Review Article

APPROACH TO SOLITARY THYROID NODULE

Nidhi Malhotra* and Ambrish Mithal**From the DNB student Endocrinology*, Senior Consultant Endocrinology**, Indraprastha Apollo Hospitals,

Sarita Vihar, New Delhi 110 076, India.Correspondence to: Dr Ambrish Mithal, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.

The solitary thyroid nodule, defined as a palpably discrete swelling within an otherwise apparently normalgland, is usually a benign lesion. Fifty per cent of patients thought on basis of physical examination to havea sol,itary nodule have multiple nodules when studied by ultrasonography. Even in patients with palpablesolitary thyroid nodules who are undergoing clinical evaluation, the overall risk that the nodule is cancerousis less than 5%. Thyroid nodules identified as an incidental finding during ultrasonography, magnetic resonanceimaging. or computed tomography do not require further evaluation unless they are palpable, greater than1 cm in size, or both.Detail evaluation of thyroid nodules includes physical examination, Biochemical test, Ultrasonography, Thyroidscanning and fine needle aspiration biopsy. Fine needle aspiration biopsy (FNAB) is presently considered tobe the most cost effective initial method. It discriminates the malignant nodules from benign and suspiciousor indeterminate nodules. For suspicious or indeterminate nodules on repeat FNAB, thyroid scanning isdone. Hot nodules are treated for hyperthyroidism and do no need further evaluation since hyperfunctioningnodules are usually benign. TSH is an important assay done to detect underlying hyper or hypothyroidism.Malignant nodules are managed surgically with total or near total thyroidectomy followed by Radioiodineablation. Benign nodules can be given a trial of levothyroxine suppressive therapy followed by yearly followup with repeat FNAB or early if symptoms develop.Key words: Solitary thyroid nodule, Malignant, Benign, FNAB, TSH, Thyroid scan, Hyperthyroidism,Hypothyroidism, Levithyroxine.

The solitary thyroid nodule, defined as a palpablydiscrete swelling within an otherwise apparently normalgland, is usually a benign lesion. Thyroid nodules arecommon in both hyperthyroid and euthyroid patients; theyare present in half of all thyroid glands that are subject tocareful pathologic examination. More than 80% of allpatients with thyroid nodules are women; palpable thyroidnodules can be detected in 1.5% of men and 6.4% ofwomen between the ages of 30 and 59.2 years. Prevalenceof thyroid nodules increases from near zero at age 15 yearsto 50% by about age 60 to 65 years [1]. Fifty percent ofpatients thought on basis of physical examination to have asolitary nodule have multiple nodules when studied byultrasonography [2].

In contrast, thyroid cancer is rare; only about 50 newcases per million persons are diagnosed each year.

Even in patients with palpable solitary thyroid noduleswho are undergoing clinical evaluation, the overall risk thatthe nodule is cancerous is less than 5%. The likelihood thatan individual nodule is a carcinoma is not much less inpatients with a multinodular goiter than it is in patients withsolitary nodule.

Apollo Medicine, Vol. 3, No. 2, June 2006 216

DIFFERENTIAL DIAGNOSIS OF THYROIDNODULE

Differential diagnosis includes the disorders listed inTable 1. Of all the thyroid glands that on surgical resectionprove to contain solitary nodules, 70-80% are benignadenomas and about 10-30% are malignant growths [3].

CLINICAL EVALUATION

History

Nodules occurring at the extremes of age, particularlyin men, are especially likely to be cancerous. Exposure toexternal irradiation, whether in low doses or high doses(40 to 50 Gy [4000 to 5000 rad]) given to patients withlymphoma or head and neck cancer, increases thelikelihood of both benign and malignant nodules [1]. Afamily history of medullary or papillary thyroid cancer orof familial polyposis (Gardner’s syndrome) increases thelikelihood that a thyroid nodule is cancerous.

Physical examination

Thyroid nodules more than 1cm are usually palpable.They are examined for site, size, tenderness, consistency,

217 Apollo Medicine, Vol. 3, No. 2, June 2006

Review Article

mobility, fixity to surrounding structures and lymph-adenopathy. A firm to hard, painful, rapidly growingnodule, fixed to surrounding structures and associatedwith lymphadenopathy and local pressure symptoms issuggestive of malignancy.

Laboratory tests

Serum TSH should be measured in all patients withthyroid nodules to determine underlying subclinicalthyrotoxicosis or unsuspected hypothyroidism.

Serum antithyroid antibodies are indicated todistinguish between Hashimoto’s thyroiditis and Hurthlecell tumours.

Serum thyroglobulin has little value in patients withthyroid nodules.

Serum calcitonin is indicated in patients with familyhistory of MTC or other components of MEN2.

Thyroid scanning

In the past, a scintiscan was usually the first imagingstudy done in patients with thyroid nodules. It is done todetermine if the nodule is hyperfunctioning. However,since hyperfuctioning nodules are uncommon andscintiscans fail to distinguish between benign andmalignant hypofunctioning nodules, a scintiscan should beperformed before needle biopsy only in patients with lowTSH concentrations. Hyper functioning or autonomousnodules are rarely malignant.

If thyroid scanning is performed first, the results willindicate whether fine-needle aspiration is required. All coldnodules greater than 1 cm should undergo aspiration,because there is a 10% to 30% chance of malignancy. Hotnodules do not need aspiration, since they are highlyunlikely to be cancerous. Radionuclide scans areparticularly useful in patients with indeterminate cytologicresults (Fig.1), because in such patients hyperfunctioningnodules are almost always benign [4].

Ultra sonography

Ultrasonography categorizes nodules as solid, cystic,or mixed with more than 90% accuracy and is the bestmethod of determining the volume of a nodule [5].Ultrasonography is particularly useful during follow-up,since it can distinguish nodular growth from intranodularhemorrhage. Thyroid ultrasonography is also used forruling out the presence of multinodular goiter and forperforming fine needle aspiration cytology.

Benign and malignant nodules cannot be differentiatedreliably by ultrasonography. There are certain ultra-sonographic features that increase the likelihood of

Table 1: Clinical and pathological classification ofthyroid nodules

• Non-neoplastic nodulesHyperplastic

SpontaneousThyroid hemiagenesisCompensatory after partial thyroidectomy

InflammatoryAcute bacterial thyroiditisSubacute thyroiditisHashimoto’s thyroiditis

• Benign neoplasiaNonfunctioning

Adenoma ( ??papillary,follicular- colloid variant, hurthle cell)CystThyroglossal cyst

FunctioningToxic (or pretoxic) adenoma

• Malignant neoplasiaPrimary carcinomas

PapillaryFollicularAnaplasticMedullaryMixed

Lymphomas (often with thyroiditis)Thyroid metastasis from other primaries

• NonthyroidallesionsCystic hygromaAneurysmParathyroid adenoma or cyst

Fig. 1. Sequence for the evaluation of patients with a thyroidnodule.

Apollo Medicine, Vol. 3, No. 2, June 2006 218

Review Article

carcinoma : Diffuse microcalcifications, hypoechogenicity,irregular margin, irregular sonolucent halo and regionallymphadenopathy [6].

Fine needle aspiration biopsy

At present, the most cost effective initial methodappears to be fine-needle aspiration; the specificity andsensitivity of this procedure are excellent [4,5]. It canusually determine if the nodule is a macrofollicular lesion(which is benign), a microfollicular or cellular lesion(which may or may not be cancerous), or a papillarymalignancy.

Incidentalomas i.e., nodules less than 1 cm detectedincidentally on imaging of neck are not usually biopsied.The risk of thyroid cancer among patients with incidentallydiscovered thyroid nodules is similar to patients withpalpable nodules. The life expectancy of patients withtumour that is smaller than 1 cm in diameter is same asthat of the general population [6].

Fine needle aspiration biopsy is advisable in all patientswith palpable solitary nodules more than 1 cm in diameter,in patients of multinodular goiter who have discretehypofunctioning nodule within the goiter, or a nodule ofuncertain functional status that is growing or a cysticnodule after fluid has been removed. The prevalence ofcarcinoma in these nodules is similar to that in solitarynodules [7]. Biopsy is also indicated in patients ofthyrotoxicosis having hypofunctioning nodules.

In about 75% of cases, the nodules are benign.Malignancy is detected in 4%. Of the remaining cases,roughly half will have indeterminate or suspicious results;the other half will lack a diagnosis because of inadequatetissue sampling. When the result is nondiagnostic, a repeataspiration should be done (this will provide a diagnosis inabout half the cases)

TREATMENT [1,6,8]

Malignant nodules: Patients with known or suspectedmalignant nodules should be referred to an experiencedthyroid surgeon. Prognosis depends on the age of thepatient, the size of the primary tumor, the presence ofextrathyroidal extension, and the type of malignancy.

Surgical options include lobectomy, near-totalthyroidectomy, and total thyroidectomy. The preferredoperation is generally near total thyroidectomy, followedby radioactive iodine ablation to destroy any remainingthyroid tissue. Patients who undergo thyroidectomy thenneed levothyroxine suppressive therapy. Simple lobectomyis not preferred for two reasons. First, the remaining lobeis the most likely site for malignant extension. Second, thepatient will not become hypothyroid spontaneously if the

second lobe remains; as a result, radioactive iodine ablationcannot be performed effectively. This will be a problem ifa malignancy is confirmed. A second operation to removethe other lobe will then be required before the remainingtissue can be destroyed with ablation.

The choice of surgical procedure should not be basedon a frozen section of the nodule obtained during theoperation. A frozen section is less likely to provide anaccurate pathologic diagnosis than is fine-needle aspirationexcept in case of follicular cancer.

Non-malignant, noncystic nodules: Thyroid nodules ineuthyroid patients are often managed with levothyroxinesuppressive therapy, but whether this form of treatmentshould be used is currently being debated. Severalprospective, double - blind studies have shown thatlevothyroxine administration either has no effect on nodulesize or produces a decrease in size in, at most, only 39% ofnodules. Furthermore, the response of a nodule tolevothyroxine indicates nothing about its pathology-malignant nodules can regress during thyroid suppression,and benign nodules may grow. A reasonable approach inmost patients may be to perform fine needle aspiration; ifthe results are negative for cancer and cysts, administerlevothyroxine (0.1 mg/d) for 6 to 12 months. (This type oftreatment is inappropriate for elderly patients because itincreases the risk of atrial fibrillation. It should also not beused in postmenopausal women who are not receivingestrogen replacement therapy, because it increases the riskof osteoporosis).

If levothyroxine is given and the nodule shrinks,continue with this form of treatment; titrate thelevothyroxine dosage to ensure minimal suppression ofTSH. A negative biopsy result, coupled with shrinkageduring treatment, will reassure you and the patient thatthe nodule is unlikely to be malignant. Furthermore,suppressive therapy may prevent the adverse effects thatwould result from continued growth of the nodule and mayreduce the incidence of second nodules.

If the nodule does not shrink, treatment should bestopped because it is doubtful that the patient is derivingany benefit. Nodules that have remained the same size withtreatment should be followed closely for evidence ofgrowth.

In general, at our centre we do not advocatethyroxine suppressive therapy for thyroidnodules.

When levothyroxine is not administered, patientsshould be reexamined regularly. At each examination, thethyroid should be checked for nodule growth. In bothgroups (those who have and those who have not been given

219 Apollo Medicine, Vol. 3, No. 2, June 2006

Review Article

Fig. 2. Scheme for evaluation and treatment of patients with solitary thyroid nodules.

Thyroid nodule

Serum thyrotropin

High Low Normal

Evaluate for hypothyroidism, Treat

if indicated

Scintiscan, preferably

Any other result

Autonomous (“hot”) nodule

Both

Evaluate for hyperthyroidism, Treat

if indicated

Fine needle biopsy

Malignant Inconclusive or repeatedly

unsatisfactory

Unsatisfactory Benign

Use scintiscan and clinical

factors to decide on surgery or observation

Surgery

Repeat fine needle biopsy. Strongly

consider ultrasound

id

Observe ± thyroxine treatment

Increase in size No change or decrease in size

Continue observation

Apollo Medicine, Vol. 3, No. 2, June 2006 220

Review Article

levothyroxine), repeat biopsy or surgical removal isindicated for nodules that continue to enlarge, are hard, orare causing cosmetic problems or patient anxiety.

Cystic nodules

Levothyroxine should not be used if the biopsy resultsindicate a cystic nodule. This type of nodule is invariablycold on thyroid scanning because of the cystic fluid. It isalso unresponsive to levothyroxine suppressive therapybecause most of its volume is cystic fluid. The cyst may besimple or complex. Simple cysts are rarely malignant andshould be drained. About 50% of simple cysts will recurfollowing an initial aspiration, however, and thus repeatdrainage is often required. The cyst fluid should undergocytopathologic examination each time it is drained.Complex cysts should also be drained, but they should thenhave their solid component sampled by fine-needleaspiration because these cysts have a higher potential formalignancy. Ultrasonic guidance can improve the accuracyof the aspiration. (Cystic degeneration is present in 20%to 30% of thyroid cancers.) If a complex cyst recurs, repeatdrainage can be attempted. However, an argument can bemade for surgical removal because current diagnostic testsare not adequate to rule out malignancy.

CONCLUSION

The evaluation of solitary thyroid nodules depends, inpart, on how they were found. Thyroid nodules identifiedas an incidental finding during ultrasonography, magneticresonance imaging, or computed tomography do notrequire further evaluation unless they are palpable, greaterthan 1 cm in size, or both.

Nodules detected during a physical examination oftenrequire assessment with fine needle aspiration and/orthyroid scanning. In addition, thyroid stimulating hormone

(TSH) and thyroid hormone assays should be ordered tolook for subclinical or symptomatic hyperthyroidism(which may be present in about half of patients with hotnodules) or hypothyroidism (which could be stimulatingnodule growth). (Fig. 2)

REFERENCES

1. Mazzaferri EL. Management of a solitary thyroid nodule.N Engl J Med 1993; 328: 553.

2. Tan GH, Gharib H, Reading CC. Solitary thyroidnodule:comparison between palpation and ultra-sonography. Arch Intern Med;115: 2418.

3. Tunbridge WM, Evered DC, Hall R, et al. The spectrum ofthyroid disease in an English community: The Wickhamsurvey. Clin Endocrinol 1977; 7: 481.

4. Ashcraft MW, Van Herle AJ. Management of thyroidnodules. II. Scanning techniques, thyroid suppressivetherapy, and fine needle aspiration. Head Neck Surg1981; 3: 297-322 [Medline].

5. Rojeski MT, Gharib H. Nodular thyroid disease: Evaluationand management. N Engl J Med 1985; 313: 428-436.[Medline]

6. Lewis E. Braverman, Robert D. Utiger.The Thyroid. 9thedn.

7. Belfiore A, LaRosa GL, LaPorta, GA, et al. Cancer risk inpatients with cold thyroid nodules.Am J Med 1992;93:363.

8. Leslie J, De Groot, J Larry Jameson. Endocrinology.5th edn, volume 2.

9. Marqusee E, Benson CB, Frates MC, et al. Usefulnesssof ultrasonography in the management of nodular thyroiddisease. Ann Intern Med 2000; 133: 696.

10. AACE clinical practice guidelines for the diagnosis andmanagement of thyroid nodules. 1996. AmericanAssociation of Clinical Endocrinologists.