotal thyroidectomy developed local recurrence in the residual thyroid gland, whereas none of the 51 patients who had total or near-total thyroidectomy developed a local recurrence, Given the high frequency of multi-focal intrathyroidal disease, loco-regional spread, and extracervical metastases, total thyroidectomy with nodal dissection and adjuvant radioiodine therapy should be offered to all young patients with differentiated carcinoma. Lifelong, close surveillance is warranted due to the risk of late recurrences and disease progresion.

Differentiated carcinoma is diagnosed during 0.1% of all pregnancies.108 There has been some concern that the hormonal factors associated with pregnancy might accelerate the progression of disease and necessitate a more aggressive management strategy. However, the outcomes of 61 pregnant women diagnosed with differentiated carcinoma did not differ from those of 528 age-matched nonpregnant women, despite a delay in definitive treatment in the pregnant women.109 In most cases, the treatment of thyroid cancer can be safely delayed until the postpartum period.

Medullary Thyroid Cancer

Medullary thyroid carcinoma (MTC) derives from the neuroendocrine parafollicular or C cells of the thyroid (Figure 83.4).110 Sporadic MTC accounts for 80% of all cases of the disease, with the remainder of patients having inherited tumor syndromes, such as multiple endocrine neoplasia (MEN) type 2A, MEN-2B, or familial medullary carcinoma (FMTC). Because the C cells are predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease typically present with upper pole nodules. Metastatic cervical adenopathy is noted in about 50% of patients at initial presentation, and symptoms of upper aerodigestive tract compression or invasion are reported in up to 15% of patients with sporadic disease.111 Symptoms from distant metastases in the lungs or bones may be elicited from 5 to 10% of patients. The ability of the tumor to oversecrete measurable quantities of calcitonin, occasionally along with other hormonally active peptides, such as adrenocorticotrophic hormone or calcitonin gene–related peptide, leads to unexplained diarrhea, symptoms of Cushing’s syndrome, or facial flushing in many patients with advanced disease. Rarely, MTC is suggested by the presence of dense calcifications seen on radiologic imaging of the anterior neck or sites of metastatic disease. The typical age of a sporadic presentation is in the fifth or sixth decade, and there may be a slight female preponderance.

Figure 83.4. Medullary thyroid carcinoma, with nests of spindle-shaped cells.

Figure 83.4

Medullary thyroid carcinoma, with nests of spindle-shaped cells. Such nests are often interspersed with clusters of round-to-oval cells, all immunostaining for calcitonin.

The diagnosis of sporadic MTC is usually suspected following FNA of a solitary nodule. At an estimated cost of $12,500 per diagnosed MTC case that would not be identified by other means, routine measurement of the serum calcitonin concentration is not recommended for the evaluation of a nodule.112

In known families with inherited MTC, prospective family screening identified disease carriers long before clinical symptoms or signs are noted.113 Using the traditional approach of stimulated secretion of calcitonin by either pentagastrin or calcium infusion, 65% of MEN-2A gene carriers will have abnormal calcitonin levels by age 20 years, and 95% by age 35 years.114 Compared with sporadic disease, the typical age of presentation for familial disease is the third decade, without gender preference, in MEN-2A, signs or symptoms of hyperparathyroidism or pheochromocytoma uncommonly present before those of MTC, even in the absence of prospective screening. All familial forms of MTC and MEN-2 are inherited in an autosomal dominant fashion. Mutations in ret, which codes for a cell membrane–associated tyrosine kinase receptor for glial cell line–derived neurotrophic factor, are found in 95% of families with familial forms of MTC.113 Mutations associated with MEN-2A and FMTC have been primarily identified in several codons of the cysteine-rich extracellular domains of exon 10, 11, and 13, whereas MEN-2B and some FMTC mutations are found within the intracellular exons 15 and 16 (Table 83.3). Somatic mutations in exons 11, 13, and 16 have also been found in at least 25% of sporadic MTC tumors, particularly the codon 918 mutation that activates the tyrosine kinase function of the receptor and is associated with poorer patient prognosis. Further, about 6% of patients with clinically sporadic MTC carry a germline mutation in ret, leading to identification of new families with multiple previously undiagnosed affected individuals.115 Genetic testing for ret proto-oncogene mutations should be offered to all patients newly diagnosed with clinically apparent sporadic MTC, as well as for screening children and adults in known families with inherited forms of MTC. On the basis of the relative frequency of mutations in certain exons, mutational analysis should start with exon 11, followed sequentially by exons 10, 16, 13, 14, and 15.113 Although common mutations can be identified by broadly available commercial testing sources, only a limited number of sites perform the more thorough analyses that are required to identify the less common mutations. Presently, a 5% error rate is generally reported, underscoring the importance for repeat testing of at least two independently obtained blood samples in more than one laboratory to minimize the likelihood of both false-positive and false-negative results.116

Table 83.3. ret Proto-oncogene Mutations in Hereditary Medullary Thyroid Carcinoma.

Table 83.3

ret Proto-oncogene Mutations in Hereditary Medullary Thyroid Carcinoma.

Three approaches to staging of medullary carcinoma in common use are TNM,25 Clinical Class,117 and NTCTCS.28 Patients < 40 years of age at diagnosis have 5- and 10-year disease-specific survival of about 95% and 75%, respectively, compared with 65% and 50% for those older than 40 years.111 Patients with inherited disease appear to have a better prognosis, even after correcting for the early age of diagnosis in familial disease. Despite being typically diagnosed during childhood, patients with MEN-2B are more likely than those with either MEN-2A or FMTC to have locally aggressive disease.118 Other factors that may be important for predicting a worse prognosis include the heterogeneity and paucity of calcitonin immunostaining of the tumor, rapidly rising serum CEA, and postoperative residual hypercalcitoninemia.

Initial Surgical Management

Even in patients with apparently sporadic disease, the possibility of MEN-2 should be considered preoperative, and serum calcium and 24-hour urinary excretion of metanephrines and catecholamines should be measured. Total thyroidectomy is indicated in all patients with MTC, especially given the high frequency of bilateral disease in both sporadic and familial disease.111 Once an MTC tumor is large enough to be palpated, there is a high frequency of metastasis to adjacent nodal tissue. Even in the absence of clinically detectable nodal metastases, central neck compartment dissection should be performed in all patients, and ipsilateral lateral neck and/or mediastinal dissections should be strongly considered when the primary tumor is > 1 cm or when central compartment disease is present. Disfiguring radical node dissections do not improve prognosis and are not indicated. In the presence of grossly invasive disease, more extended procedures with resection of involved neck structures may be appropriate, but function-preserving approaches are preferred. Postoperative thyroid hormone therapy is indicated, but TSH suppression is not appropriate as C cells lack TSH receptors.

Adjuvant Radiation Therapy

EBRT should be considered in patients after maximal surgical therapy who are considered at high risk for regional recurrence. After radiotherapy for microscopic residual disease, extraglandular invasion, or lymph node metastases, the loco-regional relapse-free rate at 10 years was 86%, compared with 52% for those patients who did not receive adjuvant therapy. Typically, 40 Gy is administered in 20 fractions to the cervical, supraclavicular, and upper mediastinal lymph nodes over 4 weeks, with subsequent booster doses of 10 Gy in five fractions to the thyroid bed.119 As for differentiated carcinoma, EBRT can be given to palliate painful bone metastases.

Persistently Elevated Calcitonin

Six months postoperatively, serum concentrations of calcitonin and CEA should be measured. Those patients whose calcitonin level is less than 10 pg/mL should undergo stimulation testing with calcium infusion.120 About 80% of patients with palpable MTC and 50% of those with nonpalpable but macroscopic MTC who undergo supposedly curative resection have stimulated serum calcitonin values of at least 10 pg/mL, indicative of residual disease. Those with near-normal values can be monitored, but those with values > 100 pg/mL should be evaluated for either residual resectable disease in the neck of the presence of distant metastases. Patients with basal serum calitonin value > 1,000 pg/mL and no obvious MTC in the neck and upper mediastinum probably have distant metastases, most likely in the liver. The prognosis for patients with postoperative hypercalitoninemia depends primarily on the extent of disease at the time of initial surgery. In a study of 31 patients (10 patients with apparently sporadic disease, 15 with MEN-2A, and 6 with MEN-2B), the 5- and 10-year survival rates were 90% and 86%, respectively.121 Two recent studies have reported higher mortality rates for patients with high postoperative serum calcitonin values, with more than half the patients having a recurrence during mean follow-up of 10 years.122,123

Given the general failure of routine lymphadenectomy or excision of palpable tumor to normalize the serum calcitonin concentrations in such patients, attention has been directed toward detection and eradication of microscopic deposits tumor. Extensive dissection to remove all nodal and perinodal tissue from the neck and upper mediastinum was first reported to normalize the stimulated serum calcitonin levels in 4 of 11 patients at least 2 years postoperatively.124 In subsequent larger studies, 20 to 40% of patients undergoing microdissection of the central and bilateral neck compartments were biochemically cured, with minimal perioperative morbidity.125,126 Preoperative assessment should include ultrasonography of the neck, CT of the chest, MRI of the abdomen, bone scintigraphic imaging, and localization of disease by catheterization of the hepatic veins, both internal jugular veins, and the innominate veins, with measurements of serum calcitonin before and after stimulation. Laparoscopic assessment of the liver can be performed if distant metastases are not detected by this diagnostic approach.126 However, in the absence of long-term outcomes, application of this approach should probably be limited to those centers experienced in this procedure; only patients with overt disease in the neck and no distant metastases should undergo reoperative neck surgery.

Prophylactic Surgery for Gene Carriers

Prophylactic thyroidectomy has been recommended for at-risk family members who are identified as carriers of a familial ret mutation.127 Of 18 patients who underwent prophylactic thyroidectomy at a median age of 14 years, nearly 80% had a histologic diagnosis of MTC but none had evidence of nodal metastases. In the 13 patients evaluated 3 years after surgery, all had normal levels of stimulated plasma calcitonin. Given the identification of patients with malignant disease as early as age 6 years, most experts advocate prophylactic thyroidectomy before the age of 6 years in MEN-2A carriers.128,129 Surveillance with stimulated calcitonin meaasurements rather than surgery is still suggested by some investigators for young gene carriers without evidence of MTC, although this approach should probably be avoided in children with the more virulent ret mutations in exons 10 and 11.113

Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinomas are aggressive undifferentiated tumors, with a disease-specific mortality approaching 100%. Patients with anaplastic carcinoma are older than those with differentiated carcinomas, with a mean age at diagnosis of about 65 years. Fewer than 10% of patients are younger than 50 years, and 60 to 70% are women.3 Approximately 50% of patients with anaplastic cancer have either a prior or coexistent differentiated carcinoma. Anaplastic carcinoma develops from more differentiated tumors as a result of one or more dedifferentiating steps, particularly loss of the p53 tumor suppressor protein.130 No precipitating events have been identified, and the mechanisms leading to anaplastic transformation of differentiated carcinomas are uncertain.

Patients with anaplastic carcinoma present with extensive local invasion, and distant metastases are found at initial disease presentation in 15 to 50% of patients.131 The lungs and pleura are the most common sites of distant metastases, being seen in up to 90% of patients with distant disease. About 5 to 15% of patients have bone metastases, 5% have brain metastases, and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands.

The diagnosis of anaplastic carcinoma is usually established by FNA or surgical biopsy. CT of the neck and mediastinum can accurately determine the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract structures.132 Most pulmonary metastases are nodules that can be detected by routine chest radiography. Bone lesions are usually lytic.

Treatment and Prognosis

There is no effective therapy for anaplastic carcinoma, and the disease is uniformly fatal. The median survival from diagnosis ranges from 3 to 7 months, and the 1 and 5 year survival rates are about 25% and 5%, respectively.131 Death is attributable to upper airway obstruction and suffocation (often despite tracheostomy) in half the patients and to a combination of complications of local and distant disease and/or therapy in the remainder. Patients with disease confined to the neck at diagnosis have a mean survival of 8 months, as compared with 3 months if the disease has extended beyond the neck.133 Other variables that may predict worse prognosis include older age at diagnosis, male gender, and dyspnea as a presenting symptom.

Except for patients whose tumors are small and confined entirely to the thyroid, total thyroidectomy with complete tumor resection does not prolong survival.133,134 EBRT, administered in conventional doses, also does not prolong survival. Although up to 40% of patients may respond initially to radiation therapy, most have local recurrence. Treatment with single-drug chemotherapy also does not improve survival or control of disease in the neck, although perhaps 20% of patients have some response in distant metastases. The introduction of hyperfractionated radiotherapy, combined with radiosensitizing doses of doxorubicin, may increase the local response rate to about 80%, with subsequent median survival of 1 year; distant metastases then become the leading cause of death.135 Similar improvement in local disease control has been reported with the combination of hyperfractionated radiotherapy and doxorubicin, followed by debulking surgery in responsive patients. However, the addition of larger doses of other chemotherapeutic drugs has not been associated with improved control of distant disease or improved survival. Paclitaxel has recently been tested in newly diagnosed patients and may provide some palliative benefit.136


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