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Endocrine-Related Cancer (2002) 9 227–247
Management of papillary and follicular
(differentiated) thyroid cancer: new
paradigms using recombinant human
thyrotropin
E L Mazzaferri 1 and N Massoll 2
1
Adjunct Professor of Medicine, University of Florida; Emeritus Professor and Chairman of Internal Medicine, Senior Research
Scholar, The Center for Health Outcome Policy Evaluation Studies, The Ohio State University, Ohio, USA
2
Department 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 world
over the past three decades, yet this has been associated with a signiﬁcant decrease in DTC mortality
rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse
rates remain high, in the order of 20–40%, depending upon the patient’s age and tumor stage at the
time 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 tumors
that 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 regression
modeling of 1510 patients without distant metastases at the time of initial treatment and including
surgical and 131I treatment, the likelihood of death from DTC is increased by several factors, including
age > 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 and
independently affected by female sex, total or near-total thyroidectomy, 131I treatment and
levothyroxine suppression of TSH. Treatments with 131I to ablate thyroid remnants and residual
disease are independent prognostic variables favorably inﬂuencing distant tumor relapse and cancer
death rates. Delay in treatment of persistent disease has a profound impact on outcome.
Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic
whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible
to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New
paradigms, however, provide alternative pathways to prepare patients for 131I treatment and to
optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease
can 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. These
new follow-up paradigms promptly identify patients with lung metastases that are not evident on
routine imaging, but which respond to 131I treatment. In addition, rhTSH can be given to prepare
patients for 131I remnant ablation or 131I treatment for metastases, especially those who are unable to
withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH
fails to increase.
Endocrine-Related Cancer (2002) 9 227–247
Endocrine-Related Cancer (2002) 9 227–247
1351-0088/02/0-9–227  2002 Society for Endocrinology Printed in Great Britain
Online version via http://www.endocrinology.org
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
The two most common forms of thyroid cancer, papillary
and follicular thyroid cancer, together termed differentiated
thyroid cancer (DTC), comprise the majority of thyroid cancers and have the best prognosis. The debate surrounding
their management has been fueled by the fact that no prospective randomized trials of treatment have been conducted
and 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 results
available in 35 years (Wong et al. 1990). Our knowledge
about treatment is woven from a patchwork of large retrospective cohort studies in which patients have been followed
for decades, providing the fabric of our management paradigms. Much of the following discussion refers to the management of DTC, because the treatments of papillary and
follicular cancer are so similar. Special emphasis is given to
new and emerging paradigms, especially those using recombinant human thyrotropin (rhTSH) and sensitive thyroglobulin (Tg) measurements, which is important because
patients with DTC often experience tumor relapse decades
after treatment.
Incidence and prevalence rates
The prevalence of thyroid cancer in the US population,
relatively high because survival is prolonged, is now about
220 000 cases, almost all of which are DTC and many of
which will recur.
Recurrence (persistent tumor) rates
Recurrence rates with DTC are high, ranging from 20% to
40% (Mazzaferri & Jhiang 1994). Distant metastases are
often discovered decades after initial treatment (Fig. 1),
underscoring the need for long-term follow-up. What is
usually termed recurrent tumor, however, is in fact often persistent disease that remains below our surveillance radar for
200
180
Number of Patients with Recurrence
Introduction
A
160
140
All Recurrences
Local Recurrences
120
Distant Recurrences
100
80
60
40
20
228
0
0
60
5
10
15
20
25
30
Years after Initial Therapy
35
40
B
50
Percent with Event
In the USA in 2001, about 9500 new cases and 1300 deaths
occurred from thyroid cancer. Its incidence in the USA has
increased nearly 50% since 1973 (Ries et al. 2000) and has
been 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 population to thyroid radiation in the form of external beam radiation used in the past to treat benign conditions in children
and in the form of atmosphere fallout of radioactive iodine
(Institute of Medicine 1999) and early diagnosis using ﬁneneedle aspiration biopsy (FNA).
Most (80%) thyroid cancers in the USA are papillary
cancers, with follicular cancer comprising only 11% of new
cases (Hundahl et al. 1998). Papillary and minimally invasive
follicular cancers are typically slow-growing tumors that
respond well to treatment. Indeed, a few believe that survival
is so good that DTC poses little risk to patients younger than
45 years at the time of diagnosis (Cady 2000). Yet the natural
history of DTC unfolds over decades. Ten-year cancerspeciﬁc mortality rates in almost 54 000 patients diagnosed
in the USA between 1985 and 1995 were about 7% for papillary, 15% for follicular and 25% for Hu¨rthle cell cancers
(Hundahl et al. 1998). Papillary cancer, the most indolent
and most likely to respond to treatment, nevertheless
accounts for more than 50% of the cancer deaths, because its
incidence is so high.
40
All recurrences
30
Cancer death
20
10
Distant recurrences
0
5-9
10-19
20-29
30-39
40-49
50-59
60-69
70-95
Age (Years) at Time of Initial Therapy
Figure 1 Tumor recurrence rates in 1528 patients after a
median of 16.6 years follow-up. There were 359 recurrences
(23.5% of patients). Local recurrence (n = 272, 17.8%) is
cervical or mediastinal; distant recurrence (n = 114, 7.5%) is
sites outside the neck. (A) Number of patients with
recurrences at 5-year intervals. (B) Cumulative percent of
recurrences, distant recurrences and cancer deaths over 40
years stratiﬁed by age at the time of initial treatment. Patients
(n = 27) with both local and distant recurrences are shown as
distant recurrence. Reproduced with permission from
Mazzaferri & Kloos (2002).
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Endocrine-Related Cancer (2002) 9 227–247
years before it reappears as clinically evident cancer. Persistent DTC, however, can now be detected very early using
newly devised testing paradigms.
Two-thirds of the cases of persistent tumor are detected
within 10 years of treatment, but the others are evident decades later (Fig. 1A) (Mazzaferri & Kloos 2001). Recurrences,
including distant metastases, are more common in those
younger than 20 and older than 60 years (Fig. 1B) (here and
elsewhere, age refers to the patient’s age at the time of initial
treatment). Many lead to death. Almost 70% of those who
died of cancer were considered disease-free after initial treatment, succumbing to the disease after a relapse. In our
experience, 30-year mortality rates are about 12% after local
relapse 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 the
result of early diagnosis and effective treatment. However,
this occurred only in women, probably because they undergo
routine examinations more often than do men, in whom thyroid cancer is typically discovered two to three decades later
than it is in women.
Risk stratiﬁcation
Cause of death from thyroid cancer
Deaths from thyroid cancer are more common in patients
older than 45 years at the time of surgery and in those with
more advanced tumor stage (Table 1) (Mazzaferri & Kloos
2001). Patients with follicular cancer have higher mortality
rates, but tend to be older and with more advanced tumor
stage at the time of diagnosis than those with papillary
cancer. Few studies give details of the exact cause of death
from thyroid cancer. One such study of patients who died of
thyroid cancer, however, shows that respiratory insufﬁciency
caused 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 uncontrolled
local tumor (15%), and circulatory failure caused by obstruction of the vena cava (15%).
Current opinions about risk
Clinicians often recommend treatment and follow-up according to their view of the risk, often without deﬁning it in terms
of disease-free survival, persistent disease and cancer death.
Certain prognostic factors indicate how, on average, DTC
will proceed (Mazzaferri 1999, Mazzaferri & Kloos 2001).
Some are patient characteristics (Table 1). Mortality rates are
low in patients younger than 40 years, but increase incrementally thereafter; however, relapse rates are high (앑40%)
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during the ﬁrst two decades of life and after the age of 60
years (Fig. 1B) (Mazzaferri & Jhiang 1994). Men have about
twice the risk of dying from DTC as do women, because
they present at a later age and with more advanced tumor
stage than do women (Mazzaferri & Jhiang 1994, Ries et al.
2000).
The second set of prognostic variables relates to the
tumor (Table 1). Histologic tumor grade (nuclear atypia,
tumor necrosis and vascular invasion) is a strong and independent prognosticator (Akslen & LiVolsi 2000). A third set
of prognosticators relates to treatment, and a fourth concerns
follow-up (Table 2).
Staging systems
There are many staging systems for thyroid cancer. Most
accurately predict mortality rates. Nevertheless, some in the
lowest risk strata in most staging systems die of cancer
(DeGroot et al. 1994, Hundahl et al. 1998), particularly when
risk is simply deﬁned dichotomously as low or high (Cady
et al. 1979, American Joint Committee on Cancer 1992). In
one study (Kitamura et al. 1999), more than 10% of the
patients dying of DTC had an American Joint Committee on
Cancer/Union Internationale Contre le Cancer (AJCC/UICC)
classiﬁcation of stage 1 or 2 (Table 3).
Another problem is that staging systems using age to
stratify risk fail to predict recurrence-free survival and
relapse, mainly because relapse rates are high in young
patients (Fig. 1B). For example, 35-year cancer relapse rates
were higher among our patients at low risk than among those
at high risk (56.8% compared with 35.2%, P < 0.001) according to the age-metastases-extent-size (AMES) staging criteria
(Cady 1997). Distant metastases occurred in the low- and
high-risk categories, respectively, in 89 and 25 patients. The
AJCC/UICC staging system poses similar problems. Most
staging systems are derived from multivariate analyses that
do not consider recurrence or the effect of treatment, and all
rely on some information that is available only after surgery.
Relapse-free status and survival cannot be assured by low
tumor stage in most staging systems.
Almost none of the multivariate analyses used to construct the clinical staging systems take into account the
effects of treatment, tacitly assuming that treatment does not
alter outcome. This shortcoming was recognized by the
authors of the European Organisation for Research and
Cancer Treatment (EORTC) staging system, the ﬁrst such
system to be devised (Byar et al. 1979). Subsequent authors
have largely ignored this caveat (Cady & Rossi 1988, Hay
1990, Hay et al. 1993, Shaha et al. 1995).
Clinical staging schemes do not permit meaningful
decisions to be made for patients at the time of surgery. They
are best reserved for epidemiologic studies, for which the
TNM classiﬁcation of the AJCC and UICC (Table 3) is perhaps most useful.
229
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
Table 1 Risk stratiﬁcation of clinical variables inﬂuencing cancer recurrence and cancer death
A. Patient
1.
2.
3.
4.
variables
Age < 15 years or > 45 years
Male sex
Family history of thyroid cancer
Previous exposure to thyroidal irradiation (external beam irradiation or exposure to radionuclides from atmospheric
fallout or other sources (children))
B. Tumor
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
variables
Tumor > 4 cm diameter
Bilateral (multifocal) thyroid tumors
Extrathyroidal tumor extension
Vascular invasion (papillary and follicular carcinoma)
Cervical, mediastinal lymph node metastases
Tumor subtypes: Hu¨rthle, tall, cell, columnar cell, diffuse sclerosis, insular variants
Advanced histologic grade: nuclear atypia, tumor necrosis, vascular invasion
Tumor that concentrates 131I poorly or not at all
Distant metastases
Tumor that concentrates ﬂuorine-18-ﬂuorodeoxyglucose uptake on PET scan
C. Treatment variables
1.
Delay in diagnosis and treatment
2.
Less than total or near-total thyroidectomy
3.
Delay in completing total thyroidectomy after lobectomy
4.
Failure to give 131I treatment
5.
Failure to suppress TSH with levothyroxine
D. Follow-up variables
1.
Failure to measure Tg and perform DxWBS
2.
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) surgery, (3) remnant ablation, (4) thyroid hormone suppression
of thyrotropin (THST), and (5) follow-up, including diagnostic studies and treatment. Management in each phase is
unique and crucial to optimal long-term outcome, but is not
always optimal.
An audit of care found many deﬁciencies in practice,
citing inadequacies in the areas of surgery (20%), suppression 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 the
USA (Hardy et al. 1995, Hundahl et al. 1998, Vanderpump
et al. 1998). Because of these deﬁciencies, leaders in Great
Britain (Kendall-Taylor 2001) called for the establishment of
guidelines for the management of thyroid cancer.
National Comprehensive Cancer Network
(NCCN) and British Thyroid Association
guidelines
Explicit guidelines, established in lieu of prospective randomized trials but based upon the current literature for the
230
diagnosis and management of thyroid cancer, were written
by a panel of multidisciplinary experts from USA Cancer
Hospitals (Mazzaferri 1999) and by the British Thyroid
Association (2002). Both guidelines give explicit advice and
assistance in the management of thyroid cancer, providing
carefully considered algorithms and comprehensive bibliographies. The British Thyroid Association Guidelines also
provide excellent material for patients.
Diagnosis
Fine-needle aspiration (FNA) cytology is the ﬁrst diagnostic
test for a thyroid nodule in a euthyroid patient. Yet diagnosis
is sometimes delayed for years because thyroid cancer occurs
in an environment teeming with benign nodules (Mazzaferri
1993a, Ross 2002). The diagnostic accuracy is considerably
enhanced by ultrasonography and Doppler studies (Marqusee
et al. 1997, Papini et al. 2002). In one study the odds ratio
of malignancy was 16.8 if ultrasonography showed indistinct
or blurred nodule margins, 14.3 with intranodular Doppler
ﬂow and 4.9 with microcalciﬁcations (Papini et al. 2002).
The sensitivity of ultrasound-guided FNA and Doppler in
evaluating 12 001 patients was 93% and the speciﬁcity was
75% (Yang et al. 2001).
Despite its efﬁcacy, FNA was not performed before sur-
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Endocrine-Related Cancer (2002) 9 227–247
Table 2 Cox regression model on cancer recurrence, distant metastasis recurrence and death due to thyroid cancer in 1501
patients with or without distant metastases at the time of initial treatment
Variable
Hazard ratio
P value
95% CI
All cancer recurrence (n = 1501)
Age*
Local tumor invasion
Lymph node metastases†
Follicular histology
Tumor size‡
Thyroid remnant 131I ablation¶
Treatment with 131I¶
Surgery more than lobectomy§
1.0
1.4
1.3
0.8
1.2
0.8
0.5
0.7
0.2
0.01
0.01
0.012
0.0001
0.016
0.0001
0.0001
0.9
1.1
1.1
0.7
1.1
0.7
0.4
0.6
to
to
to
to
to
to
to
to
1.3
2.2
1.6
0.96
1.3
0.97
0.6
0.9
Distant metastasis recurrence (n = 1501)
Age*
Follicular histology
Lymph node metastases†
Local tumor invasion
Tumor size‡
Thyroid remnant 131I ablation¶
Treatment with 131I¶
Surgery more than lobectomy§
1.3
1.0
1.6
1.6
1.2
0.6
0.4
0.8
0.0001
0.864
0.002
0.927
0.001
0.002
0.0001
0.379
1.2
0.8
1.2
0.9
1.1
0.5
0.2
0.6
to
to
to
to
to
to
to
to
1.5
1.2
2.2
2.7
1.3
0.8
0.6
1.2
Cancer mortality (n = 1501)
Age*
Time to treatment**
Follicular histology
Lymph node metastases†
Tumor size‡
Local tumor invasion
Female (versus male)
Thyroid remnant 131I ablation¶
Surgery more than lobectomy§
Treatment with 131I¶
9.5
2.4
1.4
2.0
1.2
1.1
0.6
0.5
0.5
0.4
0.0001
0.0001
0.003
0.006
0.025
0.002
0.046
0.0001
0.0001
0.010
5.3 to 17.1
1.5 to 4.0
1.1 to 1.8
1.2 to 3.4
1.02 to 1.3
1.0 to 1.2
0.4 to 0.99
0.4 to 0.7
0.4 to 0.7
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 distant
recurrences.
†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; Treatment
with 131I is postoperative treatment of patients with known residual disease.
§Bilateral thyroid surgery versus lobectomy with or without isthmusectomy.
** Time to treatment ⱕ 12 months versus > 12 months.
gery in about 40% of 5584 patients with thyroid cancer in
one study in the USA (Hundahl et al. 2000). North American
endocrinologists, however, use FNA routinely to evaluate
thyroid nodules, performing it early and relying heavily on
its results (Bennedbaek & Hegedus 2000). In contrast, evaluations by primary care physicians are more costly and more
time consuming, causing a delay of 12 months or longer in
almost 30% of the patients managed in one New York study
(Ortiz et al. 1998). This increases mortality rates signiﬁcantly. Mortality rates from thyroid cancer begin rising after
12 months’ delay in diagnosis, increasing up to 40-fold when
10 or more years has elapsed from the time a nodule is ﬁrst
palpated until its treatment (Mazzaferri & Jhiang 1994).
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Initial surgery
Although debate continues to swirl around the initial treatment of DTC (Mazzaferri & Kloos 2001), total or near total
thyroidectomy that leaves less than 2 g (2 cm2) of thyroid
tissue is performed in most large centers for the majority of
patients. Studies from the USA, Europe and Hong Kong
show that most patients at risk for relapse or death from thyroid cancer (tumors 1 cm or larger) are treated with total or
near-total thyroidectomy, usually followed by 131I and levothyroxine treatment (Van De Velde et al. 1988, Baldet et al.
1989, Solomon et al. 1996, Sherman et al. 1998, Mazzaferri
1999, Cailleux et al. 2000, Hundahl et al. 2000, Chow et al.
2002). External beam irradiation, which has a less prominent
231
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
Table 3 Deﬁnition of TNM and AJCC/UICC clinical stages
Deﬁnition of TNM
T
TX
T0
T1
T2
T3
T4
N
NX
N0
N1
M
M0
M1
Stage 1
Clinical stage
Stage 2
Stage 3
Stage 4
role in initial management and usually follows 131I treatment,
is best given postoperatively to patients older than 40 years
with TNM stage T4 tumors (Simpson et al. 1988, Farahati et
al. 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 surgery
may lead to a 5–10% recurrence rate in the opposite thyroid
lobe (Hay et al. 1987, Mazzaferri 1993b), a high tumor recurrence rate (Fig. 2) and a high (11%) rate of relapse in the
50
45
Total + T4
( n=419)
Percent Recurrence
40
35
Subtotal + T4
(n=350)
30
Subtotal + T4 + RAI
(n=67)
25
Total + T4 + RAI
(n=449)
20
15
10
5
0
05
10
15
20
25
30
35
40
Years After Initial Therapy
Figure 2 Tumor recurrence after thyroid surgery and thyroid
hormone (T4) treatment with and without 131I treatment (RAI).
Total = thyroidectomy including subtotal thyroidectomy
(ipsilateral lobectomy, isthmusectomy and near-total
contralateral lobectomy); subtotal = lobectomy with or without
isthmusectomy. Patients undergoing total thyroidectomy had
more advanced tumor stage than those undergoing subtotal
thyroidectomy (ANOVA, P < 0.001). Modiﬁed from
Mazzaferri & Kloos (2002).
232
Primary tumor
Cannot be assessed
No evidence of primary tumor
< 1 cm
1–4 cm
> 4 cm
Tumor of any size beyond thyroid capsule
Regional lymph nodes
Cannot be assessed
Not present
Present
Distant metastases
None
Present
Patients < 45 years with any T, any N, M0
Patients > 45 years with T1
Patients < 45 years with any T, any N, M1
Patients > 45 years with T2–3
Patients > 45 years with T4 or N1
Patients > 45 years with M1
form of pulmonary metastases (Massin et al. 1984). High
relapse rates with cervical lymph node metastases and multicentric tumors (Mazzaferri & Jhiang 1994) justify total or
near-total thyroidectomy and 131I ablation. If lobectomy is
performed, diagnostic 131I imaging may miss microscopic
metastases in the contralateral lobe or elsewhere when they
are most amenable to treatment. We found that surgery consisting of more than lobectomy was an independent variable
affecting cancer relapse (Table 2). Others report a similar
effect of surgery on tumor recurrence (DeGroot et al. 1994,
Chow et al. 2002).
It is more difﬁcult to demonstrate that total or near-total
thyroidectomy inﬂuences survival, although there is considerable proof that it inﬂuences relapse-free survival. One
study, for example, found no improvement in survival rates
after patients with low-risk papillary cancers (Age, Grade,
Extent, Size (AGES) score 울3.99) underwent more than
lobectomy (Hay et al. 1987). The same authors, however,
later recommended that bilateral thyroid resection should be
performed for low-risk papillary cancer, after ﬁnding that the
20-year rates for local recurrence and nodal metastasis were,
respectively, 14% and 19% after unilateral lobectomy, compared with 2% and 6% (P = 0.0001) after bilateral thyroid
resection (Hay et al. 1998). Others have demonstrated a
reduction in cancer mortality by more extensive surgery in
patients without distant metastases, but this was mainly
attributable to its effect on T4 tumors (DeGroot et al. 1994).
Postoperative 131I treatment obscures the therapeutic impact
of surgery. Patients in our study treated with total or neartotal thyroidectomy plus 131I ablation and levothyroxine had
signiﬁcantly fewer local recurrences and distant relapses than
those treated with any other combination, including total thyroidectomy and levothyroxine alone (Mazzaferri & Kloos
2001). Surgery, more than lobectomy, had an independent
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Endocrine-Related Cancer (2002) 9 227–247
effect on recurrence and cancer death distinct from 131I,
which after a median follow-up of 16.6 years reduced the
risk for mortality by 50% (Table 2) (Mazzaferri & Kloos
2001).
The NCCN guidelines
Cervical lymph node metastases are found in 50–80% of
cases of papillary cancer, most often in the central paratracheal (Level VI) compartment, followed in descending order
by mid-jugular (Level III), supraclavicular (Level IV), and
subdigastric nodes (Level I) (Mirallie et al. 1999). In our
study, lymph node metastases, especially bilateral cervical
and mediastinal, were an independent variable that affected
recurrence and survival (Mazzaferri & Kloos 2001). Some
report that systematic compartment-oriented dissection of
lymph node metastases signiﬁcantly improves recurrence
(P > 0.0001) and survival (P > 0.005) rates in patients with
T1–T3 tumors (Scheumann et al. 1994). The NCCN guidelines recommend total thyroidectomy and, if lymph nodes are
involved, bilateral central compartment dissection or lateral
modiﬁed radical neck dissection, as the primary treatment of
high-risk DTC (Mazzaferri 1999). For follicular tumors not
identiﬁed as cancer before operation, the guidelines suggest
lobectomy, followed by total thyroidectomy for minimally
invasive follicular cancers larger than 4 cm.
The British Thyroid Association guidelines
Total thyroidectomy and 131I ablation are recommended for
papillary cancers larger than 1 cm, and for papillary tumors
that are multifocal or have spread beyond the thyroid gland
by extension or have metastasized, and for familial tumors
and those due to irradiation. Removal of all lymph nodes
within the central compartment of the neck (level VI), which
includes those in the pre- and paratracheal regions, is recommended in addition to removing involved lateral lymph
nodes by selective dissection. Neither guideline recommends
routine radical neck dissection. Lobectomy is advised for follicular tumors not identiﬁed as cancer before operation. For
follicular cancers larger than 1 cm, the British guidelines
advise total thyroidectomy and 131I, and similar treatment of
smaller follicular cancers that are widely invasive.
Consensus recommendations
Most US and European specialists opt for total or near-total
thyroidectomy when the diagnosis is known (Van De Velde
et al. 1988, Baldet et al. 1989, DeGroot et al. 1994, Solomon
et al. 1996, Mazzaferri 1999, Cailleux et al. 2000, Hundahl
et al. 2000). This also applies to children and young adults,
because 60–80% have regional lymph node involvement and
10–20% have distant metastases (Mazzaferri 1991, Hay et al.
1998, Miccoli et al. 1998, Newman et al. 1998, Schlum-
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berger 1998, La Quaglia et al. 2000). Of 50 children aged 15
or 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). Although
the overall long-term survival rate in children is greater than
90%, disease-free survival is enhanced by complete tumor
resection (Scheumann et al. 1994, Newman et al. 1998).
Completion thyroidectomy
This refers to a separate operation to resect the contralateral
lobe when ipsilateral lobectomy has been done. It should be
performed when a tumor has the potential for recurrence
(Mazzaferri & Kloos 2001). Ablating a large remnant with
131
I is not recommended, because it causes radiation thyroiditis with pain and swelling, and may cause thyrotoxicosis.
Also, a large thyroid remnant prevents TSH concentrations
from increasing above 30 mU/l after the levothyroxine withdrawal that is necessary for tumor 131I uptake (Goldman et
al. 1980), without which incomplete tumor ablation results
(Burmeister et al. 1991, Maxon et al. 1992).
This surgery has a low complication rate when performed by an experienced surgeon, and may help unmask
hidden metastases and enhance survival. Cancer is found in
the contralateral lobe in about 50% of cases (Pasieka et al.
1992, Mazzaferri 2000). Lung and lymph node metastases
in more than 60% of a group of irradiated children from
Chernobyl could only be identiﬁed after completion thyroidectomy had been done (Miccoli et al. 1998). In another
important study, multivariate analysis found that patients
who underwent completion thyroidectomy within 6 months
of their initial operation developed signiﬁcantly fewer lymph
node and hematogenous recurrences and survived signiﬁcantly longer than those in whom the second operation was
delayed for longer than 6 months (Scheumann et al. 1996).
Completion thyroidectomy should be performed for any
patient who has undergone lobectomy for tumor of stage
> T1 ( > 1 cm), or has recurrent cancer or tumor in the resection margins or metastases (Mazzaferri 1999).
Radioiodine ablation of residual normal
thyroid tissue
Some 131I uptake usually is seen in the thyroid bed after total
thyroidectomy (Cholewinski et al. 2000). Destruction of this
macroscopically normal thyroid tissue with 131I is termed thyroid remnant ablation. Although a few debate this practice
(Hay 1990), there are compelling reasons for it (Mazzaferri
1997). Firstly, a large remnant can obscure 131I uptake in cervical or lung metastases (Vassilopoulou-Sellin et al. 1993,
Miccoli et al. 1998). Secondly, the high TSH concentrations
necessary to enhance tumor 131I uptake cannot be achieved
with a large thyroid remnant (which should be surgically
excised) (Goldman et al. 1980). Thirdly, measurement of
233
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
TSH-stimulated Tg is the most sensitive way to detect
cancer, providing there is no normal thyroid tissue present
(Spencer et al. 1998). Fourthly, lung metastases sometimes
are 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 may
destroy microscopic metastases or normal follicular cells
destined to become malignant (Sugg et al. 1998), preventing
late relapse from an occult cancer (Fig. 1).
Multifocal papillary cancers
Multifocality is common in papillary thyroid cancers
(Mazzaferri & Jhiang 1994). Although they have long been
considered to be intraglandular metastases and not individual
tumors arising de novo, current evidence suggests the opposite. A study found that only two of 17 patients with multifocal tumors had identical RET/PTC gene rearrangements in
microscopic multifocal tumors within the same gland,
whereas the other 15 patients had diverse RET/PTC
rearrangements in tumors within the same thyroid gland, suggesting that individual tumors arise independently in a background of genetic or environmental susceptibility (Sugg et
al. 1998). This explains why contralateral lobe recurrences
are found years after lobectomy.
Indications for thyroid
131
I remnant ablation
This decision is tightly linked to that for performing total or
near-total thyroidectomy. Remnant ablation should be done
when there is uptake in the thyroid bed in a patient without
known foci of cancer after resection of a tumor that has the
potential for recurrence (Mazzaferri & Kloos 2001). If there
is less than 0.5% thyroid bed uptake at 48 h 6–12 months
after 131I ablation, repeating the ablation is unlikely to be of
further beneﬁt. Such a small amount of 131I uptake is unlikely
to represent the source of high serum Tg concentrations
( > 10 µg/l) (Gru¨nwald et al. 1996). As a practical matter,
almost every patient who has undergone total or near-total
thyroidectomy has 1% or more 131I uptake in the thyroid bed
that requires ablation. Once levothyroxine has been withdrawn and the patient has followed a low-iodine diet for
imaging, remnant ablation can be done on the same day as a
diagnostic whole-body 131I scan (DxWBS), often on an outpatient basis (Mazzaferri & Jhiang 1994, Tsang et al. 1998).
Therapeutic efﬁcacy of
131
I remnant ablation
We found lower recurrence and mortality rates after 131I
ablation (Mazzaferri 1997, Mazzaferri & Kloos 2001), but
not all ﬁnd this (Hay 1990). Remnant ablation decreased
relapse of tumors larger than 1 cm in one study, including
low-stage tumors predicted to have a good prognosis; however, it reduced the risk of death only in those with more
234
advanced disease (DeGroot et al. 1990). In yet another study,
the rates of pulmonary metastases among 58 patients with
DTC were 11% after partial thyroidectomy, 5% after subtotal
thyroidectomy and 131I, 3% after total thyroidectomy, and
only 1.3% after total thyroidectomy and 131I (Massin et al.
1984). Among 321 patients treated with 131I in 13 Canadian
hospitals, mainly to ablate normal thyroid tissue in patients
with microscopic residual papillary or follicular cancer, local
disease was controlled more often with either postoperative
external 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 surgery
alone was less favorable (about 40%) than after treatment
with either 131I or external radiation (about 90%, P < 0.01),
whereas 131I treatment without obvious residual disease did
not increase survival (Simpson et al. 1988). In a later study
from Canada of 382 patients with DTC, thyroid ablation with
total thyroidectomy and 131I was associated with a signiﬁcantly lower rate of local relapse, regardless of tumor stage
(Tsang et al. 1998).
Among 230 patients who had undergone remnant
ablation and 789 treated with levothyroxine alone, the recurrence 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 of
18.9 years (Mazzaferri & Kloos 2001). Patients over the age
of 40 years with tumors 1.5 cm or larger experienced fewer
cancer deaths 40 years after thyroid remnant ablation than
after the other treatment strategies (P < 0.0001)
(Mazzaferri & Kloos 2001). Multivariate analyses show the
extent to which 131I ablation improves outcome. On the basis
of regression modeling for 1510 patients without distant metastases at the time of initial treatment, we found remnant
ablation was an independent variable that reduced cancer
recurrence, distant recurrences and cancer death rates (Table
2). Another study found that the prognostic variables portending cancer death were age over 45 years, postoperative
gross locoregional residual disease, distant metastasis at
presentation, and lack of 131I treatment (Chow et al. 2002).
Multivariate analysis showed that patients without distant
metastases and obvious residual tumor who underwent
thyroid ablation had fewer locoregional relapses (relative risk
(RR) = 0.29) and distant metastases (RR = 0.2) than those
treated with levothyroxine alone. Total or near-total thyroidectomy followed by 131I treatment thus results in the best
outcome.
Choosing the
ablation
131
I activity for thyroid remnant
Many use about 1110 MBq to ablate a remnant if the amount
of thyroid tissue remaining after surgery is small, because it
avoids admission to hospital, which is no longer necessary
in the USA (Brierley & Maxon 1998). Radiation exposures
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Endocrine-Related Cancer (2002) 9 227–247
of household members of patients given more than 1110
MBq are well below the limit (5.0 mSv) mandated by US
national regulations (Grigsby et al. 2000). Small 131I activities have appeal because of the lower cost and lower wholebody radiation to the patient, which has been estimated to be
6.1 mSv for 1110 MBq, 8.5 mSv for 1850 MBq, and 12.2
mSv for 2220 MBq (DeGroot & Reilly 1982). Although 3700
MBq of 131I may cause salivary injury and transient loss of
taste, it causes no permanent ovarian or testicular failure and
poses virtually no risk for leukemia (Mazzaferri 1986, 2002).
Stratifying 131I ablation treatments into two groups, a
low-dose group of 62 patients (46%) treated with 1073–1850
MBq 131I and a high-dose group of 72 patients (54%) treated
with 1887–7400 MBq, we found 30-year relapse rates were
similar in both groups (4% and 6% respectively, P = 0.1). A
meta-analysis found that high-dose remnant ablation (2775–
3700 MBq) is more efﬁcient than low-dose ablation (about
1110 MBq), particularly after less than total thyroidectomy,
suggesting DTC should be treated with total thyroidectomy
followed by a higher dose of 131I (2775–3700 MBq) for remnant ablation.
Diagnostic 131I whole-body scans and
post-therapy whole-body scans
Performing a whole-body scan is not very useful when there
is a large thyroid remnant that prevents TSH from increasing
above 30 mU/l or shows a star burst artifact from extensive
uptake in the neck obscuring tumor uptake. An RxWBS,
which otherwise often detects tumor foci not seen on the
DxWBS, should always be performed after 131I therapy
(Schlumberger et al. 1997, Cailleux et al. 2000). This is most
likely to yield important information when the Tg concentration is > 10 µg/l in a patient who is clinically free of disease
with negative DxWBS, neck ultrasonography and computed
tomography.
Thyroid stunning
Administering more than 111 MBq 131I may have a sufﬁciently harmful effect upon the tissue in which it concentrates to interfere with subsequent 131I uptake for several
weeks – a phenomenon termed ‘thyroid stunning’ (Park et
al. 1994, Leger et al. 1998, Muratet et al. 1998). Using 64
MBq or 111 MBq 131I or 20 MBq 123I for DxWBS avoids
this, but may not identify metastases (Muratet et al. 1997,
Leger et al. 1998). A DxWBS with 48–56 MBq 123I produces
good images but is very expensive (Mandel et al. 2001).
Delaying 131I treatment several weeks after performing a
DxWBS may be responsible for stunning (Leger et al. 1998,
Muratet et al. 1998), which did not occur in 172 patients
treated with 131I within 72 h of having had a 185 MBq 131I
DxWBS (Cholewinski et al. 2000). Although a DxWBS is
usually performed postoperatively to determine the optimal
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therapeutic 131I activity, another approach is to perform an
RxWBS after empirically administering 3700 MBq 131I on
the basis of high Tg concentrations.
Two studies report that stunning has no impact on 131I
ablation. One found that 21% of 378 patients showed evidence of thyroid stunning, yet follow-up scans after 131I
ablation were negative and serum Tg concentrations were
less than 3 µg/l in most of the group (Bajen et al. 2000).
Another study found ablation rates after 3700–7400 MBq 131I
were respectively 65% and 67% in patients who had or had
not undergone a DxWBS with 3700–7400 MBq 131I (Morris
et al. 2001). It thus appears that stunning has little or no
impact on therapeutic outcome.
False-positive
131
I scans
A false-positive scan, which might lead to unnecessary treatment, may be caused by 131I in body secretions, pathologic
transudates and areas of inﬂammation (Greenler & Klein
1989). Metastatic disease may be mimicked by physiologic
secretion of 131I in the nasopharynx, salivary and sweat
glands, stomach, and genitourinary tract, and from skin contaminated by urine, sputum or tears (Mitchell et al. 2000).
Diffuse hepatic 131I uptake on RxWBS, which can be mistaken for hepatic metastases, is a result of 131I-labeled Tg that
is seen in 40% of 1110 MBq scans and in 70% of 5550–
7400 MBq studies (Chung et al. 1997). This usually represents residual thyroid tissue or metastases (not to the liver)
that iodinate Tg, even when there is no visible uptake in the
thyroid bed or metastases on RxWBS (Chung et al. 1997).
Follow-up assessments after initial
surgical and 131I treatment
The aim of postsurgical follow-up for DTC is the early identiﬁcation of the small proportion of patients – usually about
20% – who have residual tumor or develop a recurrence.
When total thyroidectomy and 131I ablation have been the
initial treatment, three powerful tools are available for the
follow-up: measurement of basal and TSH-stimulated serum
Tg, whole-body radioiodine scans, and neck ultrasonography
(Pacini 2002). Serum Tg measurement is the most sensitive
and speciﬁc marker of DTC. Undetectable serum Tg concentrations that do not increase in response to TSH stimulation
are found in most patients who are disease-free, whereas
increased serum concentrations of Tg are associated with the
presence of residual normal thyroid tissue or metastatic DTC.
In the last case, whole-body radioiodine scans under TSH
stimulation (either after withdrawal of L-thyroxine treatment
or after rhTSH stimulation) and neck ultrasonography are the
most informative tests for the detection of distant or local
metastases that require further treatment. Using this strategy,
most patients will achieve deﬁnitive cure and will have a
normal quality of life.
235
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
Determination of serum Tg
Thyroglobulin mRNA
Serum Tg determinations and DxWBS are the ﬁrst tests ordinarily used to detect DTC after thyroid ablation. Neither is
reliable, however, when there is a large thyroid remnant,
because both require high serum TSH concentrations, usually
around 25–30 mU/l, to optimize their sensitivity. Although
the two tests are complementary (Torrens & Burch 1996), a
low TSH-stimulated Tg alone is often sufﬁcient to rule out
persistent tumor. The results of Tg assays may vary in different laboratories, even with the use of the international Tg
standard (Spencer et al. 1996), but low Tg concentrations
alone after TSH stimulation in an assay with a 1 µg/l functional sensitivity will identify patients who are free of disease
(Cailleux et al. 2000). Persistent tumor is rarely found when
the serum Tg values are less than 2 µg/l after rhTSH
stimulation (Haugen et al. 1999) or less than 5 µg/l after
levothyroxine withdrawal (Ozata et al. 1994). Nonetheless, a
measurable Tg is indicative of thyroid tissue – normal or
malignant – since no other tissues falsely increase it.
Six to 12 months after thyroid ablation, when patients are
clinically free of disease, the Tg alone after rhTSH can usually
serve as a guide for selecting patients who require further testing or treatment; however, the DxWBS after levothyroxine
withdrawal or rhTSH only provides evidence of the completion of 131I remnant ablation, but rarely identiﬁes residual
disease (Cailleux et al. 2000, Pacini et al. 2001c, 2002,
Mazzaferri & Kloos 2002). A 185 MBq DxWBS is relatively
useless compared with administering 3700 MBq followed by
an RxWBS when the Tg increases above some arbitrary limit
suggesting the presence of metastases – usually around 10
µg/l (Schlumberger et al. 1997, Cailleux et al. 2000).
The detection of circulating tumour cells in patients with
DTC may precede the detection of relapse by other diagnostic studies such as serum Tg measurement, and thus may
have important therapeutic and prognostic implications.
Serum Tg measured by Tg mRNA in the presence of serum
TgAb titers is more sensitive than the Tg IMA method for
the 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 mRNA
expression was found not to be speciﬁc for thyroid tissue and
not to correlate with a diagnosis of thyroid cancer
(Bellantone et al. 2001). Some ﬁnd no difference in Tg
mRNA expression in patients with or without metastasis,
reporting no correlation between serum Tg concentrations
and the Tg concentrations estimated by mRNA, raising questions regarding both the clinical applicability of Tg RT-PCR
and the quantitative measurement of Tg mRNA in peripheral
blood (Takano et al. 2001).
Antithyroglobulin antibodies (TgAb)
Found in up to 25% of patients with DTC, compared with
about 10% of the general population, TgAb concentrations
must be measured in the same serum sample in which Tg is
measured, and when present usually invalidate the serum Tg
result (Mariotti et al. 1995, Spencer et al. 1998); however,
some challenge this point (Schlumberger & Baudin 1998). In
the presence of high serum TgAb titers, immunometric assay
(IMA) methods are prone to underestimating the serum Tg
concentration, increasing the risk of a false-negative test,
whereas high Tg concentrations in this situation are likely
indicative of residual cancer. Indeed, the presence of TgAb
in the serum does not entirely render the serum Tg measurement useless. For instance, even in the presence of interfering
TgAbs, a detectable serum Tg measured by IMA is usually
indicative of disease, particularly if the concentration
increases in response to TSH stimulation. Moreover, a high
serum TgAb titer correlates with the presence of tumor, disappearing within 2 years or less of its complete ablation
(Spencer et al. 1998).
236
Withdrawal of thyroid hormone suppressive
treatment
Stopping levothyroxine for 4–6 weeks and substituting triiodothyronine (T3) until 2 weeks before doing a DxWBS and
measuring Tg has been, until recently, the standard way of
inducing hypothyroidism, which causes physical limitations
from muscle stiffness, cognitive impairment, emotional dysfunction and, in some studies (Dow et al. 1997), negative
psychological alterations and major disruption of a patient’s
family, social and work life. Many patients with DTC are
middle-aged and active, and some opt to forgo testing
because they suffer such debilitating symptoms; if they do
submit to it, most are unable or unwilling to tolerate hypothyroidism more than once yearly. After levothyroxine has been
reinstated, symptoms of hypothyroidism may persist for
weeks and TSH concentrations may remain increased for as
long as 90 days, which may induce tumor growth (Maini et
al. 1994). Some patients are unable to mount an adequate
endogenous TSH response to levothyroxine withdrawal
because of hypopituitarism, and others have medical conditions such as renal failure or heart failure that preclude
inducing hypothyroidism (Mazzaferri & Kloos 2000).
Recombinant human thyroid-stimulating
hormone
Administering rhTSH increases serum TSH concentrations
sufﬁciently to stimulate thyroidal 131I uptake and Tg release
while the patient continues taking levothyroxine (Ladenson
et al. 1997). Given on two successive days in a multicenter
study, rhTSH produced DxWBS results that were equivalent
to those after levothyroxine withdrawal in 66% of the
patients, superior in 5% and inferior in 29%, proving that it
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Endocrine-Related Cancer (2002) 9 227–247
stimulates 131I uptake, albeit with lower sensitivity than after
levothyroxine withdrawal (Ladenson et al. 1997). Another
multicenter study used different scanning methodology,
taking into account the lower renal 131I clearance in hypothyroidism than with rhTSH, and demonstrated that DxWBS
results were superior after rhTSH in 4% and after levothyroxine withdrawal in 8%, and concordant in 89% (P = NS)
(Haugen et al. 1999). The main ﬁndings were that DxWBS
and a Tg 욷2 µg/l detected 100% of those with metastatic
tumor, although rhTSH-stimulated Tg 욷2 µg/l alone, but not
the DxWBS, accomplished the same thing.
A clinical study of 289 patients, many with advanced
disease, undergoing routine follow-up testing found that the
DxWBS and serum Tg responses were not different in 161
patients prepared for testing by thyroid hormone withdrawal
and 128 patients who continued levothyroxine and received
rhTSH (Robbins et al. 2001a). No signiﬁcant differences
were found in the positive or negative predictive values
between the two groups, but the greatest negative predictive
value (97%) was in patients who received rhTSH and had
both a negative DxWBS and low rhTSH-stimulated Tg concentrations.
The recommendations are to administer rhTSH 0.9 mg
on two consecutive days, followed by at least 4 mCi 131I on
day 3 and a DxWBS and Tg measurement on day 5. Images
are acquired after 30 min of scanning or after 140 000 counts.
A Tg 욷2.0 µg/l 72 h after the last rhTSH injection indicates
that thyroid tissue – normal or malignant – is present,
which may be identiﬁed on the rhTSH-stimulated DxWBS
(Haugen et al. 1999). Mild, transient headache and nausea
are its main adverse effects, affecting about 10% of patients,
without causing the dysphoria of hypothyroidism (Ladenson
et al. 1997).
Preparation with rhTSH for treatment
Although initially approved only for diagnostic use in the
USA, rhTSH has been given to prepare patients for 131I thyroid ablation and treatment of residual disease. Since April
1995, rhTSH has been given in a compassionate-use program
to more than 100 patients in whom, for one reason or
another, levothyroxine could not be stopped (Perros 1999).
A number of small studies show its effect in preparing
patients for 131I remnant ablation and treatment of persistent
tumor.
Patients prepared by rhTSH stimulation for thyroid remnant ablation given an average of 1070 MBq 131I after surgery
were all found to have complete resolution of visible 131I
uptake in the thyroid bed within 5–13 months (Robbins et al.
2001b). In addition, rhTSH has been used to prepare patients
for 131I treatment of distant metastases.
Hepatic metastases were treated in a 46-year-old woman
with follicular thyroid cancer arising from a struma ovarii
(Rotman-Pikielny et al. 2000). After the tumor and her thy-
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roid gland were removed, an rhTSH-stimulated DxWBS
revealed 17 discrete hepatic foci of 131I uptake. An amount of
rhTSH-stimulated 131I that would deliver an optimal absorbed
radiation dose ( > 8000 rad/lesion) without injuring the liver
or bone marrow was calculated and administered without an
adverse effect. Six months later, her liver metastases showed
a signiﬁcant but partial response. This strategy, which is
reported in detail (Rotman-Pikielny et al. 2000), can be
applied to determine a safe and effective dose of 131I for the
treatment of thyroid cancer metastases that produce enough
thyroid hormone to preclude stimulation of endogenous pituitary TSH secretion.
Others have reported treating distant metastases after
stimulation with rhTSH. A study of older patients, some with
distant metastases, who were unable to tolerate levothyroxine
withdrawal, received 4000 MBq 131I after being prepared
with rhTSH (Berg et al. 2002). After one or two courses
of rhTSH-stimulated 131I treatment, clinical, laboratory and
radiological ﬁndings improved in about 50% of the patients,
including an 80% decrease in 131I uptake in metastases, lower
serum Tg concentrations, and a decrease in bone pain and
other symptoms. Patients reported an improvement in their
physical condition and quality of life. Despite being elderly
and frail, they tolerated treatment well except for transiently
increased bone pain, and an enlarging soft-tissue lesion in
one patient. Another study of patients with advanced tumor
who received rhTSH in preparation for 131I treatment showed
a 30% decrease in serum Tg concentrations, which before
treatment ranged from 25 to nearly 30 000 µg/l (Luster et al.
2000). Several patients showed clinical improvement, with
decreased or stabilized tumor size, and none had an adverse
event. The authors felt that, without the use of rhTSH, 131I
treatment of their patients would not have been possible. In
another study, patients with advanced tumor who underwent
rhTSH-stimulated 131I treatment while taking levothyroxine
all showed tumor 131I uptake on the RxWBS (Lippi et al.
2001). Serum Tg concentrations decreased in 50% of the
patients 3–12 months later, and one metastatic tumor became
smaller. Preparation with rhTSH was well tolerated, but a
few patients experienced mild transient fever and nausea and
short-lived peritumoral pain and swelling of bone metastases.
Another article (Pellegriti et al. 2001) described the treatment
of patients with metastatic DTC, with bone and lung metastases or local disease, in whom the use of rhTSH was effective in preventing complications that patients had previously
experienced during hypothyroid-induced levothyroxine withdrawal. rhTSH-stimulated 131I treatment induced a 50%
reduction in the size of bone metastases in two patients, and
the others remained stable after 131I treatment. Another article
reported the management of a man with papillary thyroid
cancer and polycystic renal disease with failure who could
not tolerate reduction of renal blood ﬂow induced by hypothyroidism. He was given rhTSH and treated with 131I on four
occasions over 3 years to ablate bilateral lung metastases that
237
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
intensely concentrated 131I on RxWBS, and showed resolution of uptake over time (Mazzaferri & Kloos 2000).
The main complications with rhTSH-stimulated 131I treatment are transient, but sometimes severe, bone pain, tumor
growth, and serious neurologic effects in patients with central
neck, 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 susceptible to causing complications by radiation-induced tumor
swelling should be pretreated with glucocorticoids if surgery
is not possible. The studies reviewed above show that rhTSH
provides sufﬁcient sodium–iodide symporter stimulation in
thyroid tissues and metastases to make it possible to treat
them with 131I.
Serum Tg concentrations during long-term
follow-up
Thyroglobulin concentrations during THST should be undetectable or low ( < 1 µg/l) in patients who are free of disease,
but are more accurate when serum TSH concentrations are
increased (Pacini et al. 1985, Haugen et al. 1999). In patients
with undetectable Tg concentrations during THST who have
no clinically apparent residual cancer, measurement of an
rhTSH-stimulated Tg concentration distinguishes those who
are truly disease-free from those with tumor who require
further diagnostic testing, therapeutic procedures, or both
(Pacini et al. 2001c, Haugen et al. 2002, Mazzaferri & Kloos
2002). Patients who are free of disease have undetectable or
very low serum Tg concentrations before and after levothyroxine withdrawal (Cailleux et al. 2000).
An increased serum Tg determination shortly after surgery might be indicative of a patient’s tumor status (Lima et
al. 2002). One study, for example, found that an initial Tg
greater than 70 µg/l had a 90% positive predictive value for
metastases (Ronga et al. 1999). Nevertheless, the Tg may
remain high for a year or more after 131I treatment before
spontaneously becoming undetectable (Cailleux et al. 2000,
Pacini et al. 2001a,b). During long-term follow-up, Tg
should be measured after levothyroxine withdrawal or rhTSH
administration, which lowers the false-negative rate well
below 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 patients
with low basal values ( < 2 µg/l) during THST remained low
after rhTSH and no 131I uptake was seen on any DxWBS,
whereas Tg in the others increased to 22.0 ± 5.75 µg/l and
half had 131I uptake visible on DxWBS (David et al. 2001).
In contrast, when basal serum Tg was > 2 µg/ml during
THST, it increased in response to rhTSH in all patients,
increasing to 55.3 ± 12.75 µg/l, yet 131I uptake on DxWBS
was not evident in 25% of the patients. The authors concluded that an rhTSH-stimulated Tg may identify persistent
disease and is of greater diagnostic value than DxWBS in
238
patients with low ( < 2 µg/l) basal serum Tg concentrations
during THST. This has been substantiated by several other
studies.
Haugen et al. (2002) found that 12% of 83 patients previously treated with total thyroidectomy and 131I ablation had
a positive DxWBS that usually (80%) showed uptake only
in the thyroid bed, and only one of ﬁve that were treated or
had further evaluation on the basis of the DxWBS ﬁndings
had a serum Tg < 2 µg/l. In contrast, 18 patients with a negative DxWBS were treated or further evaluated on the basis
of an rhTSH-stimulated Tg < 2 µg/l (23% of the study
group). The authors concluded that an rhTSH-stimulated
serum Tg is a more sensitive indicator of tumor than is the
DxWBS.
Another study of 72 patients who were clinically free of
disease and had serum Tg < 1 µg/l during THST revealed
that rhTSH-stimulated Tg measurements could be used as the
only test to identify those with persistent tumor (Pacini et al.
2001c). The Tg remained < 1 µg/l in 57% of the patients
after rhTSH stimulation and in 88% of the latter after levothyroxine withdrawal, none of whom had disease on the
hypothyroid DxWBS; in the other 12% in whom the rhTSHstimulated serum Tg remained < 1 µg/l, the hypothyroid Tg
became detectable (1.1–7.8 g/l) but the DxWBS was negative
or showed only faint uptake in the thyroid bed. In the 43%
in whom serum Tg increased from undetectable during THST
to detectable after rhTSH (1.2–23 µg/l), the hypothyroid
DxWBS was positive in 74%, showing thyroid bed uptake in
twelve, cervical lymph nodes in seven, and lung metastases
in four cases. Thus, an increased rhTSH-stimulated Tg,
despite negative DxWBS studies, detected all cases of local
or distant metastases.
A study of 107 consecutive patients who were clinically
free of disease and undergoing routine follow-up found that
10% had persistent tumor – four with pulmonary metastases
and ﬁve with regional disease – identiﬁed only by an
rhTSH-stimulated serum Tg concentration greater than 2 µg/l
(Mazzaferri & Kloos 2002). A patient’s tumor status, even
in retrospect, usually was not predictable on the basis of Tg
during THST or initial tumor stage. Among patients with
persistent tumor, Tg concentrations during THST were 0.6
µg/l or less in 88%, and tumor status in most (82%) was
T2N1 or lower. In no case did the rhTSH-stimulated DxWBS
show the site of persistent tumor. The sensitivity of an
rhTSH-stimulated Tg concentration greater than 2 µg/l was
100%, the negative predictive value was 100%, and the falsepositive rate was 9%. The rhTSH-stimulated Tg had a substantially better performance than the other tests: the falsenegative rates were 64% for Tg higher than 0.5 µg/l during
THST, 73% for rhTSH-stimulated DxWBS showing any
uptake, and zero for an rhTSH-stimulated Tg more than 2
µg/l.
Together, these studies show that tumor may exist in
patients with an undetectable or low serum Tg concentration
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Endocrine-Related Cancer (2002) 9 227–247
Figure 3 Paradigm for the follow-up of patients with DTC. When baseline serum Tg is less than 2 µg/l during thyroid hormone
suppression of TSH, the preferred pathway is to measure rhTSH-stimulated serum Tg concentrations without performing
DxWBS. T4, thyroxine; US, ultrasound; CXR, chest X-ray; CT, computed tomography.
during THST that can be identiﬁed when the rhTSHstimulated Tg concentration increases above 2 µg/l. A
DxWBS merely provides data concerning the completeness
of thyroid ablation, but not persistent tumor. This is the basis
of 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 of
local metastases that require further treatment, especially
when done with power Doppler studies (Lebkowska et al.
2001). Ultrasound and Doppler studies will characterize the
presence of cystic versus solid elements, the degree of echogenicity of solid elements, the existence of calciﬁcations, and
the regularity and deﬁnition of the nodule borders (Haber
www.endocrinology.org
2000). Although individual sonographic features of thyroid
nodules and masses are not speciﬁc for benign or malignant
lesions, a constellation of typical features, including hypoechogenicity, poorly deﬁned irregular margins, and microcalciﬁcations has more diagnostic value. One recent study found
that nodules with irregular margins, intranodular vascular
spots or microcalciﬁcations were particularly likely to be
malignant (Papini et al. 2002).
Precise localization of cervical node metastasis can be
achieved with ultrasonography. One retrospective study that
mapped the location of cervical lymph node metastases in a
series of 119 patients who had undergone total thyroidectomy
and bilateral cervical lymph node dissection provides important practical information concerning the location of cervical
metastases (Mirallie et al. 1999). Almost 61% of the patients
had cervical metastasis, which was bilateral in about 41% of
239
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
the cases. The main ipsilateral sites of tumor were paratracheal (50%), mid-jugular (37%) and supraclavicular (17%).
Contralateral paratracheal nodes were involved in 21% and
mid-jugular nodes in 10%. The lateral compartment was
sometimes involved independent of the central compartment.
High-resolution ultrasonography should be performed
before proceeding to 131I treatment, especially to exclude
malignant cervical lymph nodes that often are best treated
with modiﬁed neck dissection.
Post-treatment
131
I scans (RxWBS)
131
About 4–7 days after I treatment, an RxWBS to document
tumor 131I uptake often will show tumor foci not detected by
the DxWBS (Schlumberger et al. 1997, Cailleux et al. 2000,
Mazzaferri & Kloos 2001). An RxWBS most often elicits
critical information when the Tg concentration is increased,
especially if tumor cannot be found on examination or imaging studies such as chest X-ray, neck ultrasonography and
DxWBS. Lung metastases often are found only on an
RxWBS performed after 3700 MBq 131I (Schlumberger et al.
1997).
Tg-positive, DxWBS-negative patients
Sometimes a high serum Tg concentration is the only indication of metastases. The Tg cutoff for 131I treatment of DxWBSnegative, Tg-positive patients – albeit arbitrary – is about 10
µg/l after levothyroxine withdrawal (Mazzaferri 1995, 1999,
Schlumberger et al. 1997).
One study found that about 6% of 283 patients with a
high serum Tg who were treated with 3700 MBq 131I had
distant metastases detected on the RxWBS that were not seen
on a 74 MBq DxWBS (Schlumberger et al. 1986). The frequency of this ﬁnding depends on how patients are selected
for treatment. Among 89 pairs of DxWBS and RxWBS
studies in 79 consecutive patients with hypothyroid serum
Tg concentrations greater than 15 µg/l in our clinic, 9% had
a negative 148–185 MBq DxWBS but had lung metastases
detected on the RxWBS after 3700–5550 MBq 131I. Another
study found that 94% of patients with high Tg concentrations
had foci of 131I uptake on the RxWBS after 2275–5180 MBq
that were not seen on a 5 mCi DxWBS; more than half were
in the lung (Pacini et al. 1987). Another study found that
94% of DxWBS-negative, Tg-positive patients had uptake on
the RxWBS, 35% of which were in the lung and 65% in the
mediastinum (Pineda et al. 1995).
Some question treating patients with Tg-positive
DxWBS-negative studies, calling for prospective randomized
studies of 131I treatment (McDougall 2001). Such a trial
would be unfeasible, because the number of patients required
to provide adequate power to the study is impossibly large
(Wong et al. 1990). Moreover, 131I treatment for DTC is
widely acknowledged as the most efﬁcacious treatment for
240
tumor that cannot be surgically resected and which concentrates 131I (Mazzaferri 1999, British Thyroid Association
2002). The risk for complications of 131I treatment, albeit not
trivial (Mazzaferri & Kloos 2001), is far outweighed by the
long-term salutary effects of 131I on DTC (Wong et al. 1990).
One study reported 100% 10-year survival in patients
with lung metastases detected only by increased Tg concentrations and conﬁrmed by RxWBS (Schlumberger 1999). In
contrast, 10-year survival was 91% with a normal chest
X-ray and a positive DxWBS, and was considerably worse
when the chest X-ray was positive: 63% with lung micronodules and 11% with lung macronodules. Treating lung
metastases found only on RxWBS usually reduces the tumor
burden, but it may be difﬁcult to achieve their complete
eradication. One study of 17 patients with Tg concentrations
ranging 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 in
94% of the patients (Pineda et al. 1995). Six months to 5
years later, the RxWBS was negative in 38% after a second
treatment, 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 the
patients after the third treatment. Therapeutic efﬁcacy of 131I
for patients with increased Tg and negative DxWBS was
indicated by conversion to negative RxWBS, a statistically
signiﬁcant decrease in the mean Tg concentration, and a
reduction of serum Tg to 5 µg/l or less in 50% of patients.
In another retrospective study of patients, the outcome
was 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 a
complete remission – normalization of serum Tg after withdrawal 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. Resolution
of 131I uptake in lung metastases was observed in 89% and
in cervical node metastases in 61% of the cases. Among
patients treated only once because the RxWBS was negative,
17% were in remission, 58% had detectable Tg values without evidence of disease, 17% showed lymph-node metastases
in the mediastinum, and 8% died of lung metastases. Among
28 untreated patients, none of whom had radiological evidence of disease, serum Tg off levothyroxine became undetectable or signiﬁcantly reduced in 89%, and was
unchanged or increased in 11% of the patients, one of whom
developed lung metastases 14 years after the initial diagnosis
of cancer.
Some patients with high serum Tg and negative DxWBS
studies should not be treated with 131I. A study of patients
with metastases in the neck (62%), lung (67%), bone (25%),
mediastinum (8%), brain (8%), liver (8%), kidney (4%) and
skin (4%) seen on conventional imaging studies, which did
not concentrate 131I on an 111 MBq DxWBS and were associ-
www.endocrinology.org
Endocrine-Related Cancer (2002) 9 227–247
ated with Tg concentrations during THST ranging from 3.7
to 3185 µg/l, found little therapeutic efﬁcacy in empirical
administration of 131I treatment (Fatourechi et al. 2002).
Thus treatment with high doses of 131I may have therapeutic utility in patients with metastases manifest by high
serum Tg concentrations and negative DxWBS. If lung
metastases concentrate 131I on the ﬁrst RxWBS study, 131I
treatment should be continued until remission. However, no
treatment should be given to those with thyroid bed uptake
or no 131I uptake at all on the ﬁrst RxWBS. Surgical treatment
should be considered in patients with node metastases.
function (Venkataraman et al. 1999). The unfavorable iodide
kinetic characteristics (short half-life) of thyroid cancers can
be partially improved by thyroid ablation and low-iodide
diet. Up to two-thirds of metastases concentrate 131I, but
when tumors do not concentrate it, even after meticulous
patient preparation and large amounts of the isotope, 131I
administration provides no therapeutic beneﬁt (Neˆmec et al.
1979, Samaan et al. 1985, Schlumberger et al. 1986). This
is more common after age 40, in patients with advanced
tumors and with Hu¨rthle cell cancers and in tall cell and insular variant tumors (Samaan et al. 1985, Fatourechi et al.
2002).
Thyroid hormone suppression of thyrotropin
Recurrence rates, including those of distant metastases, are
signiﬁcantly reduced with thyroid hormone treatment
(Mazzaferri & Jhiang 1994, Mazzaferri 1997), but the optimal TSH concentration required to achieve this is debated.
A retrospective study found that relapse-free survival was
improved with a consistently suppressed TSH ( < 0.05 µU/
ml) compared with relapse when serum TSH concentrations
were always 1 µU/ml or higher; moreover, the degree of TSH
suppression was an independent predictor of recurrence
(Pujol et al. 1996). However, a prospective study of 617
patients found that disease stage, patient age and 131I treatment independently predicted disease progression, but that
the degree of TSH suppression did not (Cooper et al. 1999).
Tg concentrations often cannot be decreased by maximally
suppressing TSH concentrations (Kamel et al. 1999). These
data raise questions about suppressing TSH to undetectable,
thyrotoxic ranges to prevent relapse of cancer, although
many endocrinologists do this.
As a practical matter, the most appropriate dose of levothyroxine usually is that which reduces the serum TSH to
just below the lower limit of the normal range for the assay
being used, unless there is evidence of persistent disease,
when lower concentrations may be necessary (Mazzaferri
2000). However, the long-term effects of subclinical thyrotoxicosis on the heart and bone must be considered (Toft
2001). Low serum TSH concentrations in individuals aged
60 years or older is associated with increased mortality from
all causes, and in particular, mortality due to circulatory and
cardiovascular diseases, giving pause to decreasing TSH concentrations to 0.1 µU/ml in patients with thyrotoxicosis
(Parle et al. 2001). Subclinical thyrotoxicosis may have
arrhythmic effects on the heart (Osman et al. 2002).
Radioiodine (131I) treatment for residual
disease
The therapeutic efﬁcacy of 131I is related to the capacity of a
tumor to concentrate and retain iodine. Sodium–iodide symporter (hNIS) expression is low in some thyroid cancers and,
in others, post-transcriptional events may cause hNIS dys-
www.endocrinology.org
Low-iodine diet
Restricting iodine intake to about 50 µg can increase thyroidal 131I uptake and can double the dose of gray per 3700
MBq of 131I administered (Maruca et al. 1984); however, it
may increase total body radiation as result of delayed 131I
clearance. The diet can be very tedious, but the target iodine
intake 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 131I
treatment and continued for several days thereafter. A lowiodine cookbook is available without charge from the Thyroid Cancer Survivors’ Association (Guljord 2000). The
patient must avoid pharmaceutical agents (e.g. radiocontrast
material) with iodine.
Efﬁcacy of postoperative
residual cancer
131
I treatment of
Radioiodine therapy refers to the treatment of thyroid cancer
within the thyroid bed and in metastatic sites (Maxon 1999).
There are three approaches to 131I treatment: empiric ﬁxed
doses, upper bound limits that are set by blood and wholebody dosimetry, and quantitative tumor dosimetry
(Brierley & Maxon 1998). Full discussion of these
approaches is beyond the scope of this review, but they are
summarized elsewhere (Brierley & Maxon 1998,
(Mazzaferri & Kloos 2001).
Surgery is the preferred treatment, but if it cannot be
undertaken then 131I is the treatment of choice, providing the
tumor concentrates it (Mazzaferri 1999). In one large study
of 1599 patients with DTC, 131I treatment was the single most
important factor accounting for disease-free survival
(Samaan et al. 1992). Patients with low-risk tumors had signiﬁcantly fewer recurrences and deaths after 131I treatment
than those treated with levothyroxine alone; however, 131I
conferred only a slight advantage to patients with high-risk
tumors (Samaan et al. 1992). On the basis of regression
modeling of 1510 patients without distant metastases, we
found that 131I treatment of residual disease was an independent variable that favorably reduced the likelihood of recur-
241
Mazzaferri and Massoll: Management of papillary and follicular thyroid cancer
rence, distant recurrence and death from thyroid cancer
(Table 2).
External radiation therapy
Relapse-free survival, especially in patients older than 40
years with invasive papillary thyroid cancer (T4) and
lymph-node metastases (N1) with and without extranodal
extension, may be improved by external beam radiation treatment given as postoperative adjunctive treatment (Phlips et
al. 1993, O’Connell et al. 1994, Farahati et al. 1996, Brierley
et al. 1996, Tsang et al. 1998, Esik et al. 2001). Patients with
microscopic residual papillary cancer after surgery are more
commonly rendered disease-free by external beam radiotherapy (90%) than without it (26%) (Simpson et al. 1988).
Patients with microscopically invasive follicular cancer are
also more often rendered disease-free when external beam
radiation treatment is given (53%) than when it is not (38%)
(Simpson et al. 1988). In another study, the relative risk of
locoregional failure was reduced (RR 0.35) by postoperative
external beam radiotherapy, particularly in those with gross
postoperative regional tumor (RR 0.36) (Chow et al. 2002).
Fluorine-18-ﬂuorodeoxyglucose positron
emission tomography
Progressive dedifferentiation of thyroid cancer cells leads to
a loss of iodine-concentrating ability, with resultant falsenegative 131I DxWBS in about 20% of all DTC metastatic
lesions (Wang et al. 1999). Fluorine-18-ﬂuorodeoxyglucose
(FDG) uptake is an indicator of poor functional tumor differentiation and a poor prognosis of thyroid cancer, and should
be considered in patients suspected of having persistent DTC,
particularly those with increased serum Tg values and a
negative DxWBS, because it can localize tumor that does not
concentrate iodine but which produces Tg. A multicenter
study comparing FDG-positron emission tomography (PET)
with 131I DxWBS, and other scintigraphy tests, found that
the speciﬁcity of whole-body FDG-PET was 90% and the
sensitivity was 75% among all DTC patients (n = 222) and
75% for those with a negative 131I DxWBS (n = 166)
(Gru¨nwald et al. 1999). In contrast, the sensitivity and speciﬁcity of DxWBS were respectively 50% and 99%. Nonetheless, FDG-PET and DxWBS used together detected tumor in
93% of the patients, which was signiﬁcantly better than the
results using other scans.
FDG-PET is sensitive enough to detect small cervical
lymph node metastases, but they nonetheless remain the most
common cause of a false-negative test (Stokkel et al. 1999,
Wang et al. 1999). It localized occult DTC in 71% of patients
who had increased serum Tg concentrations and a negative
131
I DxWBS, and it changed the clinical management in 51%
of the patients (Wang et al. 1999). It had a positive predictive
value of 92% in patients with increased Tg concentrations
242
and a negative predictive value of 93% in those with low Tg
concentrations. FDG-PET scans were never positive in stage
1 tumors, but were always positive in stage 4 tumors with
increased serum Tg concentrations. Others report similar
results (Alnaﬁsi et al. 2000).
A positive FDG-PET study in a patient with lung metastases correlates well with poor 131I uptake of the isotope by
the tumor and a lack of therapeutic response. Multivariate
analysis demonstrated that the single strongest predictor of
survival with DTC was the volume of FDG-avid disease
(Wang et al. 2000). Three-year survival of patients with FDG
volumes of 울125 ml and > 125 ml was respectively 96%
and 18%. No cancer death occurred in a PET-negative patient
with distant metastases. Conversely, patients older than 45
years with distant metastases that concentrate FDG were at
the highest risk for death.
The inﬂuence of serum TSH concentrations on FDG
uptake in metastases has not yet been fully clariﬁed. Hypothyroidism has no effect on FDG uptake (Wang et al. 1999).
However, rhTSH stimulates FDG uptake by DTC (Petrich et
al. 2002).
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