The prevalence of thyroid nodules in ultrasonography (US) surveys ranges from 19%-68%. Increased prevalence is seen in females and aging individuals. Palpate nodules have a lower prevalence of about 5% for women and 1% for men. Fortunately most of thyroid nodules are benign carrying a malignant risk of 4-5%.
Nowadays fine needle aspiration biopsy (FNAB) is mandatory when studying thyroid nodules' etiology. Nodules bigger than 1cm are traditionally submitted to FNAB, even more if they present ultrasonographic features
suspicious of harbouring a cancer. Bethesda classification will be crucial for decision making on treatment. Surgery is indicated for Bethesda IV, V, VI, and recurrent Bethesda I (non-diagnosis). Bethesda III (FLUS/AUS) should be submitted to another FNAB and molecular analysis (BRAF, RAS, RET/PTC), instead of classical indication for surgery as first option. Although this is true for nodules smaller than 4cm, for thyroid nodules ≥ 4cm controversy still exists about their management in Bethesda II.
According to some literature malignancy rate for nodules ≥ 4cm reaches 24% and FNAB has limitations in large nodules. Additionally, some authors state that false-negatives increase in nodules ≥ 4cm, reason to advise operative treatment for all (even in Bethesda II). However there are authors that claim US-guided FNAB gives accurate results in large nodules and do not advise systematic operation. How can we decide? Operate or do not operate?
Nagihan Bestepe et al. from the Ankara Yildirim Beyazit University, School of Medicine, Ankara, Turkey, retrospectively analysed the FNAB results of 5561 nodules (2463 patients) and compared them with pathology results after surgery. Malignancy rate was registered among with false-negatives rate. Nodules were divided into three groups: ≥ 4cm, 1,0cm - 3,9cm, and < 1,0cm. Results were interesting and published in 2016 in "Surgery".
Malignancy was histologically found in 8,5% (0,7% in FNAB) of nodules ≥ 4cm, in 10,2% of those with 1,0cm - 3,9cm, and in 25,6% of nodules < 1,0cm. No significant difference was found between the first two groups, but a p<0,001 was found between nodules < 1,0cm and each of the two remaining groups. False-negatives rate were: 4,7% for ≥ 4cm group, 2,2% for 1,0cm - 3,9cm group, and 4,8% for < 1,0cm group. We can easily notice that nodules ≥4cm have a false-negative rate double than the 1,0cm - 3,9cm group, and that nodules < 1,0cm have a similar false-negative rate than bigger nodules. New doubts emerge from these data...
Should we spend more attention to smaller nodules? Should we operate more often patients with smaller nodules? Not exactly. From reading the article the authors explain why they had these results. While all nodules ≥ 1cm were evaluated by FNAB, nodules < 1,0cm were submitted to FNAB only if there was a family history of thyroid cancer, exposure to radiotherapy of head and neck, or suspicious US features of cancer (hypoechoic texture, microcalcifications, irregular margin, absence of peripheral halo). Meaning, there was selection bias for nodules < 1,0cm.
Returning to false-negative rate for ≥ 4cm group, Nagihan Bested et al. tried to find US features that could help differentiate benign from malignant lesions for nodules ≥ 4cm. Apart from higher prevalence of hypoechoic and lower prevalence of iso-hypoechoic in malignant nodules, there was no difference according to size, texture, microcalcification, halo presence and margin irregularity between benign and malignant lesions bigger than 4cm. Looks like US looses its predictive value for nodules ≥ 4cm.
Although some studies point out a malignancy rate for nodules ≥ 3-4cm of till 24%, there are controversial studies about nodule size and its relationship with malignancy. While some suggest an increased risk of malignancy in large nodules, others state that nodule size is not predictive of malignancy.
In conclusion the authors state that "although the rate of false-negative FNAB in ≥ 4.0cm nodules was twice as high as 1.0–3.9 cm nodules, it may still not be high enough to recommend a routine operation for patients with ≥ 4.0cm nodules". They continue advising that intervention might be indicated if the patient has compression symptoms and increase in nodule size during follow-up. We must not forget that this recommendation is only for Bethesda II.
In worldwide literature there is not a cut-off value in nodule diameter to be used as surgery indication. Because there is no guideline for benign nodules ≥ 4cm, clinical evaluation will be extremely important as well as patient counselling. Probably (or not) more studies will be helpful.
Meanwhile... I will keep operating large nodules, I think!
Link to PubMed:
Dr. Carlos Eduardo Costa Almeida
General Surgeon