Case Presentation

B.H. is a 46 yo BF with a history of enlargement of the thyroid dating to 1978 when she initially
presented to Reynolds Health Center for evaluation. At the time she was noted to have a
bilaterally enlarged gland and was referred for thyroid scan after thyroid function studies were
found to be normal. Thyroid scan revealed an asymmetrically enlarged gland with an area of
decreased uptake in the lateral portion of the right lobe of the thyroid. No definitive therapy was
instituted at the time.
In 1980, she again presented for evaluation of the thyroid gland. She underwent ultrasound of the
thyroid which revealed an asymmetric gland with a 1.5 cm solid nodule in the lateral portion of
the right lobe. Thyroid function studies were again normal, and she was started on Synthroid.
In 1982, she was evaluated via FNAB of the thyroid which revealed benign cytodiagnostic
results. She was continued on Synthroid, but for the next 12 years her care was essentially
provided through the walk-in clinic, where her Synthroid was intermittently stopped due to a
"lack of response," only to be restarted by the next physician seeing her.
When she presented in 06/95, she had not been taking Synthroid for five years. She presented to
the walk-in clinic with complaints of her neck enlarging over the previous six to eight months.
Clinical examination revealed an enlarged thyroid (two to three times normal) with a large
nodule on the right. No adenopathy was noted; no physical exam findings of hyper- or
hypothyroidism were noted. TSH was 0.7 mIU/L. She was placed on yet another attempt of
thyroid hormone suppressive therapy with Synthroid 0.05 mg/d, and follow up appointment was
arranged.
She presented for routine history and physical examination in 08/95. She denied a history of head
or neck irradiation, family history of thyroid malignancy, symptoms of hyper- or
hypothyroidism, dyspnea, hoarseness, dysphagia, or neck pain. She admitted to a one year
history of neck enlargement described as an inability "to button the top button on my blouse."
She denied however, any recent significant rapid change in the size of the gland.
PMH :
postmenopausal,
peptic ulcer disease
Medications :
Synthroid 0.05 mg/d Allergies : NKDA
Premarin 0.625 mg/d
Provera 2.5 mg/d
Social History :
remote history of tobacco use, none X several years
 denies alcohol or drug use
Family History :
mother with benign nodular goiter, otherwise noncontributory
PE :
afebrile, wt 202 lbs, BP 120/84, HR 76 regular
HEENT:
no proptosis or lid lag noted; neck revealed an enlarged gland 2-3X normal, asymmetric
with R>L lobes, isthmus enlarged. Surface was irregular with a 2 cm palpable nodule of
the R lobe laterally, the lower poles were not palpable, no thyroid bruit, no tenderness
noted.
LN SURVEY :
No palpable anterior cervical, posterior cervical, or supraclavicular adenopathy
CHEST :
clear to auscultation bilaterally
HEART:
regular rate and rhythm, no murmurs noted
ABDOMEN :
unremarkable
EXTREMITIES :
unremarkable for signs of hypo- or hyperthyroidism
LABORATORIES :
TSH 0.5 mIU/L, SMAC and CBC unremarkable

Her Synthroid dose was increased to 0.088 mg/d, and she was scheduled for follow up in 3
months.
She returned for follow up in 12/95 without significant change in her symptomatology or clinical
examination. She did admit to an increased feeling of self-consciousness over the past several
months regarding her thyroid size. She denied symptoms of hyperthyroidism.
At this time, the possible further management options were discussed with the patient,
particularly with the need to evaluate the gland for possible malignancy. FNAB was suggested,
as well as the other options of observation on or off Synthroid, as well as surgical excision and
its complications. She requested referral to a thyroid surgeon to discuss thyroidectomy due to her
increasing self consciousness relating to cosmesis. She deferred repeat FNAB until after
discussion with a surgeon.
The patient subsequently underwent subtotal thyroidectomy in 1/96. Surgical pathology revealed
a multinodular goiter with a dominant 2.7 cm nodule of the right lobe of the thyroid. There was
no malignancy documented. She was placed on Synthroid postoperatively, but has not returned
for follow up in the medicine clinic.

THE CLINICAL PROBLEM

Thyroid nodules are a common clinical problem. Physicians must be aware of the need for
further evaluation of thyroid nodules in order to rule out malignacy, even though the likelihood
of finding cancer is low. A safe, expedient, and low cost evaluation is therefore of extreme
importance4.
In an effort to help the clinician, extensive literature has been written with regards to the
evaluation and management of nodular thyroid disease. The overwhelming volume of literature,
accompanied by the conflicting opinions of well respected authors, can easily confuse even the
most astute clinician15.
The hope here, is to provide a basic understanding of the clinical evaluation and management of
nodular thyroid disease, with respect to efficiency, cost containment, and to avoid invasive
procedures in those patients with benign nodular disease for whom risk of malignancy is low.

DIFFERENTIAL DIAGNOSIS OF thyroid nodules

The differential diagnosis of the thyroid nodule is rather broad. A partial listing of the etiologies
is presented in Figure 1.

differential diagnosis of the thyroid nodule

Colloid (adenomatous) nodule Thyroid Cyst

Thyroid adenoma Pure cyst

Follicular adenoma Complex cyst

Hurthle Cell adenoma Thyroiditis

Thyroid Carcinoma Acute

Primary Subacute

Papillary Hashimoto’s
 Follicular/Hurthle Cell Graves’ Disease

Medullary Infectious diseases

Anaplastic Abscess

Metastatic/Direct invasion Tuberculosis

Renal Cell Infiltrative/Granulomatous disease

Breast Sarcoidosis

Lung Amyloidosis

Melanoma Developmental Abnormalities

Colon cancer Thyroid hemiagenesis

Gastric carcinoma Thyroglossal duct cyst

Head and Neck tumors Teratoma

Hodgkin’s disease Miscellaneous

Thyroid Lymphoma

Figure 1. Adapted from Burch, in Endocrinology and Metabolism Clinics of North America, 19954.

Prevalence of Thyroid Nodules

Thyroid nodularity is extremely common. The prevalence of thyroid nodularity has been
estimated in numerous studies. Most authors agree that the prevalence by palpation lies
somewhere in the range of 4-7% of the general population.9,17,19,22 Most thyroid nodules are not
clinically recognized, as necropsy studies reveal that the prevalence of nodularity approaches 37-
57% of the general population4,6,19,20. Ultrasonography studies estimate the prevalence of thyroid
nodularity at approximately ten times higher than that appreciated by palpation alone--i.e. 40-
50%.4,6 Also, patients felt to have solitary nodules by palpation were shown to have multiple
nodules by ultrasonography in 16-48% of cases.4
The annual incidence of new palpable nodules is estimated at 0.1%. This rate increases
approximately 20 fold in the event of prior radiation exposure.22 At this rate of development,
approximately 250,000 new nodules would come to clinical attention each year.7
The prevalence of thyroid nodules is also dependent upon age and sex. Nodules are more
frequently seen in females with prevalence ratios ranging form 1.2:1 to 4:1. A female:male ratio
is documented at 2:1 in many studies. The prevalence of nodularity increases with advancing
age--50% of men and women in their 6th decade, and greater than 80% of women and 65% of
men in their 9th decades at autopsy were shown to have nodular thyroid disease.4
In contrast to the high prevalence of nodular thyroid disease, the presence of thyroid carcinoma
is rare, accounting for approximately 5% of all palpable thyroid nodules.22 In the United States,
thyroid carcinoma represents about 1% of all malignancies, accounting for approximately 12,000
new cancers each year,13,17 resulting in about 1000 deaths per year.17
Thyroid carcinoma occurs more frequently in females due to the greater prevalence of nodular
thyroid disease. However, nodular thyroid disease in males is twice more likely to be malignant
than in females.1
The likelihood of thyroid carcinoma is greatest in patients under 25-30 years of age and in those
over age 60.4 Those individuals in the older age groups are also more likely to demonstrate
aggressive (anaplastic) subtypes of thyroid carcinoma and have more extensive disease, and
therefore a higher likelihood of dying than their younger counterparts.4
The lowest proportion of malignant nodules (2.9%) was observed in patients 31-40 years of age,
and was twice as frequent (6.5%) in patients younger than 20-25 years of age. The prevalence of
malignant nodules was 6 fold greater (16.4%) in patients over age 70.1
Until recently, it was thought that multinodular glands demonstrated lower rates of malignancy
than glands with solitary thyroid nodules. Belfiore, however, demonstrated that at operation,
4.7% of 4500 patients with solitary nodules harbor malignancy. A similar proportion (4.1%) of
1100 patients with multinodular goiters harbored malignancy, thus dispelling the belief that
multinodular goiters were at lower risk of malignant disease.2

Risk Factors for Thyroid Malignancy

RISK FACTORS FAVORING THE MALIGNANT NATURE OF THYROID NODULE
Age < 20 or > 60 fixation of the nodule to surrounding tissue

male sex firm, hard, and irregular surface

history of thyroid cancer lymph node enlargement

histroy of irradiation hoarseness

presence of solitary nodule dysphagia

rapid growth dyspnea

Figure 2. Adapted from Gupta, in Clinics in Geriatric Medicine, 199510.

In addition to the risk factors of age and sex noted previously, other risks for malignancy include
a history of exposure to ionizing radiation to the head, neck, and chest area, particularly as a
child. Here, new nodules develop at a rate of about 2% annually (20 fold greater than in
nonirradiated patients) after exposure to as little as 200 to 500 rads of ionizing radiation. The
peak incidence occurs 15-25 years after exposure, but may be seen as early as 3-5 years
following exposure.4 Both benign and malignant nodules are more frequently seen following
exposure to radiation to the head, neck, or chest,13 and may be present in as many as one third of
all nodules in patients with prior history of irradiation.19
Irradiation to the head, neck, and chest was used in the period from the 1920’s to the late 1950’s
to treat many benign conditions including tonsillitis, acne, hemangiomas, thymic enlargement,
tinea capitis, impetigo, pertussis, keloids, Bell’s palsy, and lymph node hypertrophy.21 It has been
estimated that as many as one million Americans have received radiation therapy to the head,
neck, and chest, during this time period.4
There has been an increased incidence and prevalence of thyroid disease observed in residents of
Hiroshima and Nagasaki following detonation of the atomic bomb in 1945. There has also been
an acute increase in the incidence of thyroid nodules in the population near Chernobyl following
the nuclear reactor breakdown in 1986.4 These nodules are of both the benign and malignant
subtypes.
Other risk factors for thyroid malignancy include historical and physical exam findings. A
positive family history of benign nodular thyroid disease may be reassuring. However, a history
of medullary thyroid carcinoma or MEN II syndromes, or papillary carcinoma increases the
likelihood of a malignant finding.10,13,17 Local symptoms suggestive of compression, obstruction,
or invasion including dyspnea, dysphagia, or hoarseness indicating recurrent laryngeal nerve
involvement, are suggestive of malignancy.10,19,21
Patients with a rapid growth of a solid thyroid mass,19,20 anterior or posterior cervical or
supraclavicular lymphadenopathy, fixation of the mass to surrounding tissues or structures, a
firm, hard, irregular surface, and the presence of a solitary nodule in an otherwise normal gland
or a dominant nodule in a multinodular goiter are more likely to be associated with
malignancy.5,10,13,19,20 These findings lack sensitivity and specificity for thyroid malignancy.4
Lesions greater than 3 cm in diameter are also more likely to harbor undetected malignancy than
smaller lesions. Hashimoto’s thyroiditis has been documented to be a frequent preexisting
condition in patients who ultimately develop thyroid lymphoma.4
Patients with highly suspicious lesions (defined as a positive family history of medullary
carcinoma, rapid growth, firm consistency, hoarseness, fixation to adjacent local structures, or
enlargement of regional lymph nodes) had carcinoma in 71% of cases. Patients with two or more
of these characteristics demonstrated carcinoma 100% of the time.4

Evaluation of Thyroid Nodules

Laboratory Data
Tests of thyroid function are useful only to the extent that they assist in defining the context in
which nodular thyroid disease occurs. Thyroid function testing (serum TSH, thyroxine, and
triiodothyronine) usually reveals normal results.9,17 Most authors would accept simply a serum
TSH as an adequate screen of thyroid function. However, no laboratory test can reliably
distinguish benign from malignant thyroid disease.20
A subnormal TSH may indicate a hyperfunctioning nodule, which should be evaluated further to
rule out an autonomously functioning nodule. Conversely, an elevated serum TSH may indicate
hypothyroidism, which in the United States, in the absence of prior therapy for hyperthyroidism,
is most commonly due to Hashimoto’s thyroiditis.19 The nodules may represent thyroid tissue
stimulated to enlarge under the influence of high TSH, or they may represent true neoplasia.
Antimicrosomal antibodies may be useful in the diagnosis of Hashimoto’s thyroiditis, if present
in high titer.4 Serum thyroglobulin levels are not helpful in the differentiation of benign from
malignant thyroid nodules,4 but may be useful in post surgical follow up evaluation of patients
with thyroid carcinoma.
Serum calcitonin levels are generally elevated in patients with medullary thyroid carcinoma
presenting as a palpable mass, but may require stimulation with pentagastrin and calcium to
detect disease in the earlier stage of C-cell hyperplasia.4 Although some authors have advocated
the screening of all patients with palpable thyroid masses with calcitonin levels, this is not cost
effective, since only 2-5% of all thyroid malignancies represent medullary thyroid carcinoma.9

Nuclear Medicine Scans

Radioiodine isotopes, which are trapped and organified to tyrosine residues of thyroglobulin and
subsequently stored in the colloid, are sometimes employed in the evaluation of thyroid
nodularity. 131I was commonly used in the past and remains useful particularly in the evaluation
of metastatic thyroid carcinoma. 125I has a lower radiation energy delivered to the thyroid than
131
I, but has a longer half life, and is rarely used. 123I has a short half life of approximately 13
hours, can be administered orally, lacks beta emissions, and produces a radiation dose to the
thyroid of about 1% of that delivered by 131I. Radioiodine scans overall produce a greater clarity
and lower background than technetium scans. Radioiodine isotopes are considerably more
expensive, require a cyclotron for production, and take longer to perform. Imaging at 4 hours
allows the procedure to be performed in a single day, but traditionally a 24 uptake scan is
performed, making the procedure 2 days in duration.19
THYROID SCINTIGRAPHY
ADVANTAGES DISADVANTAGES

• Will diagnose hot nodules, eliminating • Warm or cold nodules require further study
biopsy or surgery
• Cysts and hemorrhages appear cold
• Will pick up aberrant thyroid tissue
• Cost to perform
• Able to diagnose multinodular goiter
• Potential for radiation exposure
• Will confirm substernal thyroid
• May require two days to perform
• Will identify cold nodule in a patient with
Graves’ disease

Figure 3. Adapted from Dwarakanathan, in Comprehensive Therapy, 19935.

99m Technetium pertechnetate is a monovalent anion which is actively concentrated by the
thyroid gland, but unlike iodine, undergoes negligible organic binding. Its half life is
approximately 6 hours, making the radiation delivered to the thyroid very low. It is administered
as an intravenous bolus, with imaging performed 30 minutes later. Many investigators feel that
the convenience, availability, and reduced cost of 99m technetium pertechnetate make it an
acceptable imaging agent, since the slightly better quality of radioiodine scanning is of little
clinical significance.19
The major objective of radionuclide thyroid scanning with 131 I, 123I or 99m technetium
pertechnetate is to classify nodules as hot, cold, or warm depending on their ability to
differentially concentrate radioisotope. Most benign and virtually all malignant neoplastic or
nodular thyroid tissue concentrate both 99m technetium pertechnetate and radioiodine less avidly
than adjacent normal thyroid tissue, resulting in a cold appearance on thyroid scanning.
Autonomously functioning tissue will frequently concentrate both agents more avidly than
normal adjacent tissue, producing a hot appearance on scan. Three to 8% of benign or malignant
nodules will concentrate 99m technetium pertechnetate, but fail to organify radioiodine. Such
nodules appear hot, or warm / indeterminate on 99m technetium pertechnetate scans and cold on
radioiodine scans. Most authors therefore suggest that functional nodules on 99m technetium
pertechnetate scans be rescanned with radioiodine. 19
The role of thyroid scintigraphy in the initial evaluation of the thyroid nodule has recently been
questioned by several investigators. Prior to the advent of FNAB, thyroid scintiscanning was of
premier importance in guiding the management of nodular thyroid disease. Today, with the
current utility of FNAB, the role of radionuclide thyroid screening has become equivocal.
Radionuclide imaging studies cannot reliably distinguish malignant from benign nodules as
demonstrated by the data presented by Ashcraft and Van Herle. They found that in a series of
patients with nodular thyroid disease who underwent surgery and histologic examination
regardless of the findings of radionuclide screening, 84% of nodules were cold, 10.5% were
warm and 5.5% were hot -- at histologic exam 16% of cold nodules, 9% of warm nodules and
4% of hot nodules were shown to be malignant. 20
Nuclear medicine scanning of the thyroid gland has limited utility beyond the classification of
nodules according to their ability to trap radioisotope. Because the overwhelming majority of
benign and malignant nodules appear hypofunctional relative to adjacent normal thyroid tissue,
the finding of a cold nodule has relatively low specificity. 4 Radionuclide scanning has relatively
poor ability to differentiate malignant from benign lesions in nodular thyroid disease. Nuclear
scans also have poor ability to define the status of nodules located in the periphery or isthmus of
the gland17 due to the dependence of the technique on comparison of the area in question to
adjacent thyroid tissue.
Other problems associated with the use of nuclear thyroid imaging relate to the interpretation of
a nodule as warm or indeterminate. The majority of thyroid cancers under 2 cm, as well as a
minority of larger tumors, will fail to appear cold on scan because they are located anterior or
posterior to normally functioning thyroid tissue. Conversely, autonomous nodules which are
unable to adequately suppress pituitary TSH production will appear warm due to the ability of
adjacent tissue to take up radioisotope. 17
Thyroid scintigraphy does, however, have utility in the evaluation of a clinically suspected
autonomous nodule. Based on the assumption that normal tissue requires TSH to stimulate the
uptake of radioisotope, autonomous nodules are able to concentrate the isotope in the absence of
TSH. Although hot nodules rarely harbor malignancy, their propensity for subclinical or overt
hyperthyroidism usually dictates further therapy with surgery or radioablation.4
Radionuclide scanning may also be useful in the evaluation of lesions found to be indeterminate
on FNAB, as hyperfunctional nodules are rarely malignant.13 Indeterminate or suspicious lesions
are most appropriately managed with surgical excision, as will be demonstrated in a later section
of this paper. Patients with Graves’ disease and a dominant nodule on palpation that proves to be
cold on scintiscanning, have a higher risk of malignancy and should be referred to surgery for
near total thyroidectomy as definitive therapy.4

THYROID HORMONE SUPPRESSION THERAPY AS A DIAGNOSTIC TOOL

Thyroid hormone administration may also be used as a diagnostic tool. This method rests on the
assumption that benign thyroid nodules, but not malignant ones, depend on TSH for
development and growth, and that TSH secretion is regulated by feedback inhibition by thyroid
hormone. If thyroid hormone administered in suppressive doses produces regression or
disappearance of the nodule, one would assume that the nodule is benign. If there is no change,
or the nodule grows while on suppression therapy, this finding would be consistent with
malignancy and would appear to be an indication for surgical excision7.
Recent studies reveal otherwise. TSH appears to be one of many potential growth factors for
thyroid tissue. The literature further documents that many benign nodules do not respond to
suppressive therapy, while 13-15% of thyroid cancers may become smaller with suppressive
doses of levothyroxine. The use of thyroid hormone suppression to separate benign from
malignant disease should, therefore, be discouraged.4,7

ULTRASONOGRAPHY
Ultrasonography is able to help categorize nodules as solid, cystic, or mixed solid and cystic with
90+ % accuracy.13,20 Ultrasound provides greater anatomic detail than thyroid scintigraphy or
computerized tomography and is able to resolve cystic lesions as small as 2 mm and solid lesions
measuring 3 to 4 mm in size.
ULTRASONOGRAPHY
ADVANTAGES DISADVANTAGES

• Noninvasive • May miss very small nodules

• No radiation involved • Unable to identify substernal

goiter
• Differentiates cystic from solid lesions
• Unable to differentiate malignant
 • Determines exact size from benign tissue

• Can be used to guide needle aspiration

Figure 4. Adapted from Dwarakanathan, in Comprehensive Therapy, 19935.

It has been thought that solid lesions carry a higher risk of malignancy than do cystic lesions.
Recent data suggests that pure cystic lesions are rare, comprising less than one percent of all
lesions and cysts frequently represent degenerative changes of solid lesions resulting in a cystic
component. The frequency of malignancy is higher in solid lesions, but demonstration that a
lesion has a cystic component does not eliminate its potential for malignancy (13-20% vs. 0.5-
10% respectively, depending upon the series).19
Ultrasonography is relatively insensitive with regards to differentiating benign from malignant
nodules/lesions.13 In a recent review of published series, 69% of all nodules were solid, 19%
were cystic, and 12% were mixed. About 20% of solid nodules were found to be malignant while
some 10% of mixed nodules were also noted to be malignant at histological examination.7,20
Most investigators would agree that the routine use of ultrasound in the evaluation of thyroid
nodules is not cost effective. Ultrasonography does have a potential role in a number of areas. As
stated previously, ultrasonography is useful in classifying lesions as solid, cystic or mixed. It also
may be used to evaluate the size and volume of a thyroid nodule,13 as well as multiplicity of
nodules in a gland clinically suspected to have solitary nodule, as 20-40% of patients referred for
ultrasound of a solitary nodule will demonstrate one or more additional nodules.19
Ultrasonography is also useful for follow up evaluation of cystic nodules after aspiration of cyst
contents and FNAB. If a residual palpable lesion is present following aspiration, ultrasonography
can identify it as persistent cyst or solid nodule. A solid nodule should be sampled by FNAB; a
cystic lesion that reaccumulates following aspiration may have an increased risk of malignancy
(10%) compared to that of completely aspirated cyst (1%), and should be reaspirated or
surgically excised.19
Ultrasonography can also be used: (1) to accurately assess a lesion over time for evidence of
change in nodule size; (2) to preoperatively identify lymph nodes following FNAB diagnosis of
malignancy; (3) to monitor the thyroid bed for recurrence following thyroidectomy for
malignancy; and (4) to guide repeat FNAB when results initially are nondiagnostic, with small
lesions, or those situated in difficult positions to blindly access.9,19

COMPUTERIZED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING

Computed tomography and magnetic resonance imaging may occasionally be useful in
identifying the extent and location of thyroid masses. The imaging studies are generally reserved
for substernal or retrosternal thyroid masses, detection and delineation of thyroid nodules, and
identification of regional or distant metastasis.9 These studies are not cost effective with regard to
the initial management of thyroid nodules.
FINE NEEDLE ASPIRATION BIOPSY
It is relatively difficult to overstate the influence of FNAB on the management of nodular thyroid
disease. The procedure was first utilized in the 1950’s, but did not gain general acceptance until
the 1980’s.22 During the last decade, FNAB has become the most direct, and accurate diagnostic
procedure in the management of nodular thyroid disease.6,9 Most centers which have effectively
utilized FNAB have demonstrated a 35-75% reduction in the number of patients requiring
surgery, a doubling of the malignancy yield at thyroidectomy, and up to a 25% reduction in the
costs associated with thyroid nodule management.4
FINE NEEDLE ASPIRATION BIOPSY
ADVANTAGES DISADVANTAGES

• Safe, simple, quick office procedure • Unable to distinguish benign from

malignant follicular and Hurthle cell
• Yields direct cytologic information neoplasms

• Will diagnose certain cancers (papillary, • Complications (although infrequent) of

medullary, and anaplastic), as well as invasive procedure
Hashimoto’s thyroiditis, and subacute
thyroiditis with reasonable certainty • Requires experienced pathologist

• Can be repeated many times • False negative diagnoses

• Cysts can be diagnosed and cured

• Avoids unnecessary surgery

Figure 5.. Adapted from Dwarakanathan, in Comprehensive Therapy, 19935.

THE PROCEDURE
FNAB is generally performed as an outpatient procedure with the patient in the supine position
with his or her neck flexed backward slightly. The skin is cleansed with alcohol. Generally local
anesthesia is not required. A 23-25 gauge needle attached to a 10 ml disposable syringe is then
place into the nodule after localization, and suction is applied while the needle is moved back
and forth within the nodule. Suction is then released and the needle withdrawn from the nodule.
The aspirated material is then expelled onto glass slides and either air dried and stained using the
May-Grü nwald-Giemsa technique or immediately fixed with 95% alcohol and stained using a
modified Papanicolaou method.6 Generally two to four aspirations are performed, depending
upon the quality of the smears and the aspirationist.

CYTODIAGNOSIS
In order to allow for satisfactory categorization of FNAB material, the smear must contain an
adequate number of cells. The real question here is, what is adequate? Various authors have
published recommendations for determining the adequacy of FNAB smears. However, no
standardized criteria exist for judging aspirate sufficiency. Gharib and Goellner have suggested
that an adequate smear is one containing 5 or 6 groups of well preserved cells, each group
containing 10-15 cells, minimum6. Hamburger has defined a satisfactory benign aspirate as
having at least six clusters of benign appearing follicular epithelial cells on at least two slides
prepared from separate aspirates. Any malignant appearing cell automatically dictates a
cytodiagnosis of malignant. Specimens which do not meet these criteria are classified as
nondiagnostic (rather than benign) 11. Standardization of cytodiagnostic criteria for thyroid
FNAB can only serve to improve the accuracy of the technique.
Cytodiagnosis of aspirates is divided into one of four categories on the basis of cellular
appearance: benign, suspicious or indeterminate, malignant, and nondiagnostic.6 Accuracy of
cytodiagnosis is influenced by the experience of the aspirator and the cytopathologist interpreting
the smear.19

BENIGN LESIONS
Patients with a benign cytodiagnosis do not have malignancy, but rather may have a normal
thyroid gland, a colloid nodule, lymphocytic thyroiditis, subacute thyroiditis or another benign
condition.6 Most benign smears demonstrate abundant colloid material and typical follicular
cells. Approximately 70% (range 53-90%) of all nodules sampled will demonstrate benign
cytodiagnostic results.

MALIGNANT LESIONS
Patients with malignant cytodiagnostic results have findings indicating malignant cells consistent
with primary or metastatic thyroid carcinoma including papillary carcinoma, medullary
carcinoma, anaplastic carcinoma, lymphoma, or metastatic tumor.22 Rarely, a diagnosis of
follicular or Hü rthle cell carcinoma is made on the basis of thyroid FNAB. Approximately 3.5%
(range 1-10%) of all nodules will yield malignant results.6

SUSPICIOUS/INDETERMINATE LESIONS
Patients with a suspicious or indeterminate cytodiagnosis on FNAB have specimens which
demonstrate hypercellularity and a pattern suggestive of, but not diagnostic, for malignancy.6
Frequently, these lesions are follicular or Hü rthle cell neoplasms, although papillary lesions are
sometimes noted; these lesions frequently contain little colloid material.19
Follicular and Hü rthle cell neoplasms may be benign adenomas or malignant carcinomas. The
distinguishing characteristics include evidence for capsular or vascular invasion. FNAB rarely
provides enough information to classify these lesions correctly.
Approximately 10 - 15% of all cytologic specimens are labeled as suspicious for malignancy or
indeterminate. These usually are the result of the presence of follicular or Hü rthle cell
neoplasms, and about 20% of these lesions are actually malignant.9,19 This number approaches
60% when lesions suggestive of papillary carcinoma are considered.9

NONDIAGNOSTIC LESIONS
Nondiagnostic results are obtained when relatively few follicular cells are obtained by FNAB.
This occurs in approximately 15% of all aspiration attempts, but varies depending on the
experience of the aspirationist, the size and nature of the lesion, vascularity, and when the
cytopathologist has set stringent diagnostic criteria for a satisfactory smear.9
Most commonly, nondiagnostic results are due to aspiration of hemorrhagic or cystic lesions
(which constitute approximately 15-20% of all nodules) with resultant dilution of the specimen.
The finding of a cystic lesion, however, should not dissuade the physician from aggressively
pursuing the diagnosis as up to 14% of cystic lesions may be malignant.9
In the event of nondiagnostic results, repeat aspiration will usually yield a satisfactory specimen
in about 50% of cases. Even with repetitive aspirations, a residual 10% of specimens will remain
unsatisfactory for interpretation and are labeled as persistently nondiagnostic.6 It is important to
understand that a nondiagnostic result does not imply a benign specimen.19

RESULTS OF FINE NEEDLE ASPIRATION BIOPSY

Data from seven, large series of patients undergoing FNAB revealed that 18,183 specimens were
obtained and examined. The rate of benign cytodiagnosis was 53-90% (mean 69%), malignant
cytodiagnostic findings occurred in 1-10% (mean 3.5%). Suspicious or indeterminate findings
were present in 5-23% (mean 10%) and nondiagnostic specimens comprised 2-21% (mean 17%)
of all specimens. Caruso and Mazzaferri recently reported similar findings in an analysis of 10
series containing 9119 patients -- 74% benign, 4% malignant, and 22% suspicious; 10% were
nondiagnostic.6
Comparison of Diagnostic Cytologic Categories in Seven Series
SERIES COUNTR YEAR TOTAL BENIGN MALIGNA SUSPICIO NONDIAGNO
Y CASES NT US STIC

n (%) n (%) n (%) n (%) n (%)

Gardiner Canada 1986 1 465 1085 (74) 16 (1) 146 (10) 218 (15)

Hawkins Spain 1987 1 399 1253 (90) 56(4) 68 (5) 22(2)

Khafagi Australia 1988 618 404 (65) 29 (5) 68 (11) 117 (19)

Hall US 1989 795 509 (64) 81 (10) 75 (9) 130 (16)

Altavilla Italy 1990 2 433 1890 (78) 32 (1) 119 (5) 392 (16)
 Caplan US 1991 502 268 (53) 24 (5) 116 (23) 94 (19)

Gharib/ US 1991 10 971 7071 (64) 416 (4) 1192 (11) 2292 (21)
Goellner

TOTAL 18 183 12 480 (69) 654 (3.5) 1784 (10) 3265 (17)

Figure 6. Adapted from Gharib and Goellner, in Annals of Internal Medicine, 19936.

FALSE DIAGNOSES

FALSE NEGATIVE DIAGNOSES

False negative results are worrisome because they imply missed malignant lesions. They occur
secondary to sampling error or interpretive mistakes. The false negative rate is defined as the
percentage of patients with benign cytologic findings, who are subsequently found to have
malignant lesions of the thyroid. Therefore, the true false negative rate could be found only in a
series in which all patients with benign results screened by FNAB, had subsequent surgery with
histologic review. No such study has been performed. The reported false negative rates in the
seven series summarized ranged from 1.3%-11.5% with an average of 5.2%. When data from the
series are combined, only 10% of patients with benign cytologic findings underwent thyroid
surgery. Caruso and Mazzaferri found a false negative rate of 5% (range 1-6%), based on their
pooled data from 10 series in which only 14% of nodules were excised. Campbell and Pillsbury,
analyzing data from 912 patients with benign cytologic results and subsequent histologic
examination found a pooled false negative rate of 2.4%, with a range of 0.5-11.5%. Ashcraft and
Van Herle in their analysis of 1330 patients found a false negative rate of 1.7%.6 Boey and
colleagues took a different approach in 365 patients with negative/benign cytologic results and
followed them for a period of 30 months, during which time they found only 2 cancers - a false
negative rate of 2.1%. Grant and colleagues similarly followed 439 patients who had benign
results on FNAB but did not undergo immediate surgery -- 3 patients subsequently demonstrated
malignancy in a 6.1 year follow up period, for a false negative rate of 0.7%.6
Most authorities agree that the true false negative rate probably lies below 5% but an accurate
value may never be realized.6

FALSE POSITIVE DIAGNOSIS

The false positive rate is the percentage of patients with malignant results on FNAB who are
found to have benign lesions at surgery. In Gharib and Goellner’s review, the false positive rate
varied from 0-7% (mean 2.9%). These results were similar to the rates of 0.5% reported by
Ashcraft and Van Herle, 1.2% reported by Campbell and Pillsbury and 6% reported by Caruso
and Mazzaferri.6
SPECIFICITY AND SENSITIVITY
Two values used to estimate the accuracy of FNAB in the evaluation of thyroid nodules for
malignancy are sensitivity and specificity. The estimates of sensitivity and specificity depend on
how the suspicious/indeterminate category is handled. If the suspicious results are considered
positive, the sensitivity increases and specificity decreases (98% sensitive, 72% specific). If the
suspicious results are considered negative, then specificity increases and sensitivity decreases
(65% sensitive, 100% specific). An overall sensitivity of 83% and specificity of 92%, as quoted
by Gharib, translates into a diagnostic accuracy greater than 95%, thus confirming FNAB as a
reliable test.6

POSITIVE AND NEGATIVE PREDICTIVE VALUES

According to the data presented by Gharib and Goellner, and a review by La Rosa, a malignant
result on FNAB has a positive predictive value of about 96%, while a benign result suggests a
negative predictive value of 99%6,12.
PRECISION OF FINE NEEDLE ASPIRATION BIOPSY
series nodules malig- false fals sensitivity specificit accuracy
e y

operated nant neg pos

gharib

and 1750 682 2.0% 0 98% 99% 98.5%

(39%) .7%

goellner

La ROSA 827 250 1.7% 2 98% 98% 97.7%

(30%) .2%

TOTAL 2577 932

(36%)

Figure 7. Adapted from Giuffrida and Gharib, in American Journal of Medicine, 19956.

LIMITATIONS
FNAB has two major limitations : nondiagnostic results, and suspicious or indeterminate results.
Nondiagnostic results often occur in the setting of cystic or vascular lesions. Repeat biopsy may
produce satisfactory results in about half of the patients. The success of FNAB depends upon
careful aspiration, smear preparation, and cytodiagnostic interpretation. Realize that
approximately 10% of all nodules will yield nondiagnostic results regardless of the number of
aspirations performed.
The second limitation is the indeterminate result. Here, 20-30% of aspirations show suspicious
cytodiagnosis because of the difficulty differentiating benign cellular follicular and Hurthle cell
neoplasms from their malignant counterparts. About 25% of suspicious lesions are found to be
malignant at surgery. Methods of more accurately diagnosing these malignant lesions
preoperatively have been suggested, but have not significantly improved cytodiagnostic yield.6
Thyroid scintigraphy may be of benefit in identifying functioning nodules which have a lower,
but not negligible risk for malignancy, and thus avoiding surgical intervention.6

EFFECT ON THE MANAGEMENT OF THYROID NODULES

Many studies have shown that FNAB has had a significant effect on the number of patients
proceeding to surgery, and upon the incidence of carcinoma found at operation. Miller and
colleagues reported that the availability of biopsy decreased the percentage of patients
undergoing thyroid surgery from 48% to 24% while increasing the yield of malignancy from
12% to 14%. Hamburger reported that following the introduction of FNAB, the percentage of
patients undergoing surgery decreased from 67% to 43%, with the percentage of carcinomas
found in operated patients doubling from 14% to 29%. Caplan and colleagues documented
similar results, with the percentage of patients proceeding to thyroidectomy decreasing from
61% to 33%, while the yield of malignancy doubled from 18% to 39%. Alternatively, Gharib
found that FNAB resulted in a 12% increase in the frequency of surgery for benign follicular and
Hurthle cell neoplasms/adenomas, but 25% fewer thyroid operations were performed for benign
disease.6
The economic effect that FNAB has produced is considerable and has resulted in a significant
reduction in the overall cost of management by as much as 25% in some series. The main effect
in cost reduction has been the elimination of unnecessary thyroid surgery in patients with benign
lesions.6

APPROACH TO THE PATIENT WITH A THYROID NODULE

Most patients are asymptomatic when thyroid nodules are first identified, as most are discovered
incidentally. Patients will, however, present with complaints of "lumps in their neck". It is of
utmost importance to perform a careful history and physical exam, with particular attention to
risk factors for thyroid malignancy.21
Specifically, the patient should be questioned about previous history of thyroid disease, head,
neck, or chest irradiation, the pattern of progression of the nodule, as well as family history of
thyroid carcinoma. The patient should be thoroughly questioned regarding symptoms of
compression, obstruction, or invasion including dyspnea, dysphagia, hoarseness, and pain.
Physical exam should focus on identifying nodular disease in the thyroid, characterizing the
thyroid with regards to the number, quality, and distribution of nodules, gland size, texture, and
presence of lymphadenopathy.4 Effective management of the patient with a thyroid nodule
revolves around an assessment of their risk for malignancy. Although the aforementioned risk
factors, as well as age and sex of the patient, lack specificity and sensitivity, these risk factors
may influence the management decisions involving a highly suspicious nodule. Patients with
multiple risk factors (high risk) for malignancy may most safely be managed with thyroidectomy
in spite of FNAB cytodiagnosis.
There is considerable diversity and controversy in the approach to the patient with a thyroid
nodule. Some authors favor early surgical approach to patients with thyroid nodularity as they
argue that in as many as 10% of patients with thyroid nodules, histology may reveal malignancy
which is a potentially lethal condition dictating aggressive treatment. Those favoring a more
conservative approach argue that thyroid nodularity is an extremely common condition, of which
a relative few number of patients will have thyroid carcinoma. An aggressive approach therefore
may not be warranted or justified. Additionally, certain of the thyroid carcinomas are so indolent
and slow growing that most patients will die of causes unrelated to the thyroid cancers.10
Alternative approaches to immediate surgery for all nodules include use of one or more of the
following methods: radionuclide imaging, ultrasound, FNAB and trial of thyroid hormone
suppression.4
As preliminary studies, thyroid function testing is generally normal. Minor abnormalities of
thyroglobulin may be present, but this is a nonspecific finding. A suppressed TSH indicates
likely hyperthyroidism, and if a palpable nodule corresponds to a hot/hyperfunctioning nodule on
scintigraphy, the likelihood of malignancy is reduced (but not eliminated) and the patient can be
treated with either radioablative therapy or surgical excision (subtotal thyroidectomy). Many
centers still obtain both thyroid scintigraphy and ultrasound as the initial diagnostic evaluations
in a patient with a thyroid nodule. Other centers, based upon its excellent accuracy and
reliability, utilize FNAB to obtain tissue cytology as the primary step in evaluation of thyroid
nodules.19 Either approach is reasonable. The deciding factors should include the availability of
resources, patient and physician preference, and the overall clinical assessment. The availability
of a physician with adequate expertise in obtaining FNAB specimens, as well as an experienced
cytopathologist familiar with the interpretation of thyroid aspirates cannot be overemphasized
when making a management decision.19
Thyroid ultrasound and scintigraphy, with their known inability to accurately and reliably
differentiate benign from malignant disease, may be appropriate studies when the patient is
extremely anxious regarding FNAB, when no clinical risk factors for malignancy are present,
when clinical signs of toxicity are suspected or present, when the patient is anticoagulated
(although this poses little risk when FNAB is performed by an experienced operator), or when an
experienced aspirationist or cytopathologist is not available.19,20
FNAB, with its high degree of accuracy and reliability, ease of performing, and general
acceptance, is likely the most reasonable initial diagnostic procedure in the evaluation of nodular
thyroid disease. As this approach is readily available at this institution, further discussion will be
primarily based upon the approach utilizing FNAB as the major diagnostic tool.
If FNAB yields a malignant cytodiagnosis, near total thyroidectomy (with modified neck
dissection if lymph node metastases are suspected) is the procedure of choice.4,10,19,22 Nodules
which yield suspicious or indeterminate cytodiagnosis on FNAB present a special problem. No
clinical or laboratory finding will accurately predict which patients with suspicious cytologic
results, will in actuality have a malignant process.6 As stated previously, 10-30% of nodules with
suspicious cytodiagnoses will yield malignancy on histologic diagnosis.9 Typically these lesions
represent follicular or Hü rthle cell neoplasms, which cannot be adequately characterized by
FNAB alone, because capsular or vascular invasion cannot be seen. Nodules which are labeled as
suspicious for papillary thyroid carcinoma were found in one study to be malignant in about 60%
of cases at thyroidectomy.4
It is for these reasons that most authors recommend surgical excision with lobectomy and frozen
section analysis at operation to determine whether further surgical excision/dissection need to be
attempted. This is particularly emphasized if the patient demonstrates risk factors making the
likelihood of finding malignancy higher -- a male patient, older or younger age group, suspicious
characteristics, or a lesion larger than 3 cm.11
Some authors have recommended that following a diagnosis of suspicious or indeterminate,
radionuclide imaging be performed. If the nodule is cold/hypofunctional, surgery is subsequently
recommended. If the patient is euthyroid and the nodule functional, observation can be safely
undertaken.6 A hot nodule in a patient with clinical or biochemical evidence of thyrotoxicosis
could be treated with intranodular ethanol injection, radioiodine, or surgery.10 Still, even with this
approach, many patients will proceed to surgery, and potential malignancies may be missed with
conservative observation of hot nodules. Thyroid suppression therapy may also be employed.
In a lesion noted to be benign by cytodiagnosis, most authors recommend careful follow up with
periodic exams and repeat aspiration in one year if necessary.10,19 There is currently much debate
regarding whether patients with a benign thyroid nodule should be followed with simple
observation or whether levothyroxine suppression therapy should be administered.6 This issue
will be discussed further in a later section of this paper.
Nondiagnostic cytodiagnostic results are encountered in about 15% of all FNAB attempts. This
is usually due to the presence of cystic or hemorrhagic nodular material and the acquisition of an
insufficient number of thyroid follicular cells on which to make a cytodiagnosis.6 Reaspiration of
a solid nodule will yield a diagnostic specimen in about 50% of these cases, from which point
appropriate management decisions can be made. In the event that a cytodiagnosis is not obtained,
many authors recommend surgical excision with lobectomy or nodulectomy and frozen section
analysis to determine the need for further surgical intervention.4
In the case of cystic lesions, often the initial aspiration will cure the nodule, even though it does
not provide cytodiagnosis. If after initial aspiration of a cyst, a palpable nodule remains, FNAB
should again be performed on the residual tissue. Decompressed nodules that recur can be
reaspirated, but many authors recommend surgical excision, particularly if the lesion is larger
than 3 cm, as these lesions carry an increased risk of malignancy.4,6

SPECIAL CONSIDERATIONS
AUTONOMOUSLY FUNCTIONING THYROID NODULES
Autonomously functioning thyroid nodules (as identified on radionuclide scanning) often grow
insidiously and may be present for many years before overt thyrotoxicosis occurs. These nodules
function independent of TSH stimulation, and therefore should not be treated with thyroid
hormone in an attempt to suppress the tissue. Autonomously functioning tissue may be treated
with surgery, radioablative therapy, or intranodular ethanol injection. Surgical resection is used
frequently at some centers due to concerns about possible side effects of radioactive iodine
therapy, availability of tissue to rule out malignancy, and the little time required to achieve a
euthyroid state. Intranodular ethanol injection is a relatively new technique that has been used
effectively in several European centers with significant shrinkage of the nodule achieved, and
with moderate control of hyperthyroidism. The technique has been associated with transient
vocal cord paralysis, exacerbation of hyperthyroidism, and persistent subclinical
hyperthyroidism in a significant number of cases.4 No long term follow up relating to the
efficacy of this technique is currently available.
The management of the clinically euthyroid patient with a hot nodule is also controversial. In a
clinically euthyroid patient with a hot nodule less than 2.5 cm in diameter, observation is
reasonable. In patients with hot nodules greater than 2.5 cm in diameter with or without toxicity,
the presence of increased risks for osteoporosis or cardiovascular disease, and in an elderly
patient, definitive therapy with surgery or 131I radioablation is appropriate.18 Patients with
nontoxic hot nodules can be followed clinically. Serial exams and thyroid function testing should
be performed at regular intervals to ensure that the patient, particularly the elderly who often
have less symptoms than younger patients, are not thyrotoxic.18

OCCULT NODULAR THYROID DISEASE

As implied previously, clinical examination of the thyroid by palpation is relatively insensitive in
terms of identifying nodular thyroid disease. Mortensen, in an autopsy series in the 1950’s,
reported that one or more thyroid nodules were detected in 50% of patients whose glands
appeared clinically normal. In as recent publication by Ezzat et al, palpable nodules were
identified in 21% of his "normal" patient population (9% single/solitary, and 12% multiple
nodules). In contrast, 67% of these patients had one or more clinically unappreciated nodules by
ultrasonography (22% solitary, 45% multiple).9
Occult lesions of the thyroid, defined as impalpable nodules usually smaller than 2.0 cm, are a
management dilemma for physicians. Occult papillary thyroid cancers less than 1cm are
frequently found at autopsy and in surgical specimens. These tiny papillary cancers apparently
have, and are suspected of having, little clinical relevance as they are never manifest during
life.14
The incidental ultrasonographic finding of a nodule should not automatically require further
investigation. This is impractical, and there is no data on the malignant potential of such nodules.
For lesions less than 2.0 cm, a negative family history of thyroid carcinoma, and no history of
head or neck irradiation, observation of the nodule is reasonable. For nodules greater than 2.0
cm, a positive family history, presence of other risk factors suggestive of malignancy, or
ultrasongraphic characteristics suggestive of malignancy, further diagnostic evaluation with
biopsy (ultrasound guided if necessary) is warranted. Malignant or suspicious cytodiagnostic
findings should be managed surgically as noted previously.9

MULTINODULAR GOITERS
Multinodular goiters have different nodule sizes and variable radionuclide uptake, producing
irregular contour and multiple nodules that appear hotter or colder than the remainder of the
gland. Multinodular goiters are common in iodine deficient areas, but may also occur in iodine
rich areas. The rate of nodular growth is usually slow, but varies from person to person and
nodule to nodule, as some nodules are more sensitive to TSH and other growth factors.18 With
regards to the risk for malignancy, Belfiore and associates studied a group of 4,485 patients with
solitary thyroid nodules along with a group of 1,152 patients with multiple nodules and
demonstrated that the cancer rate was similar (approximately 4%) between the two groups.1 The
general, and currently accepted theory, is that multinodular goiters have a lower malignancy
potential. This new information may contradict that long-standing belief, and all patients with
thyroid masses must be considered for possible malignancy, especially when a dominant nodule
is noted. Further study in this area is warranted. Again, patients with risk factors for cancer must
be considered for possible malignancy, regardless of the type of nodule or goiter with which they
present.

GRAVES’ DISEASE
Patients with Graves’ disease who are shown by thyroid scintiscanning to harbor a cold or
hypofunctional nodule in a diffusely enlarged thyroid gland carry an increased likelihood of
malignancy, which has previously been demonstrated to be more aggressive than that found in
euthyroid patients. Surgical referral for near total thyroidectomy is recommended.22

Thyroid Hormone Suppressive Therapy

Long term levothyroxine suppression therapy to arrest growth or shrink thyroid nodules is a
practice that remains controversial. The use of thyroid hormone suppression is based upon the
belief that nodule growth is TSH dependent.4,9 There is no well documented correlation between
response to therapy and variables such as age, duration of nodule presence, size, or nodule type.9
In the past 30 years, there have been more than 20 studies examining the efficacy of thyroid
hormone suppressive therapy on thyroid nodules. Early studies were generally uncontrolled
analyses flawed by an inability to document adequate TSH suppression or document nodule
change accurately.4
In the past 10 years, nine studies have been performed to evaluate this issue further including
five randomized trials and four uncontrolled analyses. These more recent studies benefit from the
use of improved TSH assays to verify adequate suppression, FNAB to exclude malignant or
suspicious lesions, and high resolution ultrasound for accurate nodule sizing.4
The four nonrandomized trials of suppressive therapy for thyroid nodules included a total of 637
patients; 431 of these patients had previously received radiation to the head and neck. Three
studies of nonirradiated patients, utilizing second or third generation TSH assays and high
resolution ultrasound to assess nodule volume change, demonstrated response rates of 34-56%.
The basic fault of these studies is a failure to distinguish spontaneous regression from therapeutic
response. In randomized, placebo controlled trials, rates of spontaneous regression have ranged
from 1-35%.4
The five randomized trails performed include a total of 159 patients receiving thyroid hormone
and 157 untreated patients. Utilizing sensitive TSH assays and high resolution ultrasound, only a
single study found mean nodule volume to decrease in treated patients compared to untreated
controls. However, two of the four studies, with available individual patient data, demonstrated a
subgroup of patients deemed thyroxine responsive --26% of treated patients experienced
significant nodule regression compared to 15% of untreated control patients.4
In a recent randomized controlled study by La Rosa, thyroid hormone suppression therapy was
demonstrated to be effective in reducing nodular volume in 39% of treated patients compared to
0% of untreated patients. Moreover, following discontinuation of therapy, 25% of patients
previously treated with thyroid hormone demonstrated clinically significant increases in nodule
volume. In patients previously untreated who then received thyroxine, nodule volume was
subsequently shown to decrease.12

Side Effects of Thyroid Suppression Therapy

EFFECTS ON CARDIAC FUNCTION
The cardiac effects of overt hyperthyroidism have been described in detail and may be grouped
into three basic categories: (1) direct effects on cardiac myocyte protein synthesis, size and
intracellular calcium handling; (2) effects on peripheral hemodynamics and oxygen utilization;
and (3) sympathoadrenal effects. The clinical correlates of these effects include an acceleration
of the pulse rate, an increase in systolic blood pressure, an increase in the stroke volume and
cardiac output, a decrease in the systemic vascular resistance, an increase in cardiac muscle
mass, and a tendency toward atrial dysrhythmia. Correction of overt thyrotoxicosis results in a
normalization of these effects4.
Several recent studies have extended these observations to patients with subclinical
hyperthyroidism, defined as a suppression of TSH due to an increase in serum thyroid hormone
levels within the confines of the normal range4.
The most detailed work to date in this area has evaluated the effects of subclinical
hyperthyroidism on cardiac mass and chamber size, systolic time intervals, resting pulse rate,
arrhythmia, and symptom rating scale, as well as an assessment of the effects of beta adrenergic
blockade on each of these parameters. Patients undergoing thyroid hormone suppressive therapy
at doses sufficient to suppress serum TSH levels had a significant elevation in resting pulse, an
enhanced rate of atrial dysrhythmia, an increased interventricular septal and posterior wall
thickness, increased left ventricular mass, and an enhancement in indices of systolic function
when compared with age and sex matched controls. A similar group of patients undergoing
thyroid suppression therapy experienced improvements in a hyperthyroid symptom rating scale,
decreases in heart rate and incidence of atrial dysrhythmia, and a return of cardiac muscle mass
to normal values when given a 6 month course of beta blockers in addition to thyroid hormone.
These studies suggest that a wide spectrum of cardiac abnormalities may be present in patients
undergoing thyroid hormone suppressive therapy, and suggest a means of alleviating these
effects (i.e. beta blockers) in patients in whom suppressive therapy is mandated by clinical
circumstances4.
Atrial fibrillation is a well recognized complication of overt hyperthyroidism. The clinical
significance of atrial fibrillation is evidenced by the dire consequences of this arrhythmia, such
as congestive heart failure, systemic embolism, and stroke. Occult thyrotoxicosis was found in
13 of 75 consecutive patients presenting with atrial fibrillation and no identifiable cardiac cause4.

EFFECT ON BONE MINERAL DENSITY

Thyroid hormone is known to enhance osteoclastic bone reabsorption, an effect that appears to
be mediated indirectly through effects of T3 upon osteoblasts, which induce osteoclastic activity.
Studies involving skeletal effects of exogenous thyroid hormone and subclinical hyperthyroidism
in premenopausal women have yielded varying results, with either no difference from control
subjects, or diminished bone density in the hip, forearm, and lumbar spine. A recent meta
analysis involving premenopausal women, including 441 measurements of bone density in 239
patients from nine separate studies, led to a composite premenopausal woman, 39.6 years of age,
taking 164 mcg/d of levothyroxine for 8.5 years and with a theoretical bone structure consisting
of 30% distal forearm, 29% femoral neck, and 41% lumbar spine. This composite woman would
be expected to experience an excess bone mass loss of 2.7% over 8.5 years, not significantly
different from that in control subjects4.
The data are somewhat more incriminating in studies involving postmenopausal women,
although no well designed, long term, prospective studies have been performed to date. Several
studies have found significantly lower bone density in the hip, spine, and forearm in
postmenopausal women with subclinical hyperthyroidism or taking thyroid hormone when
compared with control subjects. A meta analysis involving postmenopausal women including
317 bone density measurements in 149 patients comprising eight different studies gave a
composite patient 61.2 years of age, treated with 171 mcg/d of levothyroxine for 9.9 years and
with a bone structure consisting of 42% femoral neck, 47% lumbar spine, and 11% distal
forearm. This aggregate patient would be expected to experience a significant excess bone loss
totaling 9% over 9.9 years of thyroid hormone therapy. Another study noted that women taking
estrogen, in addition to thyroid hormone therapy, experience less bone loss than those taking
thyroid hormone alone. It is likely that a spectrum of bone pathology occurs depending on the
degree and duration of subclinical thyrotoxicosis as well as the presence of other known risk
factors for osteoporosis4.

Recommendations Regarding Thyroid Hormone Suppressive Therapy

Given that the majority of patients with thyroid nodules do not experience nodule shrinkage with
suppressive therapy and in light of rising concern over the potential adverse effects associated
with subclinical hyperthyroidism, it is difficult to recommend the indiscriminate utilization of
thyroid hormone suppressive therapy in all patients with benign thyroid nodules.4
For those patients in whom thyroid hormone suppressive therapy is deemed appropriate and
attempted, a limited trial of suppressive therapy with careful follow up evaluation of nodule size
by high resolution ultrasonography and assessment of TSH is reasonable. A TSH level of
0.1mIU/L - 0.3 mIU/L should be the goal of therapy, as there has been little data demonstrating
increased suppression of thyroid nodules at lower levels.4
In postmenopausal women and in patients with a history of cardiac disease, many authors would
argue instituting therapy only if the nodule enlarges during a 6-12 month period of observation.
In postmenopausal women and premenopausal women at significant risk of osteoporosis,
suppressive therapy should be accompanied by bisphosphonate or estrogen therapy, or both.9
Apparent responders to thyroid hormone suppressive therapy should be followed closely and
therapy discontinued after the trial of suppression therapy to distinguish spontaneous regression
from therapeutic effect. Therapy is reinstituted in those patients whose nodules regrow following
discontinuation of therapy.9
If the nodule fails to shrink, the medication should be discontinued. Conversely, if the nodule
enlarges during therapy, repeat FNAB or surgery is advised.17

CONCLUSION
A tremendous effort by a number of authors has been put forth to elucidate the most efficient,
cost effective, and accurate method of evaluating and managing nodular thyroid disease. The
overwhelming volume of literature concerning this topic can easily confuse the clinician who is
faced with a patient demonstrating a thyroid nodule. One of the most important points to
remember when choosing the best method of evaluating a patient with a thyroid nodule is that
the clinical situation, assessment of risk for malignancy, and available resources must be taken
into account.
Thyroid nodules are extremely common and frequently benign. For the most accurate diagnostic
approach, fine needle aspiration biopsy should be employed. Alternative imaging techniques,
such as nuclear thyroid scanning and ultrasonography have limited clinical utility and are highly
unreliable for differentiating benign from malignant disease.
Nodules with a malignant and suspicious cytodiagnosis of FNAB should be managed with
referral to an experienced endocrine surgeon for thyroidectomy. Malignant nodules should be
managed with near total thyroidectomy, and suspicious nodules should be treated with lobectomy
with frozen section analysis to determine if further excision is required. Benign nodules on
cytology can be safely managed with observation. Nondiagnostic cytology should result in repeat
aspiration and appropriate treatment when diagnostic cytology is obtained. The nodule which
retains a nondiagnostic cytology should be excised.
Thyroid hormone suppression therapy has become a highly controversial issue in recent years,
and has been associated with adverse effects on both the cardiac and skeletal systems. The use of
levothyroxine suppression therapy should be undertaken with caution and must be closely
monitored.
ACKNOWLEDGEMENTS
I am deeply grateful to Drs. K. Patrick Ober, and William T. Cefalu for their review and
criticisms of this manuscript, and my wife, Alicia, who reviewed the manuscript on numerous
occasions, as well as tolerated and supported me during the stressful preparation of the
manuscript and presentation.

BIBLIOGRAPHY
1. Belfiore, A., et al. The Management oof Thyroid Nodules. Journal of Endocrinologic
Investigation. 1995; 18: 155-58.
2. Belfiore, Antonio, et al. Cancer Risk Prevalence in Patients with Cold Thyroid Nodules :
Relevance of Iodine Intake, Sex, Age, and Multinodularity. American Journal of Medicine.
Oct 1992; 93: 363-69.
3. Blum, Manfred. Why Do Clinicians Continue to Debate the Use of Levothyroxine in the
Diagnosis and Management of Thyroid Nodules. Annals of Internal Medicine. Jan 1, 1995;
122(1): 63-4.
4. Burch, Henry B. Evaluation and Management of the Solid Thyroid Nodule.
Endocrinology and Metabolism Clinics of North America. Dec 1995; 24(4): 663-710.
5. Dwarakanthan, Arcot A. Evaluation of Thyroid Nodules. Comprehensive Therapy. 1993;
19(5): 220-24.
6. Gharib, Hossein, and Goellner, John R. Fine Needle Aspiration Biopsy of the Thyroid: An
Appraisal. Annals of Internal Medicine. 1993; 118: 282-89.
7. Gharib, Hossein. A Strategy for the Solitary Thyroid Nodule. Hospital Practice. Sept
30,1992; : 53-60.
8. Gharib, Hossein. Subspecialty Clinics : Endocrinology/Metabolism. Fine Needle
Aspiration Biopsy of Thyroid Nodules : Advantages Limitations, and Effect. Mayo Clinic
Proceedings. Jan 1994; 69: 44-49.
9. Giuffrida, Dario, and Gharib, Hossein. Controversies in the Management of Cold, Hot, and
Occult Thyroid Nodules. American Journal of Medicine. Dec 1995; 99: 642-50.
10. Gupta, Krishan L. Neoplasm of the Thyroid Gland. Clinics in Geriatric Medicine. May
1995; 11(2): 271-290.
11. Hamburger, Joel I. Extensive Personal Experience. Diagnosis of Thyroid Nodules by Fine
Needle Biopsy : Use and Abuse. Journal of Clinical Endocrinology / Metabolism. 1994;
79(2): 335-39.
12. La Rosa, Giacomo L., et al. Levothyroxine and Potassium Iodide Are Both Effective in
Treating Benign Solitary Cold Nodules of the Thyroid. Annals of Internal Medicine. Jan 1,
1995; 122(1): 1-8.
13. Mazzaferri, Ernest L. Management of a Solitary Thyroid Nodule. Current Concepts.
Feb 25,1993; 328(8): 553-59.
14. Mazzaferri, Ernest L. Thyroid Cancer in Thyroid Nodules : Finding a Needle in a
Haystack. American Journal of Medicine. Oct 1992; 93: 359-62.
15. Molitch, Mark E. et al. The Cold Thyroid Nodule: An Analysis of Diagnostic and
Therapeutic Options. Endocrine Reviews. 1984; 5(2): 185-199.
16. Reverter, J.L., et al. Suppressive Therapy with Levothyroxine for Solitary Thyroid
Nodules. Clinical Endocrinology. 1992; 36: 25-28.
17. Rifat, Sami F., and Ruffin Mack T. Management of Thyroid Nodules. American Family
Physician. Sept 15, 1994; 50(4): 785-90.
18. Rolla, Arturo R. Thyroid Nodules in the Elderly. Clinics in Geriatric Medicine. May
1995. 11(2): 259-69.
19. Ross, Douglas S. Evaluation of the Thyroid Nodule. Journal of Nuclear Medicine.
1991; 326: 2181-2192.
20. Sheppard, M.C., and Franklyn, J.A. Management of the Single Thyroid Nodule. Clincial
Endocrinology. 1992; 37: 398-401.
21. Whitman, Eric D., and Norton Jeffrey A. Endocrine Surgical Diseases of Elderly Patients.
Surgical Clinics of North America. Feb 1994; 74(1): 127-144.
22. Woeber, Kenneth. Cost Effective Evaluation of the Patient with a Thyroid Nodule.
Endocrine Surgery. June 1995; 75(3): 357-363.