Differentiated thyroid carcinoma: deﬁning new paradigms ...erc.endocrinology-journals.org/content/20/4/R141.full.pdf · Differentiated thyroid carcinoma: deﬁning new paradigms

Endocrine-RelatedCancer

ReviewC Durante et al. DTC follow-up 20 :4 R141–R154

Differentiated thyroid carcinoma:defining new paradigms forpostoperative management

Cosimo Durante, Giuseppe Costante1,2 and Sebastiano Filetti

Department of Internal Medicine and Medical Specialties, University of Rome ‘Sapienza’, Viale del Policlinico 155,

00161 Rome, Italy1Department of Internal Medicine, Institute Jules Bordet, 1000 Bruxelles, Belgium2Department of Health Sciences, University of Catanzaro ‘Magna Graecia’, 88100 Catanzaro, Italy

http://erc.endocrinology-journals.org q 2013 Society for EndocrinologyDOI: 10.1530/ERC-13-0066 Printed in Great Britain

Published by Bioscientifica Ltd.

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Correspondence

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to S Filetti

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Abstract

The demography of differentiated thyroid cancers (DTCs) has changed considerably since the

1990s, when the vast majority of these tumors were clinically evident at the time of

diagnosis, and many were associated with regional lymph node involvement. Today’s DTCs

are more likely to be small, localized, asymptomatic papillary forms that are discovered

incidentally, during neck imaging procedure performed for other reasons or during

postoperative assessment of a gland removed for benign nodular goiter. The tools available

for diagnosing, treating, and monitoring DTCs have also changed and their diagnostic

capacities have increased. For these reasons, DTC treatment and follow-up paradigms are

being revised to ensure more appropriate, cost-effective management of the current

generation of DTCs. This review examines some of the key issues in this area, including the

assessment of risks for disease recurrence and thyroid cancer-related death, the indications

for postoperative ablation of the thyroid remnant with radioactive iodine and TSH-

suppressive doses of levothyroxine, the pros, cons, and rationales for the use of various

follow-up tools (serum thyroglobulin assays, neck ultrasound, 2-[18F]fluoro-2-deoxyglu-

cose–positron emission tomography, and whole-body 131I scintigraphy), and temporal

strategies for maximizing their efficacy. An algorithm is presented for individualized,

risk-tailored management of DTC patients.

Key Words

" differentiated thyroidcarcinoma

" radioiodine remnant ablation

" follow-up

" neck ultrasound

" thyroglobulin

" recurrence

ded

Endocrine-Related Cancer

(2013) 20, R141–R154

Introduction

The incidence of thyroid cancer has been increasing

steadily since the 1970s. Data from the Surveillance

Epidemiology and End Results Registries show an average

annual increase in the USA of 6.6% between 1997 and

2009. The estimated number of patients with thyroid

cancer on January 1, 2009, was almost half a million, and

roughly three out of four of these individuals were women

(http://seer.cancer.gov/statfacts/html/thyro.html; last

accessed 20 January 2013). These tumors are fifth on the

list of the most common incident cancers among women,

and they represent the most rapidly growing category of

cancer in both sexes (Eheman et al. 2012).

This trend is almost entirely the result of increases in

the diagnosis of differentiated thyroid cancers (DTCs), the

papillary type, in particular (Incidence rates of follicular

thyroid cancers – like those of the poorly differentiated

anaplastic and medullary forms – have remained relatively

stable over the past 20–30 years.). DTC treatment and

follow-up practices were developed on the basis of experi-

ence gained during the latter half of the 20th century.

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Review C Durante et al. DTC follow-up 20 :4 R142

During those years, papillary thyroid cancers (PTCs) were

almost always clinically evident at the time of presen-

tation, and a substantial number were associated

with regional lymph node involvement (DeGroot 1994,

Mazzaferri & Jhiang 1994). Today, the vast majority of

newly detected PTCs are small, localized, asymptomatic

tumors that are discovered incidentally (e.g. during

imaging studies of the neck performed for other reasons

or postoperatively, after thyroid gland removal for benign

nodular goiter; Leenhardt et al. 2004, Davies & Welch

2006, Hall et al. 2009). The tools at our disposal for

diagnosing, treating, and monitoring PTCs have also

changed and evolved over the past two decades (Table 1;

Cooper et al. 2009). The challenge facing us today is the

need to revise treatment and follow-up paradigms in light

of more recent evidence to ensure more appropriate, cost-

effective management of the current generation of DTCs.

This review examines some of the key issues in this

area, including the accurate assessment of risks for disease

recurrence and thyroid-cancer-related death, the indi-

cations for postoperative ablation of the thyroid remnant

with radioactive iodine, the pros and cons of various

follow-up tools, and temporal strategies for maximizing

their efficacy. Finally, an algorithm is presented for

individualized, risk-tailored management of DTC patients.

Tailoring management to risk

Given the changes that have occurred in the demography

of DTC patients, accurate risk stratification of the current

patient population is an essential first step toward

improved treatment and follow-up protocols. For patients

with DTCs, risk assessment provides the foundation for

informed, evidence-based choices regarding subsequent

management, including the administration of radioactive

iodine after surgery, the use of TSH suppression, the

strategies and methods that will be used to detect the signs

of disease recurrence, and the frequency, intensity, and

duration of the follow-up. Tailoring management

strategies to individual risk can increase the cost-

effectiveness of care and in many cases improve the

patient’s quality of life, by reducing the burden of

adverse treatment effects and the stress and costs of

ongoing surveillance.

Reliable assessment of the risks faced by an individual

patient with DTC requires the use of the right tool at the

right time during follow-up. The initial evaluation occurs

when the cancer is diagnosed and, in all probability,

surgically removed. Staging at this point is conventionally

based on the clinicopathologic system elaborated by the


American Joint Cancer Committee/Union Internationale

Contre le Cancer (AJCC/UICC), which is widely used for

all types of cancers. It is based on four variables: patient

age, the size and extension of the primary tumor (pT),

lymph node involvement (N), and the presence of distant

metastases (M).

Both the American Thyroid Association (ATA)

Practice Guidelines (Cooper et al. 2009) and the European

Thyroid Association (ETA) Consensus Statement (Pacini

et al. 2006) endorse the AJCC/UICC staging system for use

in patients with DTCs. The main problem with this

approach is that the system was designed to predict

mortality (Brierley et al. 1997, Orlov et al. 2009), whereas

clinicians planning focused follow-ups also need infor-

mation on the probability of persistent or recurrent disease

after surgery. When the AJCC/UICC system was tested in

DTC patients to see how well it predicted structural disease

recurrence during follow-up, stage IV disease was clearly

associated with the highest risk (70%), but the increase

in risk across stages I, II, and III was anything but linear

(11, 34, and 14% respectively; Tuttle et al. 2010).

The solution proposed by the ATA in its 2009

guidelines was a new system, which classifies the

probability of recurrence as high, intermediate, or low

(Table 2; Cooper et al. 2009) on the basis of pTNM

parameters plus other types of information that are

generally available shortly after the initial treatment (i.e.

thyroidectomy or lobectomy, with or without radioiodine

therapy). The latter variables include tumor histotype,

evidence of vascular invasion, the completeness of the

surgical intervention, and the results of the post-treatment

whole-body radioiodine scan (RxWBS). As expected, the

ATA system has proved to be more effective in predicting

the follow-up findings of persistent or recurrent cancer. In

a cohort of 588 patients with DTC followed at the

Memorial Sloan-Kettering Cancer Center for a median of

7 years after primary treatment, the likelihood of detecting

structural disease during the surveillance period increased

progressively with the risk level: from w3% in low-risk

patients to 21% in those with an intermediate-risk and

68% for those assigned to the high-risk category (Tuttle

et al. 2010).

Even the ATA risk assessment system, however, has

some intrinsic limitations. Little distinction is made

between PTCs and follicular thyroid cancers (FTCs),

which usually demonstrate different biological behaviors.

For instance, for FTCs, the presence of vascular invasion

appears to be the major determinant of risk. Thus, the

so-called minimally invasive follicular thyroid cancers,

which are characterized histologically by tumor capsule


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Table 1 Paradigm shifts in the management of differentiated thyroid cancers.

Old paradigms Current paradigmsa Future paradigms

What is the appropriateoperation for DTCs?

Total thyroidectomyGnecklymph node dissection

Lobectomy (very low-riskpatients)

Depending on the preoperativeestimates of the risk

Total thyroidectomyGnecklymph node dissection

Which patients should undergoRAI remnant ablation?

All patients Selectedb intermediate-riskpatients

Patients with postoperativeevidence of disease (and ahigh risk of persistentdisease?)

High-risk patientsWhich patients should receive

TSH suppression therapy andhow much suppression isappropriate?

All patients (target TSH:!0.1 mU/l)

Early follow-upc Patients with postoperativeevidence of disease (and ahigh risk of persistentdisease?)

Low-risk patients (target TSH:0.1–0.5 mU/l)

Intermediate- and high-riskpatients (target TSH:!0.1 mU/l)

Long-term follow-upHigh-risk patients (target TSH:0.1–0.5 mU/l, for 5–10 years)

Patients with persistentdisease (target TSH:!0.1 mU/l)

Which diagnostic tools shouldbe used to monitor DTCpatients after the initialtreatment?

DxWBS Early follow-upc Early follow-upc

Assay of serum Tg levels(basal and during TSH stimu-lation achieved with thyroidhormone withdrawal)

Neck US (when available)

Patients treated with RRA Neck USNeck US Long-term follow-upSerum Tg measurement

(rhTSH-stimulated levels ora high-sensitivity assay ofbasal levels)

Serial highly sensitive serumTg assay (trend over time)

DxWBS (high-riskpatients only)

Patients not treated with RRANeck USHigh-sensitivity assay of basal

serum Tg levelsLong-term follow-upNeck USSerial measurements of basalTg with a high-sensitivityassay

How long should DTC patientsbe followed?

Until death Until death Duration determined by therisk of disease recurrence

DTC, differentiated thyroid cancer; DxWBS, diagnostic whole-body scintigraphy; RAI, radioactive iodine; RRA, radioactive iodine remnant ablation; rhTSH,recombinant human TSH; Tg, thyroglobulin; US, ultrasonography.aBased on the most recently published evidence-based international guidelines (Cooper et al. 2009).bThose with higher risk clinicopathological features, such as worrisome histologic subtypes (i.e. tall cell, columnar, insular, and solid variants, as well aspoorly differentiated thyroid cancer); invasion of intrathyroidal vasculature; multifocal disease (gross or microscopic); and non-papillary histology(i.e. follicular thyroid cancer and Hurthle cell cancer with vascular invasion).c1–2 years after the initial treatment.



penetration without vascular invasion, are generally

regarded as lower risk tumors, irrespective of the tumor

size (van Heerden et al. 1992, Sanders & Silverman 1998,

D’Avanzo et al. 2004, Lo et al. 2005, Dralle et al. 2013).

Most importantly the ATA risk assessment system fails to

consider two factors that can significantly alter the odds of

recurrence and death over time: the clinical course of the

disease and its response to the initial therapy and any

interventions performed thereafter. To address this


shortcoming, the Sloan-Kettering group had previously

proposed a dynamic risk assessment strategy, which

provides for ongoing revision and refinement of the

risk estimate as new data emerge during follow-up

(Tuttle 2008). In the study cited above (Tuttle et al.

2010), the patients originally staged with the ATA

recurrence risk system were subsequently re-assessed on

the basis of treatment–response data obtained during the

first 2 years after the initial therapy (in this case, total





Table 2 The American Thyroid Association staging system for predicting the risk of disease recurrence/persistence in patients with

differentiated thyroid cancer.

Low-risk Intermediate-risk High-risk

Meets all of the following criteria: Meets at least one of the following criteria: Meets at least one of the following criteria:No aggressive tumor histotype(e.g. tall cell, insular, and columnarcell cancers)

Aggressive tumor histotype or vascularinvasion

Macroscopic extrathyroidal extension ofthe tumor

No vascular invasion; completemacroscopic resection of the tumor

Microscopic extrathyroidal extension ofthe tumor neck lymph node metastasesor131I uptake outside the thyroid bed onthe first post-treatment RxWBS

Incomplete resection of the tumor

No extrathyroidal tumor extension Distant metastasesNo local or distant metastasesNo 131I uptake outside the thyroid bed onthe first RxWBS (when done)

RxWBS, post-treatment whole-body scan.



thyroidectomy plus postoperative radioiodine ablation of

the normal thyroid remnant). Excellent responses

(absence of both structural and biochemical evidence of

disease) reduced the likelihood of finding persistent/re-

current structural disease in all three ATA risk groups

(from 3 to 2% in the low-risk category, from 21 to 2% in

the intermediate-risk groups, and from 68 to 14% in

those with high-risk disease). Similar findings later

emerged from a second retrospective, single-institution

study, in which risk was re-classified on the basis of the

disease status w1 year after the initial treatment

(Castagna et al. 2011a).

These studies showed that, regardless of the initial risk

estimate, the likelihood of recurrence in patients with no

evidence of disease at the 1–2-year follow-up is quite low

(4% in the earlier study and 3.4% in the later one; Tuttle

et al. 2010, Castagna et al. 2011a). Most importantly,

around 30% (Tuttle et al. 2010) to 50% (Castagna et al.

2011a) of the patients previously classified as ATA

intermediate–high-risk could be re-classified as low-risk

(no evidence of disease) within 1–2 years of follow-up.

With this approach, a substantial proportion of patients

with DTCs – including some whose initial staging

revealed a high risk of persistent disease – can at some

point be channeled into surveillance that is less intensive

than originally planned.

What are the current indications andcontraindications for postoperativeradioactive iodine therapy?

By the late 1990s, patients with DTCs were almost

invariably treated postoperatively with radioiodine (131I).

In the currently advocated risk- and response-based


management strategies, this approach is being used

much more selectively. Even the specific indications for

using radioiodine therapy in the early postoperative

management have been questioned over the past few

years. Current practice guidelines in Europe and the USA

(Pacini et al. 2006, Cooper et al. 2009) cite three rationales

for administering radioiodine after total thyroidectomy:

i) it eliminates any normal thyroid tissue left after surgery,

thereby simplifying subsequent detection of residual/

recurrent tumor tissue; ii) it destroys any occult micro-

scopic foci of neoplastic cells within the thyroid remnant

or elsewhere in the body, thus improving the long-term

outcome (adjuvant therapy); and iii) it can be used to treat

known tumor residual tissues. While the ATA and the ETA

have defined indications for using radioiodine, the

application of this treatment in clinical practice differs

between countries and even within them (Haymart et al.

2013). This variation is possibly due to several non-tumor-

related factors, such as different restrictions for adminis-

tering radioactive material, different cohorts of patients,

and, last but not the least, different acceptance of the

treatment strategy. The latter underlines the need for clear

recommendations for the management of DTCs and thus

for well-designed clinical trials addressing the gray areas

where evidence is ambivalent. Current indications for

postoperative radioactive iodine therapy are discussed in

more detail below.

Normal thyroid remnant ablation

Postoperative administration of radioiodine facilitates

subsequent follow-up by eliminating any normal thyroid

tissue left behind after surgery. It is widely accepted

that the presence of such tissue can diminish the







accuracy of two methods for detecting residual/recurrent

thyroid cancer.

The first is the serum thyroglobulin (Tg) assay. The

measurement of basal and stimulated Tg levels has been a

cornerstone of postoperative surveillance programs for

patients with DTCs since the 1980s (Pacini et al. 2006,

Cooper et al. 2009). Tg is produced exclusively by cells of

thyroid follicular origin, so if all normal thyroid tissues

have been eliminated by surgery and postoperative radio-

iodine remnant ablation (RRA), subsequent findings of

detectable Tg levels represent a highly specific marker of

tumor recurrence (Pacini et al. 2006, Cooper et al. 2009). If

RRA is omitted, the clinical significance of these findings

declines since the assay positivity may simply reflect Tg

production by residual nests of normal thyrocytes, and

there is no specific cutoff level that can reliably distinguish

the production of this type from that of persistent or

recurrent neoplastic thyroid tissue (Pacini et al. 2006,

Cooper et al. 2009). Consequently, the use of RRA is

advocated to preserve the diagnostic value of serum Tg

assays in the patient’s follow-up.

This is not, however, the only solution. As will be

discussed later in this article, while the predictive value of

a single serum Tg measurement is undeniably lower in

patients who have not undergone RRA, serial Tg measure-

ments can disclose changes over time that can be reliable

markers of recurrent disease. In a recent retrospective

study, the natural history of ‘benign’ Tg production by

unablated postoperative remnants of normal thyroid

tissue has been characterized in 290 patients with low-

risk PTCs (classified by the ATA system; Durante et al.

2012). Although none of these patients had undergone

RRA, around 60% had undetectable Tg levels (!0.2 ng/ml)

– without TSH suppression – within the first year of

thyroidectomy. In the other cases, Tg levels remained

detectable during the first year but declined spontaneously

and progressively thereafter. As a result, by the fifth year of

the follow-up, the proportion of patients with undetect-

able levels was close to 80%. In the other 20%, serum Tg

levels decreased to low but detectable ones and remained

stable for the duration of the follow-up. At the end of the

follow-up (median 5 years), all of these individuals were

disease-free. Only 1 of the 290 patients experienced

recurrence, and it was associated with a gradual increase

in previously stable levels of Tg. These data challenge the

notion that Tg assays are of little use in the follow-up of

patients with DTCs who have not undergone RRA. In some

cases, Tg levels will remain within a detectable range

during the early phase of the follow-up (the first 5 years),

and this will undeniably reduce the diagnostic value of


single Tg assay results. However, the temporal trend of

consecutive measurements of serum Tg can be a reliable

indicator of the presence (rising values) or absence

(declining values) of recurrent thyroid cancer in patients

undergoing total or near-total thyroidectomy. Short

postoperative serum Tg doubling-time (!1 year) has

been reported to be independently associated with

the likelihood of having loco-regional and distant

recurrence, irrespective of radioiodine administration

(Miyauchi et al. 2011).

The second follow-up tool the use of which is

complicated by the omission of RRA is 131I scintigraphy.

When there is an appreciable thyroid remnant, the normal

tissue 131I uptake can mask the uptake by microscopic foci

of neoplastic cells within or near the remnant. The

likelihood of detecting extrathyroidal tumor cells is also

reduced. In vivo studies in patients with metastatic DTCs

have shown that 131I uptake by the neoplastic foci is

consistently lower (and may even drop below the

detection level) in the presence of a normal thyroid

remnant, which is often much more efficient than the

metastatic lesions in incorporating the radioiodine

(Schlumberger et al. 2007a). By eliminating this compe-

tition, RRA can improve the sensitivity of the 131I scan

for identifying disease recurrence (Pacini et al. 2006,

Cooper et al. 2009).

It is important to recall, however, that w70% of

thyroid cancers are confined to the thyroid bed at

diagnosis, and in 85% of the remaining cases, the

extrathyroidal disease consists exclusively of regional

lymph node involvement (http://seer.cancer.gov/stat-

facts/html/thyro.html; last accessed 20 January 2013). In

these cases, 131I scintigraphy displays a low sensitivity in

the detection of persistent/recurrent disease, and enhan-

cing its specificity by ablating the normal thyroid remnant

is of considerably less use (Cailleux et al. 2000, Pacini et al.

2003, Torlontano et al. 2003, 2006). Adverse effects must

also be considered in these decisions. Exposure to radio-

iodine significantly increases the probability of second

primary malignancies, salivary gland dysfunction, and

other complications (Rubino et al. 2003, Brown et al. 2008,

Sawka et al. 2009, Van Nostrand 2009). Most of these can

have a negative effect on the patient’s quality of life. As for

the risk for second primaries, it is generally felt to be

radiation dose dependent (Rubino et al. 2003), but some

increase in the overall risk – which nonetheless remains

very low – has been reported even in patients treated

exclusively to ablate the normal remnant, presumably

with cumulative activities in the lower range (Iyer

et al. 2011).









In light of these considerations, the view that RRA is

necessary to facilitate initial staging and follow-up appears

somewhat less convincing, and postoperative radioiodine

therapy is being used with much more caution, especially

in low-risk cases (Cooper et al. 2009). If it is used, the ATA

guidelines advise using the lowest activity needed to

ensure successful remnant ablation (Cooper et al. 2009).

The validity of this approach has recently been confirmed

by the results of two prospective randomized clinical

trials conducted in low-to-intermediate-risk DTC patients

(Mallick et al. 2012, Schlumberger et al. 2012). In both

studies, low-dose (1.1 GBq (30 mCi)) and high-dose

(3.7 GBq (100 mCi)) radioiodine regimens displayed

similar efficacies in eliminating normal thyroid residual

tissue, regardless of whether the patients were prepared for

the procedure with thyroid hormone withdrawal or

recombinant human TSH (rhTSH) stimulation.

Destruction of occult foci of neoplastic cells

Postoperative 131I administration is also used as an

adjuvant procedure for destroying any residual micro-

scopic nests of thyroid cancer cells that may be present in

the thyroid remnant or elsewhere in the body (Cooper

et al. 2009). The elimination of these potential foci is

thought to reduce the risk of recurrence and improve the

long-term outcome. This rationale is supported largely by

data from retrospective studies conducted in the 1990s. In

the landmark study by Mazzaferri & Jhiang (1994), 1355

patients with DTC were followed for over 40 years (median

15.7 years). At 30 years, the rates of both recurrence and

cancer-related death were approximately threefold lower

in the patients who had undergone RRA. Similar con-

clusions emerged from other studies, which found that

RRA significantly reduced disease recurrence (Samaan et al.

1992, DeGroot 1994) and disease-specific mortality rates

(Samaan et al. 1992). The publication of these reports was

followed by dramatic increases in the use of postoperative131I administration, and by the late 1990s, it was being

performed in almost all patients.

Other large studies, however, have kindled debates on

the true effectiveness of this approach: they found that

radioiodine adjuvant therapy had no significant effect on

long-term outcomes in patients with DTCs (Hundahl et al.

1998, Hay et al. 2002). The conflicting results that emerged

from these efforts are largely a reflection of

the heterogeneity of the study populations in terms of

the risks of recurrence and disease-specific mortality. Even

the investigators who had reported benefits with RRA

acknowledged that these benefits seemed to be restricted


to patients with larger primary tumors (i.e. 1.5 cm or more;

DeGroot 1994, Mazzaferri & Jhiang 1994). More recent

studies have looked at the effectiveness of RRA as a

function of disease stage (Jonklaas et al. 2006, Sacks et al.

2010). The National Thyroid Cancer Treatment Coopera-

tive Study Group (NTCTCSG) has published its experience

with 2936 DTC patients who were prospectively followed

for a median period of 3 years (Jonklaas et al. 2006).

Benefits from radioiodine therapy were documented only

for patients with advanced-stage cancers (NTCTCSG stages

III and IV): in this setting, there were significant

improvements in the risk ratios for both disease-free

survival (1.32, 95% CI 1.02–1.68, PZ0.035) and disease-

specific survival (1.46, 95% CI 1.13–1.87, PZ0.0045). RRA

had no effect, however, on either of these outcomes in

patients with stage I or II DTCs.

In light of these findings, it is becoming increasingly

clear that radioiodine adjuvant therapy needs to be used

selectively, and this strategy shift is reflected in the 2009

ATA guidelines (Cooper et al. 2009), which recommend

tailoring case management to individual risk levels.

A recent multicenter study conducted in Italy (Durante

et al. 2010) has retrospectively examined the long-term

outcomes of 175 DTC patients with very-low-risk primary

tumors (intrathyroidal, unifocal, subcentimeter PTCs with

no known high-risk features) who had not received RRA.

In a median follow-up of 6.7 years (range 5–23), there were

no recurrences and no thyroid-cancer-related deaths.

Shortly thereafter, Vaisman et al. (2011) reported that

the omission of radioactive iodine therapy is compatible

with very low rates of recurrence, even in selected patients

with estimated risks classified as low to intermediate. In

120 non-ablated patients with primary tumors measuring

1–4 cm, little or no extrathyroidal extension, and minimal

or absent cervical lymph node involvement, the rate of

structural disease recurrence was only 4.1% (5 out of 120)

after a median follow-up of 5 years (range 0.5–34).

A similar approach has been advocated for FTC histotype,

for which the absence or the presence of histopathological

vascular invasion better discriminates between low-

and high-risk patients respectively. In particular, the

occurrence of vascular invasion (widely invasive FTCs)

should prompt RRA therapy (Cooper et al. 2009, Dralle

et al. 2013).

Accurate risk assessment thus appears to be the key to

identifying DTC patients who are likely to benefit from

postoperative radioiodine therapy. In this regard, prophy-

lactic central and/or lateral neck dissection has been

advocated to optimize staging (Hartl et al. 2012). However,

the prognostic significance of subclinical microscopic





Table 3 Features predicting radioiodine-refractory disease.

Clinicopathological features Age O40 yearsPoorly differentiated thyroid

cancerLarge metastasesBone metastases

Functional imaging findings RAI scan: at least one lesionwithout RAI uptake

18FDG–PET scan: FDG-avidlesions, irrespective of their



cervical lymph node metastases has been recently ques-

tioned (Randolph et al. 2012). Firm conclusions on this

issue will have to be based on data regarding the effects of

radioiodine not only on recurrence but also on disease-

specific survival. These aspects are being addressed in one

multicenter prospective randomized trial in low-risk

thyroid cancer patients, which is now underway in

Europe (http://clinicaltrials.gov/show/NCT01398085; last

accessed 31 January 2013).
RAI uptake
Response to therapy At least one lesion that pro-gresses during the first yearafter RAI therapy

Persistent disease after treat-ment with cumulative RAIactivity of O22 GBq(600 mCi)

RAI, radioactive iodine; 18FDG–PET, 2-[18F]fluoro-2-deoxyglucose–positronemission tomography; GBq, gigabecquerel.

Elimination of documented residual disease foci

For DTC patients with gross residual disease that is

inoperable, radioiodine therapy is currently the most

effective treatment that we have to offer. Indeed, it is the

only approach that has been demonstrated to significantly

improve disease-free survival (Samaan et al. 1992) and,

most important, overall survival (Durante et al. 2006),

which represents the main outcome in clinical oncology.

For several reasons, however, the use of radioiodine for

this purpose is also becoming more selective (Tuttle et al.

2011), and clinicians are being encouraged to base their

decisions on a careful risk–benefit analysis.

Aside from the risk of long- and short-term adverse

effects, one of the main reasons for this shift is the growing

awareness that RAI is ineffective in some patients with

advanced disease. The selectivity of radioiodine therapy

for DTC cells depends on the functional integrity of the

complex network of specialized proteins (e.g. the sodium

iodide symporter and thyroperoxidase) involved in phys-

iological iodine metabolism and hormonogenesis

(Schlumberger et al. 2007a). These functions are usually

preserved to some extent in the cells of primary DTCs

(Arturi et al. 2001), although varying degrees of impair-

ment can be caused by genetic and epigenetic events

involved in the malignant transformation process

(Trapasso et al. 1999, Puppin et al. 2005, Durante et al.

2007, Russo et al. 2011). Complete loss of these functions

is characteristic of undifferentiated and anaplastic

primaries. Iodine uptake in some metastatic thyroid

cancer cells is also less efficient than that in their primary

tumor counterparts. This phenomenon, too, can be

attributed to dedifferentiation, although the iodine-

trapping capacity of metastatic thyrocytes may also vary

with the site of the lesion (i.e. lymph nodes, bone, lung,

and liver; Arturi et al. 2000). Table 3 presents some of the

clinical, pathlogical, and radiological findings associated

with radioiodine-refractory thyroid cancer. It is also

important to note that promising therapeutic alternatives

to radioiodine are finally becoming available. Several


novel, molecularly targeted drug therapies are already

being tested for this purpose in clinical trials, and others

will begin such testing soon (Schlumberger & Sherman

2012).

Which patients stand to benefit from TSHsuppression therapy and what degree ofsuppression is appropriate?

Thyroid cancer cells generally remain responsive to the

effects of circulating TSH, which stimulates a variety of

cellular processes including cell proliferation (Biondi et al.

2005). This is the rationale cited for the use of TSH-

suppressive doses of thyroid hormone therapy, which has

been reported to significantly decrease recurrence rates

and cancer-related mortality in DTC patients (Mazzaferri

& Kloos 2001, McGriff et al. 2002). However, the degree of

suppression required to achieve these goals is uncertain.

The reduction of TSH levels to !0.1 mU/l has been

associated with better clinical outcomes in high-risk

thyroid cancer patients (Cooper et al. 1998), but the

possibility that milder reductions (0.1–0.5 mU/l) might

offer the same benefits has never been explored. Further-

more, TSH suppression produces a state of subclinical

hyperthyroidism, which can have negative effects on the

bone and heart (Cooper & Biondi 2012). The 2009 ATA

guidelines stress the importance of striking a

balance between the potential risks and benefits of TSH

suppression (Cooper et al. 2009). At the beginning of the

follow-up, the degree of TSH suppression should be chosen



http://clinicaltrials.gov/show/NCT01398085





on the basis of the individual patient’s risk for persistent

or recurrent disease. Later on, suppression might be

discontinued if there is no documented evidence of

disease (Table 1).

What are the best diagnostic methods fordetecting persistent/recurrent disease and foridentifying patients who are cured and howshould these tools be used?

The early phase of the postoperative follow-up of patients

with DTCs (i.e. the first year or 2 years after the initial

treatment) has a twofold purpose: to detect persistent

disease, which may require additional therapy or at least

more active surveillance, and to identify probable cures.

As has been discussed previously, most patients will

belong to the latter group, and in some the likelihood of

recurrence will be low enough to justify less intensive

surveillance than that planned on the basis of the initial

ATA- or ETA-based risk estimate (Tuttle et al. 2010,

Castagna et al. 2011a,b). For the patients who appear to

be disease free, the main goal of the successive, long-term

phase of the follow-up is the prompt detection of

possible recurrence.

Reliable detection of persistent or recurrent disease

requires diagnostic tools with a high positive predictive

value; those with high negative predictive values are

suitable for identifying cases that have been cured. The

ATA (Cooper et al. 2009) and the ETA (Pacini et al. 2006)

concur that serum Tg assays and neck ultrasonography

(US) are the essential tools for monitoring patients with

DTCs, but neither association offers any details on the

merits or shortcomings of these tools or on how and when

should they be used.

Serum Tg assays

As has been discussed above, the serum Tg level is a highly

specific marker of persistent or recurrent disease in a

patient treated with total thyroidectomy and RRA. In

patients whose surgery consisted of sub-total thyroid-

ectomy or lobectomy or those who had a total thyroid-

ectomy without RRA, the specificity of a positive Tg assay

plummets, since the Tg detected may well be coming from

the normal thyroid remnant (Pacini et al. 2006, Cooper

et al. 2009). The importance of this shortcoming is highest

during the initial postoperative evaluation/phase of the

follow-up: as the follow-up continues, the value of the

Tg assay increases. Recent studies have shown, in fact,

that Tg production by the normal remnant declines


spontaneously and sometimes becomes undetectable

within the first year of the follow-up. After 5 years, levels

are likely to be undetectable in the vast majority of cases

(almost 80%) – just as they are in patients who have

undergone total thyroidectomies plus RRA (see the

previous section for details; Durante et al. 2012). In

addition, although benign Tg production in some non-

ablated patients never ceases completely, it does stabilize.

In contrast, ‘malignant’ Tg production tends to increase

over time, and this trend is highly predictive of persistent

or progressive neoplastic disease, regardless of whether or

not nests of normal thyrocytes are still present (Baudin

et al. 2003, Torlontano et al. 2004, Miyauchi et al. 2011). In

short, in non-ablated patients – who represent an

increasingly large proportion of the individuals with

DTCs – the initial postoperative serum Tg measurement

is per se an unreliable marker of persistent disease, but its

specificity increases when it is examined with subsequent

measurements: increasing Tg production documented

with serial determinations over the course of the follow-

up is associated with a positive predictive value for

persistent/recurrent disease of roughly 100%. In particu-

lar, a Tg doubling-time of !1 year appears to be the

strongest correlate of recurrence and cancer-specific

survival (Miyauchi et al. 2011).

The sensitivity of a serum Tg measurement varies

depending on the patient’s TSH level at the time of the

assay. Small foci of neoplastic tissue may not be detected if

the Tg assay is done while the patient is on levothyroxine

(especially at TSH-suppressive doses) (Mazzaferri et al.

2003, Bachelot et al. 2005). To maximize sensitivity, Tg

production must be measured during endogenous or

exogenous TSH stimulation (the former elicited by

levothyroxine withdrawal and the latter by the adminis-

tration of rhTSH; Eustatia-Rutten et al. 2004, Schlumberger

et al. 2007b). The latter approach, however, is generally

reserved for patients who have undergone RRA (Pacini

et al. 2006, Cooper et al. 2009). In these cases, one can be

reasonably certain that normal thyroid cells are no longer

present, and TSH stimulation will be targeting only

residual cancerous cells (if any are present).

The need to measure TSH-stimulated Tg is expected to

decline as the availability of high-sensitivity Tg assays

increases inclinical settings (Smallridge et al. 2007, Castagna

et al. 2011a,b, Malandrino et al. 2011). These assays, which

have functional sensitivities of !0.2 ng/ml, may allow

earlier detection of ‘malignant’ Tg production even while

patients are still taking levothyroxine. A study conducted in

2007 has compared the diagnostic values of seven pro-

gressively sensitive Tg assays (Schlumberger et al. 2007b).







A detection limit of 0.9 ng/ml was associated with a low

sensitivity in identifying persistent disease (40%). Sensi-

tivity doubled (almost 80%) when the assays with the

lowest detection limits (0.11 and 0.02 ng/ml) were tested,

but the cost of this improvement was a considerable loss in

specificity. Based on their data, the authors concluded that

the best trade-off was a functional assay sensitivity

between 0.2 and 0.3 ng/ml, which offers an improved

diagnostic sensitivity (about 65%) without significantly

diminishing the specificity (Schlumberger et al. 2007b).

However, the true diagnostic accuracies of the high-

sensitivity Tg assays still need to be validated in larger

prospective studies. At present, they can be exploited to

study the trend of serial serum Tg determinations, which

still offers the highest negative (decreasing levels) and

positive (rising levels) predictive values (Baudin et al. 2003,

Torlontano et al. 2004).

In the presence of serum Tg antibodies, both

conventional measurements of TSH-stimulated Tg levels

and high-sensitivity assays of basal Tg production may fail

to identify patients with clinically significant tumor foci

(Spencer et al. 1999). In these cases, serial serum anti-Tg

antibody quantification using the same methodology may

serve as an imprecise surrogate marker of residual normal

thyroid tissue or tumor (Spencer et al. 1998, Chiovato et al.

2003). In a large series of patients with DTC who

underwent RRA, those showing a more than 50% decrease

in serum anti-Tg antibodies within 6–12 months of

ablation had a significantly lower recurrence rate than

patients with lower reduction or increasing levels of the

antibodies (Kim et al. 2008).

Neck US

Aside from the safety and relatively low cost of ultrasound

imaging in general, one of the main reasons neck

sonography is so valuable in the postoperative follow-up

of PTC patients (Durante & Filetti 2011) is that disease

spread or recurrence is almost always associated first with

cervical lymphadenopathy. In addition, unlike serum Tg

assays and 131I WBS, it performs equally well in patients

who have not undergone RRA, it requires no hormone

withdrawal or administration of rhTSH, and it provides

valuable information for surgeons on the location and

preoperative tattooing of the involved nodes.

Neck US has been widely used in patients with DTCs

since the 1990s, and the sonographic criteria for identify-

ing cervical lymph node metastases are well established

(Leboulleux et al. 2007). In terms of sensitivity, it has

repeatedly proved to be superior to stimulated Tg assays


and diagnostic WBS in detecting cervical node involve-

ment (Antonelli et al. 1995, Pacini et al. 2003, Torlontano

et al. 2003, 2004). In 335 PTC patients whose Tg levels

remained undetectable after TSH stimulation at the 1-year

postoperative follow-up, neck US disclosed cervical

metastases in 7 (2%) cases (Torlontano et al. 2004).

Another important advantage of neck US over Tg assays

is its high negative predictive value, which approaches

100% in cases of very low-risk DTCs. In a large, long-term

study of 312 patients with this type of PTC, those with

negative findings on the first postoperative US study (3–12

months after surgery) were all disease free at the end of the

follow-up (Durante et al. 2010). To improve the specificity

of the examination, nodules that appear suspicious can be

biopsied immediately under US guidance (Pacini et al.

2006, Cooper et al. 2009) and the sample submitted for

cytologic analysis and/or measurement of Tg levels in the

needle-washout fluid (Uruno et al. 2005).

Neck US is thus becoming the mainstay of the

postoperative follow-up of DTCs, especially during the

early months, when, in the increasingly large proportion

of patients with low- or very-low-risk tumors who have not

undergone RRA, Tg assay results are difficult to interpret.

When the initial postoperative scan is negative, the

probability of a favorable long-term outcome is quite

high, regardless of serum Tg levels. Even in low-risk

patients, however, metastatic disease can still be discov-

ered, sometimes several years after the initial treatment

(Ross et al. 2009), so surveillance must be continued. As

has been discussed above, the value of serum Tg assays

increases with time, as consecutive measurements

accumulate and allow increasingly reliable assessments

of production trends. In the later phases of the follow-up,

greater reliance might be placed on basal Tg assays, which

are less expensive and easier to schedule than neck US

(Fig. 1). Additional research is needed, of course, to assess

the sensitivity of this approach.

All the above-mentioned arguments apply mainly to

PTC histotype. As for FTCs, while lymph node metastases

involve almost 20% of patients with widely invasive

forms, distant metastases are present in as many as one-

third of the patients, often in the absence of nodal

involvement (Dralle et al. 2013). Thus, staging FTCs

requires further complementary imaging modalities

(Table 4). Finally, it is important to recall that one of the

inherent features of sonographic imaging is inter-operator

variability. To reduce the effect of this potential limitation,

neck US, as an integral part of thyroid cancer follow-up

protocols, should be performed using standardized proto-

cols and in strict compliance with guidelines and criteria





Yes No

Diseasefree

Diseasefree

Evidence ofdisease

Postoperative RAI therapy

Stimulated Tg orbasal Tg assay

Neck US

Cross sectional/functional studies(high-risk patients, FTC)

Basal Tg assay

Neck US

Earlyfollow-up

1–2 years afterinitial surgery

Therapy oractive

surveillance

Latefollow-up

>2 years afterinitial surgery

Serial serum Tg determination (trend)

Neck US

Figure 1

Diagnostic tools in the early and long-term follow-up of DTC patients. RAI, radioactive iodine; Tg, thyroglobulin; US, ultrasound;

FTC, follicular thyroid cancer.



recommended by the scientific societies. Uniform quality

may also be more likely when the examinations are done

by specially trained physicians with close and continuous

involvement in the overall care of the patient with DTC.

Other tools

Whenever US and/or Tg data are suggestive of persistent/

recurrent disease, additional imaging studies may be

warranted. These include both cross-sectional modalities

such as computed tomography or magnetic resonance

imaging and nuclear medicine procedures, such as WBS

and 2-[18F]fluoro-2-deoxyglucose–positron emission

tomography (18FDG–PET;Table 4; Pacini et al. 2006, Cooper

et al. 2009). In addition to detecting neoplastic foci, 18FDG–

PET also has important prognostic and treatment impli-

cations. Several studies have shown, in fact, that FDG-avid


lesions are unresponsive to high-dose radioiodine therapy,

and this type of disease carries the highest risk for thyroid

cancer-related mortality (Robbins et al. 2006).

How long should the patients who areapparently disease free be followed?

Life-long follow-up is still the rule for patients with DTCs.

Once again, however, this practice is rooted largely in data

on the outcomes of cases treated at least 20 or 30 years ago

(DeGroot 1994, Mazzaferri & Jhiang 1994). Today, in light

of the numbers of PTCs being diagnosed, the changing

profile of the PTC patient population, and improvements

in the methods available for detecting postoperative

recurrence, the cost-effectiveness of protracted surveil-

lance is being questioned. In 1994, Mazzaferri & Jhiang

analyzed 1077 PTC patients treated during the last four





Table 4 Second-line imaging studies for the work-up of

persistent/recurrent disease in patients with DTCs.

Imaging procedures Clinical applications

Contrast-enhanced computedtomography

To detect lesions in the brain,neck, chest, and abdomen(triple-phase scanning isrequired for liver studies)

Magnetic resonance imaging To detect brain, liver, and bonelesions

Diagnostic 131I whole-bodyscan

To identify the source ofpersistent Tg production inintermediate-/high-riskpatients

To stage patients at a higherrisk of persistent/recurrentdisease, including individ-uals with widely invasive FTC

Bone scintigraphy To detect skeletal lesions18FDG–PET To identify occult metastases in

patients with elevated Tglevels and negative whole-body scans

To stage patients with poorlydifferentiated thyroid canceror Hurthle cell carcinoma

To identify patients with dis-tant metastases at a highestrisk for cancer-relatedmortality

To identify patients unlikely torespond to RAI therapy

To evaluate responses tosystemic or local treatment

DTC, differentiated thyroid cancer; RAI, radioactive iodine; Tg, thyro-globulin; FTC, follicular thyroid cancer; 18FDG–PET, 2-[18F]fluoro-2-deoxyglucose–positron emission tomography.



decades of the 20th century and found a recurrence rate of

more than 20%. After O5 years of follow-up, 40% of the

recurrences were identified, and around 20% were

detected after the tenth year. In 2013, Durante et al.

(2013) conducted a similar analysis of 1020 patients

treated between 1990 and 2008. The recurrence rate was

markedly lower (1.4%); over 75% of the recurrences were

discovered within 5 years of the initial treatment, and

none were detected after the eighth year of the follow-up.

The demography of DTC patients seen in general

thyroid disease practices has clearly changed. Roughly

three out of four of the patients in the 2013 study had

stage I tumors. This is approximately five times higher

than the percentage reported by Mazzaferri & Jhiang

(even allowing for the fact that the staging criteria used in

the two studies were slightly different). In addition, almost

half the cases analyzed in the 1994 study were charac-

terized by regional lymph node involvement at the time of

the initial therapy – almost twice the rate reported in the


2013 study. Finally, the past 30 years have witnessed a

progressive decline in the use of 131I WBS during

the follow-up of DTC patients and greater reliance on

high-resolution neck US and increasingly sensitive serum

Tg assays.

Concluding remarks

Figure 1 shows an algorithm for individualized, risk-

tailored management of the DTC patients being seen by

today’s endocrinologists. This approach reflects current

recommendations made by the ATA and ETA, and it is

clearly different from the approaches that had been used

5–10 years ago (Table 1). As our knowledge of the biology

and natural history of these tumors expands, the manage-

ment strategies that we use will continue to evolve. In all

probability, the trend will be toward increasingly indivi-

dualized treatment aimed at optimizing treatment – in

terms of efficacy, cost, and quality of life benefits – for all

patients with DTCs (right column, Table 1).

Declaration of interest

The authors declare that there is no conflict of interest that could be

perceived as prejudicing the impartiality of the review reported.

Funding

This review did not receive any specific grant from any funding agency in

the public, commercial or not-for-profit sector.

Acknowledgements

The authors acknowledge the following funding sources: The Umberto Di

Mario Foundation and the ‘Banca d’Italia’. The authors thank Marian

Everett Kent, BSN, for editing the manuscript.

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Received in final form 31 March 2013Accepted 9 April 2013Made available online as an Accepted Preprint9 April 2013





http://dx.doi.org/10.1210/jc.2006-0993

http://dx.doi.org/10.1210/jc.2006-0993

http://dx.doi.org/10.1210/jc.83.4.1121



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http://dx.doi.org/10.4158/EP.14.6.764



http://dx.doi.org/10.1007/s00268-004-7701-0

http://dx.doi.org/10.1111/j.1365-2265.2011.04002.x

http://dx.doi.org/10.1111/j.1365-2265.2011.04002.x




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