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Thyroid Cancer: Latest Approaches to Canada’s Fastest Growing Cancer
Alon Vaisman, H.B.Sc. (1T1), Faculty of Medicine, University of Toronto
Steven Orlov, B.Sc. (1T0), Faculty of Medicine, University of Toronto
Jonathan Yip, H.B.Sc. (1T3), Faculty of Medicine, University of Toronto
David Orlov, H.B.Sc., M.D. (0T9), Faculty of Medicine, McMaster University
Abstract
Thyroid cancer is the most common endocrinological malignancy worldwide and its incidence is
increasing faster than any other cancer. The majority of this increase has been in well
differentiated thyroid carcinoma (i.e. papillary and follicular histology) which comprise 90% of
all thyroid cancers. Recent advancements in the diagnosis, surgical treatment, and long-term
monitoring have enhanced the detection of primary and recurrent disease, as well as treatment
modalities. These developments have prompted institutions to revise their guidelines on the
management of thyroid disorders. In the diagnosis of thyroid nodules, recommendations have
been made regarding initial evaluation, use of TSH and radionuclide studies, clinical and
ultrasound criteria for fine-needle aspiration biopsy (FNAB), and the interpretation of FNAB
results. Thyroidectomy (removal of gross thyroid tissue) and lymph node dissection have been
established as efficacious initial therapy to reduce disease recurrence; howeve, the extent of
surgical resection is hotly debated. Following surgical therapy, appropriate use of radioactive
iodine remnant ablation (RAI) to destroy microscopic disease has been advised. However, RAI
decision-making has been controversial, as some groups base decisions on preoperative and
intraoperative features, while others argue that these are not reliable predictors of disease.
Guidelines for long-term management include recommendations on the use of TSH suppression
therapy, surveillance of recurrent disease using ultrasound & serum thyroglobulin, and the
treatment of recurrent/metastatic disease. Here, we review the recent developments and
recommendations in the management of well differentiated thyroid carcinoma.
Introduction
In North America, the incidence of thyroid cancer is increasing faster than for any other
cancer1. It is currently the most common endocrinological malignancy worldwide, and the most
common carcinoma in young females, where its incidence has increased by 10% since 19971. In
the United States, 37,200 new cases of thyroid cancer are diagnosed annually and incidence has
increased almost three-fold since 19732, 3. The majority of this increase has been in well
differentiated thyroid carcinoma (WDTC), which includes papillary and follicular cancers, and
comprises 90% of all thyroid malignancies4.
The increase in incidence can also be attributed to advancements in the detection of
thyroid nodules through the use of ultrasound and needle biopsies. Fortunately, despite the
significant rise in incidence, mortality rates have remained stable, with a 5-year relative survival
ratio of 98% due to earlier diagnosis and improved treatment efficacy1.
The focus of the present review is to examine the latest research in the diagnosis,
treatment, and management of patients with WDTC. This includes recent developments in the
diagnostic evaluation of thyroid nodules, the need for adequate surgery, and the use of
radioactive iodine therapy following thyroidectomy.
Diagnosis
The Thyroid Nodule
The diagnosis of thyroid cancer often begins with the detection of a thyroid nodule, either
by palpation or neck ultrasound. A nodule is defined as a discrete lesion within the thyroid
gland that is distinct from the surrounding thyroid tissue5. The detection of a thyroid nodule
should be followed by a complete history and physical examination focusing on the thyroid
gland and lymph nodes of the neck. The prevalence of thyroid nodules in adults is approximately
5% in women and 1% in men by palpation, but can be as high as 50% by high-resolution
ultrasound6, 7. Non-palpable nodules (i.e. detected only on ultrasound) have the same risk of
malignancy as palpable nodules of the same size8.
The 2009 American Thyroid Association guidelines for the management of thyroid
cancer state that generally, only nodules larger than 1 cm should be evaluated for their potential
to become significant cancers5. Investigation of smaller nodules may be indicated in the presence
of suspicious ultrasound findings and/or history that places an individual at higher risk for
malignancy. History of head and neck irradiation, a first-degree relative with a history of thyroid
carcinoma, and exposure to ionizing radiation or nuclear fallout are three risk factors that place
an individual at higher risk for thyroid carcinoma9. Suspicious physical examination findings
may include new-onset dysphonia secondary to vocal cord paralysis, cervical lymph node
enlargement, and/or a fixed/irregular nodule.
TSH and Radionuclide Studies
Work-up for suspicious nodules should include a serum thyroid stimulating hormone
(TSH) level and imaging studies. A high serum TSH warrants further investigation by
ultrasound, as studies have shown that high serum TSH is associated with increased risk of
malignancy10. An abnormally low serum TSH value indicates the need for radionuclide thyroid
scanning, either with technetium (99mTc pertechnetate) or iodine (123I) isotopes. A “cold”
(hypofunctioning) nodule on such a scan warrants further investigation by ultrasound to rule out
malignancy, whereas a “warm” or “hot” (hyperfunctioning) nodule needs no further
investigation. Currently, serum thyroglobulin and calcitonin measurements are not recommended
in the diagnosis of thyroid cancer due to their poor sensitivity, specificity, and lack of cost
effectiveness11, 12.
Ultrasound Guided Fine Needle Aspiration Biopsy
Thyroid ultrasonography should be performed in all patients with one or more suspicious
thyroid nodules. This modality allows for accurate examination of the size and associated
characteristics of the nodule itself. Worrisome qualities on ultrasound include solid/complex
appearance, hypoechoicity, micro-calcifications, and blurry margins13 (Figure 1).
Ultrasound also facilitates the most accurate method of thyroid nodule evaluation - fine
needle aspiration biopsy (FNAB). Studies continue to show that biopsying suspicious nodules
using ultrasound guidance is both cost-effective and highly accurate14. Ultrasound-guided FNAB
is also recommended for nodules that are non-palpable, cystic, or posteriorly located in the
thyroid gland.
FNAB results are divided into four categories: (1) benign, (2) indeterminate or
suspicious, (3) malignant (>95% risk of malignancy), and (4) non-diagnostic (i.e. repeat FNAB
is required)13. Malignant cytology warrants surgical therapy, while benign nodules need no
further investigation aside from serial follow-up with ultrasound. Nodules of indeterminate
cytology—which have an approximately 25% chance of being malignant—may also require
surgical treatment depending on the results of a radionuclide scan15. Recently, attempts to use
18
fluorodeoxyglucose positron emission tomography (18FDG-PET) to distinguish between benign
and malignant indeterminate nodules have shown the scan to be of high sensitivity but poor
specificity, and is therefore not recommended at this time16, 17. Screening for malignant
molecular markers such as BRAF, RAS, and RET/PTC in indeterminate nodules may be useful
in helping guide further therapy. Unfortunately, these markers are not readily available in many
clinical laboratories18-20.
Surgical Therapy
Thyroidectomy
The initial therapy for malignant thyroid nodules is total (removal of all grossly visible
thyroid tissue) or near-total (removal of grossly visible thyroid tissue leaving <1g of tissue
remaining) thyroidectomy5, 13. Total thyroidectomy is also indicated for patients with
indeterminate nodules on FNAB in the presence of high risk features on history or physical
examination (described above)21.
For primary tumours <1 cm in the absence of high-risk features, current guidelines
mainly recommend a thyroid lobectomy (removal of one thyroid lobe)5, 13 although certain
schools of thought favour total thyroidectomy on the basis of decreased cancer recurrence and
health care costs22, 23.
Another important consideration in determining the extent of a thyroid tissue resection is
surgical expertise. The complication rate of thyroidectomy has been negatively associated with
the experience of surgeons, and the reported rate is 2-3% in those who do more than 20 cases per
year24, 25. Complications of a thyroidectomy include transient or permanent hypocalcemia,
transient or permanent recurrent laryngeal nerve injury, and neck hematoma25.
Lymph Node Dissection
Lymph node metastases are common in WDTC. Standard histological examination of
lymph nodes removed at the time of thyroidectomy reveals metastases in 20-50% of patients, and
the incidence of palpable lymph node disease is 5-10%26. Though lymph node involvement has
been shown to increase recurrence rates, its impact on survival is relatively small25.
Consequently, lymph node dissections are usually performed at the time of thyroidectomy, and
serve to aid in local control and future disease prevention.
Current surgical guidelines recommend the removal of nodal groups in the central and/or
lateral neck compartments only when there is clinical or pathologic indication of lymph node
abnormalities as evidenced on physical examination, preoperative ultrasound, and/or
intraoperative assessment5, 25. Features suggestive of metastatic lymph nodes on preoperative
ultrasound include loss of the fatty hilus, rounded shape, hypoechogenicity, cystic change,
calcifications, and peripheral vascularity. Intraoperative lymphadenopathy or positive frozen
section pathology also warrant excision27, 28.
The role of prophylactic lymph node dissections, involving the extensive removal of
lymph nodes with no clinical evidence of disease, is a hotly debated topic25. A consensus on the
benefits in recurrence rates with this approach has not been reached, as this practice appears to
be associated with high morbidity, including recurrent laryngeal nerve damage and transient
hypoparathyroidism,29.
Post-Operative Staging
Accurate postoperative staging of patients permits: (1) assessment of prognosis, (2)
tailoring of adjuvant therapy, and (3) facilitation of decision-making regarding frequency and
intensity of follow-up5, 13. The most commonly used staging system for WDTC is the pTNM
(pathological tumour-node-metastasis) staging developed by the American Joint Committee on
Cancer/International Union Against Cancer (AJCC/UICC)30 (Table 1).
Radioactive Iodine Therapy
Following initial surgical therapy, radioactive iodine (RAI) remnant ablation is
commonly used as adjuvant treatment to destroy residual microscopic disease. This therapy also
facilitates the detection of recurrent disease with serum thyroglobulin (see below) by ablating
normal remaining thyroid tissue 31. Although large retrospective studies have shown that RAI
can decrease the rate of disease recurrence32, 33 and cause-specific mortality33, 34, a recent metaanalysis could not confirm the same benefit for early stage thyroid cancers35, which make up the
majority of all thyroid carcinomas. Currently, prescription of RAI therapy is largely based on
advanced patient age, larger tumour size, and the presence of local and/or distant metastases5. A
recent study has explored the utility of a post-surgical TSH-stimulated thyroglobulin (discussed
below) to improve RAI decision-making36.
Once patients are selected to undergo post-surgical RAI therapy, they should adhere to a
low-iodine diet and discontinue any oral thyroid hormone supplementation (T4 or T3). Such
action results in a stimulated level of serum TSH (>30mU/L) via negative feedback on the
hypothalamic-pituitary-thyroid axis and facilitates greater radioactive iodine uptake at the time
of RAI therapy37. Alternatively, an elevated level of serum TSH can be achieved using an
injection of recombinant human TSH (rhTSH)38. Although radioactive iodine doses generally
range from 30-100 mCi, higher doses may be required for more extensive disease5.
Long Term Follow-up
The goal of long term follow-up is to monitor for cancer recurrence and/or metastatic
spread following initial surgical and radioactive therapies. Follow-up generally relies on
measuring serum thyroglobulin (Tg) - a protein involved in thyroid hormone synthesis, which is
increased when stimulated by TSH and should be undetectable in individuals without thyroid
tissue35. Thyroglobulin can be measured while patients are on thyroid hormone replacement
(TSH-suppressed Tg) or when thyroid hormone is discontinued (TSH-stimulated Tg).
Alternatively, an injection of rhTSH can be used to measure TSH-stimulated Tg. Increased levels
of serum Tg suggest the presence of residual or recurrent diseased tissue.
Annual neck ultrasound is also a common modality to monitor for residual or recurrent
disease21, 39.
Patients appropriately treated for thyroid cancer have excellent outcomes, in terms of life
span and mortality. Recent studies have shown that the life span of those treated with total
thyroidectomy and RAI therapy is similar to the general population40.
Serum Thyroglobulin (Tg)
Serial serum Tg measurement is the cornerstone of thyroid cancer follow-up.
Unfortunately, up to 20% of the population has anti-Tg antibodies that interfere with the validity
of existing Tg assays41. Without the interference of antibodies, serum Tg has high sensitivity and
specificity for the detection of recurrent thyroid cancer following total thyroidectomy and RAI
therapy42-44. The sensitivity of serum Tg for recurrent thyroid cancer can be further improved by
performing a TSH-stimulated Tg using thyroid hormone withdrawal or an injection of rhTSH.
Specifically, rhTSH-stimulated serum Tg values less than 0.5 ng/mL (undetectable levels)
identifies 99.5% of tumour free patients45. Further, a single undetectable TSH-stimulated Tg test
does not require subsequent simulation testing46.
A TSH-stimulated Tg performed after thyroidectomy but prior to RAI therapy may also
predict disease free remission, future recurrence, metastases, and mortality47-49. This association
forms the basis of a strategy to use TSH-stimulated Tg to help identify patients who
subsequently require RAI and those who may not (i.e. surgery alone may have been curative)36.
TSH Suppression
Since thyroid tissue growth relies on thyroid stimulating hormone (TSH), long-term TSH
suppression (below 0.1 mU/L) has become a commonly used practice to treat post-operative
patients50. TSH suppression is accomplished by using supra-physiologic doses of thyroid
hormones which downregulates TSH via negative feedback in the hypothalamic-pituitary-thyroid
axis. A meta-analysis has shown that TSH suppression can prevent disease recurrence and is
particularly effective in patients diagnosed with advanced stage thyroid cancer51.
Disease Recurrence/Metastatic Disease
Patients found to have elevated or rising serum Tg levels after thyroidectomy must be
investigated for the possibility of recurrent or metastatic disease5. Ultrasound studies are helpful
in identifying recurrent disease in the neck and all suspicious lymph nodes (described above)
should be biopsied to assess for malignancy. 18FDG-PET scanning has proven helpful in patients
with suspected metastatic disease as part of staging, prognosis, and to evaluate the effectiveness
of therapy52.
In the event that metastatic/recurrent disease has been confirmed, additional surgery and
RAI is required. In patients with incurable metastatic cancer, surgery may also be used to
eliminate disease in important locations such as the central nervous system or aerodigestive
locations5. As well, external beam irradiation can be used in such patients to treat painful bone
metastases and metastatic lesions in critical locations53. Althought there is a limited for the
adjunctive use of chemotherapy in patients with WDTC, other treatments such as radiofrequency
ablation, ethanol ablation, or chemo-embolization may be used instead13. Distant metastatic
thyroid cancer foci (brain, bone, lung) that do not respond to surgery or radiotherapy have poor
outcome54.
Conclusion
According to Canadian Cancer Society statistics, thyroid cancer accounted for 2.7% of all
new Canadian cancer cases in 2009, placing it eighth behind prostate, lung, breast, colorectal
cancer, Non-Hodgkin’s lymphoma, bladder cancer, and melanoma, respectively1. Although its
incidence continues to climb faster than for any other malignancy, it is highly treatable and
currently ranks high in terms of survival post-diagnosis.
Developments over the past few decades have drastically improved diagnostic efficacy
and treatment modalities for this entity. As such, cases of thyroid cancer are diagnosed earlier,
managed multi-modally, and followed longitudinally for recurrence with serial measurement of
serum thyroglobulin. Stable survival despite a rising incidence is a testament to the current
success in treatment of this condition.
Current thyroid cancer research has turned to discovering novel biomarkers to improve
diagnosis and follow-up, risk-stratification of patients post-thyroidectomy to potentially bypass
RAI therapy and its associated side-effects, and further elucidation of thyroid cancer mechanisms
on a molecular level. In all, it is hopeful that all of these future avenues will further improve the
success of managing thyroid malignancy for future patients.
Acknowledgements
The authors would like to acknowledge the support for their research into thyroid cancer from
the Joseph Mildred Sonshine Centre for Head and Neck Diseases at Mount Sinai Hospital, under
the mentorship of Dr. Paul G. Walfish, Alex and Simona Shnaider Research Chair in Thyroid
Oncology. They would also like to acknowledge the Comprehensive Research Experience for
Medical Students, who previously provided funding for the research two of the authors of this
review (A.V., S.O.).
Figures
Table 1. Pathological tumour-node-metastasis (pTNM) staging for well-differentiated
thyroid carcinoma (WDTC).
Figure 1. Thyroid ultrasound showing an isoechoic nodule with well-defined margins and
microcalcifications.
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