ANZ J. Surg. 2006; 76: 381–386 doi: 10.1111/j.1445-2197.2006.03727.

CONTINUING MEDICAL EDUCATION

SOLITARY THYROID NODULE: CURRENT MANAGEMENT

LEIGH DELBRIDGE
University of Sydney, Endocrine Surgical Unit, Department of Surgery, Royal North Shore Hospital,
Sydney, New South Wales, Australia

Clinically, solitary thyroid nodules are common, being present in up to 50% of the elderly population. The majority are benign with
thyroid cancer representing an uncommon clinical problem. Investigation should include careful history and examination and thyroid
function tests. Toxic or autonomous nodules are rarely malignant and require radionuclide scan for assessment. If euthyroid, then fine
needle biopsy provides direct specific information about the cytology of the nodule from which the histology can be inferred. Thyroid
‘incidentalomas’ are a common management problem. Non-palpable nodules greater than 1.0 to 1.5 cm represent an absolute
indication to perform an ultrasound-guided fine needle biopsy. An atypical fine needle biopsy mandates formal diagnostic excision.
Because it is not possible to distinguish a follicular carcinoma from a follicular adenoma on cytological grounds alone, this category
must simply be interpreted as indicating a follicular tumour and up to 20% will be malignant. Hemithyroidectomy via a ‘collar’
incision, with submission of the specimen to formal pathological examination, remains the standard of care, with completion total
thyroidectomy for cancers other than low risk papillary cancer and ‘minimally invasive’ follicular cancer without vascular invasion.
The issue of whether follicular adenomas can potentially develop into follicular carcinomas has yet to be satisfactorily resolved. The
major challenge in the management of the solitary thyroid nodule remains the assessment as to which nodules require surgical
excision and which can be followed conservatively.

Key words: thyroid nodule, thyroid cancer, thyroidectomy.

INTRODUCTION ule is the same as in a true solitary nodule, and so the approaches
to investigation and management are identical.4 Less common
Thyroid nodules are common, being found in up to 7% of the
benign causes of solitary thyroid nodules are rare disorders such
adult population on clinical palpation.1 These are even more com-
as the solitary fibrous tumour (thyroid fibroma) or the hyalinizing
mon if ultrasound is used as a screening tool, being present in
trabecular tumour or non-thyroidal conditions such as an intra-
more than 50% of the elderly population.2 Of those, the majority
thyroidal dermoid cyst.
are benign, with thyroid cancer representing an uncommon clin-
The most recent 2004 World Health Organization (WHO) clas-
ical problem. As such, one of the biggest challenges in the man-
sification of thyroid cancer retains its traditional separation into
agement of the solitary thyroid nodule is the assessment as to
the four major groups of papillary, follicular, undifferentiated
which nodules require surgical excision and which can be fol-
(anaplastic) and medullary carcinoma based on morphology and
lowed conservatively.
clinical features, no longer grouping the papillary and follicular
together as ‘differentiated thyroid carcinoma’.5 This classification
PATHOLOGY is strongly supported by advances in molecular studies showing
the involvement of distinct genes in these four groups with little
Solitary thyroid nodules are most commonly because of benign
overlap. However, some areas require further clarification. For
conditions such as a colloid nodules, simple thyroid cysts or thy-
example, the follicular variant of papillary thyroid carcinoma
roiditis (in 80% of cases), with benign follicular adenomas com-
shares oncogene changes with follicular tumours whereas Hurthle
prising 10–15% and thyroid cancers only 5%.3 In fact, the
cell (oncocytic) cancers show genetic similarities to papillary
commonest apparent solitary thyroid nodule seen in clinical prac-
cancer.5
tice, at least in an Australian context, is actually a dominant col-
Thyroid cancer is exceedingly rare as a clinical problem in the
loid nodule in a multinodular goitre, where the nodular change in
community overall, representing less than 0.6% of all cancers in
the remainder of the gland is subclinical, that is, not palpable.
men and 2.5% of cancers in women in New South Wales (NSW)
From the practical point of view, that is not an issue as the inci-
in 2002 although, interestingly, the NSW Cancer Council data
dence of malignancy in such a clinically apparent dominant nod-
shows it to be one of the most rapidly increasing cancers in
L. Delbridge MD FRACS. women with crude incidence rates having risen from 2 per
100 000 in 1972 to 10.6 per 100 000 in 2002.6 Death from thyroid
Correspondence: Dr Leigh Delbridge, Department of Endocrine and cancer is even rarer, representing only 0.2% of all male cancer
Oncology Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, deaths and 0.5% of all female cancer deaths.6 Because benign
Australia.
Email: leighd@med.usyd.edu.au
thyroid nodules are, on the other hand, exceedingly common,
one of the biggest challenges in the management of the solitary
Accepted for publication 26 November 2005. thyroid nodule is the assessment as to which of the nodules
Ó 2006 Royal Australasian College of Surgeons
382
require surgical excision and which of them (the majority) can be
followed conservatively.
INDICATIONS FOR SURGERY
Tables 1 and 2 show the experience of our unit over a 10-year
period from January 1995 to January 2005 and details the indica-
tions for surgical excision of clinically solitary thyroid nodules.
Surgery for clinically solitary thyroid nodules is carried out most
commonly as a diagnostic procedure because of the risk of malig-
nancy. Generally, this follows a fine-needle biopsy (FNB) of the
nodule that has reported either the presence of cancer cells or else
an atypical pattern suspicious of either a benign or a malignant
follicular thyroid tumour. It may also be indicated because of the
clinically suspicious features of the nodule, such as those of being
very hard or fixed, or being associated with enlarged lymph
nodes. The next most common indication for surgery is the pres-
ence of local obstructive symptoms associated with a large nod-
ule. These include a sensation of pressure, choking or a cough due
to impingement on the trachea, difficulty with swallowing due to
pressure on the oesophagus, a hoarse voice due to compression of
the recurrent laryngeal nerves, fullness of the face especially with
the arms above the head due to pressure on the internal jugular
veins (Pemberton’s sign). Other indications for surgery include
thyrotoxicosis, retrosternal extension of the nodule, a history of
having received excessive radiation as a child or a family history
of thyroid cancer. Excision of thyroid nodules is also commonly
undertaken in association with surgery for hyperparathyroidism.
INVESTIGATIONS
A flow chart for the management of a clinically solitary thyroid
nodule is shown in Figure 1. A detailed history and clinical exam-
ination remains the key to the initial assessment of the solitary
thyroid nodule. Specific issues that need to be raised in the history
include the presence of symptoms (often unsuspected), a history
of previous radiation exposure and a family history of thyroid
cancer, as these may well increase the likelihood of referral for
surgery. A good example is in children exposed to previous ther-
apeutic scatter irradiation for the management of childhood
malignancy such as leukaemia. In these patients, the presence
of thyroid nodules detected clinically should lead to early discus-
sion of total thyroidectomy as an alternative to serial FNB because
of the significantly higher risk of malignancy.7 Clinical examina-
tion should aim to assess both the specific features of the nodule,
as well as the presence of any abnormal cervical lymph nodes,
although many thyroid cancers are smooth and not particularly
hard and some benign nodules can be hard because of calcifica-
tions.1 However, any nodule that is very hard or irregular, is fixed
to adjacent structures, is growing rapidly or is associated with
lymphadenopathy should be removed.
Table 1. Indications for surgery for all thyroid procedures carried
out over 10 years from January 1995 to January 2005 (n = 4608)
Clinical presentation n (%)
Multinodular goitre 1913 (42)
Clinically solitary nodules 1180 (26)
Incidental during parathyroidectomy 883 (19)
Graves’ disease 391 (8)
Other 241 (5)
DELBRIDGE
The initial investigation required in all patients with a clinical
solitary nodule is a biochemical assessment of thyroid function, as
clinical assessment alone is not a good discriminator of thyroid
dysfunction.8 If the patient is euthyroid then subsequent FNB,
a technique, which has been established for several decades, is
now accepted as the most accurate assessment of the likelihood of
malignancy.9 A suppressed level of serum thyroid stimulating
hormone, on the other hand, will alert the clinician to the possi-
bility that the clinically solitary nodule may be an autonomous of
toxic thyroid nodule.2 Alternatively, it may also be part of a toxic
multinodular goitre or a single nodule in a patient with Graves’
disease. FNB should not be carried out as an ‘atypical’ biopsy
may be reported because of the hypercellularity that is commonly
associated with autonomously functioning nodules and a radionu-
clide scan is the preferred initial investigation.
Apart from the circumstance so described, as part of the routine
investigation of the solitary nodule, thyroid imaging with radio-
nuclide scanning has no role to play. Although this imaging tech-
nique may provide information about underlying structural changes
in the thyroid gland, and whether the nodule is ‘hot’ or ‘cold’, these
results do not, by themselves, lead to any alteration in clinical
management. The incidence of malignancy in ‘cold’ nodules has
been reported to be 16%, compared to 9% in ‘warm’ nodules and
4% in ‘hot’ nodules.10 As such, the scan characteristics of nodules
are not informative enough to enable informed clinical decision-
making. Likewise, the finding of additional nodules on radionu-
clide scanning that are not clinically apparent does not alter the
risk of cancer in a clinically palpable nodule.3
The routine use of ultrasound becomes more controversial,
with some authors claiming that ultrasound significantly alters
the management of the majority of patients attending a thyroid
clinic.11 As noted, the chance finding of further clinical nodules
by any imaging technique does not alter management decisions,
and information as to whether a nodule is cystic or solid on ultra-
sound will be provided equally well by FNB. For that reason, it is
our unit policy not to use ultrasound other than as a tool to assist
FNB.
Fine-needle biopsy provides direct specific information about
the cytology of a clinical solitary nodule, from which the hist-
ology can generally be inferred. It can be carried out in the office
with direct palpation used to guide needle placement or, more
often nowadays, with ultrasound guidance. The use of the ultra-
sound decreases false negatives due to the misplacement of the
needle and increases the rate of successful diagnostic aspirates.12
It also increases the diagnostic accuracy in cystic lesions by
allowing sampling of the solid component. There is now increasing
Table 2. Indications for surgery in clinically solitary nodules (n =
1180) together with the incidence of cancer on final pathology
Indications for surgery n (%)
Incidence of cancer
Obstructive symptoms 199 (17)
Toxic/autonomous single nodule 79 (7)
Substernal single nodule 11 (1)
Other indications 92 (8)
Risk of malignancy 799 (67)
Cancers where indication was ‘risk of malignancy’ 243 (21)
Papillary cancer 175 (15)
Follicular cancer 49 (4)
Medullary cancer 12 (1)
Anaplastic/lymphoma/other 7 (1)
Ó 2006 Royal Australasian College of Surgeons
SOLITARY THYROID NODULE
Fig. 1. Management of the solitary thy-
roid nodule. FNB, fine-needle biopsy.
Clinical indication
Definitive
surgery
Malignant
Definitive
surgery
support for the view that thyroid cervical ultrasound is best
carried out by clinicians, including surgeons, and that more
clinicians should master and use this technology for diagnostic
purposes.13 Although cervical endocrine ultrasound is accurate
in the hands of a dedicated radiologist, when a surgeon carries
out an ultrasound, he or she can use it as an extension of their
physical examination.14 Endocrinologists and endocrine sur-
geons worldwide are now being encouraged and trained to adopt
this technology. For example, the Section of Endocrine Surgeons
Royal Australian College of Surgeons conducted a course on
ultrasound for surgeons at the 2004 Annual Scientific Congress
in Melbourne, and the American Association of Clinical Endocri-
nology conducts regular thyroid ultrasound and fine-needle aspi-
ration biopsy (FNAB) accreditation courses, which have become
a mandatory component of training for clinical endocrinolo-
gists.15 Table 3 outlines the accepted categories of cytological
reports from thyroid FNB as well as recommended management.
The reported incidence for each category is as follows: unsatis-
factory, 15%; benign, 65%; atypical, 15%; malignant, 5%.16 The
importance of the ‘atypical’ (‘atypical follicular pattern’, ‘suspi-
cious’ or ‘consistent with follicular neoplasm’) reports need to be
emphasized. There is no test that can currently differentiate fol-
licular thyroid carcinoma from a benign follicular adenoma, as the
diagnosis of malignancy rests upon the demonstration of follicular
cells outside the capsule or within blood vessels. Because it is not
possible to distinguish a follicular carcinoma from a follicular
adenoma on cytological grounds alone, this category must simply
be interpreted as indicating a follicular tumour, either benign or
malignant, requiring a formal diagnostic excision biopsy, as up to
20% will be malignant.9 Some authors claim that subsequent
radionuclide scanning of ‘atypical’ nodules can reduce the need
for surgery by showing a functioning (or autonomous) nodule.
However, if thyroid function tests had actually been carried out
before FNB, then most autonomous nodules would probably have
already been diagnosed.17 An inadequate biopsy needs to be
repeated. If the FNB remains non-diagnostic, then excision biopsy
should be carried out. This is especially true for large cystic
Ó 2006 Royal Australasian College of Surgeons
383
Thyroid nodule
History and examination
Thyroid function tests Toxic or autonomous
Normal Radionuclide scan
FNB Radioiodine/medication
or curative surgery
Atypical Benign Inadequate
Repeat FNB
Benign Inadequate
Diagnostic Follow up with Diagnostic
surgery repeat FNB or surgery
diagnostic
surgery if grows
lesions, as these may be degenerate cystic papillary carcinomas.
Although there are a number of published criteria that help cytol-
ogists to differentiate between cystic papillary carcinomas and
benign cysts, ultrasound-guided FNAB of cystic lesions has an
accuracy of only approximately 80%.18 Because the malignancy
rate is not negligible and no clinical parameter can reliably predict
it,19 persistent cystic lesions with non-diagnostic cytology should
be excised.20
Benign colloid nodules may be treated conservatively, although
this implies long-term clinical follow up. Although some argue
that the follow up of nodules that are benign on FNB is of limited
usefulness and is not cost-effective,21 the American Thyroid
Association has published guidelines for the management of thy-
roid nodules, which state that ‘patients with thyroid nodules in
whom malignancy has been excluded or determined to be improb-
able require long-term periodic clinical observation’.1 The sub-
sequent appearance of cancer after a false-negative FNB with
a benign report is most often associated with a progressive growth
of the nodule, so that any nodule that continues to increase in size
should either have a repeat biopsy or undergo surgical excision.
Thyroid ‘incidentalomas’ are a common management problem.
Non-palpable nodules that greater than 1.0–1.5 cm are an abso-
lute indication to carry out an ultrasound-guided FNB because
this is the size limit for dividing thyroid nodules into probably
innocuous or potentially dangerous categories and because the
cytological diagnosis of nodules of this size is sufficiently reli-
able.22 For smaller, incidentally discovered thyroid nodules fol-
lowing ultrasound, individual discussion with patients in relation
to the risk of malignancy and the options for follow up should
guide any decision about the need for FNB.
SURGICAL MANAGEMENT
For those patients requiring surgical excision of a solitary thyroid
nodule, hemithyroidectomy by a ‘collar’ incision, with submission
of the specimen to formal pathological examination, remains the
384
Table 3. Fine-needle biopsy (FNB) report categories
Category Cytological features
Inadequate Insufficient epithelial cells for diagnosis
Benign (benign follicular pattern) Abundant colloid with benign follicular cells
Atypical Minimal colloid, follicular cells in microfollicular
(suspicious, follicular neoplasm, pattern or cellular atypia
atypical follicular pattern)
Malignant Features specific to the type of malignancy
(papillary, anaplastic, medullary, lymphoma)
Thyroiditis Inflammatory cells
standard of care. The technique of hemithyroidectomy should be
identical to that of total thyroidectomy, confined to one side only,
with need for the same careful attention to the use of capsular
dissection, routine identification of the external branch of the supe-
rior laryngeal nerve ‘encountering’ the recurrent laryngeal nerve,
paying of attention to the anatomical vagaries of the tubercle of
Zuckerkandl (a small prominence arising from the posterolateral
surface of the thyroid) and ready autotransplantation of apparently
non-viable parathyroid glands.23 It is not acceptable to pay less
attention to the parathyroid glands, simply because the procedure
is unilateral, as contralateral surgery may be required at some future
time. Hemithyroidectomy should be able to be carried out as an
overnight or a 23-h procedure and should be associated with a per-
manent complication rate of less than 1%.
If the specimen removed is a benign solitary thyroid nodule, then
no further treatment is required. The risk of developing overt hypo-
thyroidism following hemithyroidectomy is approximately 12%,
although subclinical hypothyroidism may develop in up to 35%,
especially when there is any underlying thyroiditis.24 Even if the final
pathology indicates underlying subclinical multinodular change, the
risk of recurrent disease in the contralateral lobe is low (12.5%) in the
absence of clinically apparent contralateral nodules.25
If thyroid cancer is diagnosed in the final pathology, then fur-
ther surgery in the form of a completion thyroidectomy may be
required, although a number of low-risk thyroid cancers can be
safely managed with hemithyroidectomy alone. Frozen section
now has virtually no role in intraoperative decision-making as
most clinically significant papillary thyroid cancers will have
already been diagnosed on FNB, most incidentally discovered
papillary microcarcinomas will fall into a low-risk category, and
minimally invasive follicular carcinoma can virtually never be
diagnosed on frozen section alone.26 Follicular thyroid cancer is
classified as minimally invasive or widely invasive.27 Minimally
invasive follicular cancer with capsular invasion only does not
require completion thyroidectomy or radioiodine ablation
because of its excellent prognosis.28 The presence of vascular
invasion, however, increases the risk of metastatic disease signif-
icantly and, in some schemes, the term ‘minimally invasive car-
cinoma’ is now confined to tumours showing only capsular
invasion, with those showing vascular invasion being termed
‘angioinvasive follicular carcinoma’.27 Virtually, the only indica-
tion for completion thyroidectomy following previous hemithyr-
oidectomy therefore is for a widely invasive follicular carcinoma
that was not suspected preoperatively, a ‘minimally invasive’ fol-
licular cancer with angioinvasion, or a high-risk papillary cancer
that failed to be diagnosed on preoperative FNB.29 The issue of
the management of Hurthle cell cancers remains an area of con-
troversy with some regarding them as a separate entity, given their
genetic basis, the reduced uptake of radioiodine and propensity
for lymph node involvement. Nonetheless, the current WHO clas-
DELBRIDGE
Management
Repeat FNB
Conservative
Diagnostic surgery
Definitive surgery
Conservative management
sification still considers them to be a variant of follicular cancer,
and so the approach to treatment should be the same.5
FUTURE DIRECTIONS
A great deal of research effort has been expended in attempting to
differentiate benign from malignant follicular thyroid tumours, on
the assumption that only 20% of ‘atypical’ nodules will eventu-
ally turn out to be cancer and therefore that the remaining 80% of
surgery is ‘unnecessary’. Unfortunately, there has been no real
advance in research since the introduction of FNAB several dec-
ades ago, and the distinction between benign and malignant fol-
licular neoplasms still remains the bane of the thyroid cytologist.30
A number of cytological and nuclear features characteristic of
malignancy have been reported, for example, staining with anti-
bodies to thyroperoxidase.31 However, whereas many of these
features have been shown to be more commonly associated with
follicular thyroid cancers than with follicular adenomas, none has
achieved a level of specificity sufficient to allow conservative
management of follicular nodules yet. Magnetic research spec-
troscopy (MRS) showed initial promise with in vitro studies, but
has yet to find a clinical application.32 A number of promising
single genetic markers of thyroid cancer have also been reported
including PAX8-PPARgamma, Galectin-3, hTERT and MET, but
none is sufficiently sensitive enough to act as a screening test
without the significant risk of missing a cancer.33 One of the more
promising techniques recently reported is gene expression pro-
filing. A recent study has shown the ability to discriminate
between benign and malignant thyroid nodules with a sensitivity
of 91% and a specificity of 96%.33 The same techniques have also
been able to differentiate between benign neoplastic follicular
lesions (follicular adenoma) and hyperplastic follicular lesions
(hyperplastic nodules), thus distinguishing between nodules with
malignant potential.34 Although this appears to be a powerful tool,
more studies are clearly required before it is likely to enter clinical
practice. The major issue with gene profiling will be the sensitiv-
ity of the test if it is to be used to avoid surgery on neoplastic
thyroid nodules that do not have true ‘malignant potential’.
An alternative approach to the definitive diagnosis of follicular
lesions is that of minimal access thyroid surgery (MATS). A
number of techniques for MATS have now been described includ-
ing various endoscopic approaches,35 video-assisted approaches36
and minimal incision lateral focused techniques.37,38 Whereas
most descriptions of minimal access techniques still emphasize
the role of a complete lobectomy as the minimum procedure, the
issue of nodule excision with a margin of surrounding thyroid
tissue by a minimal approach for the purposes of diagnosis,
although controversial, is now the subject of discussion and it
may well find a (somewhat limited), place in the endocrine
surgeon’s armamentarium in the future. The advantage of such
Ó 2006 Royal Australasian College of Surgeons
SOLITARY THYROID NODULE
a surgical approach is that it provides a diagnostic excision
biopsy, with complete removal of the lesion, without the require-
ment for a formal ‘collar’ thyroidectomy scar. Although MATS
should still be regarded as a developing technique that should be
confined to formal research studies, it may well play a very useful
role in the diagnosis of small solitary atypical thyroid nodules,
obviating the need for potentially expensive tests such as MRS or
gene profiling, or for long-term follow up.1
The other advantage of surgical excision is that the potential for
future malignant change is removed, whereas all other diagnostic
techniques still require lifelong evaluation. However, the issue of
whether follicular adenomas can potentially develop into follicu-
lar carcinomas has yet to be satisfactorily resolved. A proposed
multistep model for thyroid tumourigenesis was first proposed by
Fagin in 1992.39 A number of modifications to the model have
since been proposed40 with separate pathways for papillary can-
cer, follicular cancer and Hurthle cell cancers. However, not all
studies support the concept of evolution from benign follicular
adenoma to thyroid cancer and it is unlikely that true colloid
nodules have malignant potential, so that it remains true that most
benign thyroid nodules do not require surgical excision.41 There
is, however, increasing genetic support for the concept that a sub-
group of benign follicular neoplasms do have malignant potential.
Clearly, follicular adenomas and carcinomas are two closely
related neoplasms with potentially markedly different clinical
outcomes,42 and gene profiling has now provided data to show
that minimally invasive follicular thyroid carcinomas cluster with
follicular adenomas but not with the angioinvasive carcinomas,42
consistent with an adenoma–carcinoma sequence.
CONCLUSION
Solitary thyroid nodules are common, with investigation primar-
ily directed at excluding the presence of thyroid cancer. Clinical
evaluation, thyroid function testing and FNB are the mainstays
of investigation. Surgical excision is required for symptomatic
nodules, nodules with a suspicion of malignancy or where the cy-
tology is atypical or shows malignant cells.
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Ó 2006 Royal Australasian College of Surgeons