Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1382_Библиотеки_им_академика_М_И_Перельмана.pdf
140
ENDOCRINE SURGERY
containing iodine in patient that are likely to
requireRAIsincethelargeamountofstable
iodine present in CT contrast will render RAI
ineffective for at least 2–3 months.
In many cases, the adequacy of surgical resection cannot be determined by the pathology
report alone. For example, a pathology report
that notes ‘‘positive margins’’ or ‘‘extrathyroidal
extension’’ could reflect either (a) minor extension into perithyroidal adipose tissue, or minor
invasion into strap muscles that was completely
resected, or (b) the surgical margin of gross disease that was not completely resectable. Clearly,
the risk stratification and subsequent therapeutic
recommendations in these two situations could
vary markedly.
Therefore, it is critical that the intraoperative
findings be transmitted to the endocrinologists/
nuclear medicine physicians in a format that is
easily understandable to the nonsurgeon. Unfortunately, while the dictated operative reports
contain the details of the surgical procedure,
often in excruciating detail, they are difficult
for nonsurgeons to decipher and understand.
Therefore, either (a) direct communication,
or (b) an operative note with a section clearly
marked as ‘‘intraoperative findings,’’ or (c) a
separate note (or diagram) succinctly explaining the surgical procedure and intraoperative
findings will dramatically improve the endocrinologists understanding of the intraoperative
findings.
Once the endocrinologist has a thorough understanding of the preoperative and intraoperative findings, a careful review of the pathology
description will provide invaluable information
that can be used to further guide risk stratification and treatment recommendations. While
the size of the primary tumor is the major determinant of clinical outcome, the presence of vascular invasion, extrathyroidal (or extranodal)
extension, lymphatic involvement, and worrisome histological subtypes of thyroid cancer
(such as tall cell variants, columnar variants,
insular variants, and poorly differentiated subtypes) may also be associated with an increased
risk of recurrence and/or death. Therefore,
regardless of size of the primary, these additional worrisome features will increase our
estimate for risk of recurrence and risk of
death and often lead to more aggressive additional therapies.
Over the last several years, our understanding of the molecular biology of thyroid cancer
has increased dramatically [21]. Several authors
have suggested that the presence of specific
molecular abnormalities can provide important
information as to the risk of recurrence [22–24].
For example, it has recently been demonstrated
that tumors harboring BRAF mutations appear
to display a more aggressive clinical course [25,
26]. Since, many pathology departments now
offer molecular analysis of malignancies, it is
likely that molecular profiling will be added to
our risk stratification schemes in the years to
come.
In our practice, we use a serum Tg measurement, about 10 days after thyroidectomy, to
guide our risk stratification. This is particularly
important in low-risk patients that we are considering following with observation alone without RAI ablation. While the precise cutoff values
for ‘‘normal post-op’’ Tg are not well defined, we
generally consider a serum Tg value less than
10 ng/mL (with a TSH of about 1–2 mIU/mL)
about 10 days after surgery to be consistent with
normal remnant thyroid. Usually, the Tg continues to decline over several weeks such that by
4–6 weeks postoperatively the serum Tg (with
mild TSH suppression) is less than 3–5 ng/mL
and often less than 1 ng/mL. Therefore, if the
serum Tg is elevated at the 10-day visit, a repeat
valueisobtained4weekslatertoobtaina
nadir postoperative value. Serum Tg levels that
remain above these arbitrary cutoff values
about 1 month after total thyroidectomy would
raise the suspicion for persistent disease and
lead to additional cross-sectional and nuclear
medicine imaging.
Goals of Initial Therapy
The goals of initial therapy are to surgically
remove or destroy all thyroid cancer cells while
minimizing treatment and disease-related morbidity [2]. Our initial therapies, if successful,
should result in a decrease in both local and
distant recurrence as well as disease-specific
mortality. Because every treatment has potential
risk and side effects, it is imperative that the
risks associated with our treatment recommendations are justified by the risk of recurrence or
disease-specific death.
141
POSTOPERATIVE MANAGEMENT OF WELL-DIFFERENTIATED THYROID CANCER
Extent of Initial Thyroid
Surgery
Most of the published guidelines recommend
total thyroidectomy as the procedure of choice
in patients with biopsy-proven papillary thyroid
cancer [14]. In most large series, a total thyroidectomy is associated with lower recurrence
rates than unilateral thyroid surgeries [10, 17,
27]. However, a unilateral lobectomy achieves
the same excellent disease-specific survival rates
in patients at very low or low risk of dying from
thyroid cancer (see Table 10.1) [28]. With careful
follow up (primarily neck ultrasonography), the
few recurrences that develop years later in lowrisk patients initially treated with less than total
thyroidectomy are usually readily detectable and
easily treated with additional surgery with or
without postoperative RAI. Therefore, less than
total thyroidectomy is still considered an acceptable surgical option for patients at low risk of
dying from thyroid cancer.
However, for patients at intermediate or high
risk of either (a) dying from thyroid cancer (see
Table 10.1) or (b) having a clinically evident
recurrence (see Table 10.2), we routinely recommend total thyroidectomy. In most series, bilateral thyroid surgery in high-risk patients has been
shown to have a beneficial effect on both diseasespecific survival and risk of recurrence[2, 14].
Additionally, since radioactive iodine ablation
is routinely used in these high-risk patients,
a total thyroidectomy is required as initial
management.
Very often small papillary thyroid cancers
(<1 cm) are detected after lobectomy for predominantly benign thyroid disease. These
tumors are at very low risk of disease-specific
death (<1%) and low risk for having cervical or
distant metastases (less than 2–3%). Two recent
publications have detailed the controversies
embodied in the management of these low-risk
patients [29, 30]. In our opinion, in the absence
of other evidence of disease in the contralateral
lobe (multifocal disease), neck lymph nodes
or distant sites, patients with classic primary
papillary thyroid cancers less than 1 cm detected
at the time of lobectomy for predominantly
benign disease can be followed with observation without the need for a completion thyroidectomy or RAI ablation. Obviously, the
development of suspicious lesions in the contralateral lobe or cervical lymph nodes would
prompt additional evaluations and likely completion thyroidectomy.
The most controversial patients are those with
well-differentiated thyroid cancers, confined to
the thyroid, that are between 1 and 4 cm in size.
By nearly all staging systems,these patients are at
low risk for death from thyroid cancer but are
variously classified as either low or intermediate
risk for recurrence. In many centers, the endocrinologists want to give RAI ablation to these
intermediate-risk patients, and therefore completion thyroidectomy is mandated. However,
in our center, if the primary tumor is less than
3–4 cm, confined to the thyroid without worrisome histologic features, the contralateral lobe
is normal on ultrasound without evidence of
lymph node involvement, and the serum Tg is
in the expected postoperative range, we do not
feel that additional surgery or RAI ablation will
improve disease-specific survival and therefore
do not routinely recommend either radioactive
iodine ablation (if total thyroidectomy was done)
or a completion thyroidectomy (if a unilateral
surgical procedure was done). However, since
this an area of continued controversy, we do
discuss in great detail the risk and benefits of a
completion thyroidectomy with or without RAI
ablation in these patients at intermediate risk for
recurrence. That being said, most of our intermediate-risk patients chose to follow without
additional surgery or RAI ablation unless
abnormalities are subsequently detected on
follow-up neck ultrasonography or serum Tg
levels.
In some cases, the final pathology report results
in upstaging a patient initially thought to be low
risk based on preoperatively and intraoperative
findings. If this is the case, then a completion
thyroidectomy is recommended. For example, a
patient with a 1.5-cm tumorthatwastentatively
staged as low risk prior to and during surgery may
require a subsequent completion thyroidectomy if
on final pathology worrisome histologic features
(e.g., microscopic vascular invasion, worrisome
histologic subtype, and microscopic extrathyroidal extension) are detected. Because the final
pathology report is required for an accurate final
risk assessment, many argue for a total thyroidectomy in all patients with a preoperative diagnosis
of well-differentiated thyroid cancer. While this is
142
ENDOCRINE SURGERY
not an unreasonable approach, it will subject
many low-risk patients to the risks of a bilateral
thyroid surgical procedure while achieving little, if
any, survival benefit.
Very often the extent of initial surgery is influenced by the follow-up methods and paradigms
that will be used by the referring endocrinologists. If RAI ablation is planned, then total thyroidectomy is required to minimize the volume
of normal thyroid tissue that would preferentially
concentrate the RAI and prevent detection/therapy of metastatic lesions. Total thyroidectomy
and RAI ablation has the additional benefit of
resulting in serum Tg levels that are either very
low or undetectable. The maximum sensitivity
and specificity of serum Tg is achieved when all
normal thyroid tissue has been destroyed (total
thyroidectomy and RAI ablation). While not
required for follow up in patients at low to
in termediate risk for recurrence, many endocrinologists are much more comfortable following thyroid cancer patients previously treated
with total thyroidectomy and RAI ablation. As
such, they will often prefer total thyroidectomy
and RAI ablation in nearly all but the very lowrisk patients.
From a practical standpoint, it appears that
the wide spread use of neck ultrasonography
has resulted in fewer unilateral thyroid procedures and more total thyroidectomy procedures even in low-risk patients. It is hard to
imagine doing less than a total thyroidectomy
with biopsy-proven papillary thyroid cancer if
structural abnormalities are present in the contralateral lobe (even though the vast majority of
these abnormalities will be benign). Furthermore, follow-up ultrasonography commonly
detects abnormalities in the contralateral lobe
that is likely part of the normal aging process
of the thyroid or subsequent development of
benign thyroid disease that is common as
patient’s age, but that will be, nonetheless, worrisome to both the patient and the treating physician. Based on these practical follow-up issues
and a potential benefit of decreased recurrence,
many low-risk patients opt for a total thyroidectomy as their initial surgical procedure
even though this approach provides no substantial survival benefit and probably increases
the risk of operative complications (hypoparathyroidism, injury to recurrent laryngeal
nerve).
Radioactive Iodine Remnant
Ablation
The use of RAI in the post-thyroidectomy setting to destroy the microscopic residual thyroid
bed tissue has become know as RAI remnant
ablation (RRA). Because RRA has been shown
to decrease recurrence rates and disease-specific
mortality rates in high-risk patients, it must
also have a tumoricidal effect on thyroid cancer
deposits. While all of the published guidelines
support the routine use of RRA in patients at
moderate to high risk of recurrence or death,
there continues to be considerable controversy
over RRA in low-risk patients [14].
While the final decision regarding RAI ablation is made during a careful discussion of the
risks and benefits with an individual patient,
in general we would recommend RAI ablation in
patients at intermediate to high risk of dying
from thyroid cancer (Table 10.1) or high risk of
recurrence (Table 10.2). We see little clinical
benefit in routine use of RAI ablation in patients
at very low risk of dying from thyroid cancer or
at low risk of recurrence.
In high-risk patients, RRA probably reduces
recurrence and improves overall survival. However, it is unlikely that RRA will improve the
already excellent survival of low-risk patients.
Likewise, data on decreasing recurrence rates
in low-risk patients is much less convincing.
Therefore, the potential benefits of RAI in lowrisk patients probably has more to do with an
increased sensitivity for detection of recurrent
disease with RAI scanning and serum Tg measurementsthanitdoesforatruesurvivalor
recurrence benefit. However, without a documented survival benefit, it is hard to justify the
routine use of RAI in low-risk patients.
The few recurrences that develop in this lowrisk group of patients are usually readily detectable on follow-up ultrasonography or a rising
serum Tg. Unlike 30 years ago when the primary method for detection of recurrent disease
was physical examination, routine use of neck
ultrasonography and serum Tg measurements
during follow up should identify the few recurrences that develop in these low-risk patients
at an early stage in which they can be easily
treated with additional surgery or radioactive
iodine.
143
POSTOPERATIVE MANAGEMENT OF WELL-DIFFERENTIATED THYROID CANCER
Fortunately, RAI is a very safe targeted therapy that has been used since the late 1940s in the
treatment of thyroid cancer. Following an initial
ablative administered activity of 75–100 mCi,
many patients will develop temporary alterations
in taste that last for about a month, or salivary
gland swelling/tenderness that may last for a few
months. Unfortunately, 1–2% will develop persistent salivary gland swelling and pain, often
with dry mouth which can lead to difficulty in
swallowing, persistent taste alterations, gum
disease, and dental cavities. Second malignancies, such as leukemia, are associated with multiple doses over time and are not associated with
the usual dose of RAI given as initial RRA. The
rate of permanent side effects increases with
increasing administered activity both as single
doses and cumulative doses over time.
In the past, RRA required a prolonged period
(4–6 weeks) of thyroid hormone withdrawal to
elevate the TSH to more than 30–40 mIU/mL so
that the RAI would be adequately concentrated
by both the normal thyroid tissue and malignant thyroid cells [14]. In late 2007, recombinant human TSH (Thyrogen, Genzyme) was
approved by the US Food and Drug Administration as an adjunct to RRA. From a practical standpoint, patients can be discharged on
levothyroxine after total thyroidectomy with the
goal of achieving appropriate TSH suppression (discussed below). The patient remains on
levothyroxine suppression during RRA, and
recombinant human TSH (two injections of
0.9 mg on two consecutive days) is used to raise
the TSH to levels sufficient to stimulate the
uptake of RAI into normal and malignant thyroid cells. In our center, a tracer dose of
administered immediately after the second rhTSH
injection. A pretherapy whole-body scan is performed the following day after which the ablation
dose of
avoids the marked hypothyroid symptoms associated with thyroid hormone withdrawal that used
to be a necessary part of RRA.
RAI into thyroid cells is also maximized by the
patient following a low-iodine diet. Most nuclear
medicine groups recommend a low-iodine diet
for 1–2 weeks prior to RRA in order to deplete
the body stores of iodine [14]. In this way, the
relatively small amounts of RAI given are preferentially concentrated by the thyroid cells (rather
131
I is given to the patient. This approach
In addition to an elevated TSH, the uptake of
123
Iis
than the stable, nonradioactive iodine present in
our foods). It is for this reason that it is important to avoid iodinated contrast materials in
patients likely to need RRA. The huge load of
iodine contained in these iodinated contrast
materials take several months to be excreted
from the body and will markedly diminish the
diagnostic and therapeutic utility of RAI for
several months.
TSH Suppression
TSH suppression with supraphysiologic doses
of levothyroxine has been a cornerstone of thyroid cancer therapy for more than 40 years [31,
32]. However, over the last 10–15 years, an
increased appreciation of the risk of atrial fibrillation and osteoporosis associated with mild hyperthyroidism has led to a more critical analysis of
the degree of thyroid hormone suppression that
is necessary based on the risk stratification of the
patient.
Several studies now suggest that aggressive
TSH suppression (less than 0.1 mIU/mL) may
be beneficial in high-risk patients but the data in
low- to intermediate-risk patients are less convincing [33, 34]. Therefore, while we routinely
recommendaggressive TSH suppression inhighrisk patients, the goal TSH formost other thyroid
cancer patients ranges from 0.1 to 0.4 mIU/mL
[2, 5]. However, we are much less aggressive in
patients at low or very low risk for recurrence or
death allowing the TSH to range from 0.5 to
1.5 mIU/mL. This approach balances the risk of
recurrence and death with the risks of therapy
and should provide adequate suppression based
on the individual patient risk. During follow up,
the degree of TSH suppression is re-evaluated
every few years to make sure the goal TSH continues to correlate with therisk ofrecurrence and
death.
External Beam Irradiation
Fortunately, external beam radiotherapy (EBRT)
is seldom necessary as part of the initial therapy
of papillary thyroid cancer [18, 35]. However,
EBRT does have a very well-defined role in
patients who present with inoperable disease or
144
ENDOCRINE SURGERY
gross disease remaining after attempted surgical
removal. Usually, these are older patients with
RAI refractory, poorly differentiated histologies.
In addition, EBRT probably has a role in older
patients presenting with gross extrathyroidal
extension, in which, even though all the evidence
of gross disease was removed, they have persistent microscopic or low-volume disease that is
unlikely to respond to RAI therapy [36]. We will
often use postoperative 18 FDG PET scanning in
conjunction with diagnostic RAI scanning to
identify patients with FGD PET-positive, RAInegative residual disease that are at high risk of
local recurrence.In these patients,the risk of RAI
refractory recurrence outweighs the risks and
side effects of EBRT therapy.
Outside the neck, EBRT is a useful tool to treat
macroscopic disease that is unlikely to respond to
RAI treatment [35]. These are often bone metastases in which EBRT is remarkably effective in
palliating pain and preventing disease progression that could result in structural instability of
the bone. EBRT is also a useful tool in treating
brain metastases that cannot be safely resected.
Systemic Therapy for Distant
the potential benefit. However, patients with
distant metastasis that are structurally progressive (usually FDG PET positive) have a lifethreatening disease that warrants strong consideration for systemic therapy. Unfortunately, the
traditional chemotherapy regimens used (platinum or adriamycin based) have been very disappointing with meaningful, durable response
rates of less than 10–15%.
Over the past 5 years, a renewed interest in
clinical trials in thyroid cancer has resulted in
several phase 2 trials, specific to thyroid cancer, being opened both in the USA and abroad
[19]. Many of these trials are using targeted
therapy to inhibit key steps in the receptor tyrosine kinase pathways such as vascular endothelial growth factor receptor, RET, and BRAF.
Both the American Thyroid Association (http://
www.thyroidtrials.org/) and the National Cancer
Institute (http://www.cancer.gov/clinicaltrials/
search) maintain a list of currently available clin-
ical trials on their respective websites. Eligibility
for most of these trials is usually structurally
progressive diseasewith a minimum target lesion
size of about 1 cm that is RAI refractory and not
amenable to surgical resection.
Metastases
Although distant metastases are present at initial
presentation in less than 5% of patients with
papillary thyroid cancer, they can be identified
in long-term follow up in as many as 10% of
patients with papillary thyroid cancer and 20%
of patients with follicular thyroid cancer [2]. In
essentially all cases, RAI is the initial attempted
therapy. Fortunately, this is a quite effective therapy for small-volume, well-differentiated thyroid
cancer. Unfortunately, it is much less effective in
treating large-volume, well-differentiated thyroid cancer even if the metastatic disease concentrates RAI. Recently, 18 FDG PET scanning has
emerged as a powerful tool to predict disease
progression, responsiveness to RAI, and even disease-specific mortality [20]. In general, metastatic
lesions that are markedly positive on FDG PET
scanning are not-RAI avid and do not respond to
even very high dose RAI therapy [37].
Many patients have distant metastases detectable by cross-sectional imaging that are slow
growing (usually FDG PET negative) in which
the risks of systemic therapy probably outweigh
Strategy for Detecting
Persistent/Recurrent Disease
Just as risk stratification informed our initial
therapeutic choices, so should it guide our follow-up management paradigm [15, 16]. Disease
detection tools should be selected based on the
risk of recurrence and likely sites of recurrence.
Clearly, the most likely site of recurrence in
well-differentiated thyroid cancer patients is
the neck: either in the thyroid bed, in cervical
lymph nodes, or soft tissue at the site of initial
surgical removal. Therefore, it is not surprising
that neck ultrasonography has gained increasing popularity as our primary tool for detection
of recurrent disease.
Similarly, serum Tg has become our main
tool for detecting the presence of persistent or
recurrent disease in the neck or elsewhere in
the body [38]. Most recurrences are heralded
by a rise in serum Tg either on suppression or
after stimulation. However, serum Tg will often
miss very small-volume cervical lymph node
metastases and may be less reliable in poorly
145
POSTOPERATIVE MANAGEMENT OF WELL-DIFFERENTIATED THYROID CANCER
differentiated thyroid cancers that tend to make
Tg more poorly. In addition, serum Tg determinations are not reliable in the presence of antiTg antibodies that are present in 20–25% of
thyroid cancer patients [39]. Often the anti-Tg
antibodies interfere with the Tg assay, usually
resulting in a false lowering of the Tg value. To
complicate matters further, serum Tg values
vary dramatically (as much as 5–10 ng/mL) when
the same blood sample is run in different commercial assays [40]. Therefore, in order to obtain
maximal sensitivity and specificity in serum Tg
values, serial determinations over time in the
same lab assay, without interfering anti-Tg antibodies, is required.
The common follow-up paradigm for patients
at low to intermediate risk of recurrence or death
from thyroid cancer usually includes physical
examination, TSH, Free T4, Tg, and anti-Tg antibodies every 6 months for the first 2–3 years
with a thyroid ultrasound obtained 6–12 months
after initial therapy, then yearly for several years
[14]. This paradigm has excellent sensitivity and
specificity for detection of recurrent disease in
low- to intermediate-risk patients with welldifferentiated thyroid cancers which make copious amounts of Tg and in whom the most likely
site of recurrence is in the neck.
However, this paradigm will be less sensitive
for high-risk patients with less well-differentiated
tumors that maymake Tg poorly and could recur
outside the neck. These high-risk patients would
likely benefit from additional cross-sectional
imaging as part of their initial risk stratification
(CT of the chest, MRI of the brain, and 18 FDG
PET scanning) and occasionally as part of their
follow-up disease detection management. The
intensity and timing of these more aggressive
follow-up studies cannot be easily proscribed in
a general follow-up paradigm but requires careful individual risk assessment and follow up.
Assessing Response
to Therapy
After making therapeutic interventions based
on our initial risk stratification, follow-up data
are obtained that should modify our initial risk
assessments. In the first several years after initial
therapy, serum Tg values are obtained every
6 months and neck ultrasonography is done on
a yearly basis [14]. The positive and negative
predictive values of these diagnostic tests can be
used to either increase or decrease our initial
risk estimates.
One simplistic approach to the classification
of response to therapy is outlined in Table 10.4
as either excellent, acceptable, or incomplete
[15, 16]. Patients with an excellent response to
therapy have no detectable disease on crosssectional imaging and undetectable serum Tg
both on suppression and with stimulation. While
these patients need lifelong yearly follow up, they
are likely to be at very low risk of recurrence and
death from thyroid cancer and can probably be
followed with yearly physical examination and
suppressed Tg with the occasional neck ultrasound evaluation.
Patients with an incomplete response to therapy at 6–12 months after initial therapy should
be evaluated for potential additional treatment
options. Most patients with incomplete response
to initial therapy will benefit from additional
treatments (either surgery, EBRT, or RAI). However, in some cases, patients with an incomplete
response who have structural disease progression may require systemic therapy or clinical
trials of novel agents.
In our experience, many patients are classified as having an acceptable, but not excellent,
response to initial therapy. These patients often
have low-level serum Tg on suppression (less
than 1 ng/mL) or after stimulation (less than
10 ng/mL). Without identification of structural
disease, it is difficult to know if this low-level Tg
represents residual normal tissue or small-volume
persistent thyroid cancer. In the absence of structurally identifiable disease, the natural history of
many of these patients is a slow, gradual decline
inserumTgovermanyyearswithoutadditional
RAI therapy [41]. So our usual approach to
these patients with acceptable response defined
by low-level Tg values is cautious observation,
reserving additional RAI for rising Tg values
over time.
As ultrasonography becomes the cornerstone
of follow up in thyroid cancer, we are identifying
many patients with very small-volume disease
manifest by millimeter-sized lymph nodes with
abnormal ultrasonographic characteristics that
probably represent residual thyroid cancer.
These are often found in patients at low risk
for death from thyroid cancer and either low
or intermediate risk for clinically evident
ENDOCRINE SURGERY
Table 10.4. Response to therapy variables
Excellent response* Acceptable response Incomplete response
Suppressed Tg** Undetectable Detectable but <1 ng/mL >1 ng/mL
Stimulated Tg** Undetectable <10 ng/mL >10 ng/mL
Trend in suppressed
Tg***
Anti-Tg antibodies Absent Absent or declining Persistent or rising
Neck examination Normal Normal Palpable disease
Neck ultrasonography No evidence of disease Nonspecific changes in
Diagnostic RAI
WBS****
Cross-sectional
imaging (MRI,
CT)****
FDG PET scanning**** No evidence of disease Nonspecific changes
*Patients deemed to have an excellent or acceptable response to therapy generally warrant observation without additional specific therapy,
while patients with an incomplete response are likely to require additional evaluation and treatment.
**Stimulated and suppressed Tg value cutoffs optimized for patients treated with total thyroidectomy and RAI remnant ablation.
***While most sensitive and specific in patients s/p total thyroidectomy and RAI remnant ablation, a rising Tg over time should also prompt
further evaluation in patients treated with less than total thyroidectomy or with total thyroidectomy without RAI remnant ablation. This
highlights the crucial importance of measuring serum Tg in the same laboratory in order to ensure comparability amongst samples over time.
****While these studies are not routinely recommended for all patients without additional high-risk features or clinical suspicion of persistent/
recurrent disease, results from these studies can be used as additional response to therapy measures if done.
Remains undetectable Declining Stable or rising
Evidence of structurally significant
thyroid bed
Probable inflammatory
lymph nodes
Stable millimeter-sized
cervical LN even if
abnormal by US criteria
No evidence for RAI
avid disease
No evidence of disease Nonspecific changes Structural disease present
No evidence for RAI avid
disease
Very faint uptake in thyroid
bed only
consistent with normal
variants or inflammatory
changes
recurrent/persistent disease in the
thyroid bed (>1 cm)
Cervical lymph nodes (>1 cm), or
distant metastases, particularly if
structurally progressive or FDG avid
Persistent/recurrent RAI avid disease
present
FDG avid disease present
146
recurrence on initial staging. While the first
inclination would be toward an aggressive surgical approach to any identifiable disease, we
must carefully weigh the risks associated with
lymph node dissection with the potential benefit
of removing very small-volume disease. Just as
with low-level Tg positivity, we follow these
small abnormal lymph nodes (<1 cm) with
serial ultrasounds (every 6–9 months), reserving intervention for structural disease progression. Because FDG PET positivity is a predictor
of more aggressive clinical outcomes, we have a
lower threshold for surgical resection of PETpositive lesions than for similar-sized lesions
that are not FDG avid.
Conclusion
Individualized thyroid cancer management
requires a careful initial risk stratification that
can accurately estimate the risk of recurrence
and the risk of death from thyroid cancer. This
initial risk stratification should guide our initial
treatment recommendations with regard to
extent of initial surgery, need for RAI ablation,
degree of TSH suppression, need for external
beam irradiation, and potential role of systemic
therapy.
The selection of follow-up studies to detect
recurrent/persistent disease should be based on
147
POSTOPERATIVE MANAGEMENT OF WELL-DIFFERENTIATED THYROID CANCER
both the initial risk stratification and an understanding of the likely sites of recurrence. This
risk-adapted approach will allow the clinician to
tailor the aggressiveness of therapy and follow
up to the risk of recurrence and death in individual patients.
References
1. British Thyroid Association and Royal College of Physicians: Guidelines for the management of thyroid cancer
in adults 2002. british-thyroid-association.org. Accessed
Nov 1, 2006.
2. Cooper DS, DohertyGM, HaugenBR, et al. Management
guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109–42.
3. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW,
Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol.
2006;154(6):787–803.
4. National Comprehensive Cancer Network, clinical practice guidelines in oncology, thyroid cancer V.2.2007,
2007. http://www.nccn.org/professionals/physician_gls/
PDF/thyroid.pdf. Accessed Nov 23, 2007.
5. Thyroid Carcinoma Task Force. AACE/AAES medical/
surgical guidelines for clinical practice: management of
thyroid carcinoma. American Association of Clinical
Endocrinologists. American College of Endocrinology.
Endocr Pract 2001;7(3):202–20.
6. AJCC Cancer Staging Manual, 6th ed. New York:
Springer-Verlag; 2002.
7. Byar DP, Green SB, Dor P, et al. A prognostic index
for thyroid carcinoma. A study of the E.O.R.T.C.
Thyroid Cancer Cooperative Group. Eur J Cancer.
1979;15(8):1033–41.
8. Cady B, Rossi R. An expanded view of risk-group
definition in differentiated thyroid carcinoma. Surgery. 1988;104(6):947–53.
9. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant
CS. Predicting outcome in papillary thyroid carcinoma:
development of a reliable prognostic scoring system ina
cohort of 1779 patients surgically treated at one institution
during 1940 through 1989. Surgery. 1993;114(6):1050–7;
discussion 7–8.
10. Hay ID, Grant CS, TaylorWF, McConaheyWM. Ipsilateral
lobectomy versus bilateral lobar resection in papillary
thyroid carcinoma: a retrospective analysis of surgical
outcome using a novel prognostic scoring system. Surgery. 1987;102(6):1088–95.
11. Mazzaferri EL, Jhiang SM. Differentiated thyroid cancer
long-term impact of initial therapy. Trans Am Clin Climatol Assoc. 1994;106:151–68; discussion 68–70.
12. Shaha AR, Loree TR, Shah JP. Prognostic factors and
risk group analysis in follicular carcinoma of the thyroid. Surgery. 1995;118(6):1131–6; discussion 6–8.
13. Sherman SI, Brierley JD, Sperling M, et al. Prospective
multicenter study of thyroid carcinoma treatment:
initial analysis of staging and outcome. National Thyroid
Cancer Treatment Cooperative Study Registry Group.
Cancer. 1998;83(5):1012–21.
14. Tuttle RM, Leboeuf R, Martorella AJ. Papillary thyroid
cancer: monitoring and therapy. Endocrinol Metab Clin
North Am. 2007;36(3):753–78, vii.
15. Tuttle RM, Leboeuf R. Follow up approaches in thyroid
cancer: a risk adapted paradigm. Endocrinol Metab Clin
North Am. 2008;37:419–35.
16. Tuttle RM, Leboeuf R, Shaha A. Medical management of
thyroid cancer: a risk adapted approach. J Surg Oncol.
2008;97:712–16.
17. Mazzaferri EL, Kloos RT. Clinical review 128: Current
approaches to primary therapy for papillary and
follicular thyroid cancer. J Clin Endocrinol Metab.
2001;86(4):1447–63.
18. Lee N, Tuttle RM. External beam radiation for differentiated thyroid cancer. Endocrine Rela Cancers. 2006;
13:971–77.
19. Tuttle RM, Leboeuf R. Investigational therapiesfor metastatic thyroid carcinoma. J Natl Compr Canc Netw.
2007;5(6):641–6.
20. RobbinsRJ,WanQ,GrewalRK,etal.Real-timeprognosis
for metastatic thyroid carcinoma based on 2-[18F]fluoro2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab. 2006;91(2):498–505.
21. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms
in thyroid follicular-cell neoplasia. Nat Rev Cancer.
2006;6(4):292–306.
22. Baloch ZW, LiVolsi VA. Prognostic factors in well-differentiated follicular-derived carcinoma and medullary
thyroid carcinoma. Thyroid. 2001;11(7):637–45.
23. Nikiforova MN, Nikiforov YE. Molecular genetics of
thyroid cancer: implications for diagnosis, treatment
and prognosis. Expert Rev Mol Diagn. 2008;8(1):83–95.
24. Ward LS, Morari EC, Leite JL, et al. Identifying a risk
profile for thyroid cancer. Arq Bras Endocrinol Metabol.
2007;51(5):713–22.
25. Kebebew E, Weng J, Bauer J, et al. The prevalence and
prognostic value of BRAF mutation in thyroid cancer.
Ann Surg. 2007;246(3):466–70; discussion 70–1.
26. Lupi C, Giannini R, Ugolini C, et al. Association of BRAF
V600E mutation with poor clinicopathological outcomes
in 500 consecutive cases of papillary thyroid carcinoma.
J Clin Endocrinol Metab. 2007;92(11):4085–90.
27. Hay ID, ThompsonGB, Grant CS, et al.Papillary thyroid
carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy
and long-term outcome in 2444 consecutively treated
patients. World J Surg. 2002;26(8):879–85.
28. Shaha AR, Shah JP, Loree TR. Low-risk differentiated
thyroid cancer: the need for selective treatment. Ann
Surg Oncol. 1997;4(4):328–33.
29. Hay ID. Management of patients with low-risk papillary
thyroid carcinoma. Endocr Pract. 2007;13(5):521–33.
30. Mazzaferri EL. Management of low-risk differentiated
thyroid cancer. Endocr Pract. 2007;13(5):498–512.
31. Biondi B, Filetti S, Schlumberger M. Thyroid-hormone
therapy and thyroid cancer: a reassessment. Nat Clin
Pract Endocrinol Metab. 2005;1(1):32–40.
32. McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F,
Sarlis NJ. Effects of thyroid hormone suppression therapy on adverse clinicaloutcomes in thyroid cancer. Ann
Med. 2002;34(7–8):554–64.
33. Cooper DS, Specker B, Ho M, et al. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National
148
ENDOCRINE SURGERY
Thyroid Cancer Treatment Cooperative Registry. Thyroid. 1998;8(9):737–44.
34. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol
C. Degree of thyrotropin suppression as a prognostic
determinant in differentiated thyroid cancer. J Clin
Endocrinol Metab. 1996;81(12):4318–23.
35. Brierley JD, Tsang RW. External-beam radiation therapy in the treatment of differentiated thyroid cancer.
Semin Surg Oncol. 1999;16(1):42–9.
36. Keum KC, Suh YG, Koom WS, et al. The role of postoperative external-beam radiotherapy in the management
of patients with papillary thyroid cancer invading the
trachea. Int J Radiat Oncol Biol Phys. 2006;65(2):474–80.
37. Wang W, Larson SM, Tuttle RM, et al. Resistance of
[18f]-fluorodeoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioactive
iodine. Thyroid. 2001;11(12):1169–75.
38. Spencer CA. Serum thyroglobulin measurements: clinical utility and technical limitations in the management
of patients with differentiated thyroid carcinomas.
Endocr Pract. 2000;6(6):481–4.
39. Spencer CA. Challenges of serum thyroglobulin (Tg)
measurement in the presence of Tg autoantibodies. J
Clin Endocrinol Metab. 2004;89(8):3702–4.
40. Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S,
LoPresti JS. Clinical impact of thyroglobulin (Tg) and
Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas.
J Clin Endocrinol Metab. 2005;90(10):5566–75.
41. PaciniF,AgateL,EliseiR,etal.Outcomeofdifferentiated
thyroid cancer with detectable serum Tg and negative
diagnostic (131)I whole body scan:comparison of patients
treated with high (131)I activities versus untreated
patients. J Clin Endocrinol Metab. 2001;86(9):4092–7.
11
Medullary Thyroid Cancer
Rebecca S. Sippel and Herbert Chen
Introduction
First described in 1959, medullary thyroid cancer (MTC) currently accounts for 5–10% of all
thyroid cancers. MTC consists of a spectrum of
disease that ranges from an extremely indolent
tumor that can go unchanged for years to an
aggressive variant that is associated with a high
mortality rate. The majority of MTC are sporadic, but up to 25% of MTC are due to a germline
genetic mutation. Hereditary MTC can be seen
in isolation [familial MTC (FMTC)] or as part of
the multiple endocrine neoplasia syndrome
type 2 (2A or 2B).
MTC originates from the parafollicular C-cells
of the thyroid gland. The C-cells are derivatives
of the neural crest that during development
incorporate into the lateral thyroid anlages.
C-cells are located throughout the thyroid
gland, but the majority of C-cells are located at
the junction of the upper third and lower two
thirds of the thyroid gland. C-cells secrete a variety of peptides and hormones; the most common
of which is calcitonin. Other substances secreted
by the C-cells include carcino-embryonic antigen
(CEA), corticotrophin, somatostatin, vasoactive
intestinal peptide, and serotonin. Calcitonin has
proven to be the most useful clinical marker,
because calcitonin levels correlate well with
tumor burden. This makes calcitonin an ideal
marker for following patients longitudinally
after tumor resection. An elevated or rising
calcitonin level is often the first sign of recurrent
or persistent disease. CEA is also used as a marker of disease, and may be preferentially
expressed in less differentiated tumors.
Pathologically, MTCs are whitish-gray in
color and firm to palpation (Fig. 11.1). In
sporadic cases, the tumors are usually unifocal,
but in hereditary disease tumors are frequently
multifocal and bilateral. Histologically, MTC
forms nests of uniform cells that are characterizedbythepresenceofstromalamyloid
(Fig. 11.2). Several histologic features are associated with more aggressive disease including
vascular invasion, lymphatic invasion, invasion of the thyroid capsule, and extranodal
spread of the tumor.
C-cell hyperplasia is seen in many patients
with hereditary disease and is felt to be a precursor to malignant transformation. C-cell
hyperplasia is defined as more than six C-cells
per follicle or more than 50 C-cells per low power
field. Despite its clear association with malignancy in hereditary disease, the significance of
C-cell hyperplasia in nonhereditary disease is
uncertain.
FMTC is inherited in an autosomal dominant
pattern, with variable expressivity and penetrance. The genetic mutation is found in the
RET (REarranged during Transfection) protooncogene, which in 1991 was mapped to chromosome 10q11.2. The RET gene encodes a
transmembrane tyrosine kinase receptor. Since
RET is a protooncogene, only a single-point
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_11, Ó Springer-Verlag London Limited 2009
149