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1 Evaluation of a Thyroid Nodule Michael E. Decherd, MD Matthew W. Ryan, MD January 23, 2002

Evaluation of a Thyroid Nodule

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Page 1: Evaluation of a Thyroid Nodule

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Evaluation of a Thyroid Nodule

Michael E. Decherd, MDMatthew W. Ryan, MD

January 23, 2002

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The Big Question

Is it cancer?

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A Brief History of the Thyroid

• 1812 – Gay-Lussac discovers iodine in seaweed-water (was corroding the copper vats of Napoleon’s gunpowder industry)

• 1816 – Prout successfully treats goiter with Iodine

• 1835-40 – Graves and von Basedow describe “Merseburg triad” of goiter, exophthalmos, and palpitations

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A Brief History of the Thyroid

• 1836 – Cruveilhier establishes as ductless gland (bronchocele theory discarded)

• mid 1800’s – Iodine abused as “miracle drug” – falls into disrepute

• 1870’s – Fagge links thyroid hypofunction to cretinism

• 1886 – Horsley postulates thyroid hypersecretion as cause of Graves’ Disease

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A Brief History of the Thyroid

• 1891 – Murray cures myxedema with hypodermic extract of sheep thyroid

• 1893 – Muller links thyroid to metabolic activity• 1910 – Marine – shown that “cancer” in brook

trout really goiter due to iodine deficiency• Marine – “Akron experiment” – dietary

enrichment of iodine decreases goiter in schoolchildren

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A Brief History of the Thyroid

• 1915 – Kendall crystallizes thyroxine• 1923 – Goler – adds iodide to Rochester water

supply (furor over “invasion of privacy”)• 1929 – TSH identified• 1934 – Fermi – produces radioactive Iodine• 1950 – Duffy – associates XRT with thyroid

cancer• 1970’s – FNA comes into use

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History of Thyroid Surgery

• Condemned for years as heroic and butchery

• 1850 – French Academy of Medicine proscribed any thyroid surgery

• mid 1800’s – only 106 documented thyroidectomies– Mortality 40%: exsanguination and sepsis

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History of Thyroid Surgery

• 1842 – Crawford Long uses ether anesthesia• 1846 – Morton demonstrates at MGH• 1867 – Lister describes antisepsis (Lancet)• 1874 – Pean – invents hemostat• 1883 – Neuber – Cap & gown (asepsis)

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History of Thyroid Surgery

• 1870’s-80’s – Billroth – emerges as leader in thyroid surgery (Vienna)– Mortality 8%– Shows need for RLN preservation– Defines need for parathyroid preservation (von

Eiselberg)– Emphasis on speed

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History of Thyroid Surgery

• Kocher – emerges as leader in thyroid surgery (Bern)– Mortality:

• 1889 – 2.4%• 1900 – 0.18%

– Emphasis on meticulous technique– Performed 5000 cases by death in 1917– Awarded 1909 Nobel Prize for efforts

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History of Thyroid Surgery

• Halstead– Studied under Kocher and Billroth– Returned to US 1880– Worked at Hopkins with Cushing, Osler, Welch– Laid groundwork for thyroid specialists Mayo,

Lahey, Crile

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Epidemiology

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Epidemiology – Nodule

• Nodules common, whereas cancer relatively uncommon

• Goal is to minimize “unnecessary” surgery but not miss any cancer

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Epidemiology – Nodule

• Framingham study– Ages 35 – 59

• Women 6.4 %• Men 1.5 %

– Acquisition rate of 0.09 % per year• Mayo study (autopsy series – no thyroid hx)

– 21% had 1 or more nodules by direct palpation• Of those, 49.5% had histological nodules• 35.5% greater than 2 cm

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Epidemiology – Nodule

• Palpation versus ultrasound/autopsy

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Epidemiology – Nodule

• Increases with age– Autopsy – 9th decade – 80% women, 65% men

• Higher in women (1.2:1 4.3:1)• Estimated 5-15% of nodules are cancerous• Although cancer more common in women,

a nodule in a man is more likely to be cancer

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Epidemiology – Pregnancy

• Pregnancy increases risk– One study: u/s detection nodules –

• 9.4% nulliparous women• 25% women previously pregnant

– Attributed to increased renal iodide excretion and basal metabolic rate

– Rosen: Nodules presenting during pregnancy –• 30 patients, 43% were cancer• HCG may be growth promoter (TSH-like activity)

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Recommendations – Pregnancy

• Some author recommendations:– Surgery done for cancer before end of 2nd

trimester, else post-partum– Women with h/o thyroid cancer – avoid

pregnancy

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Epidemiology – Radiation

• 1 million Americans – XRT to head & neck between 20’s and 50’s for benign disease

• 1946 – Nobel prize awarded to Muller for linking radiation to genetic mutations

• 1950 – Duffy & Fitzgerald link thyroid cancer to childhood XRT exposure

• 1976 – NIH initiates “recall” program to encourage medical screening for previous XRT patients

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Epidemiology – Radiation

• Marshall Islanders exposed to nuclear fallout:– Nodules in 33%, 63% children < 10 at time

• Japanese: increased nodules in residents of Hiroshima / Nagasaki circa 1945– Increased occult thyroid ca in Japanese without

direct radiation exposure• Chernobyl – possible increase in neoplasms• Therapeutic XRT for malignancy raises risk

for thyroid neoplasia

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Epidemiology – Radiation

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Radiation

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Epidemiology – Radiation

• Appears to be dose-dependent– ERR 7.7 at 100 cGy

• Maximum risk approximately 30 years later• Nodule in radiated patient: 35-40% cancer• Data suggest no more agggresive behavior

over spontaneously-occuring cancers, but may be larger at presentation

• Only unequivocal environmental cause of thyroid cancer

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Childhood Radiation

• Younger age – greater risk• Suppression may help decrease risk

– One study: 35.8% 8.4%• I-131: risk of leukemia with high doses

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Epidemiology – Children

• Nodule more likely to be cancer than adults– 1950s: 70% – Current: approx 20%

• 10% thyroid cancer age <21• Thyroid ca 1.5-2.0% all pedi malignancies• More likely to present with neck mets• Most common cause thyroid enlargement is

chronic lymphocytic thyroiditis

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Epidemiology – Children

• Medullary Thyroid Carcinoma– FMTC, MEN 2A, MEN 2B– RET proto-oncogene (chromosome 10)– Calcium / Pentagastrin stimulation– Prophylactic thyroidectomy recommended age

2-6

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Epidemiology – Other

• Higher rate of nodules found in patients:– Who have hyperparathyroidism– Are undergoing hemodialysis

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Epidemiology – Carcinoma• Occult carcinoma in 6 – 35 % of glands at autopsy

(usu 4-10 mm)– Biologic behavior difficult to predict

• 12,000 new thyroid cancers / year• 1000 deaths / year• Surgically removed nodules:

– 42-77 % colloid nodules– 15-40 % adenomas– 8-17 % carcinomas

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Epidemiology – Cancer

• Histological subtype– Papillary – 70%– Follicular – 15%– Medullary – 5-10%– Anaplastic – 5%– Lymphoma – 5%– Mets

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Thyroid Mets• Breast• Lung• Renal• GI• Melanoma

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Papillary Carcinoma

• “Orphan Annie” nuclei

• Psamomma bodies

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Follicular Carcinoma

• Capsular invasion must be present• FNA inadequate for diagnosis

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Thyroid Physiology

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Evaluation

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Differential Diagnosis

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History

• Age • Gender • Exposure to Radiation• Signs/symptoms of hyper- / hypo- thyroidism• Rapid change in size

– With pain may indicate hemorrhage into nodule– Without pain may be bad sign

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History

• Gardner Syndrome (familial adenomatous polyposis)– Association found with thyroid ca– Mostly in young women (94%) (RR 160)– Thyroid ca preceded dx of Garners 30% of time

• Cowden Syndrome– Mucocutaneous hamartomas,

keratoses,fibrocystic breast changes & GI polyps– Found to have association with thyroid ca (8/26

patients in one series)

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History

• Familial h/o medullary thyroid carcinoma– Familial MTC vs MEN II

• Family hx of other thyroid ca• H/o Hashimoto’s thyroiditis (lymphoma)

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History

• History elements suggestive of malignancy:– Progressive enlargement– Hoarseness– Dysphagia– Dyspnea– High-risk (fam hx, radiation)

• Not very sensitive / specific

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Physical Exam

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Physical

• Thyroid exam generally best from behind• Check for movement with swallowing

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Physical

• Complete Head & Neck exam• Vocal cord mobility (?Strobe)• Palpation thyroid• Cervical lymphadenopathy• Ophthalmopathy

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Physical

• Physical findings suggestive of malignancy:– Fixation– Adenopathy– Fixed cord– Induration– Stridor

• Not very sensitive / specific

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Graves Ophthalmopathy

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Neck Bruising

• Suggests hemorrhage into nodule

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Lingual Thyroid

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Lingual Thyroid

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H&P vs FNAB

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Workup

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Serum Testing

• TSH – first-line serum test– Identifies subclinical thyrotoxicosis

• T4, T3• Calcium• Thyroglobulin

– Post-treatment good to detect recurrence• Calcitonin – only in cases of medullary• Antibodies – Hashimoto’s• RET proto-oncogene

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Flow Chart

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Graph

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Fine-Needle Aspiration Biopsy

• Emerged in 1970s – has become standard first-line test for diagnosis

• Concept• Results comparable to large-needle biopsy, less

complications• Safe, efficacious, cost-effective• Allow preop diagnosis and therefore planning• Some use for sclerosing nodules

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Fine-Needle Aspiration Biopsy

• Results – Benign– Malignant– Suspicious/Indeterminate– Insufficient/Inadequate

• Pooled data from 9 series, 9119 pts:– 74, 4, 11, 11%, respectively

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Fine-Needle Aspiration Biopsy

• Technique:– 25-gauge needle– Multiple passes– Ideally from periphery of lesion– Reaspirate after fluid drawn– Immediately smeared and fixed– Papanicolaou stain common

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Fine-Needle Aspiration Biopsy

• Hamberger study: addition of FNA – Changed # pts undergoing surgery 67 43%– Carcinoma yield 14 29%– Reduced cost per pt 25%

• Campbell & Pillsbury: pooled 10 studies– All pts operated on regardless of FNA

• False neg rate: 2.4%• False pos rate: 1.2%

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Fine-Needle Aspiration Biopsy

• Problems:– Sampling error

• Small (<1 cm)• Large (>4 cm)

– Hashimoto’s versus lymphoma– Follicular neoplasms– Fluid-only cysts– Somewhat dependent on skill of cytopathologist

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FNA of Papillary Ca

• NG: nuclear grooves

• IC: intranuclear inclusions

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Imaging

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Plain Films

• Not routinely ordered• May show:

– Tracheal deviation– Pulmonary metastasis– Calcifications (suggests papillary or medullary)

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Tracheal Deviation

• May be incidentally noted

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MRI of Last Patient

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Ultrasonography

• Thyroid vs. non-thyroid– Good screen for thyroid presence in children

• Cystic vs. solid• Localization for FNA or injection• Serial exam of nodule size

– 2-3 mm lower end of resolution• May distinguish solitary nodule from

multinodular goiter– Dominant nodule risks no different

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Ultrasonography

• Findings suggestive of malignancy:– Presence of halo– Irregular border– Presence of cystic components– Presence of calcifications– Heterogeneous echo pattern– Extrathyroidal extension

• No findings are definitive

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Nuclear Medicine• Concept• Uses

– Metabolic studies– Imaging

• Iodine is taken up by gland and organified• Technetium trapped but not organified• Usually only for papillary and follicular• Rectilinear scanner (historical interest) vs.

scintillation camera

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Nuclear Medicine

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Rectilinear Scan

• Provided life-size images

• Not common today

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Thyroid Hormone Metabolites

• Can give T3 for longer before I-131 ablation

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Nuclear Medicine

• Radioisotopes:– I-131– I-123– I-125– Tc-99m– Thallium-201– Gallium 67

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Nuclear Medicine• Technetium 99m

– Most commonly used isotope (some authors)– 99m: “m” refers to metastable nuclide

• Decay product of Molybdenum-99• Long half-life before decaying into Tc-99

– Administered as pertechnate (TcO4-)– Images can be obtained quickly

• “One-Stop” evaluation

– Hot nodules need f/u Iodine scan• Discordant nodules higher risk of malignancy

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Hot Nodule

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Nuclear Medicine• Iodine

– 127 – only stable isotope of iodine– 123 – cyclotron product

• Half-life 13.3 hr• Expensive, limited availability• Low radiation-exposure to patient

– 131 – fission product• Half-life 8 days• Cheap, widely available• Better for mets (diagnostic and therapeutic) (high radiation exposure)

– 125 – no longer used• Long half-life (60 days); high radiation exposure with poor

visualization

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Nuclear Medicine

• Tc-99m versus I-123

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Nuclear Medicine

• Thallium-201– Expensive, role poorly defined– Can detect (but not treat) mets– Not trapped or organified – mechanism unclear

• Potassium analogue– Potential advantages:

• Not necessary to be off thyroid replacement• Patients with large body iodine pool (ex: recent CT

with contrast) or hypofunctioning gland • Can sometimes image medullary

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Nuclear Medicine

• Gallium-67– Generally lights up inflammation

• Hashimoto’s

– Uses in thyroid imaging limited• Anaplastic• Lymphoma

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Nuclear Medicine

• Other imaging agents– Tc-99m sestamibi– Tc-99m pentavalent DMSA– Radioiodinated MIBG

• Developed for medullary (APUD derivative)

– Radiolabeled monoclonal antibodies

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Nuclear Medicine

• Hurthle-cell neoplasms– Better imaged with Technetium sestamibi

• Concentrates in mitochondira

– Poorly imaged with iodine

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Hot, Warm, Cold

• Study: 4457 patients with nodules– All scanned, all surgery– Results

• Cold 84% 16% cancer• Warm 10% 9% cancer• Hot 5.5% 4% cancer

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Hot Nodules

• Most authors feel that hot nodule in hyperthyroid pt has low malignancy risk

• Nodule in clinically hyperthyroid pt may be cold nodule against background of Graves, so scan may help

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Other Imaging Modalities

• CT– Keep in mind iodine in contrast

• MRI• PET

• Not first-line, but may be adjunctive

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Thyroid Suppression• Concept is that

cancerous nodule is independent of TSH, whereas benign nodule is TSH-responsive

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Thyroid Suppression

• Studies– 5 randomized, controlled studies of benign

nodules– Data suggest that thyroxine not much better

than placebo • Additionally, some malignant nodules

regress with suppression

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Thyroid Suppression

• Theoretical risk of osteoporosis– Highest in post-menopausal women– Decreased bone density in some, not all studies– No documented increase in fractures

• Controversy – level of suppression• Many no longer recommend • Exception – childhood radiation• Postop / diffuse goiter – different issues

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Controversy

• Incidentally-found non-palpable nodule– One author’s recommendations:

• Ultrasound-guided FNA for– H/o radiation– >1.0 cm– Positive family history– Suspicious u/s features

• Else– 6-12 mo f/u

– Of course, keep overall clinical picture in mind

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Pearls from an Expert (Mazzaferri)• No imaging on asymptomatic pts with normal

glands by palpation – too many false positives• Symptoms suggestive of invasion need tissue dx• Two or more suspicious features (Hamming study)

need surgery, regardless of FNA• Multinodular goiter carries a substantial risk of

cancer• Greater suspicion of nodules in males• Male over 60: consider surgery regardless of FNA,

due to high likelihood of cancer

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Flowchart 1

• Most recommend surgery after 2 insufficient FNA’s

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Flowchart 2

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Flowchart 3

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Management

• Easy in our institution to get FNA and TSH drawn on same day

• I would consider scan in hyperthyroid pt without other surgical indication

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Conclusion

• Fine-needle aspiration initial test of choice• Role for TSH, ultrasound, nuclear scan• As always, knowledge of pathophysiology

and constant vigilance key to optimum patient care

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Evaluation of a Thyroid Nodule

Michael E. Decherd, MDMatthew W. Ryan, MD

January 23, 2002

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patients with nodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds. Arch Intern Med 150:113-6, 1990.• 13) Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 338:1438-47, 1998.• 14) Jones M. management of nodular thyroid disease: the challenge remains identifying which palpable nodules are malignant. British Medical Journal

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Radiotherapy, Falk SA, (ed). Lippincott-Raven: Philadelphia, 1997.• 33) Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study on the incidence of thyroid

malignancy. Ann Intern Med 1968;69:537-40. • 34) Woeber KA. The year in review: the thyroid. Ann Int Med 131(12):959-62, 1999 Dec.• 35) Wilson GA, O'Mara RE. Uptake tests, thyroid, and whole body imaging with isotopes. In Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine,

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