Papillary and Follicular Thyroid Cancer

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Diagnosis

The role of imaging in the investigation of patients with suspected thyroid cancer is controversial, reflecting the high incidence of nodules in the normal population and low prevalence of thyroid malignancy.

In a patient with a palpable nodule in the thyroid, the simple technique of imaging the thyroid using 99mTc pertechnetate will identify whether the palpable nodule is functioning or nonfunctioning. Thyroid cancer typically appears as a hypofunctioning "cold" nodule on 99mTc pertechnetate thyroid imaging but this is a nonspecific finding (Figure 27.1A). Specificity varies with the iodine status of the population studied. In Austria, prior to iodine supplementation, the incidence of thyroid cancer in cold thyroid nodules was 3.5% [19] compared with 21% in the iodine-replete USA [20].

In 1978, Tonami et al. [21] described the use of 201Tl in investigating patients with cold thyroid nodules. However, Harada et al. [22] demonstrated that 201Tl could not distinguish between benign and malignant nodules. Alternative tumor-seeking radiopharmaceuticals such as 99mTc sestamibi, 99mTc tetrofosmin and 18fluorodeoxyglucose have proved unreliable in differentiating benign and malignant thyroid nodules. In practice, many centers now proceed to fine-needle aspiration cytology under ultrasound guidance without prior imaging. A combined scintigraphy/ultrasound approach

Gland activity (scan time) = 89.3 MBq

System sensitivity = 75.0 cps / MBq a

Gland activity (scan time) = 89.3 MBq

System sensitivity = 75.0 cps / MBq a

Figure 27.1 A WmTc pertechnetate scan of a patient with toxic diffuse goiter (Graves' disease). Clinically nonpalpable cold nodule detected which was proven to be papillary thyroid cancer on fine-needle aspiration. B 99mTc pertechnetate scan of a patient with a multinodular goiter diagnosed on palpation. The dominant cold nodule was investigated with fine-needle aspiration and a colloid nodule was diagnosed.

Figure 27.1 A WmTc pertechnetate scan of a patient with toxic diffuse goiter (Graves' disease). Clinically nonpalpable cold nodule detected which was proven to be papillary thyroid cancer on fine-needle aspiration. B 99mTc pertechnetate scan of a patient with a multinodular goiter diagnosed on palpation. The dominant cold nodule was investigated with fine-needle aspiration and a colloid nodule was diagnosed.

reduces the number of unnecessary fine-needle aspirations performed on functioning nodules and improves sampling accuracy in dominant, nonfunctioning nodules arising from multin-odular glands (Figure 27.1B).

18FDG-PET has been able to detect thyroid cancer during studies for other pathologies. An

Papillary Thyroid Cancer Pet Scan
Figure 27.2 Sixty-two-year-old man undergoing staging investigations for carcinoma of the bronchus with 18FDG-PET.The primary lung lesion was visualized but an additional area of high uptake in the lower left neck was identified. Further investigation confirmed a follicular carcinoma of thyroid.

intense area of focal uptake in the thyroid region warrants further evaluation as a number of such identified lesions have been proven to be thyroid cancer on fine-needle aspiration and surgery (Figure 27.2). Uptake of 18FDG in a thyroid nodule, however, is not specific for thyroid cancer. Adler et al. in a study of 9 thyroid nodules demonstrated uptake in 2 of 3 nodules that were malignant but also in 3 out of 4 benign adenomas [23].

Uematsu et al. demonstrated standardized uptake values (SUVs) greater than 5 in proven cancers, differentiating them from benign nodules with lower SUVs. A patient with chronic thyroiditis had an SUV of 6.3, however [24].

Management Following Surgery

Radionuclide imaging is used following surgery to establish the presence of remnant thyroid tissue thereby identifying patients who require 131I ablation therapy. Following successful ablation of remnant thyroid tissue, 131I imaging is routinely used to identify patients with biochemical evidence of remnant or recurrent tumor and may also be used to plan the amounts of radioiodine to be administered.

Whilst the use of imaging with tracer doses of 131I to establish the presence of remnant thyroid tissue following surgery for differentiated thyroid carcinoma has been an established practice for many decades, recent concerns that the tracer dose of 131I may influence the efficacy of the subsequent therapy dose of 131I-iodine have been raised.

Standard practice has been to undertake an 131I tracer study using administered activities ranging from 74 to 370MBq (2 to 10mCi). The tracer study permits identification of residual thyroid tissue and also may identify metastatic disease. Whole-body imaging plus local views of the head and neck area are routinely performed, with imaging taking place 48 hours after administration of the tracer dose. As it is essential that TSH levels are elevated to ensure good uptake of the tracer dose, imaging should not be performed less than 4 weeks after surgery or 4 weeks after discontinuing thyroxine (T4) or 2 weeks after discontinuing triiodothyronine (lio-thyronine, T3). An awareness of the normal biodistribution of 131I is essential in interpreting tracer images, and regions of normal biodistribution are listed in Table 27.2. Artifacts due to urine contamination and saliva must also be recognized.

Numerous authors have raised the issue of "stunning" which results in the reduction of uptake of a therapy dose of 131I iodine following a high dose diagnostic tracer scan. The concept of the "stunned" thyroid has raised controversy as to the dose of 131I to be used for these diagnostic studies. Many believe that a large dose is essential, Waxman et al. [25], for example, having shown that identification of an increasing number of remnants was associated with increasing the tracer dose up to 100 MBq (30 mCi) or more. However, several authors have observed that the uptake of a therapeutic dose may be less than that of a preceding diagnostic dose. Even a dose of 5 mCi was found sufficient to reduce the uptake of a therapeutic dose by 54% [26]. Various strategies have been proposed to overcome the problem of stunning. These include using low tracer scan doses of 131I (<185MBq, 5mCi). Whilst data confirms that this strategy reduces the problem of stunning, lower tracer scan doses will reduce the sensitivity of imaging for detecting metastatic disease. Reporting that the induction of the "stunned" thyroid by 370 MBq (10mCi) diminished thyroidal uptake of a 3.7GBq (100mCi) treatment dose, Park et al. [27] recommended that pretherapy scanning should be undertaken with 123I. Murphy et al. [28] have shown that 123I has a sensitivity of 75% compared with 131I if activities of 74MBq (2mCi) are used.

If only an estimate of the amount of remaining normal tissue is required, 99mTc can be used (Figure 27.3A, B)[29], but when, in follow-up studies, identification of possible metastases is sought, an iodine isotope is essential because of the relatively poor trapping avidity of neoplas-tic tissue for 131I.

Another proposed strategy is to assume that the majority of patients undergoing total thy-roidectomy for differentiated thyroid cancer will have small remnants of thyroid tissue and patients are therefore treated with an ablation therapy dose of 131I without prior imaging. Whilst this strategy avoids the problem of stun-ning,it prevents therapy dose adjustment on the

Figure 27.3 A 99mTc pertechnetate scan of a patient's neck after surgical ablation of thyroid for papillary cancer.A small remnant is demonstrated (arrow). B 131I-iodine tracer scan in same patient showing identical pattern of uptake.

basis of the size of the thyroid remnant or dosi-metric calculations to be performed.

Selection of Ablation Dose

Many centers opt for a fixed 131I ablation dose, but others opt for a varied 131I dose based on the size of the thyroid remnant and retention of the tracer dose of 131I. If an 131I tracer study is performed, data may be used to determine an appropriate ablation dose using the following formula. There are few data to suggest that dosi-metric calculations improve the first time ablation rate following a first therapy dose.

A posttherapy 131I scan should be performed in all patients, particularly those who have not undergone an 131I tracer scan prior to ablation therapy. The posttherapy high activity scan has a higher sensitivity for detecting unsuspected metastatic disease compared with the low activity 131I tracer scan (Figure 27.4).

Postablation Management

Following the successful ablation of remnant thyroid tissue, the 131I whole-body scan will show no abnormal foci of uptake in the absence of metastatic disease. It is appropriate to monitor these patients subsequently with thy-roglobulin measurements and to utilize the 131I tracer scan in patients whose thyroglobulin measurements become elevated. Patients who have metastatic disease at the time of diagnosis will require regular 131I tracer scans between treatments to determine the efficacy of 131I therapy (Figure 27.5A, B, C). Tracer scans with 131I should be undertaken using doses of 185 MBq (5 mCi) or less to avoid effects of stunning, although stunning has been only clearly proven as a problem with remnant thyroid tissue. Tracer scans using 131I are not normally performed in less than 6 months following 131I treatment and as the TSH levels must be elevated to optimize the sensitivity of the 131I tracer scan, patients should discontinue thyroid replacement hormone for an appropriate interval or receive human recombinant TSH used to transiently elevate TSH levels [30].

A percentage of patients will be found to have elevated thyroglobulin levels with negative iodine tracer scans. This is a particular issue in patients with Hurthle cell carcinomas in whom only 10% of tumors are iodine avid. Patients

Figure 27.4 131I iodine postablation scan in a patient demonstrating unsuspected widespread metastases from papillary thyroid cancer.

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Figure 27.5 A 131I-iodine posttherapy scan in a patient with metastatic papillary thyroid cancer. B 99mTc diphosphonate bone scan in same patient demonstrating lower sensitivity for detecting bone metastases than 131I-iodine scan. C 131I-iodine scan in same patient following two therapies with 5.5GBq of radioiodine. Significant resolution of many metastatic sites is demonstrated.

ANTERIOR POSTERIOR

with papillary and follicular carcinomas in whom dedifferentiation occurs may also continue to have raised thyroglobulin levels, but become iodine tracer scan negative as a feature of dedifferentiation. Various strategies have been proposed in patients in whom dedifferentiation is suspected. These include a proposal to use to retinoic acid to cause tumor redifferentiation and restoration of tumor iodine uptake capabilities. A number of studies have been published confirming that retinoids will cause redifferentiation in approximately 30% of patients but the duration of this redifferentiation appears short and the longer-term benefit of retinoid treatment remains unclear.

Alternative imaging agents may also be used to identify the location of recurrent disease in 131I scan negative patients to determine oper-ability. The sensitivities of 201Tl and 99mTc tetro-fosmin are comparable with that of 131I for detecting distant metastases (0.85, 0.85, 0.78), although 131I is more sensitive than the other two for detecting postsurgical residual thyroid tissue [31]. Scintigraphic imaging with 201Tl has been thought to reflect the abnormal DNA characteristic of poor prognosis in differentiated thyroid carcinoma [32].

MIBI has been proved to be clinically more useful than 201Tl in detecting lung, lymph node, and bone metastases from differentiated thyroid carcinoma, as image quality was better. The overall sensitivity of the two techniques is not, however, significantly different [33]. The superiority of MIBI in detecting lymph node disease before initial 131I treatment has also been described by Ng et al. [34],who noted that MIBI is not as sensitive as 131I scanning for thyroid remnants or lung metastases.

Both MIBI and 201Tl yield high specificity and positive predictive value for residual thyroid cancer in patients with negative 131I scans who have an increased risk of recurrence after 131I therapy. Both imaging agents have been shown to detect residual cancer and cause a change in management in more than half the patients in whom conventional imaging techniques were unreliable [35].

Another myocardial imaging agent, 99mTc tetrofosmin, has a high sensitivity in detecting metastases and recurrences of thyroid cancer [36]. 99mTc tetrofosmin is both sensitive (86%) and specific for detecting recurrence in patients taking thyroxine and also has a sensitivity of

74% for detecting the sites of recurrence in patients with 131I scan negative disease [37]. Preliminary reports suggest a role for 111In octreotide in this setting [38]. 18FDG-PET has proved useful in detecting cervical nodes and can direct surgical intervention. It can also be used to identify metastases in the mediastinum, thorax, and skeleton. The main value of 18FDG-PET in the management of thyroid carcinoma patients, like that of the other methods above, lies in its ability to demonstrate metastatic sites after negative iodine scanning. Its accuracy is high, particularly for cervical lymph nodes where it has proved particularly helpful for directing surgical management. It can also identify metastases in the mediastinum, thorax, and bone. Studies on patients with thyroglobulin positive and iodine scan negative disease gave sensitivities of between 70% and 90% for detecting iodine negative disease [39,40]. A multicenter study compared the sensitivity of 18FDG-PET,201Tl,and 99mTc-MIBI in 131I scan negative disease. The 90% sensitivity of 18FDG-PET was significantly higher than that of the other scanning agents [41]. The increased metabolic activity of dedifferentiating, aggressive tumors would explain the high 18FDG uptake compared with much lower uptake seen in iodine avid tumors. The 3-year survival of patients with 18FDG positive scans is markedly reduced compared with patients whose scans are negative [42].

Recently, the importance of TSH stimulation in the uptake of 18FDG has been appreciated. In a number of studies, patients have been imaged whilst on TSH suppressive dose of thyroxine and when off thyroxine with a high endogenous TSH. Several studies have confirmed the increased sensitivity of tumor detection in patients off thyroxine [43]. A recent study by Petrich et al. [44] has confirmed that the use of recombinant human TSH prior to imaging with 18FDG increases imaging sensitivity.

In patients with iodine negative, thyroglobulin positive disease, these studies, in conjunction with anatomical imaging, will assist in patient management decisions by identifying whether the recurrence is operable or inoperable due to location or multifocality. 18FDG-PET scanning has the highest sensitivity for detecting dedif-ferentiating recurrent disease, particularly with the patient off thyroxine or after recombinant TSH administration.

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