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incomplete or debulking procedures, with 37%
of patients exhibiting local relapse of disease in
the neck postoperatively.
Rates of locoregional recurrence within the
tumor bed or in cervical lymph nodes are high
after surgical resection alone for UTC. UTC has
a clear propensity for metastatic dissemination
and locoregional recurrence and is not treatable
with radioactive iodine, and for these reasons
adjuvant treatment with chemotherapy and
radiotherapy has been recommended to maximize the chance of achieving local control and
to reduce the risk of distant recurrence [27, 37,
39, 43]. Doxorubicin has been the chemotherapy agent most frequently used in this setting, as
monotherapy or in combination with cisplatin,
and has been associated with acceptable toxicity
[37, 43, 81]. In a study of 33 patients at the
University of California, San Francisco, complete surgical resection could be performed in
eight cases and was followed by adjuvant chemoradiotherapy. The complete resection group
had an improved survival compared with
incompletely resected or nonresected tumors,
with four long-term survivors following complete resection [43]. In a smaller series reported
by Tan and coworkers, complete resection of
the tumor was achieved in five of 21 patients
with UTC and was followed by adjuvant chemoradiotherapy, with three of these patients
surviving longer than 2 years [37].
In series that report long-term survival after
complete surgical resection of UTC, surviving
patients received postoperative radiotherapy
and/or chemotherapy in the majority of cases
[22, 27, 37, 39, 42, 43, 82]. Given the aggressive
behavior of UTC, adjuvant treatment with chemotherapy and radiotherapy is recommended
to reduce the risk of recurrent disease following
complete resection in patients with small or
incidentally found tumors.
Clinical Scenario 2: Extensive
Locoregional Disease
Extrathyroidal invasion is present in as many as
82% of UTC, and achieving local control of disease in this setting is difficult [22, 37–39, 41]. In
the presence of extensive local invasion of adjacent structures, such as the trachea, esophagus,
and major vascular structures, complete surgical resection is not possible and other treatment
modalities must be used to obtain control of
local tumor growth. Extensive or radical resection of the invaded trachea or esophagus with
complex reconstruction is rarely indicated due
to the high likelihood of local recurrence in the
neck or death from disseminated disease. Progressive airway compromise from unchecked
local invasion is highly distressing to the patient
and is the mode of death in 15% of cases [44].
The aim of treatment in patients with extensive
local disease to achieve local control of tumor
growth, for the palliation of symptoms and to
extend the duration of life where possible.
Multimodality treatment with chemotherapy
and radiotherapy has been used in the setting of
advanced local disease to achieve control of
tumor growth. Downsizing of tumor volume in
the neck may also enable surgical resection in
patients who respond to this treatment. One of
the first reports of effective treatment for locally
advanced UTC was from Memorial Sloane Kettering hospital where radiotherapy was given in
combination with doxorubicin for nine patients
with UTC, of which only one had complete
resection of disease prior to treatment [83].
Complete response to treatment was observed
in eight patients, and in six of these responders
local control was maintained until death from
other causes.
A multimodality treatment protocol developed in Sweden has shown to be effective in
the management of locally advanced UTC. The
first protocols reported by this group used
external beam radiotherapy in combination
with bleomycin, 5–fluorouracil, and cyclophosphamide [84]. These chemotherapy agents
were replaced with doxorubicin in subsequent
protocols [85, 86]. Response to this protocol
enabled surgical resection to be subsequently
performed in 73% of patients, which was macroscopically complete in 85% of operative cases
[86]. Life-threatening complications did not
occur, and toxicity did not prevent patients
from completing chemoradiotherapy. A reduction in deaths from complications of uncontrolled local tumor invasion was seen with this
treatment protocol, occurring in only 24% of
cases [84, 86]. Local recurrence was seen in
only 40% of cases, and in only 18% of patients
where surgical resection was performed. This
strategy was effective in controlling the effects
of local tumor growth, but survival was limited
by the onset of disseminated disease. Mean
131
POORLY DIFFERENTIATED AND UNDIFFERENTIATED THYROID CANCER
survival durations of 2–4.5 months were
reported in the groups studied, with an overall
1 year survival rate of only 16%. However, longterm survival (>2 years) was seen in 10% of
patients [84].
Results of multimodality therapy from other
centers confirm a role for this strategy in the
management of locally advanced UTC. In a
report of 30 patients with UTC from a French
group, of which extrathyroidal invasion was
present in 26, chemotherapy with doxorubicin
and cisplatin was combined with radiotherapy
and given prior to surgical resection or postoperatively [82]. In seven patients with unresectable disease at presentation, tumor response
to therapy enabled subsequent complete resection in three cases. In total, surgical resection
was performed in 24 cases and was macroscopically complete in 12. Complete surgical resection was associated with a significant survival
advantage in this setting. A complete local
response to therapy was found in 63% of
patients. Overall 3-year survival was 27% (median survival 10 months), with 68% of deaths due
to complications of metastatic disease and only
5% due to locoregional failure. Seven patients
remained disease free at follow up (3-year disease-free survival rate 24%). There was, however, a high rate of toxicity in this study from
neutropenia and bone marrow suppression
(seen in 70%), limiting its role in the management of frail or elderly patients.
Newer chemotherapy agents for the systemic
treatment of UTC have been studied and associated with better results from treatment than
standard regimes. A phase 2 trial of paclitaxel
has been reported which has shown the effectiveness of this agent [87]. In this trial of 20
patients with locally advanced or metastatic
UTC (including 42% who had previously undergone surgical resection), response to therapy
was observed in 53% of patients and was complete in one patient only. The treatment protocol was well tolerated and associated with an
acceptable risk profile. The addition of taxolbased chemotherapy to multimodality treatment protocols may improve the long-term
results of treatment for UTC.
For patients with extensive locoregional
disease, combination chemotherapy and radiotherapy can be effective in controlling local complications. In patients who respond to a trial of
chemoradiotherapy, a sufficient downsizing of
disease in the neck may enable subsequent surgical resection of disease to be performed.
Clinical Scenario 3: Distant
Metastatic Disease
Disseminated metastatic disease is present in
43–64% of patients with UTC at the time of first
assessment [22, 25, 27, 28, 38, 43]. Where disseminated disease is present, prognosis is extremely poor with very few patients surviving for
more than 12 months [22, 25]. Systemic therapy
for metastatic disease has a very limited role in
the management of metastatic UTC, and the
results after treatment with existing chemotherapy regimes remain disappointing [88]. In a
report of nine patients undergoing chemotherapy with doxorubicin and bleomycin for metastatic UTC at the University of Padova, clinical
response was seen in onlya single patient and the
group had a median survival of only 5.7 months
[89]. A larger study of chemotherapy for
advanced thyroid cancer including 39 patients
with UTC comparing monotherapy with doxorubicin with combination therapy with doxorubicin and cisplatin showed a clinical response in
26% of patients receiving the combined treatment, of which half displayed a complete
response [90]. Significantly more patients had a
complete response to treatment after combination chemotherapy in this study. Combination
therapy was however associated with considerable toxicity, causing life-threatening complications in 12% of patients. Chemotherapy with
newer agents such as paclitaxel has been associated with improvements in clinical response
with lower rates of toxicity. In the phase 2 trial
of paclitaxel for locally advanced and metastatic
UTC, few patients had toxicities more severe
than grade 2, and no life-threatening complications were reported [87]. Fifty-three percent of
patients exhibited a clinical response to paclitaxel and had a mean duration of survival of 32
weeks, compared with 10 weeks for nonresponders, although this differencewas not statistically
significant.
In patients with UTC where distant metastases are present, complications of disseminated
disease will be the determinant of survival in
most cases, and aggressive multimodality treatment with chemoradiotherapy and surgical
resection will in most cases not influence
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survival. An exception to this may be where
extensive local disease is also present and
where external beam radiotherapy and chemotherapy can be given for local control of the
tumor mass with palliative intent [84, 86]. The
distress of progressive airway compromise and
other local complications are considerable, and
chemoradiotherapy for local control has been
recommended in the setting of disseminated
metastatic disease for this reason [84, 86].
Radiotherapy also has a role in the palliation
of metastatic disease and can be directed to sites
of skeletal or brain metastases for control of
local symptoms [91].
Scenario 4: Acute Airway
Compromise
Invasion of the larynx or trachea is present in up
to 50% of UTC at the time of presentation, and
less commonly (18% of cases) UTC can present
with symptoms of acute airway obstruction
necessitating urgent intervention [38, 39]. In
many of these cases, endotracheal intubation is
performed as an emergency procedure to
achieve control of the airway, allowing subsequent clinical evaluation of the obstructing
mass with appropriate imaging and diagnostic
pathology. CT imaging of the neck and mediastinum can assess the extent of local invasion
into the airway and other adjacent vital structures, and can be used to assess the feasibility of
surgical debulking or resection in relieving the
obstruction (Fig. 9.7). Metastatic disease to
mediastinal lymph nodes or the lungs may also
be seen. Flexible bronchoscopy and esophagoscopy should be performed to assess whether
invasion into the lumen of the airway or esophagus has occurred and can be used to obtain
biopsy material of the tumor if this is present.
FNA biopsy should be performed to confirm
UTC and rule out other thyroid malignancies
which may be more responsive to treatment.
More definitive control of the airway can be
achieved by surgical intervention or by the
insertion of a tracheal stent. Surgical options
for the relief of airway obstruction consist of
surgical resection, division of the isthmus,
tumor debulking, or by the formation of tracheostomy. Complete surgical resection of
UTC is rarely possible in the setting of acute
airway obstruction due to the advanced nature
a
b
Fig. 9.7. (A) Cross-sectional computed tomography appear-
ance of undifferentiated thyroid cancer arising within a longstanding multinodular goiter in a 58-year-old female. The
patient presented with acute airway compromise and distress.
Invasion and compression of the trachea and esophagus are
demonstrated. (B) Chest radiograph of the patient showing
compression and deviation of the trachea (arrow).
of local invasion. Tracheostomy has been performed in 7–33% of patients with UTC in published series and can be technically difficult due
the extent and bulk of local disease [37, 38]. In a
study of 69 patients who underwent tracheostomy in the setting of locally advanced thyroid
cancer, patients with UTC had a survival rate of
only 25% at 3 months [92]. Survival was worse
for patients with UTC after tracheostomy compared with those who did not undergo this procedure, although this probably represented the
selection of more aggressive and advanced
malignancies. More recently, the insertion of
self-expanding stents under bronchoscopic
control to traverse the region of obstruction has
133
POORLY DIFFERENTIATED AND UNDIFFERENTIATED THYROID CANCER
been performed for longer-term airway control
[93–95]. This technique can be combined with
balloon dilation of the narrowed segment and
laser ablation of invasive intraluminal disease,
and has been successful in achieving airway
control in 92% of patients with obstruction
from thyroid malignancy [95]. Potential complications of this technique include stent
migration, stent obstruction, and in-growth of
tumor into the stent causing recurrent obstruction [95].
Outcomes and Prognosis
Despite improvements in diagnosis, surgical
technique and the development of newer multimodal chemotherapy and radiation therapy
protocols, the prognosis of patients with UTC
remains poor (Table 9.1). Complications of disseminated metastatic disease are frequently the
cause of death and limit survival even where
effective local control can be achieved with
aggressive surgical resection and radiotherapy.
The majority of patients with UTC will die from
complications of disseminated metastatic disease (usually pulmonary) or invasion of vital
structures within the neck [44]. Airway obstruction due to tumor invasion is the cause of death
in 16–50% of cases [37, 44].
studies, with median survival durations of 3–7
months, and only a small proportion of patients
surviving for longer than 1 year [27, 28, 37–39,
43]. A survival analysis of 516 cases of UTC from
the SEER database found a disease-specific mortality of 80.7% at 12 months, with patient age less
than 60 years, tumor confined to the thyroid and
surgical resection of the tumor combined with
radiotherapy being associated with a greater
probability of survival on multivariate analysis
[25]. Studies involving smaller series of patients
with UTC have found that younger age at presentation, smaller tumor size (<5–6 cm), the
absence of disseminated metastatic disease, and
complete surgical removal of the tumor have all
been associated with an improved probability of
survival or longer survival duration [22, 27, 28,
37–39, 43]. Where complete macroscopic resection of the tumor can be performed, aggressive
multimodality treatment with surgery followed
by chemoradiotherapy has been associated with
long-term survival in a small proportion of
selected patients [43]. Many of the longer-term
survivors reported in case series of UTC are
patients with small foci of anaplastic carcinoma
seen within larger well-differentiated tumors or
where UTC is found incidentally at thyroidectomy [28, 40–42]. Such patients represent a small
but distinct subgroup of UTC associated with a
more favorable prognosis.
Table 9.1. Outcomes after treatment for undifferentiated thyroid carcinoma
Author Year Patients Surgical resection (%) Survival (%) Mean survival (months)
McIvor [22] 1949–1999 134 72 9.7% – 1 year 3
Venkatesh [27] 1950–1987 121 73 14% – 2 year 7.2
Nilsson [84] 1971–1997 81 52 10% – 2 year 2.5–5.4
Pierie [28] 1969–1999 67 67 16% – 3 year ND
Sugitani [39] 1976–1999 44 59 16% – 1 year 6
Sugino [42] 1989–1999 40 65 20% – 2 year ND
Lo [38] 1968–1997 38 47 4% – 2 year 1.3
Haigh [43] 1973–1998 33 79 20% – 2 year 3.8
De Crevoisier [82] 1990–2000 30 80 27% – 3 year 10
Tan [37] 1968–1992 22 81 14% – 2 year 4.5
ND – not described
The 134 patients with UTC managed in a
50-year period at the Mayo Clinic had a median
survival of only 3 months with only 9.7% of
patients surviving beyond 1 year [22]. Similar
outcomes have been documented in other
The development of metastatic disease is most
frequently the determinant of survival in patients
with UTC, and research into novel systemic
therapies has been undertaken in an effort to
improve the dismal outlook for patients with
134
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disseminated disease. Targeted molecular therapy with the proteosome inhibitor bortezomib
and the selective tyrosine kinase inhibitor imatinib mesylate have shown activity against UTC in
vitro [96, 97]. Adenovirus-mediated gene therapy
targeting the p53 gene mutation has also been
attempted [98]. Redifferentiation of UTC cells to
promote the uptake of radioactive iodine has also
been examined experimentally, using reverse
transcriptase inhibitors and virus-mediated thyroid transcription factor-1 gene transfer [99, 100].
Until such time as effective systemic therapies are
discovered, multimodality therapy with chemotherapy and radiotherapy followed by complete surgical resection when possible offers the
greatest chance of achieving local control, palliation, and extension of survival in patients with
this highly aggressive malignancy.
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10
Postoperative Management of Well-Differentiated Thyroid Cancer
R. Michael Tuttle and Rebecca Leboeuf
Introduction
For the nonsurgeon, postoperative management
of thyroid cancer usually begins a few days or
weeks after surgery when the patient returns to
the office to discuss the final pathology report
and determine if any additional therapy is necessary. Depending on the specifics of theindividual
case, additional therapies that may be required
can include further surgery, radioactive iodine
ablation, thyroid-stimulating hormone (TSH)
suppression with levothyroxine, external beam
irradiation, or other systemic therapies.
The decision to recommend additional treatments beyond the initial thyroid surgery should
be based on an accurate assessment of risk of
recurrence and death from thyroid cancer for
each individual patient. Recently, several international authorities on thyroid cancer have published guidelines in which estimates of risk of
recurrence and risk of disease-specific death are
used to guide both initial treatment and followup recommendations [1–5].
In this chapter, we will review a practical approach to risk stratification for well-differentiated
thyroid cancer that can be used to estimate both
theriskofrecurrenceandtheriskofdeathfrom
thyroid cancer. By balancing the risk and benefits
of additional therapies with this understanding of
the likely clinical course, a rationale treatment and
follow-up plan can be developed for individual
patients.
Initial Risk Stratification
Over the years, several staging systems have been
published that can accurately identify patients
at either low or high risk of dying from thyroid
cancer [6–13]. These staging systems predict disease-specific mortality based on clinical data that
can be considered either as patient-related factors (age and gender) or tumor-related factors
(size of primary, histology, gross extrathyroidal extension, completeness of resection, cervical
lymph node involvement, or distant metastasis)
[14]. From a simplified clinical perspective, these
important clinical factors can be used to stratify
the risk of dying from thyroid cancer into very
low, low, intermediate, and high (see Table 10.1)
[15, 16].
In thyroid cancer, the risk of recurrence
does not always parallel the risk of diseasespecific death [17]. This is particularly apparent in the young thyroid cancer patients where
the risk of recurrence is very high, but the risk
of death is very low. Therefore, in addition to
determining the risk of disease-specific death
in thyroid cancer patients, it is also necessary
to separately estimate the risk of recurrence.
In many cases, additional treatments may be
effective at decreasing recurrence, but have little impact on overall survival, especially in
young patients who are at high risk of recurrence but very low risk of death from thyroid
cancer [2, 14].
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_10, Ó Springer-Verlag London Limited 2009
137
ENDOCRINE SURGERY
Table 10.1. Risk of death from thyroid cancer
Very low risk Low risk Intermediate risk High risk
Age at diagnosis <45 years <45 years Young patients (<45 years)
Classic PTC > 4cm
Or vascular invasion
Or extrathyroidal
extension
Or worrisome histology of
any size**
Primary tumor
size
<1 cm 1–4 cm Older patients (>45 years)
Classic PTC < 4cm
Or extrathyroidal
extension
Or worrisome histology
< 1–2 cm confined to
the thyroid**
Histology Classic PTC, confined
to the thyroid
gland*
Completeness
Complete resection Complete resection Complete resection Incomplete tumor
Classic PTC, confined
to the thyroid
gland*
Histology in conjunction with
age as above
of resection
Lymph node
None apparent Present or absent*** Present or absent*** Present or
involvement
Distant metastasis None apparent None apparent None apparent Present
*Confined to the thyroid gland (even if multifocal) with no evidence of vascular invasion or extrathyroidal extension
**Worrisome histologies includes histologic subtypes of papillary thyroid cancer such as tall cell variant, columnar variant, insular variant,
and poorly differentiated thyroid cancers.
***Cervical LN metastases in older patients, but probably not in younger patients, may confer an increased risk of death from disease.
Only those patients meeting all criteria within the respective column would be classified as very low risk or low risk. Older patients with either
incomplete tumor resection or presence of distant metastasis are considered high risk irrespective of tumor size and specific histology. Patients
with a combination of risk factors (age, histology, and tumor size) crossing over between columns are classified as intermediate-risk patients.
>45 years
>4 cm classic PTC
Worrisome
histology
>1–2 cm**
resection
absent***
138
Table 10.2. Risk stratification for the likelihood of clinically evident thyroid cancer recurrence following complete resection
of primary tumor in patients with no evidence of distant metastases at initial evaluation
Low risk Intermediate risk High risk
Age at diagnosis Any age 20–60 years <20 or >60 years
Primary tumor size <1 cm 1–4 cm >4cm
Histology Classic PTC, confined
to the thyroid
gland
Lymph node
None apparent Present or absent Present
Classic PTC, minor extrathyroidal
extension, or vascular invasion,
or multifocal disease
Other than classic PTC, gross
extrathyroidal extension or vascular
invasion
involvement
Patients with incomplete tumor resection or distant metastasis at diagnosis are very likely to have persistent disease even after aggressive
initial therapy and therefore are dealt with differently than the more usual patient without evidence of distant metastasis in which all gross
evidence of disease has been resected and are therefore not included in this risk stratification scheme.
139
POSTOPERATIVE MANAGEMENT OF WELL-DIFFERENTIATED THYROID CANCER
Based on manyof the same clinical and pathological characteristics that are used in the staging
systems that predict death from thyroid cancer,
the risk of recurrence can be estimated in an
individual patient to be either low, intermediate,
or high (see Table 10.2) [15, 16]. To be conservative, patients with a histology more worrisome
than classic papillary thyroid cancer (PTC),
microscopic multifocal disease, or microscopic
extrathyroidal extension are considered to be at
intermediate risk. Additional research is needed
to make sure that we arenot unnecessarily upstaging these patients, particularly when the primary tumor is quite small.
Patients with incomplete tumor resection or
known distant metastases at presentation almost
always require additional therapy [2, 18, 19].
They require individualized therapy and careful
assessment of response to therapy evaluations
to guide their management.
Initial Postoperative Visit
Accurate risk stratification begins with a careful
analysis of all the available clinical data that have
been obtained for that individual patient. At this
initial postoperative visit,all data obtainedduring
the preoperative evaluation, the intraoperative
procedure, as well as the postoperative pathology
report and lab data are analyzed in an attempt to
understand both the extent of disease and likely
clinical course so that we can tailor specific treatment recommendations for an individual patient
(see Table 10.3).
It is important to emphasize that the thyroid
pathology report does not provide all the data
necessary for accurate risk stratification. In
order to properly risk stratify patients, it is critical
that treating clinicians have a very good understanding of the preoperative, intraoperative, and
postoperative findings inorder to gain a full appreciation of the extent and potential aggressiveness
of an individual patient’s thyroid cancer. Unfortunately, patients are often classified as either low
or high risk based on the pathology report alone
without incorporating all other available clinical
information into the risk stratification scheme.
This can result in either an overestimate or underestimate of the risk for death or recurrence.
For example, a 35-year-old female patient
with a 1.5-cm papillary thyroid cancer could
be inappropriately classified as having a low
Table 10.3. Data necessary for accurate risk stratification
Preoperative findings Physical examination
Vocal cord function
Cross-sectional imaging
(if obtained)
Intraoperative findings Extent of thyroid surgery
Extent of lymph node dissection
Presence of gross extrathyroidal
extension
Involvement of major structures
in the neck
Completeness of tumor
resection
Pathology findings Histopathology
Molecular characterization
Laboratory findings Serum thyroglobulin
Calcium, albumin, PTH
TSH, Free T4
risk for disease-specific death and recurrence
if the ‘‘extrathyroidal extension’’ described on
the pathology report was mistakenly assumed
to reflect minimal microscopic extracapsular
extension rather that the margin of extrathyroidal gross tumor invading into major neck
structures.Similarly,eveninthesettingofa
very small papillary or follicular thyroid cancer, the presence of pulmonary nodules on a
preoperative chest radiograph or a postoperative serum thyroglobulin (Tg) of 1,500 ng/mL
would raise the suspicion of distant metastases
and likely lead to additional diagnostic evaluations and therapies.
While most patients have a neck ultrasound
and chest radiograph prior to surgery, additional use of cross-sectional imaging studies is
not routinely recommended unless the patient
is at an increased risk for distant metastases
[2, 3]. Since patients classified as high risk for
recurrence or death are also often at significant
risk for distant metastases, cross-sectional imaging of the lungs and brain is recommended
to identify other sites of disease that may
need therapy or close observation. Likewise,
aggressive histologies such as Hurthle cell carcinoma, tall cell or poorly differentiated variants of papillary thyroid may concentrate
radioactive iodine (RAI) poorly and therefore
are often better detected with 18 FDG PET
scanning than RAI scanning [2, 14, 20].
It is important to avoid intravenous contrast