CONCEPTS IN THE MANAGEMENT OF THYROID AND PARATHYROID DISEASE
Educational Objectives
| The goal of this program is to improve the management of pediatric papillary thyroid malignancy and hyperparathyroidism,
and assess a model for determining the most cost-effective management of low-risk papillary thyroid cancer.
After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Describe the basic standard of treatment in pediatric papillary thyroid carcinoma.
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| 2. Review potential side effects of radioiodine therapy.
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| 3. Explain the surgical and medical management of 1°HPT.
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| 4, Distinguish bone loss due to 1°HPT from bone loss due to osteoporosis.
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| 5. Illustrate use of a Markov model in evaluating cost-effective management of low-risk papillary thyroid carcinoma.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning
committee reported nothing to disclose.
Acknowledgements
Drs. Thompson and Kronenberg were recorded at Surgery of the Thyroid and Parathyroid Glands, held November 9-11,
2007, in Boston, MA, and sponsored by the Department of Otolaryngology, Massachusetts Eye and Ear Infirmary,
Department of Surgery, Massachusetts General Hospital, and the Department of Continuing Education, Harvard
Medical School. Dr. Shrime gave his scientific lecture at the Annual Combined Otolaryngology Spring Meetings (COSM)
symposium of the American Head and Neck Society (ANHS) held April 28-29, 2007, in San Diego, CA. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| PEDIATRIC PAPILLARY THYROID MALIGNANCY —Geoffrey B. Thompson, MD, Professor of Surgery, Mayo
Clinic College of Medicine, Rochester, MN
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| Etiology: most cases sporadic; exposure to low-dose ionizing head and neck irradiation associated with increased
incidence of thyroid carcinoma
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| Basic standard of treatment: total or near total thyroidectomy; central compartment node dissection; selective
neck dissection of lateral lymph nodes (when involved); radioiodine remnant ablation; thyroid hormone-suppressive
therapy
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| Total or near total thyroidectomy: reduces rate of local recurrence (multifocal and bilateral prevalence in papillary
thyroid carcinoma [PTC]); facilitates radioiodine remnant ablation; increases sensitivity of radioiodine whole
body scanning, efficiency of 131 I therapy, and subsequent ability to use serum thyroglobulin as tumor marker
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| 131 I therapy: children tend to have more extensive locoregional disease and distant metastases than adults; metastases
in children appear more sensitive to effects of radioiodine, favoring use of complete thyroid ablation and
whole-body scanning more often in children than in low-risk adults; goals of treatment—negative whole-body scan;
negative neck ultrasonography (US); undetectable thyroglobulin levels with hormone withdrawal or recombinant
thyrotropin (TSH) stimulation; side effects—painful swelling of remnant or metastases; nausea and vomiting; loss
of taste and smell; sialadenitis (potentially permanent, with dental deterioration); transient bone marrow depression;
increased risk for miscarriage reported during first year after treatment; azoospermia reported in adults receiving
>300 mCi total cumulative dose; concerns about pulmonary fibrosis when treating macronodular metastases or
when interstitial disease present at outset (when retained activity in lungs >80 mCi); total cumulative dose should
not exceed 500 mCi in children or 800 mCi in adolescents because of higher lifetime risk for leukemia; increased
risk for secondary tumors (breast, stomach, salivary gland, parathyroid, and bladder)
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| Long-term prognosis: long-term survival rate excellent; deaths rare, but may occur decades later; children tend to
have more locally advanced and distant disease, compared to adult counterparts (question whether more aggressive
approach than in adult low-risk patients warranted); study data—comparison of 58 children with 981 adults with
PTC found no difference at 30 yr in cause-specific mortality; children in this study more likely to have nodal metastases,
extrathyroidal invasion, distant metastases, local soft tissue recurrences, regional nodal recurrences, and
late distant metastases; percentage of nondiploid tumors lower in children
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| Management (at speaker’s institution): initially managed with total or near-total thyroidectomy; minority
given postoperative radioactive iodine (unusual in literature); treated postoperatively with thyroxine (T4)-suppressive
therapy; locoregional recurrences found in ≈30%, and managed with additional surgery, therapeutic radioiodine,
or percutaneous US-guided ethanol ablation; distant metastases far more common than in adults, but
almost never resulted in death
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| Long-term study: 210 children with PTC, starting in 1940 and followed to March 2007; MACIS (metastasis, age,
completeness of surgery, invasion, and size of tumor) characteristics — 6% with lung metastases at diagnosis; median
age 16 yr; 5% had incomplete resection; 19% had extrathyroidal invasion; mean tumor size 2.6 cm; 79% had initial
positive neck nodes; during changes in initial therapy (1940 to 2005) — change from unilateral lobectomy to bilobar
operations in mid 1950s; routine use of radioiodine remnant ablation peaked in 1980s, when slightly >50%
received this therapy (now only ≈25% receive ablation); recurrences — rate high (approximately one-third of patients;
double that of adults); most recurrences in lymph nodes; statistically significant difference in recurrence
rates when comparing unilateral lobectomy to bilobar resection; no difference whether children received near-total
or total thyroidectomy, with or without radioiodine remnant ablation; mortality — no deaths at 20 yr, one
death from PTC at 27 yr, and one at 30 yr; cumulative mortality rate 2% at 50 yr; 21 observed deaths in cohort (9
expected; 76% died of malignancies, of which 88% nonthyroid); 30% mortality from all causes during 50-yr period
(premature deaths in 40s, 50s, and 60s of nonthyroid malignancies); role of radiation in excessive mortality
rates — among non-PTC cancer deaths, nearly 80% of patients had radiation exposure; extent of initial surgery,
but not radioiodine remnant ablation, influenced recurrence rates
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| Conclusion: childhood and adolescent PTC not lethal diagnosis; overaggressive postoperative treatment could have
long-term (possibly fatal) consequences; occurrence of second malignancies never addressed specifically in childhood
thyroid cancer; significantly increased incidence in adults of second cancers and leukemias observed in patients
treated with high cumulative doses of 131 I
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| HYPERPARATHYROIDISM AND ITS SURGICAL INDICATIONS —Henry M. Kronenberg, MD, Professor of
Medicine, Harvard University School of Medicine, and Chief, Endocrine Unit, Massachusetts General Hospital, Boston
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| Hypercalcemia: accurate measurement of calcium level not always straightforward; half of calcium protein-bound
(when protein low, must adjust calcium); nomograms for adjusting calcium do not work well (especially in inpatient
setting [ie, acute illness]); measurement of ionized calcium—electrodes measure ionized calcium accurately; blood
must be kept cold until measurement and measured within few minutes of being drawn; no universal standardization
among laboratories; normocalcemic primary hyperparathyroidism (1°HPT)—artifact of problem of population
means; normal value of calcium in population goes up to 10.4 mg/dL, but modest elevation within normal range
may represent elevation for individual patient; many people having parathyroid hormone (PTH) checked in diagnosis
of osteoporosis have high normal calcium (ionized and total) with elevated PTH, and after follow-up for few
years, develop clear-cut 1°HPT (discovering disease earlier); secondary hyperparathyroidism—parathyroid gland response
to low calcium in diet, bisphosphonate therapy, vitamin D deficiency, or renal failure; familial hypocalciuric
hypocalcemia (FHH)—mutated calcium sensing receptor in parathyroid cell and kidney tubules makes parathyroid
sense blood calcium level lower than actual; parathyroid then produces PTH in response to make blood calcium
higher, and kidneys retain calcium inappropriately; patients hypercalcemic since birth; autosomal dominant disease;
urine calcium/creatinine clearance ratio helpful diagnostic test; rare disease; drugs—lithium can cause true
1°HPT, and thiazides can make it worse
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| Measurement of PTH: intact PTH assay—assay good at separating those with 1°HPT from those with hypercalcemia
for non-PTH-associated reasons; upper limit of normal (ULN) lower in younger people than in older people;
lower in calcium- and vitamin D-sufficient populations (eg, those in sunny areas); 10% of people with
1°HPT have PTH levels in normal range but inappropriately elevated for their level of calcium; new PTH
assays—measure only 1-84 molecule and not other fragments of PTH; clinical utility unknown; important to
know calcium level of patient along with PTH value (almost no overlap in patients with 1°HPT and those with
cancer-associated hypercalcemia, but overlap exists in some people with high-normal calcium)
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| Treatment: in past, operated on patients with overtly symptomatic disease, ie, kidney stones, skeletal problems;
however, currently, patients present with elevated calcium and no symptoms or vague complaints, eg, depression,
trouble concentrating; no large randomized trials of surgery using clinically significant end points (symptomatic
hypercalcemia, kidney stones, fractures, or death); National Institutes of Health (NIH) consensus conference recommendations
(2002)—surgery in those with serum calcium >1 mg/dL above ULN; 24-hr urinary calcium >400 mg; creatinine
clearance reduced by >30%, compared with age-matched controls; bone density >2.5 SD below mean (T
score) at distal radius, spine, or hip; age <50 yr
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| Bone loss: osteoporosis—less bone and less structurally sound trabecular meshwork; primary hyperparathyroid
disease—dramatic loss of bone in cortex but not in trabecular meshwork; little data on risk for fracture in those
with bone loss from parathyroid disease; retrospective study (Mayo Clinic) showed that people with 1°HPT 3 times
more likely to have vertebral fractures and 2 times as likely to have distal forearm fractures; study criticized because
those with 1°HPT more likely to have serial x-rays; need to know whether surgery makes bones better; recent
data (Columbia)—10-yr data on patients with 1°HPT showed that bone density in lumbar spine increased 8% to
10% in years after surgery; similar data in femoral neck and some increase in radius; data suggest that successful
surgery for mild asymptomatic disease improves bone density; in those who did not have surgery, while bone mass
did not improve, blood calcium, blood PTH, urinary calcium, and 1,25-dihydroxyvitamin D did not substantially
change (new steady-state achieved, and disease does not progress); over 15-yr follow-up, many patients in nonsurgical
group eventually met criteria for surgery
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| Data on surgery: 3 randomized controlled trials on surgery vs no surgery for mild asymptomatic 1°HPT; trials not
ideal (not blinded; follow-up only 1-2 yr; surrogate markers of success); trials provide growing pattern of information;
followed biochemical criteria, bone density, and quality of life questionnaires (questionnaires parameter that
varied most between studies); studies showed that in randomized population, lumbar spine bone density and total
hip bone density improve 1 to 2 yr after parathyroid surgery, compared to those who do not have surgery (consistent
finding, but improvement not as dramatic as in data from Columbia)
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| Medical therapy: cinacalcet—calcimimetic drug; helpful in those with renal failure and secondary hyperparathyroidism;
lowers blood calcium in people with mild asymptomatic hyperparathyroidism, lowers PTH (generally
not to normal range), but does not change bone density; drug not approved for treatment of 1°HPT;
bisphosphonates—data from several randomized blinded studies show that they increase bone mass; study using
alendronate for first 2 yr, or nothing for first year and alendronate for second year, showed 6% increase in
bone density over 2 yr; similar data as for lumbar spine in patients in surgical randomized trials; no fracture
information; in those getting alendronate, blood calcium did not change, and blood PTH increased initially,
but then went back down; potentially satisfactory strategy in older people
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| LOW-RISK PAPILLARY THYROID CARCINOMA: COST-EFFECTIVE MANAGEMENT —Mark Shrime, MD,
Fellow, Head and Neck Oncologic and Reconstructive Surgery, University of Toronto Health Network and Mount Sinai
Hospital, Toronto, ON
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| General: optimal surgical management of low-risk papillary thyroid carcinoma varies by institution (hemithyroidectomy;
total thyroidectomy); no randomized controlled trials
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| Incremental cost effectiveness ratio: utility curve—utility defined as happiness, satisfaction, and other values;
curve tells that for whatever commodity looking at (health care, houses), more you pay, happier you are; point on
curve represents having paid certain amount of money for certain amount of happiness; getting more happiness (moving
up curve) involves more cost; cost per packet of utility describes marginal utility cost; can replace “happiness”
with “effectiveness”; marginal effectiveness cost called incremental cost-effectiveness ratio (ICER); example—
treatment of otitis media (OM); 2 drugs (A and B) to treat OM; drug A costs $50 and treats 90% of patients effectively;
drug B costs $55 and treats 91% of patients effectively; ICER of 2 drugs compared against one another equals
$500 (for every additional effectively treated patient with drug B, healthcare system must pay $500); if drug B becomes
less expensive and remains more effective, ICER becomes negative number, and drug B dominates drug A
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| Markov modeling: decision tree potentially iterated over and over to represent multiple time periods; at end of each
iteration, patients end up in particular disease state (ie, well or sick); start next iteration of decision tree from that disease
state; example—patients with breast cancer; apply certain treatment; 1 of 3 things can happen, they get better
(move from cancer state to well state), not get better (stay in cancer state), or die; next time around, cancer patients
have same 3 choices; dead patients have no choices and well patients have 3 choices (stay well, have recurrence, or
die)
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| Model: 20-yr follow-up of patients with low-risk papillary thyroid cancer; 19-state Markov model; populated
model with costs, effectiveness, and probability to move from one health state to another; literature search found
31 studies with 15,000 patients; costs—national inpatient sample (hospital charges for any inpatient procedure)
and Medicare reimbursements (for outpatient costs); total thyroidectomy cost $6300 on average to perform;
hemithyroidectomy cost $5600; cost-specific survival—99% over 20 yr
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| Findings: at 20 yr, cost of initially treating patient with total thyroidectomy equals $14,000; at 20 yr, cost of initially
treating patient with hemithyroidectomy $15,000; overall cost-specific survival same for both, but recurrence-free
survival better for patients with total thyroidectomy; hemithyroidectomy more costly and as effective or less effective
than total thyroidectomy; therefore, total thyroidectomy dominates as way to treat patients; sensitivity
analysis—take variable, vary value of variable across wide range of values and try to find point where hemithyroidectomy
becomes more cost-effective (model sensitive to that variable); found model sensitive to recurrence
rates and cost of follow-up; model does not include recombinant human thyrotropin (Thyrogen) because not widely
used and use debated
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| Conclusions: total thyroidectomy currently most cost effective treatment for low-risk papillary thyroid cancer; recommendation
potentially institution-dependent
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Suggested Reading
Ambrogini E et al: Surveillance for mild asymptomatic 1°HPT: A prospective, randomized clinical trial. J Clin Endocrinol
Metab 92:3114, 2007; Bardet S et al: Macroscopic lymph-node involvement and neck dissection predict
lymph-node recurrence in papillary thyroid carcinoma. Eur J Endocrinol 158:551, 2008; Brown AP et al: The risk
of second primary papillary malignancies up to three decades after the treatment of differentiated thyroid cancer. J
Clin Endocrinol Metab 93:504, 2008; Gingalewski CA, Newman KD: Seminars: controversies in the management
of pediatric thyroid malignancy. J Surg Oncol 94:748, 2006; Handkiewicz-Junak D et al: Total thyroidectomy
and adjuvant radioiodine treatment independently decreases locoregional recurrence risk in childhood and adolescent
differentiated thyroid cancer. J Nucl Med 48:879, 2007; Ji QH et al: Long-term impact of initial surgical and medical
therapy on young patients with papillary thyroid cancer and bilateral cervical metastases. Chin Med J 121:63,
2008; Miccoli P et al: Papillary thyroid cancer: pathological parameters as prognostic factors in different classes of
age. Otolaryngol Head Neck Surg 138:200, 2008; Shrime MG et al: Cost-effective management of low-risk papillary
thyroid carcinoma. Arch Otolaryngol Head Neck Surg 133:1245, 2007; Vasko V et al: Papillary and follicular
thyroid cancers in children. Endocr Dev 10:140, 2007.
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