By Ashleigh Elkins

This article discusses the management of patients who have atypical thyroid nodules. Thyroid nodules are quite common in the general population. Thyroid nodules may be detected because some people feel a lump in their neck or throat, whilst in other people there are no symptoms and the nodule is found incidentally on ultrasound examination.

Thyroid nodules are usually investigated with a fine needle aspiration (FNA) of cells from the nodule, to determine whether the nodule is benign or malignant, and therefore to guide patient management.

Bethesda Classification System

Thyroid FNA results obtained from patients with thyroid nodules are usually reported according to the Bethesda classification system. This system is made up of six categories which correlate to an estimated risk of malignancy. The Bethesda system is used to help guide the appropriate management of the patient with a thyroid nodule.(1)

The Bethesda classification is summarised in the following table.

Diagnostic Category	Diagnostic category name	Risk of malignancy	Typical management
I	Non-diagnostic or unsatisfactory	1-4%	Repeat FNA under ultrasound guidance
II	Benign	0-3%	Clinical follow-up
III	Atypia of undetermined significance or follicular lesion of undetermined significance	5-15%	Repeat FNA, further investigation
IV	Follicular neoplasm or suspicious for follicular neoplasm	15-30%	Surgical lobectomy
V	Suspicious for malignancy	60-75%	Near-total thyroidectomy or surgical lobectomy
VI	Malignant	97-99%	Near-total thyroidectomy

Table 1: Overview of the Bethesda classification, associated risk of malignancy and typical management of patients.(1)

Bethesda Classification Category III

The results of FNA cytology that fall into the Bethesda category III do not easily fit within the benign, malignant or suspicious for malignancy categories. Bethesda category III is the least common result obtained from FNA of a thyroid nodule.(2)

There are many different findings which can be classified within the Bethesda category III. Some of these scenarios include:

1. The cells obtained from the FNA are made up primarily of microfollicles, but the sample does not meet the criteria for category IV; follicular neoplasm/suspicious for follicular neoplasm
2. Sample consists mainly of Hurthle cells and scant colloid
3. The cellular atypia are difficult to interpret due to artifacts which have occurred during the preparation of the slide for analysis; such as clotting or air-drying.
4. Sample predominantly made up of Hurthle cells, and clinical features suggest a benign nodule, such as in patients with Hashimoto’s thyroiditis or multinodular goitre
5. Some features suggestive of papillary thyroid carcinoma, but overall, the sample appears benign. This is usually seen in samples obtained from patients with Hashimoto’s thyroiditis
6. Some cells lining a cyst have some features which look atypical, but the remainder of the sample is largely benign
7. A small number of follicular cells display nuclear enlargement and/or prominent nucleoli. This pattern is typically seen in patients who have undergone radioactive iodine treatment, or those with cystic degeneration/haemorrhage
8. Atypical lymphoid infiltrate, but the degree of atypia is not sufficient to be classified as suspicious for malignancy.(2)

Management of patients who have atypical thyroid nodules

Because many different results are placed into Bethesda category III, the clinical management of patients with these nodules is varied, and there is no consensus as to the best approach to management.(3) Patients may undergo a repeat FNA assessment, generally three months after the initial FNA. In the majority of cases, a repeat FNA will return a more definitive result. However, in approximately 20% of cases, repeat FNA will also return a result of Bethesda category III.(2) Other potential management strategies include observation, further investigation, such as with ultrasound and in some cases, referral for surgery.

Ultrasound can be used to guide FNA to ensure the sampled cells are taken from the nodule. It can also be used to evaluate the characteristics of the nodule, including echogenicity, irregular margins, presence of microcalcifications and vascularity.(3) These sonographic features have been associated with an increased risk of malignancy in Bethesda III nodules.(4) Norlen et al (3) found that if ultrasound in patients with Bethesda III nodules did not show any hypoechogenicity, irregular margins or microcalcifications, the risk of the patient having a malignant nodule was very low. Hence, ultrasound assessment of the nodule may help to guide the patient’s management.

The management of Bethesda category III nodules is dependent on patient and clinical factors. Patients who are thought to be at a low risk of malignancy may be observed clinically for a period of time, or have a repeat FNA assessment three months later. Patients who have an FNA result revealing a Bethesda category III nodule who are thought to be at a high risk of malignancy may be referred directly for surgery without a repeat FNA. These patients are typically young, and have sonographic or clinical features which are concerning for malignancy. Male patients are also more likely to be referred for surgery directly than female patients.(5)

When to operate and which operation?

The surgical management of an atypical thyroid nodule depends upon patient and clinical factors. Nodulectomy is not routinely performed in the setting of atypical thyroid nodules. This is a procedure which removes the nodule and a small section of surrounding tissue. When malignancy is suspected, this procedure is not recommended for several reasons. Firstly, only a small amount of tissue is resected and this may not be sufficient to remove all potentially malignant cells. Secondly, there is also the potential to spread potentially cancerous cells into other compartments of the neck during nodulectomy. Finally, the risk of post-operative bleeding complications is significantly higher following nodulectomy.

The size of the nodule is often used to determine whether a hemithyroidectomy or total thyroidectomy is performed. For nodules which are smaller than 1cm in diameter and are suspicious for malignancy, a hemithyroidectomy is usually performed.(6) However, a limitation of performing a hemithyroidectomy is that patients may later develop disease in the remaining thyroid lobe and hence may require completion thyroidectomy at a later stage.

For nodules greater than 1cm in diameter which are suspicious for malignancy, a total thyroidectomy is usually the preferred surgical procedure. Other indications for total thyroidectomy include pathology in both lobes of the thyroid gland, and if there is suspicion of metastatic spread to the lymph nodes of the neck.(6) Patients who are found to have papillary thyroid cancer will usually undergo total thyroidectomy, and may also require a central lymph node dissection. This is because there are high rates of metastatic disease to the lymph nodes with papillary thyroid cancer, estimated to be found in approximately 20-50% of patients. In order to reduce the risk of recurrence, a central lymph node clearance is often performed in patients with known papillary thyroid cancer.(7)

References

[1] Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda system for reporting thyroid cytopathology: A meta-analysis. Acta Cytologica 2012;56:333–339.

[2] Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol 2009;132:658-665.

[3] Norlen O, Popadich A, Kruijff S, Gill AJ, Sarkis LM, Delbridge L, Sywak M, Sidhu S. Bethesda III thyroid nodules: The role of ultrasound in clinical decision making. Ann Surg Oncol (2014) 21:3528–3533.

[4] Gweon HM, Son EJ, Youk JH, Kim JA. Thyroid nodules with Bethesda system III cytology: Can ultrasonography guide the next step? Ann Surg Oncol (2013) 20:3083–3088.

[5] Nagarkatti SS, Faquin WC, Lubitz CC, Garcia DM, Barbesino G, Ross DS, Hodin RA, Daniels GH, Parangi S. The management of thyroid nodules with atypical cytology on fine needle aspiration biopsy. Ann Surg Oncol. 2013 January ; 20(1):

[6] Chung YS, Yoo C, Jung JH, Choi HJ, Suh YJ. Review of atypical cytology of thyroid nodule according to the Bethesda system and its beneficial effect in the surgical treatment of papillary carcinoma. J Korean Surg Soc. 2011 Aug; 81(2): 75–84.

[7] Calo PG, Pisano G, Medas F, Marcialis J, Gordini L, Erdas E, Nicolosi A. Total thyroidectomy without prophylactic central neck dissection in clinically node-negative papillary thyroid cancer: is it an adequate treatment? World Journal of Surgical Oncology 2014, 12:152

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