B-ENT, 2007, 3, Suppl. 6, 93-102 Management of nodules

J. P. Monnoye*, M. Hamoir**, C. de Burbure***, G. Chantrain****, P. Gasmanne*****, P. Levie*, R. Loncke******, O. Desgain*, V. Monnoye* and Ch. Malherbe******* *Department of Otolaryngology, Cliniques Ste Anne-St Remi, Brussels; **Department of Otolaryngology, Head and Neck Surgery, St Luc University Hospital, Catholic University of Louvain, Brussels; ***Pathology, St-Luc University Hospital, Catholic University of Louvain, Brussels; ****Department of Otolaryngology, University Hospital St-Pierre, ULB, Brussels; *****Department of Otolaryngology, CHU Charleroi, Charleroi; ******Department of Otolaryngology, H. Hartziekenhuis, Roeselare; *******Internal Medicine Department, Endocrine-Metabolic Unit, Brussels

Key-words. Guidelines; thyroid nodules; review; management

Abstract. Management of thyroid nodules. These Belgian guidelines for ENT surgeons about thyroid nodules were elaborated in the light of personal practical experience and the recent advances in diagnosis and management described in the literature. Thyroid nodules are a common finding, particularly in women and in areas of iodine depletion. The prevalence in the general population averages 3 to 7% on palpation and almost 50% on ultrasound. The major difficulty facing the clinician is how best to assess and manage these thyroid nodules. The authors have attempted to simplify the assessment of thyroid nodules, to classify them, and to present the most common current therapeutic management options.

1. Introduction in men and the prevalence 2. Benign nodules increases in areas with iodine The following guidelines are deficiency and ionizing radiation 2.1. Adenomas based on recent peer-reviewed exposure.10 2.1.1. Follicular adenoma is a articles evaluated by the authors to On ultrasonography the preva- common thyroid tumour, with a rate between Ia and III according lence ranges from 19% to 46% in greater incidence in women than to Belgian evidence levels the general population, may be in men. (BEL).1-9 even higher at autopsy, and may reach 49.5% in clinically healthy Around 90% of solitary thyroid 1.1. Definition people.11 nodules are adenomas, which may undergo haemorrhagic transforma- A thyroid nodule is a tumefaction tion, cystic or necrotic degenera- of a part of the thyroid gland. 1.3. Classification of thyroid tion. Malignant transformation is Its prevalence and incidence nodules rare. Most patients are euthyroid can vary greatly according to Thyroid nodules are either benign and consult for a painless tume- the investigations carried out, the or malignant and are further faction but rapid growth due to population studied, gender, age as subdivided following on histo- haemorrhage may cause neck pain. well as the patients’ past medical pathology. Benign nodules are At histopathology, a follicular history. classified into adenomas, cysts adenoma is an encapsulated and other benign lesions.12 tumour that consists of cells repro- 1.2. Epidemiological overview Malignant tumours are predomi- ducing the thyroid architecture. The finding of thyroid nodules by nantly epithelial in nature, and are It is either round or oval and simple palpation increases by either classified into differentiated surrounded by a fibrous capsule. 0.1% every year of life of the types which can be papillary, It is 4-5 times more frequent patient with a prevalence averaging follicular or medullary carcino- than . Several types exist, 3 to 7% in the general population. mas or into undifferentiated namely: macrofollicular (colloid), Thyroid nodules are four times tumours such as insular and microfollicular (fetal), trabecular more common in women than anaplastic carcinomas. (embryonic) and normofollicular. 94 J. P. Monnoye et al.

2.1.2. Variants: 30 and 40 years of age, is two to tion, which makes it difficult to three times more frequent in distinguish from a follicular ade- Ð A toxic adenoma is a benign women, and has a good prognosis. noma: differential diagnosis is thyroid tumour that has It presents as a firm, mostly non- based on signs of capsular and escaped pituitary control. It encapsulated mass. vascular invasion, a high mitotic corresponds to a solitary nodule At histopathology, there are index and the presence of metas- with autonomous function. some purely papillary carcinomas, tases. Ð Hürthle cell adenoma is a some with a follicular predomi- There are particular types of totally encapsulated tumour nance, a diffuse sclerosing variant, follicular carcinomas, such as composed mainly of oncocytic tall and columnar cell variants, Hürthle cell carcinomas, or fol- cells (75%), and is synony- and they may also present as licular carcinomas with oxyphilic mous with oxyphilic or microcarcinomas. The histologi- cells. They are in fact uncommon Askenazy’s adenoma. cal criteria of a papillary carcino- aggressive variants of follicular ma are the presence of papillae carcinomas and account for 3-6% 2.2. Cysts formed by cells bordering a of thyroid tumours.14,15 They Cystic nodules account for 15 fibrovascular axis, the presence of generally present as a hot solitary to 25% of thyroid nodules, laminated calcified nodules nodule at scintigraphy and are are benign and are the result of (psammoma bodies, found in 50% more frequent in women in their degenerative changes either within of the cases), and voluminous pale fifties. Malignancy indicators are the normal thyroid parenchyma or nuclei with early lymphatic inva- clear vascular and capsular inva- a nodular goitre. Malignant change sion. sion. can occur in 20% of nodules larger Papillary carcinoma has the 3.1.3. Medullary carcinoma than 4 cm. Cystic nodules can best prognosis among the various appear rapidly as a mass that is types of thyroid with the Medullary carcinomas originate often very sensitive. risk of recurrence increasing after from the C cells of the thyroid the age of 40. Microcarcinomas gland and represent 5-10% of thy- 2.3. Other benign nodules (smaller than 1 cm) have an excel- roid carcinomas. Parafollicular C lent prognosis. Patients with cells do not capture iodine and are Other benign nodules can be seen extension outside the thyroid and not regulated by TSH. A genetic in Hashimoto’s thyroiditis, de distant and lymphatic metastases enquiry has to be pursued in every Quervain’s thyroiditis and rarely at diagnosis have a less favourable case as there is a familial form in cases of infection. prognosis.13 transmitted in an autosomal domi- nant mode and in which both thy- 3. Malignant nodules 3.1.2. Follicular carcinoma roid lobes can be affected from the Follicular carcinoma constitutes start. The existence of specific 3.1. Well differentiated carcino- 10-20% of thyroid cancers. It is tumour markers facilitates diagno- mas typically a solitary, encapsulated sis. Well differentiated carcinomas of nodule with a greyish-white Medullary carcinomas have a the thyroid represent 80-85% of macroscopic appearance, and firm consistency at histopatholo- thyroid cancers. They are divided metastasizes by vascular invasion gy, their colour varies from according to their histopathology to the lung and bone. Follicular brown-yellow to pale pink and into papillary, follicular and less carcinoma with minimal invasion they have regular nuclei and abun- commonly, medullary carcino- has an excellent prognosis, while dant granular cytoplasm. The mas. the invasive form less so. It occurs diagnosis is confirmed by at a later age than papillary carci- immunohistochemistry with anti- 3.1.1. Papillary carcinoma noma (50-60 years of age) and its calcitonin antibodies and carcino- Papillary carcinoma is the com- prevalence increases by a factor of embryonic antigen. monest thyroid cancer with 2 in areas that are iodine deficient. Medullary carcinoma tends to 12,000 new cases per year in the At histopathology, this malig- metastasize to the cervical and United States. It is often multifo- nant epithelial tumour of the thy- mediastinal lymph nodes and less cal, has a peak incidence between roid has a follicular differentia- frequently to the lung, liver and Management of thyroid nodules 95 bone. In suspected familial cases types and accounts for less than carcinoma, and a medullary of medullary carcinoma, the close 5% of thyroid cancers. It usually carcinoma or an intrathyroid relatives should have calcitonin occurs in patients above the age of . levels measured as well as a pen- 50 with a goitre or a thyroid Survival is not modified by tagastrin test from the age of 5. nodule and has a peak incidence surgery, radiotherapy or chemo- The prognosis varies according to around 70 years of age. The therapy, averages 2-6 months and the age at first treatment and the tumour is rapidly invasive and rarely beyond 12 months. 10-year survival rate is around metastasizes readily to the lung, 85% in patients under the age of bone, brain and liver. 3.3. Other malignant tumours 30 who have no metastases or The tumour is composed of These consist mainly of sarcomas, lymphadenopathy and a tumour giant fusiform or polygonal cells lymphomas, histiocytosis, ter- diameter less than 4 cm. For the at histopathology. There is often a atomas and metastases from the other patients, the 10-year survival mixture of several cell types, breast, kidney, lung, colon or a rate drops to 10%. The sporadic along with keratinised, osteoblas- melanoma (see Table 1). forms have a worse prognosis than tic or sarcomatous cells. Epithelial the familial forms. structures are often present. Immunohistochemical studies 4. Management of a thyroid 3.2. Poorly differentiated carci- have to be performed systemati- nodule3,6,8,9,15,16 nomas cally. Keratin is the most useful epithelial marker and is present in Ð Anamnesis is essential, taking 3.2.1. Insular carcinoma 40-100% of the cases. Other anti- into account family history, The insular thyroid carcinoma bodies will enable discrimination gender, age (under 20, above usually presents as a nodule with between lymphoma or more rarely 60 years of age), any past or without an associated goitre. a poorly differentiated follicular medical history of irradiation to At histopathological examina- tion, insular carcinomas have a leveled architecture filled with Table 1 cavities. The association of carci- TNM classification of thyroid carcinomas noma cells of both follicular and papillary types is frequent, sug- TNM classification of thyroid carcinomas:28 gesting this type of carcinoma may TX: Primary tumour cannot be assessed well represent an intermediate T0: No evidence of primary tumour stage in the differentiation process. T1: The tumour is 2 cm (slightly less than an inch) or smaller T2: Tumour is between 2 cm and 4 cm (slightly less than 2 inches) This tumour also displays colla- T3: Tumour is larger than 4 cm or has extended slightly outside the thyroid gland gen-rich dense areas, which is the T4a: Tumour of any size and has grown beyond the thyroid gland to invade adjacent reason for which some have been tissues of the neck wrongly diagnosed as medullary T4b: Tumour has grown either back to the spine or into adjacent large blood vessels carcinomas. Thyroglobulin but not The values for N are: calcitonin is positive. The prognosis is intermediate NX: Regional (nearby) lymph nodes cannot be assessed N0: No regional lymph node spread between those of well differentiated N1: Spread to lymph nodes and anaplastic tumours. Local N1a: Spread to lymph nodes in the neck (cervical lymph nodes) recurrence is frequent and metas- N1b: Spread to lymph nodes in the upper chest (upper mediastinal lymph nodes) tases to the lung occur in 40% and The values for M are: to bone in 20% of the cases. Metastasis is often early and early MX: Presence of distant metastasis (spread) cannot be assessed aggressive treatment is warranted. M0: No distant metastasis M1: Distant metastasis is present, involving non-regional lymph nodes, internal 3.2.2. Anaplastic carcinoma organs, bones, etc. Separate stage groupings are recommended for papillary or follicular, medullary, and Anaplastic carcinoma of the thy- anaplastic (undifferentiated) carcinomas according to the age of the patient (under or above 45 years of age) (see association for online resources). roid is one of the most aggressive 96 J. P. Monnoye et al.

or associated with other nodules, its situation within the gland and enables the search for cervical lymph nodes. Ultrasonography enables the visualisation of solid nodules measuring at least 3 mm and fluid-filled nodules of at least 1 mm in diameter. Hypo- echogenicity and an irregular shape increase the probability of a nodule being malignant. Its wider use has enabled the Figure 1 discovery of a large number Regulation of thyroid synthesis. TRH: thyrotropin of micronodules. When these releasing hormone, TSH: thyroid stimulating hormone (thy- rotropin), T3: tri-iodothyronine, T4: thyroxine. are smaller than 1.5 cm, con- servative management is pro- posed to the patient, whilst when the nodule size is above 5 mm, ultrasound guided fine- the cervical area, the presence of almost all hyperthyroid conditions needle biopsy will be recom- any pain, rapid nodular growth linked to a primary pathology, this mended.17,18 and compression symptoms. measurement alone should theo- ÐFine-needle aspiration (FNA) Ð Clinical examination: by palpa- retically indicate the diagnosis of results will greatly depend on tion, the size of the nodule can hyperthyroidism. the experience of the operator be assessed along with the pres- Ð Antibodies: anti-thyroglobulin as well as that of the patholo- ence of tenderness, induration, and anti-peroxidase antibodies, gist. On average, two to three glandular fixation, plunging when present, direct the diag- punctures will be performed on goitre, or lymphadenopathy. nosis towards an auto-immune each nodule in order to get 5 to Ð Paraclinical examinations have pathology. 6 glass slides. FNA is the most to be focused if only from an Ð Calcitonin and carcino-embry- reliable and least invasive economical point of view. onic antigen are measured examination for the distinction Ð Biological assessment (TSH, when there is a suspicion of between a benign and malig- T3 and T4) will enlighten the medullary carcinoma of the nant nodule, and enables a clinician about the functional thyroid. When positive, a better selection of patients state of the gland and on the phaeochromocytoma should be requiring surgery. eventual presence of a toxic excluded by measuring urinary The FNA is reliable in 85-95% adenoma. catecholamines. Pentagastrin of the cases and has a 1-11% Ð TSH: thyrotropin or thyroid tests are only useful in infra- false negative and 1-8% false stimulating hormone (TSH) clinical familial medullary car- positive rate. The lesions are stimulates thyroid secretion cinoma or in the postoperative benign in 69% of FNA, are and is released by the thy- follow-up of patients. suspect in 10%, malignant in rotropic cells of the pituitary ÐThyroid ultrasonography is the 4% and indeterminate in gland. Its secretion is in turn most common examination 17%.14,19-22 regulated by the circulating performed and enables the Ð Scintigraphy: This examina- levels of the thyroid study of the morphology of the tion reflects mainly the func- (see Figure 1). thyroid, the description of a tional aspect of the thyroid The new ultra-sensitive measure- nodule that had been found gland and does not distinguish ment technique of TSH levels is by palpation, the distinction between benign and malignant currently available everywhere in between solid and cystic nodules with sufficient speci- Belgium. As TSH levels are low in nodules, whether it is isolated ficity. This functional evalua- Management of thyroid nodules 97

tion enables the distinction diagnose benign versus malig- tion. Should a treatment with between cold nodules with low nant thyroid lesions. Due to its radio-iodine be necessary, thy- fixation from hot nodules that high sensitivity and specificity, roxine should only be given at are hyperfixating. The majority this technique may prove use- the end of the treatment. In of cold nodules is benign but ful to diagnose the malignant case of a papillary carcinoma, 10% are malignant; only 4% of potential of thyroid nodules the dose of thyroxine has to be hot nodules are malignant.23 preoperatively.24,25 adapted so as to obtain TSH Moreover, 33% of the echo- levels just above the minimal graphic nodules, including the 4.1. Medical treatment levels. TSH levels must be infracentimetric nodules, are reduced in case of a follicular not visible at scintigraphy. Thyroxine carcinoma and normal but ÐFor cold nodules: thyroxine is rather low in cases of Hyperfixating hot nodules will very often prescribed when medullary of anaplastic carci- show up toxic adenomas as well surgery is not indicated, and nomas. It is important not to as hyperthyroidism, toxic adeno- most often when there is an give too much thyroxine in mas with preclinical hyperthy- associated goitre. It has little cases of carcinoma in order to roidism, and Hürthle cell adeno- effect on the size of the prevent osteoporosis that could mas. The risk of malignancy in nodules but decreases the size set in after several years of these is 4%. Hypofixating cold of the goitre as a whole and treatment. nodules represent 80% of thyroid may prevent the apparition of nodules. As 10% of cold thyroid 131 further nodules, by rducing the Radio-iodine I nodules are malignant, scintigra- metabolic activity of the thy- Ð This treatment is unnecessary phy is recommended if TSH is roid gland. The dose has to be in cases of medullary or low. adapted so as to achieve low- anaplastic carcinomas. The most commonly used iso- normal TSH levels, taking into Ð It is indicated in papillary and topes are iodine I131 and tech- account tolerance and eventual mainly follicular carcinomas netium Tc99. Technetium is cur- associated pathologies. It is although this is still a matter of rently the main isotope used for unnecessary if TSH is already debate. the initial exploration of thyroid inhibited. Thyroxine is also Ð It is unnecessary when the pap- pathology. Results obtained by prescribed postoperatively in illary carcinoma is <1 cm, if it Tc99 are comparable to those from order to maintain euthyroidism is localised and non-invasive I131 in 98% of the cases. This and prevent the occurrence of and treated by a simple lobec- examination is not routinely pro- new nodules in the remaining tomy. However, although its posed to the patient in several thyroid parenchyma, in cases use is absolutely classic in case European countries, although it is of partial . The of follicular carcinoma, it is a part of daily practice in Belgium. aim is again to maintain low- little more controversial in ÐThe CT scan is only useful normal TSH levels. papillary carcinoma treated by when complex surgery is ÐFor hot nodules: thyroxine is total thyroidectomy. planned or in cases of major usually not indicated, and it is Ð It is usual to wait for one tissue invasion. The use of iod- unnecessary if TSH is low or month prior to prescribing I131, inated contrast medium is con- inhibited. In case of surgery as TSH levels have to be tra-indicated in cases of hyper- (often a unilateral lobectomy), >30 µU/ml. The usual dose is thyroidism. An NMR is pre- its prescription is recommend- 100 mC. ferred though rarely per- ed to ensure euthyroidism and Ð For papillary carcinomas, a formed. to avoid hypertrophy of the single dose is usually suffi- ÐThe PET-scan is used for residual lobe or hypothy- cient. searching for distant metas- roidism if the remaining lobe is Ð For follicular carcinomas, tases. too small. treatment has to be repeated Ð Genetic studies: a 6-gene ÐFor carcinomas: thyroxine is every six months and always array-based predictor model frequently given to the patient follows a weaning-off period has recently been developed to following a surgical interven- of . This con- 98 J. P. Monnoye et al.

tinues until there is no fixation ination. Should the cyst not The morbidity of total thy- on a Total Body Scan. disappear, ultrasonography roidectomy is low when it is Ð Thereafter, monitoring can be should follow and a decision performed by an experienced limited to thyroglobulin levels regarding surgery has to be surgeon. (with or without a Total Body made. Surgery is always indi- However, complications include Scan) following stimulation by cated in cases of suspicious or recurrent nerve palsy and hypo- TSH-rh (Thyrogen), which positive cytology. parathyroidism, both of which can should enable continued treat- Ð In case of a cold nodule: be either transient or permanent ment with L-Thyroxine (more ultrasound-guided fine-needle (approximately 2% for both). comfortable but expensive). biopsy has become the most In both medullary carcinoma important examination in and Hürthle cell carcinoma, total Ideally this treatment should be therapeutic management (see thyroidectomy is paramount. repeated at six months, then after above). In anaplastic carcinoma, surgery a year, two years and five years. will depend on tumour size, since Thyroglobulin levels must remain External Radiotherapy survival won’t be modified by the <1 ng/ml. If it is above 1 ng/ml, This treatment is reserved for procedure. one should repeat the I131 Total anaplastic carcinomas, certain When reoperation is envisaged Body Scan with a view to comple- lymphomas and sarcomas as well at a later stage, such as in toxic menting the treatment. as very particular cases of exten- multi-nodular goitres and particu- Follow-up with cervical ultra- sive differentiated carcinomas that larly in the presence of recurrent sonography should also be per- 131 do not fix I . nerve palsy or hypoparathy- formed. roidism, it is well worth consider- It is important to note that I131 is ing radio-iodine as a satisfactory also used in case of toxic nodules 4.2. Surgical management alternative. Indeed, the risk of (with inhibited TSH and raised T3 It is mandatory to obtain frozen complications such as recurrent levels) that do not require an oper- sections of the tumour during the nerve palsy is doubled at reopera- ation (<3 cm, not causing any dis- surgical intervention. tion. comfort) and particularly when the patient is elderly or has too Total lobectomy plus isthmusecto- Lymph node clearance my with recurrent nerve dissection high an operative risk. In follicular carcinoma, functional and parathyroid gland exposure is clearance is performed if lym- Calcium the basic treatment of benign nod- phadenopathy is present. Ð Calcium is indicated in cases ules. In papillary carcinoma, homo- of postoperative hypoparathy- It can also be performed for small lateral lymph node clearance is roidism and is either given per unifocal papillary carcinomas as performed if lymphadenopathy os or is depending on the well as for minimal invasion fol- is found peroperatively (recurrent severity. Hypoparathyroidism licular carcinomas. nerve chain, pre- and latero- becomes persistent in +/- 2% Total thyroidectomy with careful tracheal lymph nodes and the of total and dissection of the recurrent nerves inferior part of the homolateral calcium is often needed in and parathyroid glands (respect- jugulo-carotid chain). association with vitamin D ing vascularisation) is recom- In medullary carcinoma, func- (Rocaltrol). This is constraining mended in cases of multicentric tional bilateral lymph node clear- and expensive as calcium papillary carcinomas either with ance, including the recurrent and therapy is not reimbursed by lymphadenopathy or a poor prog- jugulo-carotid chains is manda- the INAMI. nosis as well as in follicular carci- tory. Fine-needle biopsy nomas that are either invasive or Ð in the case of a cyst: the FNA larger than 1.5 cm in diameter. A Conclusions procedure is often therapeutic, decrease in the recurrence risk particularly when the cyst is within the contra-lateral lobe and Rapid, efficient and financially haemorrhagic. It also yields a easy patient follow-up will play in sustainable diagnostic procedural diagnosis on cytological exam- favour of total thyroidectomy.26,27 steps are essential for the benefit Management of thyroid nodules 99

Figure 2 Management flow-chart of the thyroid nodule

of the patient and should consist niques,…) be proposed to the References of biological tests including TSH, patient with a view to optimizing T4, ultrasound and fine-needle management. 1. AACE/AAES medical/surgical guide- lines for clinical practice: manage- aspirate (see Figure 2). In case of Therapeutic management should ment of thyroid carcinoma. American an uncertain diagnosis, a fine- be installed and followed-up by Association of Clinical Endocrino- needle aspirate can be repeated in an endocrinologist. Surgical treat- logists. American College of order to decide on the most appro- ment should be performed by a Endocrinology. Thyroid Carcinoma priate treatment. Only in a few cervical surgeon, ENT or other Task Force. Endocr Pract. 2001;7(3): 202-220. particular cases should the other surgeon, whereas radiotherapy 2. Kim N, Lavertu P. Evaluation of a thy- technical procedures (scintigra- will usually be managed by the roid nodule. Otolaryngol Clin North phy, further histological tech- various disciplines involved. Am. 2003;36:17-33. 100 J. P. Monnoye et al.

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CME questions

1. What percentage of the population will present with a thyroid nodule on palpation of the thyroid gland?

AÐ1% BÐ5% C Ð 10% D Ð 20% E Ð 50%

2. What percentage of a solitary thyroid nodule will be an adenoma?

A Ð 10% B Ð 20% C Ð 50% D Ð 70% E Ð 90%

3. Which is the most common type of thyroid carcinoma?

A Ð Papillary B Ð Follicular C Ð Insular D Ð Anaplastic E Ð Medullary

4. Which type of thyroid carcinoma has the most favourable prognosis?

A Ð Papillary B Ð Follicular C Ð Insular D Ð Anaplastic E Ð Medullary

5. The Hürthle cell carcinoma is usually classified among which type of thyroid carcinoma?

A Ð Papillary B Ð Follicular C Ð Insular D Ð Anaplastic E Ð Medullary

6. What is the first test that should be performed when facing a patient with a thyroid nodule?

A Ð Limited biological assay B Ð Complete biological assay C Ð Fine-needle aspiration D Ð Ultrasound examination E Ð Scintigraphy 102 J. P. Monnoye et al.

7. What percentage of “cold” nodules are malignant tumours?

AÐ2% BÐ5% C Ð 10% D Ð 15% E Ð 25%

8. The risk of developing a recurrent nerve palsy following reoperation increases by:

A Ð 10% B Ð 25% C Ð 50% D Ð 75% E Ð 100%

9. Should the fine-needle aspiration cytology report be non-diagnostic, one has to:

A Ð Operate B Ð Treat medically C Ð Re-aspirate D Ð Perform a scintigraphy E Ð Perform a CT-scan

10. In the presence of a thyroid nodule, which of the following presents a greater risk of having a carcinoma?

A Ð A woman aged 20 to 60 years B Ð A man aged 20 to 60 C Ð A multi-nodular goitre D Ð A hot nodule E Ð Hashimoto’s thyroiditis

Answers: 1B; 2E; 3A; 4A; 5B; 6A; 7C; 8E; 9C; 10B