Management of papillary and follicular (differentiated) thyroid cancer

Endocrine-Related Cancer (2002) 9 227–247

Management of papillary and follicular(differentiated) thyroid cancer: newparadigms using recombinant humanthyrotropin

E L Mazzaferri1 and N Massoll 21Adjunct Professor of Medicine, University of Florida; Emeritus Professor and Chairman of Internal Medicine, Senior ResearchScholar, The Center for Health Outcome Policy Evaluation Studies, The Ohio State University, Ohio, USA2Department of Pathology, University of Florida, Florida, USA

(Requests for offprints should be addressed to E L Mazzaferri, 4020 SW 93rd Drive, Gainesville FL 32608–4653, USA; Email:[email protected])

Abstract

The incidence of differentiated thyroid cancer (DTC) has increased in many places around the worldover the past three decades, yet this has been associated with a significant decrease in DTC mortalityrates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapserates remain high, in the order of 20–40%, depending upon the patient’s age and tumor stage at thetime of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment,but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumorsthat are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 (131I),followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regressionmodeling of 1510 patients without distant metastases at the time of initial treatment and includingsurgical and 131I treatment, the likelihood of death from DTC is increased by several factors, includingage > 45 years, tumor size > 1.0 cm, local tumor invasion or regional lymph-node metastases,follicular histology, and delay of treatment > 12 months. Cancer mortality is favorably andindependently affected by female sex, total or near-total thyroidectomy, 131I treatment andlevothyroxine suppression of TSH. Treatments with 131I to ablate thyroid remnants and residualdisease are independent prognostic variables favorably influencing distant tumor relapse and cancerdeath rates. Delay in treatment of persistent disease has a profound impact on outcome.

Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnosticwhole-body scans (DxWBS) require high concentrations of TSH, which until recently were possibleto achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. Newparadigms, however, provide alternative pathways to prepare patients for 131I treatment and tooptimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult diseasecan now be identified within the first year after initial treatment by recombinant human(rh)TSH-stimulated serum Tg concentrations greater than 2 µg/l, without performing DxWBS. Thesenew follow-up paradigms promptly identify patients with lung metastases that are not evident onroutine imaging, but which respond to 131I treatment. In addition, rhTSH can be given to preparepatients for 131I remnant ablation or 131I treatment for metastases, especially those who are unable towithstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSHfails to increase.


Endocrine-Related Cancer (2002) 9 227–247 Online version via http://www.endocrinology.org1351-0088/02/0-9–227 2002 Society for Endocrinology Printed in Great Britain

Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer

Introduction

The two most common forms of thyroid cancer, papillaryand follicular thyroid cancer, together termed differentiatedthyroid cancer (DTC), comprise the majority of thyroid can-cers and have the best prognosis. The debate surroundingtheir management has been fueled by the fact that no pros-pective randomized trials of treatment have been conductedand none are likely to be done. Each arm of such a study,however, would require nearly 4000 patients to detect a 10%reduction in thyroid cancer mortality after 25 years.Enrollment would take 10 or more years, making the resultsavailable in 35 years (Wong et al. 1990). Our knowledgeabout treatment is woven from a patchwork of large retro-spective cohort studies in which patients have been followedfor decades, providing the fabric of our management para-digms. Much of the following discussion refers to the man-agement of DTC, because the treatments of papillary andfollicular cancer are so similar. Special emphasis is given tonew and emerging paradigms, especially those using recom-binant human thyrotropin (rhTSH) and sensitive thyroglo-bulin (Tg) measurements, which is important becausepatients with DTC often experience tumor relapse decadesafter treatment.

Incidence and prevalence rates

In the USA in 2001, about 9500 new cases and 1300 deathsoccurred from thyroid cancer. Its incidence in the USA hasincreased nearly 50% since 1973 (Ries et al. 2000) and hasbeen increasing in many other countries, including Canada(Liu et al. 2001), Sweden (Pettersson et al. 1996), Norway(Akslen et al. 1993) and Great Britain (Dos Santos Silva &Swerdlow 1993). This is likely due to exposure of the popu-lation to thyroid radiation in the form of external beam radi-ation used in the past to treat benign conditions in childrenand in the form of atmosphere fallout of radioactive iodine(Institute of Medicine 1999) and early diagnosis using fine-needle aspiration biopsy (FNA).

Most (80%) thyroid cancers in the USA are papillarycancers, with follicular cancer comprising only 11% of newcases (Hundahl et al. 1998). Papillary and minimally invasivefollicular cancers are typically slow-growing tumors thatrespond well to treatment. Indeed, a few believe that survivalis so good that DTC poses little risk to patients younger than45 years at the time of diagnosis (Cady 2000). Yet the naturalhistory of DTC unfolds over decades. Ten-year cancer-specific mortality rates in almost 54 000 patients diagnosedin the USA between 1985 and 1995 were about 7% for papil-lary, 15% for follicular and 25% for Hurthle cell cancers(Hundahl et al. 1998). Papillary cancer, the most indolentand most likely to respond to treatment, neverthelessaccounts for more than 50% of the cancer deaths, because itsincidence is so high.

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The prevalence of thyroid cancer in the US population,relatively high because survival is prolonged, is now about220 000 cases, almost all of which are DTC and many ofwhich will recur.

Recurrence (persistent tumor) rates

Recurrence rates with DTC are high, ranging from 20% to40% (Mazzaferri & Jhiang 1994). Distant metastases areoften discovered decades after initial treatment (Fig. 1),underscoring the need for long-term follow-up. What isusually termed recurrent tumor, however, is in fact often per-sistent disease that remains below our surveillance radar for

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Figure 1 Tumor recurrence rates in 1528 patients after amedian of 16.6 years follow-up. There were 359 recurrences(23.5% of patients). Local recurrence (n = 272, 17.8%) iscervical or mediastinal; distant recurrence (n = 114, 7.5%) issites outside the neck. (A) Number of patients withrecurrences at 5-year intervals. (B) Cumulative percent ofrecurrences, distant recurrences and cancer deaths over 40years stratified by age at the time of initial treatment. Patients(n = 27) with both local and distant recurrences are shown asdistant recurrence. Reproduced with permission fromMazzaferri & Kloos (2002).


years before it reappears as clinically evident cancer. Persis-tent DTC, however, can now be detected very early usingnewly devised testing paradigms.

Two-thirds of the cases of persistent tumor are detectedwithin 10 years of treatment, but the others are evident dec-ades later (Fig. 1A) (Mazzaferri & Kloos 2001). Recurrences,including distant metastases, are more common in thoseyounger than 20 and older than 60 years (Fig. 1B) (here andelsewhere, age refers to the patient’s age at the time of initialtreatment). Many lead to death. Almost 70% of those whodied of cancer were considered disease-free after initial treat-ment, succumbing to the disease after a relapse. In ourexperience, 30-year mortality rates are about 12% after localrelapse and 43% after distant recurrence.

Declining mortality rates

Thyroid cancer mortality rates in the USA have fallen 20%between 1973 and 1996 (Ries et al. 2000), probably as theresult of early diagnosis and effective treatment. However,this occurred only in women, probably because they undergoroutine examinations more often than do men, in whom thy-roid cancer is typically discovered two to three decades laterthan it is in women.

Risk stratification

Cause of death from thyroid cancer

Deaths from thyroid cancer are more common in patientsolder than 45 years at the time of surgery and in those withmore advanced tumor stage (Table 1) (Mazzaferri & Kloos2001). Patients with follicular cancer have higher mortalityrates, but tend to be older and with more advanced tumorstage at the time of diagnosis than those with papillarycancer. Few studies give details of the exact cause of deathfrom thyroid cancer. One such study of patients who died ofthyroid cancer, however, shows that respiratory insufficiencycaused by pulmonary metastases led to 43% of the deaths(Kitamura et al. 1999). Other causes are airway obstruction(13%) and massive hemorrhage as a result of uncontrolledlocal tumor (15%), and circulatory failure caused by obstruc-tion of the vena cava (15%).

Current opinions about risk

Clinicians often recommend treatment and follow-up accord-ing to their view of the risk, often without defining it in termsof disease-free survival, persistent disease and cancer death.Certain prognostic factors indicate how, on average, DTCwill proceed (Mazzaferri 1999, Mazzaferri & Kloos 2001).Some are patient characteristics (Table 1). Mortality rates arelow in patients younger than 40 years, but increase incremen-tally thereafter; however, relapse rates are high (�40%)

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during the first two decades of life and after the age of 60years (Fig. 1B) (Mazzaferri & Jhiang 1994). Men have abouttwice the risk of dying from DTC as do women, becausethey present at a later age and with more advanced tumorstage than do women (Mazzaferri & Jhiang 1994, Ries et al.2000).

The second set of prognostic variables relates to thetumor (Table 1). Histologic tumor grade (nuclear atypia,tumor necrosis and vascular invasion) is a strong and inde-pendent prognosticator (Akslen & LiVolsi 2000). A third setof prognosticators relates to treatment, and a fourth concernsfollow-up (Table 2).

Staging systems

There are many staging systems for thyroid cancer. Mostaccurately predict mortality rates. Nevertheless, some in thelowest risk strata in most staging systems die of cancer(DeGroot et al. 1994, Hundahl et al. 1998), particularly whenrisk is simply defined dichotomously as low or high (Cadyet al. 1979, American Joint Committee on Cancer 1992). Inone study (Kitamura et al. 1999), more than 10% of thepatients dying of DTC had an American Joint Committee onCancer/Union Internationale Contre le Cancer (AJCC/UICC)classification of stage 1 or 2 (Table 3).

Another problem is that staging systems using age tostratify risk fail to predict recurrence-free survival andrelapse, mainly because relapse rates are high in youngpatients (Fig. 1B). For example, 35-year cancer relapse rateswere higher among our patients at low risk than among thoseat high risk (56.8% compared with 35.2%, P < 0.001) accord-ing to the age-metastases-extent-size (AMES) staging criteria(Cady 1997). Distant metastases occurred in the low- andhigh-risk categories, respectively, in 89 and 25 patients. TheAJCC/UICC staging system poses similar problems. Moststaging systems are derived from multivariate analyses thatdo not consider recurrence or the effect of treatment, and allrely on some information that is available only after surgery.Relapse-free status and survival cannot be assured by lowtumor stage in most staging systems.

Almost none of the multivariate analyses used to con-struct the clinical staging systems take into account theeffects of treatment, tacitly assuming that treatment does notalter outcome. This shortcoming was recognized by theauthors of the European Organisation for Research andCancer Treatment (EORTC) staging system, the first suchsystem to be devised (Byar et al. 1979). Subsequent authorshave largely ignored this caveat (Cady & Rossi 1988, Hay1990, Hay et al. 1993, Shaha et al. 1995).

Clinical staging schemes do not permit meaningfuldecisions to be made for patients at the time of surgery. Theyare best reserved for epidemiologic studies, for which theTNM classification of the AJCC and UICC (Table 3) is per-haps most useful.


Table 1 Risk stratification of clinical variables influencing cancer recurrence and cancer death

A. Patient variables1. Age < 15 years or > 45 years2. Male sex3. Family history of thyroid cancer4. Previous exposure to thyroidal irradiation (external beam irradiation or exposure to radionuclides from atmospheric

fallout or other sources (children))

B. Tumor variables1. Tumor > 4 cm diameter2. Bilateral (multifocal) thyroid tumors3. Extrathyroidal tumor extension4. Vascular invasion (papillary and follicular carcinoma)5. Cervical, mediastinal lymph node metastases6. Tumor subtypes: Hurthle, tall, cell, columnar cell, diffuse sclerosis, insular variants7. Advanced histologic grade: nuclear atypia, tumor necrosis, vascular invasion8. Tumor that concentrates 131I poorly or not at all9. Distant metastases10. Tumor that concentrates fluorine-18-fluorodeoxyglucose uptake on PET scan

C. Treatment variables1. Delay in diagnosis and treatment2. Less than total or near-total thyroidectomy3. Delay in completing total thyroidectomy after lobectomy4. Failure to give 131I treatment5. Failure to suppress TSH with levothyroxine

D. Follow-up variables1. Failure to measure Tg and perform DxWBS2. Failure to recognize high serum Tg as an indicator of persistent disease

Modified from the National Comprehensive Cancer Network guidelines for the diagnosis and treatment of thyroid cancer(Mazzaferri 1999).

Initial management

Management plan

The five phases of management are: (1) diagnosis, (2) sur-gery, (3) remnant ablation, (4) thyroid hormone suppressionof thyrotropin (THST), and (5) follow-up, including diagnos-tic studies and treatment. Management in each phase isunique and crucial to optimal long-term outcome, but is notalways optimal.

An audit of care found many deficiencies in practice,citing inadequacies in the areas of surgery (20%), sup-pression of thyroxine (T4) (20%), monitoring by serum Tg(15%) and the use of 131I treatment (12%) (Kumar et al.2001). Others identify similar problems in Europe and theUSA (Hardy et al. 1995, Hundahl et al. 1998, Vanderpumpet al. 1998). Because of these deficiencies, leaders in GreatBritain (Kendall-Taylor 2001) called for the establishment ofguidelines for the management of thyroid cancer.

National Comprehensive Cancer Network(NCCN) and British Thyroid Associationguidelines

Explicit guidelines, established in lieu of prospective ran-domized trials but based upon the current literature for the


diagnosis and management of thyroid cancer, were writtenby a panel of multidisciplinary experts from USA CancerHospitals (Mazzaferri 1999) and by the British ThyroidAssociation (2002). Both guidelines give explicit advice andassistance in the management of thyroid cancer, providingcarefully considered algorithms and comprehensive biblio-graphies. The British Thyroid Association Guidelines alsoprovide excellent material for patients.

Diagnosis

Fine-needle aspiration (FNA) cytology is the first diagnostictest for a thyroid nodule in a euthyroid patient. Yet diagnosisis sometimes delayed for years because thyroid cancer occursin an environment teeming with benign nodules (Mazzaferri1993a, Ross 2002). The diagnostic accuracy is considerablyenhanced by ultrasonography and Doppler studies (Marquseeet al. 1997, Papini et al. 2002). In one study the odds ratioof malignancy was 16.8 if ultrasonography showed indistinctor blurred nodule margins, 14.3 with intranodular Dopplerflow and 4.9 with microcalcifications (Papini et al. 2002).The sensitivity of ultrasound-guided FNA and Doppler inevaluating 12 001 patients was 93% and the specificity was75% (Yang et al. 2001).

Despite its efficacy, FNA was not performed before sur-


Table 2 Cox regression model on cancer recurrence, distant metastasis recurrence and death due to thyroid cancer in 1501patients with or without distant metastases at the time of initial treatment

Variable Hazard ratio P value 95% CI

All cancer recurrence (n = 1501)Age* 1.0 0.2 0.9 to 1.3Local tumor invasion 1.4 0.01 1.1 to 2.2Lymph node metastases† 1.3 0.01 1.1 to 1.6Follicular histology 0.8 0.012 0.7 to 0.96Tumor size‡ 1.2 0.0001 1.1 to 1.3Thyroid remnant 131I ablation¶ 0.8 0.016 0.7 to 0.97Treatment with 131I¶ 0.5 0.0001 0.4 to 0.6Surgery more than lobectomy§ 0.7 0.0001 0.6 to 0.9

Distant metastasis recurrence (n = 1501)Age* 1.3 0.0001 1.2 to 1.5Follicular histology 1.0 0.864 0.8 to 1.2Lymph node metastases† 1.6 0.002 1.2 to 2.2Local tumor invasion 1.6 0.927 0.9 to 2.7Tumor size‡ 1.2 0.001 1.1 to 1.3Thyroid remnant 131I ablation¶ 0.6 0.002 0.5 to 0.8Treatment with 131I¶ 0.4 0.0001 0.2 to 0.6Surgery more than lobectomy§ 0.8 0.379 0.6 to 1.2

Cancer mortality (n = 1501)Age* 9.5 0.0001 5.3 to 17.1Time to treatment** 2.4 0.0001 1.5 to 4.0Follicular histology 1.4 0.003 1.1 to 1.8Lymph node metastases† 2.0 0.006 1.2 to 3.4Tumor size‡ 1.2 0.025 1.02 to 1.3Local tumor invasion 1.1 0.002 1.0 to 1.2Female (versus male) 0.6 0.046 0.4 to 0.99Thyroid remnant 131I ablation¶ 0.5 0.0001 0.4 to 0.7Surgery more than lobectomy§ 0.5 0.0001 0.4 to 0.7Treatment with 131I¶ 0.4 0.010 0.2 to 0.8

Reproduced with permission from Mazzaferri & Kloos (2002).*Age stratified as less than 40 years versus 40 years and older for cancer mortality, and by decade for recurrences and distantrecurrences.†Lymph node metastases present versus absent.‡Tumor diameter stratified into 1 cm increments from tumors smaller than 1 cm to > 5 cm.¶Remnant ablation is the use of 131I in patients with uptake only in the thyroid bed and no evidence of residual tumor; Treatmentwith 131I is postoperative treatment of patients with known residual disease.§Bilateral thyroid surgery versus lobectomy with or without isthmusectomy.** Time to treatment � 12 months versus > 12 months.

gery in about 40% of 5584 patients with thyroid cancer inone study in the USA (Hundahl et al. 2000). North Americanendocrinologists, however, use FNA routinely to evaluatethyroid nodules, performing it early and relying heavily onits results (Bennedbaek & Hegedus 2000). In contrast, evalu-ations by primary care physicians are more costly and moretime consuming, causing a delay of 12 months or longer inalmost 30% of the patients managed in one New York study(Ortiz et al. 1998). This increases mortality rates signifi-cantly. Mortality rates from thyroid cancer begin rising after12 months’ delay in diagnosis, increasing up to 40-fold when10 or more years has elapsed from the time a nodule is firstpalpated until its treatment (Mazzaferri & Jhiang 1994).


Initial surgery

Although debate continues to swirl around the initial treat-ment of DTC (Mazzaferri & Kloos 2001), total or near totalthyroidectomy that leaves less than 2 g (2 cm2) of thyroidtissue is performed in most large centers for the majority ofpatients. Studies from the USA, Europe and Hong Kongshow that most patients at risk for relapse or death from thy-roid cancer (tumors 1 cm or larger) are treated with total ornear-total thyroidectomy, usually followed by 131I and levo-thyroxine treatment (Van De Velde et al. 1988, Baldet et al.1989, Solomon et al. 1996, Sherman et al. 1998, Mazzaferri1999, Cailleux et al. 2000, Hundahl et al. 2000, Chow et al.2002). External beam irradiation, which has a less prominent


Table 3 Definition of TNM and AJCC/UICC clinical stages

Definition of TNM T Primary tumorTX Cannot be assessedT0 No evidence of primary tumorT1 < 1 cmT2 1–4 cmT3 > 4 cmT4 Tumor of any size beyond thyroid capsuleN Regional lymph nodesNX Cannot be assessedN0 Not presentN1 PresentM Distant metastasesM0 NoneM1 Present

Clinical stage Stage 1 Patients < 45 years with any T, any N, M0Patients > 45 years with T1

Stage 2 Patients < 45 years with any T, any N, M1Patients > 45 years with T2–3

Stage 3 Patients > 45 years with T4 or N1Stage 4 Patients > 45 years with M1

role in initial management and usually follows 131I treatment,is best given postoperatively to patients older than 40 yearswith TNM stage T4 tumors (Simpson et al. 1988, Farahati etal. 1996, Tsang et al. 1998, Mazzaferri 1999, Chow et al.2002) or unresectable gross residual disease (Simpson et al.1988, Mazzaferri 1999).

Performing lobectomy alone as the definitive surgerymay lead to a 5–10% recurrence rate in the opposite thyroidlobe (Hay et al. 1987, Mazzaferri 1993b), a high tumor recur-rence rate (Fig. 2) and a high (11%) rate of relapse in the

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Figure 2 Tumor recurrence after thyroid surgery and thyroidhormone (T4) treatment with and without 131I treatment (RAI).Total = thyroidectomy including subtotal thyroidectomy(ipsilateral lobectomy, isthmusectomy and near-totalcontralateral lobectomy); subtotal = lobectomy with or withoutisthmusectomy. Patients undergoing total thyroidectomy hadmore advanced tumor stage than those undergoing subtotalthyroidectomy (ANOVA, P < 0.001). Modified fromMazzaferri & Kloos (2002).


form of pulmonary metastases (Massin et al. 1984). Highrelapse rates with cervical lymph node metastases and multi-centric tumors (Mazzaferri & Jhiang 1994) justify total ornear-total thyroidectomy and 131I ablation. If lobectomy isperformed, diagnostic 131I imaging may miss microscopicmetastases in the contralateral lobe or elsewhere when theyare most amenable to treatment. We found that surgery con-sisting of more than lobectomy was an independent variableaffecting cancer relapse (Table 2). Others report a similareffect of surgery on tumor recurrence (DeGroot et al. 1994,Chow et al. 2002).

It is more difficult to demonstrate that total or near-totalthyroidectomy influences survival, although there is con-siderable proof that it influences relapse-free survival. Onestudy, for example, found no improvement in survival ratesafter patients with low-risk papillary cancers (Age, Grade,Extent, Size (AGES) score �3.99) underwent more thanlobectomy (Hay et al. 1987). The same authors, however,later recommended that bilateral thyroid resection should beperformed for low-risk papillary cancer, after finding that the20-year rates for local recurrence and nodal metastasis were,respectively, 14% and 19% after unilateral lobectomy, com-pared with 2% and 6% (P = 0.0001) after bilateral thyroidresection (Hay et al. 1998). Others have demonstrated areduction in cancer mortality by more extensive surgery inpatients without distant metastases, but this was mainlyattributable to its effect on T4 tumors (DeGroot et al. 1994).Postoperative 131I treatment obscures the therapeutic impactof surgery. Patients in our study treated with total or near-total thyroidectomy plus 131I ablation and levothyroxine hadsignificantly fewer local recurrences and distant relapses thanthose treated with any other combination, including total thy-roidectomy and levothyroxine alone (Mazzaferri & Kloos2001). Surgery, more than lobectomy, had an independent


effect on recurrence and cancer death distinct from 131I,which after a median follow-up of 16.6 years reduced therisk for mortality by 50% (Table 2) (Mazzaferri & Kloos2001).

The NCCN guidelines

Cervical lymph node metastases are found in 50–80% ofcases of papillary cancer, most often in the central paratra-cheal (Level VI) compartment, followed in descending orderby mid-jugular (Level III), supraclavicular (Level IV), andsubdigastric nodes (Level I) (Mirallie et al. 1999). In ourstudy, lymph node metastases, especially bilateral cervicaland mediastinal, were an independent variable that affectedrecurrence and survival (Mazzaferri & Kloos 2001). Somereport that systematic compartment-oriented dissection oflymph node metastases significantly improves recurrence(P > 0.0001) and survival (P > 0.005) rates in patients withT1–T3 tumors (Scheumann et al. 1994). The NCCN guide-lines recommend total thyroidectomy and, if lymph nodes areinvolved, bilateral central compartment dissection or lateralmodified radical neck dissection, as the primary treatment ofhigh-risk DTC (Mazzaferri 1999). For follicular tumors notidentified as cancer before operation, the guidelines suggestlobectomy, followed by total thyroidectomy for minimallyinvasive follicular cancers larger than 4 cm.

The British Thyroid Association guidelines

Total thyroidectomy and 131I ablation are recommended forpapillary cancers larger than 1 cm, and for papillary tumorsthat are multifocal or have spread beyond the thyroid glandby extension or have metastasized, and for familial tumorsand those due to irradiation. Removal of all lymph nodeswithin the central compartment of the neck (level VI), whichincludes those in the pre- and paratracheal regions, is rec-ommended in addition to removing involved lateral lymphnodes by selective dissection. Neither guideline recommendsroutine radical neck dissection. Lobectomy is advised for fol-licular tumors not identified as cancer before operation. Forfollicular cancers larger than 1 cm, the British guidelinesadvise total thyroidectomy and 131I, and similar treatment ofsmaller follicular cancers that are widely invasive.

Consensus recommendations

Most US and European specialists opt for total or near-totalthyroidectomy when the diagnosis is known (Van De Veldeet al. 1988, Baldet et al. 1989, DeGroot et al. 1994, Solomonet al. 1996, Mazzaferri 1999, Cailleux et al. 2000, Hundahlet al. 2000). This also applies to children and young adults,because 60–80% have regional lymph node involvement and10–20% have distant metastases (Mazzaferri 1991, Hay et al.1998, Miccoli et al. 1998, Newman et al. 1998, Schlum-


berger 1998, La Quaglia et al. 2000). Of 50 children aged 15or younger in our study, 28% developed distant metastases,usually to lung. Only 8% were found on initial presentation,the remaining 20% appearing as relapses (Fig. 1B). Althoughthe overall long-term survival rate in children is greater than90%, disease-free survival is enhanced by complete tumorresection (Scheumann et al. 1994, Newman et al. 1998).

Completion thyroidectomy

This refers to a separate operation to resect the contralaterallobe when ipsilateral lobectomy has been done. It should beperformed when a tumor has the potential for recurrence(Mazzaferri & Kloos 2001). Ablating a large remnant with131I is not recommended, because it causes radiation thyroid-itis with pain and swelling, and may cause thyrotoxicosis.Also, a large thyroid remnant prevents TSH concentrationsfrom increasing above 30 mU/l after the levothyroxine with-drawal that is necessary for tumor 131I uptake (Goldman etal. 1980), without which incomplete tumor ablation results(Burmeister et al. 1991, Maxon et al. 1992).

This surgery has a low complication rate when per-formed by an experienced surgeon, and may help unmaskhidden metastases and enhance survival. Cancer is found inthe contralateral lobe in about 50% of cases (Pasieka et al.1992, Mazzaferri 2000). Lung and lymph node metastasesin more than 60% of a group of irradiated children fromChernobyl could only be identified after completion thyroid-ectomy had been done (Miccoli et al. 1998). In anotherimportant study, multivariate analysis found that patientswho underwent completion thyroidectomy within 6 monthsof their initial operation developed significantly fewer lymphnode and hematogenous recurrences and survived signifi-cantly longer than those in whom the second operation wasdelayed for longer than 6 months (Scheumann et al. 1996).Completion thyroidectomy should be performed for anypatient who has undergone lobectomy for tumor of stage> T1 ( > 1 cm), or has recurrent cancer or tumor in the resec-tion margins or metastases (Mazzaferri 1999).

Radioiodine ablation of residual normalthyroid tissue

Some 131I uptake usually is seen in the thyroid bed after totalthyroidectomy (Cholewinski et al. 2000). Destruction of thismacroscopically normal thyroid tissue with 131I is termed thy-roid remnant ablation. Although a few debate this practice(Hay 1990), there are compelling reasons for it (Mazzaferri1997). Firstly, a large remnant can obscure 131I uptake in cer-vical or lung metastases (Vassilopoulou-Sellin et al. 1993,Miccoli et al. 1998). Secondly, the high TSH concentrationsnecessary to enhance tumor 131I uptake cannot be achievedwith a large thyroid remnant (which should be surgicallyexcised) (Goldman et al. 1980). Thirdly, measurement of


TSH-stimulated Tg is the most sensitive way to detectcancer, providing there is no normal thyroid tissue present(Spencer et al. 1998). Fourthly, lung metastases sometimesare seen only on the post-treatment whole-body scan(RxWBS) after 131I remnant ablation (Schlumberger et al.1997, Wartofsky et al. 1998). Lastly, remnant ablation maydestroy microscopic metastases or normal follicular cellsdestined to become malignant (Sugg et al. 1998), preventinglate relapse from an occult cancer (Fig. 1).

Multifocal papillary cancers

Multifocality is common in papillary thyroid cancers(Mazzaferri & Jhiang 1994). Although they have long beenconsidered to be intraglandular metastases and not individualtumors arising de novo, current evidence suggests the oppo-site. A study found that only two of 17 patients with multifo-cal tumors had identical RET/PTC gene rearrangements inmicroscopic multifocal tumors within the same gland,whereas the other 15 patients had diverse RET/PTCrearrangements in tumors within the same thyroid gland, sug-gesting that individual tumors arise independently in a back-ground of genetic or environmental susceptibility (Sugg etal. 1998). This explains why contralateral lobe recurrencesare found years after lobectomy.

Indications for thyroid 131I remnant ablation

This decision is tightly linked to that for performing total ornear-total thyroidectomy. Remnant ablation should be donewhen there is uptake in the thyroid bed in a patient withoutknown foci of cancer after resection of a tumor that has thepotential for recurrence (Mazzaferri & Kloos 2001). If thereis less than 0.5% thyroid bed uptake at 48 h 6–12 monthsafter 131I ablation, repeating the ablation is unlikely to be offurther benefit. Such a small amount of 131I uptake is unlikelyto represent the source of high serum Tg concentrations( > 10 µg/l) (Grunwald et al. 1996). As a practical matter,almost every patient who has undergone total or near-totalthyroidectomy has 1% or more 131I uptake in the thyroid bedthat requires ablation. Once levothyroxine has been with-drawn and the patient has followed a low-iodine diet forimaging, remnant ablation can be done on the same day as adiagnostic whole-body 131I scan (DxWBS), often on an out-patient basis (Mazzaferri & Jhiang 1994, Tsang et al. 1998).

Therapeutic efficacy of 131I remnant ablation

We found lower recurrence and mortality rates after 131Iablation (Mazzaferri 1997, Mazzaferri & Kloos 2001), butnot all find this (Hay 1990). Remnant ablation decreasedrelapse of tumors larger than 1 cm in one study, includinglow-stage tumors predicted to have a good prognosis; how-ever, it reduced the risk of death only in those with more


advanced disease (DeGroot et al. 1990). In yet another study,the rates of pulmonary metastases among 58 patients withDTC were 11% after partial thyroidectomy, 5% after subtotalthyroidectomy and 131I, 3% after total thyroidectomy, andonly 1.3% after total thyroidectomy and 131I (Massin et al.1984). Among 321 patients treated with 131I in 13 Canadianhospitals, mainly to ablate normal thyroid tissue in patientswith microscopic residual papillary or follicular cancer, localdisease was controlled more often with either postoperativeexternal beam radiotherapy or 131I therapy, or both together,than with levothyroxine alone (P < 0.001) (Simpson et al.1988). Survival at 20 years of patients treated by surgeryalone was less favorable (about 40%) than after treatmentwith either 131I or external radiation (about 90%, P < 0.01),whereas 131I treatment without obvious residual disease didnot increase survival (Simpson et al. 1988). In a later studyfrom Canada of 382 patients with DTC, thyroid ablation withtotal thyroidectomy and 131I was associated with a signifi-cantly lower rate of local relapse, regardless of tumor stage(Tsang et al. 1998).

Among 230 patients who had undergone remnantablation and 789 treated with levothyroxine alone, the recur-rence rate with levothyroxine alone was fourfold(P < 0.0001) and the rate of distant relapse fivefold (P < 0.02)that following remnant ablation after a median follow-up of18.9 years (Mazzaferri & Kloos 2001). Patients over the ageof 40 years with tumors 1.5 cm or larger experienced fewercancer deaths 40 years after thyroid remnant ablation thanafter the other treatment strategies (P < 0.0001)(Mazzaferri & Kloos 2001). Multivariate analyses show theextent to which 131I ablation improves outcome. On the basisof regression modeling for 1510 patients without distant met-astases at the time of initial treatment, we found remnantablation was an independent variable that reduced cancerrecurrence, distant recurrences and cancer death rates (Table2). Another study found that the prognostic variables por-tending cancer death were age over 45 years, postoperativegross locoregional residual disease, distant metastasis atpresentation, and lack of 131I treatment (Chow et al. 2002).Multivariate analysis showed that patients without distantmetastases and obvious residual tumor who underwentthyroid ablation had fewer locoregional relapses (relative risk(RR) = 0.29) and distant metastases (RR = 0.2) than thosetreated with levothyroxine alone. Total or near-total thyroid-ectomy followed by 131I treatment thus results in the bestoutcome.

Choosing the 131I activity for thyroid remnantablation

Many use about 1110 MBq to ablate a remnant if the amountof thyroid tissue remaining after surgery is small, because itavoids admission to hospital, which is no longer necessaryin the USA (Brierley & Maxon 1998). Radiation exposures


of household members of patients given more than 1110MBq are well below the limit (5.0 mSv) mandated by USnational regulations (Grigsby et al. 2000). Small 131I activi-ties have appeal because of the lower cost and lower whole-body radiation to the patient, which has been estimated to be6.1 mSv for 1110 MBq, 8.5 mSv for 1850 MBq, and 12.2mSv for 2220 MBq (DeGroot & Reilly 1982). Although 3700MBq of 131I may cause salivary injury and transient loss oftaste, it causes no permanent ovarian or testicular failure andposes virtually no risk for leukemia (Mazzaferri 1986, 2002).

Stratifying 131I ablation treatments into two groups, alow-dose group of 62 patients (46%) treated with 1073–1850MBq 131I and a high-dose group of 72 patients (54%) treatedwith 1887–7400 MBq, we found 30-year relapse rates weresimilar in both groups (4% and 6% respectively, P = 0.1). Ameta-analysis found that high-dose remnant ablation (2775–3700 MBq) is more efficient than low-dose ablation (about1110 MBq), particularly after less than total thyroidectomy,suggesting DTC should be treated with total thyroidectomyfollowed by a higher dose of 131I (2775–3700 MBq) for rem-nant ablation.

Diagnostic 131I whole-body scans andpost-therapy whole-body scans

Performing a whole-body scan is not very useful when thereis a large thyroid remnant that prevents TSH from increasingabove 30 mU/l or shows a star burst artifact from extensiveuptake in the neck obscuring tumor uptake. An RxWBS,which otherwise often detects tumor foci not seen on theDxWBS, should always be performed after 131I therapy(Schlumberger et al. 1997, Cailleux et al. 2000). This is mostlikely to yield important information when the Tg concentra-tion is > 10 µg/l in a patient who is clinically free of diseasewith negative DxWBS, neck ultrasonography and computedtomography.

Thyroid stunning

Administering more than 111 MBq 131I may have a suf-ficiently harmful effect upon the tissue in which it concen-trates to interfere with subsequent 131I uptake for severalweeks – a phenomenon termed ‘thyroid stunning’ (Park etal. 1994, Leger et al. 1998, Muratet et al. 1998). Using 64MBq or 111 MBq 131I or 20 MBq 123I for DxWBS avoidsthis, but may not identify metastases (Muratet et al. 1997,Leger et al. 1998). A DxWBS with 48–56 MBq 123I producesgood images but is very expensive (Mandel et al. 2001).Delaying 131I treatment several weeks after performing aDxWBS may be responsible for stunning (Leger et al. 1998,Muratet et al. 1998), which did not occur in 172 patientstreated with 131I within 72 h of having had a 185 MBq 131IDxWBS (Cholewinski et al. 2000). Although a DxWBS isusually performed postoperatively to determine the optimal


therapeutic 131I activity, another approach is to perform anRxWBS after empirically administering 3700 MBq 131I onthe basis of high Tg concentrations.

Two studies report that stunning has no impact on 131Iablation. One found that 21% of 378 patients showed evi-dence of thyroid stunning, yet follow-up scans after 131Iablation were negative and serum Tg concentrations wereless than 3 µg/l in most of the group (Bajen et al. 2000).Another study found ablation rates after 3700–7400 MBq 131Iwere respectively 65% and 67% in patients who had or hadnot undergone a DxWBS with 3700–7400 MBq 131I (Morriset al. 2001). It thus appears that stunning has little or noimpact on therapeutic outcome.

False-positive 131I scans

A false-positive scan, which might lead to unnecessary treat-ment, may be caused by 131I in body secretions, pathologictransudates and areas of inflammation (Greenler & Klein1989). Metastatic disease may be mimicked by physiologicsecretion of 131I in the nasopharynx, salivary and sweatglands, stomach, and genitourinary tract, and from skin con-taminated by urine, sputum or tears (Mitchell et al. 2000).Diffuse hepatic 131I uptake on RxWBS, which can be mis-taken for hepatic metastases, is a result of 131I-labeled Tg thatis seen in 40% of 1110 MBq scans and in 70% of 5550–7400 MBq studies (Chung et al. 1997). This usually rep-resents residual thyroid tissue or metastases (not to the liver)that iodinate Tg, even when there is no visible uptake in thethyroid bed or metastases on RxWBS (Chung et al. 1997).

Follow-up assessments after initialsurgical and 131I treatment

The aim of postsurgical follow-up for DTC is the early iden-tification of the small proportion of patients – usually about20% – who have residual tumor or develop a recurrence.When total thyroidectomy and 131I ablation have been theinitial treatment, three powerful tools are available for thefollow-up: measurement of basal and TSH-stimulated serumTg, whole-body radioiodine scans, and neck ultrasonography(Pacini 2002). Serum Tg measurement is the most sensitiveand specific marker of DTC. Undetectable serum Tg concen-trations that do not increase in response to TSH stimulationare found in most patients who are disease-free, whereasincreased serum concentrations of Tg are associated with thepresence of residual normal thyroid tissue or metastatic DTC.In the last case, whole-body radioiodine scans under TSHstimulation (either after withdrawal of L-thyroxine treatmentor after rhTSH stimulation) and neck ultrasonography are themost informative tests for the detection of distant or localmetastases that require further treatment. Using this strategy,most patients will achieve definitive cure and will have anormal quality of life.


Determination of serum Tg

Serum Tg determinations and DxWBS are the first tests ordi-narily used to detect DTC after thyroid ablation. Neither isreliable, however, when there is a large thyroid remnant,because both require high serum TSH concentrations, usuallyaround 25–30 mU/l, to optimize their sensitivity. Althoughthe two tests are complementary (Torrens & Burch 1996), alow TSH-stimulated Tg alone is often sufficient to rule outpersistent tumor. The results of Tg assays may vary in differ-ent laboratories, even with the use of the international Tgstandard (Spencer et al. 1996), but low Tg concentrationsalone after TSH stimulation in an assay with a 1 µg/l func-tional sensitivity will identify patients who are free of disease(Cailleux et al. 2000). Persistent tumor is rarely found whenthe serum Tg values are less than 2 µg/l after rhTSHstimulation (Haugen et al. 1999) or less than 5 µg/l afterlevothyroxine withdrawal (Ozata et al. 1994). Nonetheless, ameasurable Tg is indicative of thyroid tissue – normal ormalignant – since no other tissues falsely increase it.

Six to 12 months after thyroid ablation, when patients areclinically free of disease, the Tg alone after rhTSH can usuallyserve as a guide for selecting patients who require further test-ing or treatment; however, the DxWBS after levothyroxinewithdrawal or rhTSH only provides evidence of the comple-tion of 131I remnant ablation, but rarely identifies residualdisease (Cailleux et al. 2000, Pacini et al. 2001c, 2002,Mazzaferri & Kloos 2002). A 185 MBq DxWBS is relativelyuseless compared with administering 3700 MBq followed byan RxWBS when the Tg increases above some arbitrary limitsuggesting the presence of metastases – usually around 10µg/l (Schlumberger et al. 1997, Cailleux et al. 2000).

Antithyroglobulin antibodies (TgAb)

Found in up to 25% of patients with DTC, compared withabout 10% of the general population, TgAb concentrationsmust be measured in the same serum sample in which Tg ismeasured, and when present usually invalidate the serum Tgresult (Mariotti et al. 1995, Spencer et al. 1998); however,some challenge this point (Schlumberger & Baudin 1998). Inthe presence of high serum TgAb titers, immunometric assay(IMA) methods are prone to underestimating the serum Tgconcentration, increasing the risk of a false-negative test,whereas high Tg concentrations in this situation are likelyindicative of residual cancer. Indeed, the presence of TgAbin the serum does not entirely render the serum Tg measure-ment useless. For instance, even in the presence of interferingTgAbs, a detectable serum Tg measured by IMA is usuallyindicative of disease, particularly if the concentrationincreases in response to TSH stimulation. Moreover, a highserum TgAb titer correlates with the presence of tumor, dis-appearing within 2 years or less of its complete ablation(Spencer et al. 1998).


Thyroglobulin mRNA

The detection of circulating tumour cells in patients withDTC may precede the detection of relapse by other diagnos-tic studies such as serum Tg measurement, and thus mayhave important therapeutic and prognostic implications.Serum Tg measured by Tg mRNA in the presence of serumTgAb titers is more sensitive than the Tg IMA method forthe detection of DTC, but the test is not widely available(Ringel et al. 1998, Wingo et al. 1999, Biscolla et al. 2000).Moreover, some question its clinical value. Tg mRNAexpression was found not to be specific for thyroid tissue andnot to correlate with a diagnosis of thyroid cancer(Bellantone et al. 2001). Some find no difference in TgmRNA expression in patients with or without metastasis,reporting no correlation between serum Tg concentrationsand the Tg concentrations estimated by mRNA, raising ques-tions regarding both the clinical applicability of Tg RT-PCRand the quantitative measurement of Tg mRNA in peripheralblood (Takano et al. 2001).

Withdrawal of thyroid hormone suppressivetreatment

Stopping levothyroxine for 4–6 weeks and substituting tri-iodothyronine (T3) until 2 weeks before doing a DxWBS andmeasuring Tg has been, until recently, the standard way ofinducing hypothyroidism, which causes physical limitationsfrom muscle stiffness, cognitive impairment, emotional dys-function and, in some studies (Dow et al. 1997), negativepsychological alterations and major disruption of a patient’sfamily, social and work life. Many patients with DTC aremiddle-aged and active, and some opt to forgo testingbecause they suffer such debilitating symptoms; if they dosubmit to it, most are unable or unwilling to tolerate hypothy-roidism more than once yearly. After levothyroxine has beenreinstated, symptoms of hypothyroidism may persist forweeks and TSH concentrations may remain increased for aslong as 90 days, which may induce tumor growth (Maini etal. 1994). Some patients are unable to mount an adequateendogenous TSH response to levothyroxine withdrawalbecause of hypopituitarism, and others have medical con-ditions such as renal failure or heart failure that precludeinducing hypothyroidism (Mazzaferri & Kloos 2000).

Recombinant human thyroid-stimulatinghormone

Administering rhTSH increases serum TSH concentrationssufficiently to stimulate thyroidal 131I uptake and Tg releasewhile the patient continues taking levothyroxine (Ladensonet al. 1997). Given on two successive days in a multicenterstudy, rhTSH produced DxWBS results that were equivalentto those after levothyroxine withdrawal in 66% of thepatients, superior in 5% and inferior in 29%, proving that it


stimulates 131I uptake, albeit with lower sensitivity than afterlevothyroxine withdrawal (Ladenson et al. 1997). Anothermulticenter study used different scanning methodology,taking into account the lower renal 131I clearance in hypo-thyroidism than with rhTSH, and demonstrated that DxWBSresults were superior after rhTSH in 4% and after levothyr-oxine withdrawal in 8%, and concordant in 89% (P = NS)(Haugen et al. 1999). The main findings were that DxWBSand a Tg �2 µg/l detected 100% of those with metastatictumor, although rhTSH-stimulated Tg �2 µg/l alone, but notthe DxWBS, accomplished the same thing.

A clinical study of 289 patients, many with advanceddisease, undergoing routine follow-up testing found that theDxWBS and serum Tg responses were not different in 161patients prepared for testing by thyroid hormone withdrawaland 128 patients who continued levothyroxine and receivedrhTSH (Robbins et al. 2001a). No significant differenceswere found in the positive or negative predictive valuesbetween the two groups, but the greatest negative predictivevalue (97%) was in patients who received rhTSH and hadboth a negative DxWBS and low rhTSH-stimulated Tg con-centrations.

The recommendations are to administer rhTSH 0.9 mgon two consecutive days, followed by at least 4 mCi 131I onday 3 and a DxWBS and Tg measurement on day 5. Imagesare acquired after 30 min of scanning or after 140 000 counts.A Tg �2.0 µg/l 72 h after the last rhTSH injection indicatesthat thyroid tissue – normal or malignant – is present,which may be identified on the rhTSH-stimulated DxWBS(Haugen et al. 1999). Mild, transient headache and nauseaare its main adverse effects, affecting about 10% of patients,without causing the dysphoria of hypothyroidism (Ladensonet al. 1997).

Preparation with rhTSH for treatment

Although initially approved only for diagnostic use in theUSA, rhTSH has been given to prepare patients for 131I thy-roid ablation and treatment of residual disease. Since April1995, rhTSH has been given in a compassionate-use programto more than 100 patients in whom, for one reason oranother, levothyroxine could not be stopped (Perros 1999).A number of small studies show its effect in preparingpatients for 131I remnant ablation and treatment of persistenttumor.

Patients prepared by rhTSH stimulation for thyroid rem-nant ablation given an average of 1070 MBq 131I after surgerywere all found to have complete resolution of visible 131Iuptake in the thyroid bed within 5–13 months (Robbins et al.2001b). In addition, rhTSH has been used to prepare patientsfor 131I treatment of distant metastases.

Hepatic metastases were treated in a 46-year-old womanwith follicular thyroid cancer arising from a struma ovarii(Rotman-Pikielny et al. 2000). After the tumor and her thy-


roid gland were removed, an rhTSH-stimulated DxWBSrevealed 17 discrete hepatic foci of 131I uptake. An amount ofrhTSH-stimulated 131I that would deliver an optimal absorbedradiation dose ( > 8000 rad/lesion) without injuring the liveror bone marrow was calculated and administered without anadverse effect. Six months later, her liver metastases showeda significant but partial response. This strategy, which isreported in detail (Rotman-Pikielny et al. 2000), can beapplied to determine a safe and effective dose of 131I for thetreatment of thyroid cancer metastases that produce enoughthyroid hormone to preclude stimulation of endogenous pitu-itary TSH secretion.

Others have reported treating distant metastases afterstimulation with rhTSH. A study of older patients, some withdistant metastases, who were unable to tolerate levothyroxinewithdrawal, received 4000 MBq 131I after being preparedwith rhTSH (Berg et al. 2002). After one or two coursesof rhTSH-stimulated 131I treatment, clinical, laboratory andradiological findings improved in about 50% of the patients,including an 80% decrease in 131I uptake in metastases, lowerserum Tg concentrations, and a decrease in bone pain andother symptoms. Patients reported an improvement in theirphysical condition and quality of life. Despite being elderlyand frail, they tolerated treatment well except for transientlyincreased bone pain, and an enlarging soft-tissue lesion inone patient. Another study of patients with advanced tumorwho received rhTSH in preparation for 131I treatment showeda 30% decrease in serum Tg concentrations, which beforetreatment ranged from 25 to nearly 30 000 µg/l (Luster et al.2000). Several patients showed clinical improvement, withdecreased or stabilized tumor size, and none had an adverseevent. The authors felt that, without the use of rhTSH, 131Itreatment of their patients would not have been possible. Inanother study, patients with advanced tumor who underwentrhTSH-stimulated 131I treatment while taking levothyroxineall showed tumor 131I uptake on the RxWBS (Lippi et al.2001). Serum Tg concentrations decreased in 50% of thepatients 3–12 months later, and one metastatic tumor becamesmaller. Preparation with rhTSH was well tolerated, but afew patients experienced mild transient fever and nausea andshort-lived peritumoral pain and swelling of bone metastases.Another article (Pellegriti et al. 2001) described the treatmentof patients with metastatic DTC, with bone and lung metast-ases or local disease, in whom the use of rhTSH was effec-tive in preventing complications that patients had previouslyexperienced during hypothyroid-induced levothyroxine with-drawal. rhTSH-stimulated 131I treatment induced a 50%reduction in the size of bone metastases in two patients, andthe others remained stable after 131I treatment. Another articlereported the management of a man with papillary thyroidcancer and polycystic renal disease with failure who couldnot tolerate reduction of renal blood flow induced by hypo-thyroidism. He was given rhTSH and treated with 131I on fouroccasions over 3 years to ablate bilateral lung metastases that


intensely concentrated 131I on RxWBS, and showed resol-ution of uptake over time (Mazzaferri & Kloos 2000).

The main complications with rhTSH-stimulated 131I treat-ment are transient, but sometimes severe, bone pain, tumorgrowth, and serious neurologic effects in patients with centralneck, bone, brain or vertebral metastases (Braga et al. 2001,Vitale et al. 2002). As with hypothyroid 131I treatment,patients prepared with rhTSH who have metastases suscep-tible to causing complications by radiation-induced tumorswelling should be pretreated with glucocorticoids if surgeryis not possible. The studies reviewed above show that rhTSHprovides sufficient sodium–iodide symporter stimulation inthyroid tissues and metastases to make it possible to treatthem with 131I.

Serum Tg concentrations during long-termfollow-up

Thyroglobulin concentrations during THST should be unde-tectable or low ( < 1 µg/l) in patients who are free of disease,but are more accurate when serum TSH concentrations areincreased (Pacini et al. 1985, Haugen et al. 1999). In patientswith undetectable Tg concentrations during THST who haveno clinically apparent residual cancer, measurement of anrhTSH-stimulated Tg concentration distinguishes those whoare truly disease-free from those with tumor who requirefurther diagnostic testing, therapeutic procedures, or both(Pacini et al. 2001c, Haugen et al. 2002, Mazzaferri & Kloos2002). Patients who are free of disease have undetectable orvery low serum Tg concentrations before and after levothy-roxine withdrawal (Cailleux et al. 2000).

An increased serum Tg determination shortly after sur-gery might be indicative of a patient’s tumor status (Lima etal. 2002). One study, for example, found that an initial Tggreater than 70 µg/l had a 90% positive predictive value formetastases (Ronga et al. 1999). Nevertheless, the Tg mayremain high for a year or more after 131I treatment beforespontaneously becoming undetectable (Cailleux et al. 2000,Pacini et al. 2001a,b). During long-term follow-up, Tgshould be measured after levothyroxine withdrawal or rhTSHadministration, which lowers the false-negative rate wellbelow that of DxWBS (Pacini et al. 1985, Haugen et al.1999, Cailleux et al. 2000).

One study revealed that the serum Tg in 76% of patientswith low basal values ( < 2 µg/l) during THST remained lowafter rhTSH and no 131I uptake was seen on any DxWBS,whereas Tg in the others increased to 22.0 ± 5.75 µg/l andhalf had 131I uptake visible on DxWBS (David et al. 2001).In contrast, when basal serum Tg was > 2 µg/ml duringTHST, it increased in response to rhTSH in all patients,increasing to 55.3 ± 12.75 µg/l, yet 131I uptake on DxWBSwas not evident in 25% of the patients. The authors con-cluded that an rhTSH-stimulated Tg may identify persistentdisease and is of greater diagnostic value than DxWBS in


patients with low ( < 2 µg/l) basal serum Tg concentrationsduring THST. This has been substantiated by several otherstudies.

Haugen et al. (2002) found that 12% of 83 patients pre-viously treated with total thyroidectomy and 131I ablation hada positive DxWBS that usually (80%) showed uptake onlyin the thyroid bed, and only one of five that were treated orhad further evaluation on the basis of the DxWBS findingshad a serum Tg < 2 µg/l. In contrast, 18 patients with a nega-tive DxWBS were treated or further evaluated on the basisof an rhTSH-stimulated Tg < 2 µg/l (23% of the studygroup). The authors concluded that an rhTSH-stimulatedserum Tg is a more sensitive indicator of tumor than is theDxWBS.

Another study of 72 patients who were clinically free ofdisease and had serum Tg < 1 µg/l during THST revealedthat rhTSH-stimulated Tg measurements could be used as theonly test to identify those with persistent tumor (Pacini et al.2001c). The Tg remained < 1 µg/l in 57% of the patientsafter rhTSH stimulation and in 88% of the latter after levo-thyroxine withdrawal, none of whom had disease on thehypothyroid DxWBS; in the other 12% in whom the rhTSH-stimulated serum Tg remained < 1 µg/l, the hypothyroid Tgbecame detectable (1.1–7.8 g/l) but the DxWBS was negativeor showed only faint uptake in the thyroid bed. In the 43%in whom serum Tg increased from undetectable during THSTto detectable after rhTSH (1.2–23 µg/l), the hypothyroidDxWBS was positive in 74%, showing thyroid bed uptake intwelve, cervical lymph nodes in seven, and lung metastasesin four cases. Thus, an increased rhTSH-stimulated Tg,despite negative DxWBS studies, detected all cases of localor distant metastases.

A study of 107 consecutive patients who were clinicallyfree of disease and undergoing routine follow-up found that10% had persistent tumor – four with pulmonary metastasesand five with regional disease – identified only by anrhTSH-stimulated serum Tg concentration greater than 2 µg/l(Mazzaferri & Kloos 2002). A patient’s tumor status, evenin retrospect, usually was not predictable on the basis of Tgduring THST or initial tumor stage. Among patients withpersistent tumor, Tg concentrations during THST were 0.6µg/l or less in 88%, and tumor status in most (82%) wasT2N1 or lower. In no case did the rhTSH-stimulated DxWBSshow the site of persistent tumor. The sensitivity of anrhTSH-stimulated Tg concentration greater than 2 µg/l was100%, the negative predictive value was 100%, and the false-positive rate was 9%. The rhTSH-stimulated Tg had a sub-stantially better performance than the other tests: the false-negative rates were 64% for Tg higher than 0.5 µg/l duringTHST, 73% for rhTSH-stimulated DxWBS showing anyuptake, and zero for an rhTSH-stimulated Tg more than 2µg/l.

Together, these studies show that tumor may exist inpatients with an undetectable or low serum Tg concentration


Figure 3 Paradigm for the follow-up of patients with DTC. When baseline serum Tg is less than 2 µg/l during thyroid hormonesuppression of TSH, the preferred pathway is to measure rhTSH-stimulated serum Tg concentrations without performingDxWBS. T4, thyroxine; US, ultrasound; CXR, chest X-ray; CT, computed tomography.

during THST that can be identified when the rhTSH-stimulated Tg concentration increases above 2 µg/l. ADxWBS merely provides data concerning the completenessof thyroid ablation, but not persistent tumor. This is the basisof a new paradigm for the follow-up of patients with DTC(Fig. 3).

High-resolution ultrasonography

This is one of the most informative tests for the detection oflocal metastases that require further treatment, especiallywhen done with power Doppler studies (Lebkowska et al.2001). Ultrasound and Doppler studies will characterize thepresence of cystic versus solid elements, the degree of echo-genicity of solid elements, the existence of calcifications, andthe regularity and definition of the nodule borders (Haber


2000). Although individual sonographic features of thyroidnodules and masses are not specific for benign or malignantlesions, a constellation of typical features, including hypo-echogenicity, poorly defined irregular margins, and microcal-cifications has more diagnostic value. One recent study foundthat nodules with irregular margins, intranodular vascularspots or microcalcifications were particularly likely to bemalignant (Papini et al. 2002).

Precise localization of cervical node metastasis can beachieved with ultrasonography. One retrospective study thatmapped the location of cervical lymph node metastases in aseries of 119 patients who had undergone total thyroidectomyand bilateral cervical lymph node dissection provides impor-tant practical information concerning the location of cervicalmetastases (Mirallie et al. 1999). Almost 61% of the patientshad cervical metastasis, which was bilateral in about 41% of


the cases. The main ipsilateral sites of tumor were paratra-cheal (50%), mid-jugular (37%) and supraclavicular (17%).Contralateral paratracheal nodes were involved in 21% andmid-jugular nodes in 10%. The lateral compartment wassometimes involved independent of the central compartment.

High-resolution ultrasonography should be performedbefore proceeding to 131I treatment, especially to excludemalignant cervical lymph nodes that often are best treatedwith modified neck dissection.

Post-treatment 131I scans (RxWBS)

About 4–7 days after 131I treatment, an RxWBS to documenttumor 131I uptake often will show tumor foci not detected bythe DxWBS (Schlumberger et al. 1997, Cailleux et al. 2000,Mazzaferri & Kloos 2001). An RxWBS most often elicitscritical information when the Tg concentration is increased,especially if tumor cannot be found on examination or imag-ing studies such as chest X-ray, neck ultrasonography andDxWBS. Lung metastases often are found only on anRxWBS performed after 3700 MBq 131I (Schlumberger et al.1997).

Tg-positive, DxWBS-negative patients

Sometimes a high serum Tg concentration is the only indica-tion of metastases. The Tg cutoff for 131I treatment of DxWBS-negative, Tg-positive patients – albeit arbitrary – is about 10µg/l after levothyroxine withdrawal (Mazzaferri 1995, 1999,Schlumberger et al. 1997).

One study found that about 6% of 283 patients with ahigh serum Tg who were treated with 3700 MBq 131I haddistant metastases detected on the RxWBS that were not seenon a 74 MBq DxWBS (Schlumberger et al. 1986). The fre-quency of this finding depends on how patients are selectedfor treatment. Among 89 pairs of DxWBS and RxWBSstudies in 79 consecutive patients with hypothyroid serumTg concentrations greater than 15 µg/l in our clinic, 9% hada negative 148–185 MBq DxWBS but had lung metastasesdetected on the RxWBS after 3700–5550 MBq 131I. Anotherstudy found that 94% of patients with high Tg concentrationshad foci of 131I uptake on the RxWBS after 2275–5180 MBqthat were not seen on a 5 mCi DxWBS; more than half werein the lung (Pacini et al. 1987). Another study found that94% of DxWBS-negative, Tg-positive patients had uptake onthe RxWBS, 35% of which were in the lung and 65% in themediastinum (Pineda et al. 1995).

Some question treating patients with Tg-positiveDxWBS-negative studies, calling for prospective randomizedstudies of 131I treatment (McDougall 2001). Such a trialwould be unfeasible, because the number of patients requiredto provide adequate power to the study is impossibly large(Wong et al. 1990). Moreover, 131I treatment for DTC iswidely acknowledged as the most efficacious treatment for


tumor that cannot be surgically resected and which concen-trates 131I (Mazzaferri 1999, British Thyroid Association2002). The risk for complications of 131I treatment, albeit nottrivial (Mazzaferri & Kloos 2001), is far outweighed by thelong-term salutary effects of 131I on DTC (Wong et al. 1990).

One study reported 100% 10-year survival in patientswith lung metastases detected only by increased Tg concen-trations and confirmed by RxWBS (Schlumberger 1999). Incontrast, 10-year survival was 91% with a normal chestX-ray and a positive DxWBS, and was considerably worsewhen the chest X-ray was positive: 63% with lung micro-nodules and 11% with lung macronodules. Treating lungmetastases found only on RxWBS usually reduces the tumorburden, but it may be difficult to achieve their completeeradication. One study of 17 patients with Tg concentrationsranging from 8 to 480 µg/l who were treated with 5550–11 100 MBq 131I found undiagnosed recurrences in the neck(35%), mediastinum (65%) and lung (36%) on RxWBS in94% of the patients (Pineda et al. 1995). Six months to 5years later, the RxWBS was negative in 38% after a secondtreatment, and in 60% of the patients after a third treatment;Tg concentrations decreased in 81% after the first treatment,in 90% after the second treatment, and in 100% of thepatients after the third treatment. Therapeutic efficacy of 131Ifor patients with increased Tg and negative DxWBS wasindicated by conversion to negative RxWBS, a statisticallysignificant decrease in the mean Tg concentration, and areduction of serum Tg to 5 µg/l or less in 50% of patients.

In another retrospective study of patients, the outcomewas reported for 42 131I-treated and 28 untreated patients,after follow-up of 6.7 ± 3.8 and 11.9 ± 4.4 years respectively.At the end of follow-up, 33% of the treated patients had acomplete remission – normalization of serum Tg after with-drawal of levothyroxine and a negative DxWBS – and 30%had a negative RxWBS and reduced but detectable serum Tg,37% had a detectable Tg and a positive RxWBS. Resolutionof 131I uptake in lung metastases was observed in 89% andin cervical node metastases in 61% of the cases. Amongpatients treated only once because the RxWBS was negative,17% were in remission, 58% had detectable Tg values with-out evidence of disease, 17% showed lymph-node metastasesin the mediastinum, and 8% died of lung metastases. Among28 untreated patients, none of whom had radiological evi-dence of disease, serum Tg off levothyroxine became un-detectable or significantly reduced in 89%, and wasunchanged or increased in 11% of the patients, one of whomdeveloped lung metastases 14 years after the initial diagnosisof cancer.

Some patients with high serum Tg and negative DxWBSstudies should not be treated with 131I. A study of patientswith metastases in the neck (62%), lung (67%), bone (25%),mediastinum (8%), brain (8%), liver (8%), kidney (4%) andskin (4%) seen on conventional imaging studies, which didnot concentrate 131I on an 111 MBq DxWBS and were associ-


ated with Tg concentrations during THST ranging from 3.7to 3185 µg/l, found little therapeutic efficacy in empiricaladministration of 131I treatment (Fatourechi et al. 2002).

Thus treatment with high doses of 131I may have thera-peutic utility in patients with metastases manifest by highserum Tg concentrations and negative DxWBS. If lungmetastases concentrate 131I on the first RxWBS study, 131Itreatment should be continued until remission. However, notreatment should be given to those with thyroid bed uptakeor no 131I uptake at all on the first RxWBS. Surgical treatmentshould be considered in patients with node metastases.

Thyroid hormone suppression of thyrotropin

Recurrence rates, including those of distant metastases, aresignificantly reduced with thyroid hormone treatment(Mazzaferri & Jhiang 1994, Mazzaferri 1997), but the opti-mal TSH concentration required to achieve this is debated.A retrospective study found that relapse-free survival wasimproved with a consistently suppressed TSH ( < 0.05 µU/ml) compared with relapse when serum TSH concentrationswere always 1 µU/ml or higher; moreover, the degree of TSHsuppression was an independent predictor of recurrence(Pujol et al. 1996). However, a prospective study of 617patients found that disease stage, patient age and 131I treat-ment independently predicted disease progression, but thatthe degree of TSH suppression did not (Cooper et al. 1999).Tg concentrations often cannot be decreased by maximallysuppressing TSH concentrations (Kamel et al. 1999). Thesedata raise questions about suppressing TSH to undetectable,thyrotoxic ranges to prevent relapse of cancer, althoughmany endocrinologists do this.

As a practical matter, the most appropriate dose of levo-thyroxine usually is that which reduces the serum TSH tojust below the lower limit of the normal range for the assaybeing used, unless there is evidence of persistent disease,when lower concentrations may be necessary (Mazzaferri2000). However, the long-term effects of subclinical thyro-toxicosis on the heart and bone must be considered (Toft2001). Low serum TSH concentrations in individuals aged60 years or older is associated with increased mortality fromall causes, and in particular, mortality due to circulatory andcardiovascular diseases, giving pause to decreasing TSH con-centrations to 0.1 µU/ml in patients with thyrotoxicosis(Parle et al. 2001). Subclinical thyrotoxicosis may havearrhythmic effects on the heart (Osman et al. 2002).

Radioiodine (131I) treatment for residualdisease

The therapeutic efficacy of 131I is related to the capacity of atumor to concentrate and retain iodine. Sodium–iodide sym-porter (hNIS) expression is low in some thyroid cancers and,in others, post-transcriptional events may cause hNIS dys-


function (Venkataraman et al. 1999). The unfavorable iodidekinetic characteristics (short half-life) of thyroid cancers canbe partially improved by thyroid ablation and low-iodidediet. Up to two-thirds of metastases concentrate 131I, butwhen tumors do not concentrate it, even after meticulouspatient preparation and large amounts of the isotope, 131Iadministration provides no therapeutic benefit (Nemec et al.1979, Samaan et al. 1985, Schlumberger et al. 1986). Thisis more common after age 40, in patients with advancedtumors and with Hurthle cell cancers and in tall cell and insu-lar variant tumors (Samaan et al. 1985, Fatourechi et al.2002).

Low-iodine diet

Restricting iodine intake to about 50 µg can increase thy-roidal 131I uptake and can double the dose of gray per 3700MBq of 131I administered (Maruca et al. 1984); however, itmay increase total body radiation as result of delayed 131Iclearance. The diet can be very tedious, but the target iodineintake can be achieved by restricting the use of iodized salt,dairy products, eggs and seafood (Lakshmanan et al. 1988).Dietary restrictions should be started 2 weeks before 131Itreatment and continued for several days thereafter. A low-iodine cookbook is available without charge from the Thy-roid Cancer Survivors’ Association (Guljord 2000). Thepatient must avoid pharmaceutical agents (e.g. radiocontrastmaterial) with iodine.

Efficacy of postoperative 131I treatment ofresidual cancer

Radioiodine therapy refers to the treatment of thyroid cancerwithin the thyroid bed and in metastatic sites (Maxon 1999).There are three approaches to 131I treatment: empiric fixeddoses, upper bound limits that are set by blood and whole-body dosimetry, and quantitative tumor dosimetry(Brierley & Maxon 1998). Full discussion of theseapproaches is beyond the scope of this review, but they aresummarized elsewhere (Brierley & Maxon 1998,(Mazzaferri & Kloos 2001).

Surgery is the preferred treatment, but if it cannot beundertaken then 131I is the treatment of choice, providing thetumor concentrates it (Mazzaferri 1999). In one large studyof 1599 patients with DTC, 131I treatment was the single mostimportant factor accounting for disease-free survival(Samaan et al. 1992). Patients with low-risk tumors had sig-nificantly fewer recurrences and deaths after 131I treatmentthan those treated with levothyroxine alone; however, 131Iconferred only a slight advantage to patients with high-risktumors (Samaan et al. 1992). On the basis of regressionmodeling of 1510 patients without distant metastases, wefound that 131I treatment of residual disease was an indepen-dent variable that favorably reduced the likelihood of recur-


rence, distant recurrence and death from thyroid cancer(Table 2).

External radiation therapy

Relapse-free survival, especially in patients older than 40years with invasive papillary thyroid cancer (T4) andlymph-node metastases (N1) with and without extranodalextension, may be improved by external beam radiation treat-ment given as postoperative adjunctive treatment (Phlips etal. 1993, O’Connell et al. 1994, Farahati et al. 1996, Brierleyet al. 1996, Tsang et al. 1998, Esik et al. 2001). Patients withmicroscopic residual papillary cancer after surgery are morecommonly rendered disease-free by external beam radiother-apy (90%) than without it (26%) (Simpson et al. 1988).Patients with microscopically invasive follicular cancer arealso more often rendered disease-free when external beamradiation treatment is given (53%) than when it is not (38%)(Simpson et al. 1988). In another study, the relative risk oflocoregional failure was reduced (RR 0.35) by postoperativeexternal beam radiotherapy, particularly in those with grosspostoperative regional tumor (RR 0.36) (Chow et al. 2002).

Fluorine-18-fluorodeoxyglucose positronemission tomography

Progressive dedifferentiation of thyroid cancer cells leads toa loss of iodine-concentrating ability, with resultant false-negative 131I DxWBS in about 20% of all DTC metastaticlesions (Wang et al. 1999). Fluorine-18-fluorodeoxyglucose(FDG) uptake is an indicator of poor functional tumor differ-entiation and a poor prognosis of thyroid cancer, and shouldbe considered in patients suspected of having persistent DTC,particularly those with increased serum Tg values and anegative DxWBS, because it can localize tumor that does notconcentrate iodine but which produces Tg. A multicenterstudy comparing FDG-positron emission tomography (PET)with 131I DxWBS, and other scintigraphy tests, found thatthe specificity of whole-body FDG-PET was 90% and thesensitivity was 75% among all DTC patients (n = 222) and75% for those with a negative 131I DxWBS (n = 166)(Grunwald et al. 1999). In contrast, the sensitivity and speci-ficity of DxWBS were respectively 50% and 99%. Nonethe-less, FDG-PET and DxWBS used together detected tumor in93% of the patients, which was significantly better than theresults using other scans.

FDG-PET is sensitive enough to detect small cervicallymph node metastases, but they nonetheless remain the mostcommon cause of a false-negative test (Stokkel et al. 1999,Wang et al. 1999). It localized occult DTC in 71% of patientswho had increased serum Tg concentrations and a negative131I DxWBS, and it changed the clinical management in 51%of the patients (Wang et al. 1999). It had a positive predictivevalue of 92% in patients with increased Tg concentrations


and a negative predictive value of 93% in those with low Tgconcentrations. FDG-PET scans were never positive in stage1 tumors, but were always positive in stage 4 tumors withincreased serum Tg concentrations. Others report similarresults (Alnafisi et al. 2000).

A positive FDG-PET study in a patient with lung metas-tases correlates well with poor 131I uptake of the isotope bythe tumor and a lack of therapeutic response. Multivariateanalysis demonstrated that the single strongest predictor ofsurvival with DTC was the volume of FDG-avid disease(Wang et al. 2000). Three-year survival of patients with FDGvolumes of �125 ml and > 125 ml was respectively 96%and 18%. No cancer death occurred in a PET-negative patientwith distant metastases. Conversely, patients older than 45years with distant metastases that concentrate FDG were atthe highest risk for death.

The influence of serum TSH concentrations on FDGuptake in metastases has not yet been fully clarified. Hypo-thyroidism has no effect on FDG uptake (Wang et al. 1999).However, rhTSH stimulates FDG uptake by DTC (Petrich etal. 2002).

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Management of papillary and follicular (differentiated) thyroid cancer