Low malignancy risk of thyroid follicular lesion of undetermined significance in patients from post-endemic areas

in European Journal of Endocrinology

Objective

New classification of the thyroid fine-needle aspiration biopsy (FNAB) results tries to stratify the risk of malignancy of thyroid follicular lesions using ‘follicular lesion of undetermined significance’ (FLUS) subcategory. Clinical significance of this category in the endemic (or post-endemic) areas has not been clearly established.

Design

The aim of the study was to determine the risk of malignancy for FLUS as well as to evaluate ultrasound (US) malignancy risk features (MRF) in such nodules in comparison with ‘suspicious for neoplasm’ (SFN) and ‘benign lesions’ (BL).

Methods

The US images and cytological diagnoses of 589 thyroid follicular lesions were analysed from January 2010 to July 2012. Cytological follow-up was assessed in 110 cases and surgical one in 100 cases.

Results

FLUS was diagnosed in 340 cases (3.8% of all cytological diagnoses and 57% of thyroid follicular lesions). Altogether, clinical and/or surgical follow-up revealed thyroid cancer in 3.2% patients with FLUS nodules. Repeat FNAB led to more specific diagnosis in 74.4% of FLUS (3.5%, papillary cancers or their suspicion; 2.3%, SFN; 68.6%, BL). The histopathological examination showed thyroid cancer in 6.4% cases of FLUS and 7.0% of SFN and follicular adenoma in 8.5% of FLUS and 11.6% of SFN (NS, FLUS vs SFN). FLUS showed MRF of intermediate values between BL and SFN; SFN more often than FLUS showed at least two MRF (53 vs 30%, P<0.0001).

Conclusions

The risk of cancer in FLUS in areas with recently corrected iodine supply is low. In such areas, repeated biopsy leads to more precise cytological diagnosis in about 3/4 cases.

Abstract

Objective

New classification of the thyroid fine-needle aspiration biopsy (FNAB) results tries to stratify the risk of malignancy of thyroid follicular lesions using ‘follicular lesion of undetermined significance’ (FLUS) subcategory. Clinical significance of this category in the endemic (or post-endemic) areas has not been clearly established.

Design

The aim of the study was to determine the risk of malignancy for FLUS as well as to evaluate ultrasound (US) malignancy risk features (MRF) in such nodules in comparison with ‘suspicious for neoplasm’ (SFN) and ‘benign lesions’ (BL).

Methods

The US images and cytological diagnoses of 589 thyroid follicular lesions were analysed from January 2010 to July 2012. Cytological follow-up was assessed in 110 cases and surgical one in 100 cases.

Results

FLUS was diagnosed in 340 cases (3.8% of all cytological diagnoses and 57% of thyroid follicular lesions). Altogether, clinical and/or surgical follow-up revealed thyroid cancer in 3.2% patients with FLUS nodules. Repeat FNAB led to more specific diagnosis in 74.4% of FLUS (3.5%, papillary cancers or their suspicion; 2.3%, SFN; 68.6%, BL). The histopathological examination showed thyroid cancer in 6.4% cases of FLUS and 7.0% of SFN and follicular adenoma in 8.5% of FLUS and 11.6% of SFN (NS, FLUS vs SFN). FLUS showed MRF of intermediate values between BL and SFN; SFN more often than FLUS showed at least two MRF (53 vs 30%, P<0.0001).

Conclusions

The risk of cancer in FLUS in areas with recently corrected iodine supply is low. In such areas, repeated biopsy leads to more precise cytological diagnosis in about 3/4 cases.

Introduction

Fine-needle aspiration biopsy (FNAB) is the main procedure followed in preoperative diagnosis of the nodular goitre; however, FNAB does not allow for differentiation among certain forms of nodular goitre, follicular adenoma, follicular carcinoma and frequently also follicular variant of papillary carcinoma of the thyroid (1). Aspirates from above follicular lesions usually show monotonous population of thyroid follicular cells (TFC) arranged in three-dimensional groups including microfollicles and decreased or absent colloid (2). Difficulties in diagnosis of follicular lesions are the main limitation of FNAB, especially in endemic regions. In such areas, patients with nodular goitre and follicular neoplasms (FNs) predominate and the percentage of FNABs with equivocal diagnoses is high, but in contrast to iodine-rich regions, the risk of cancer related to such outcomes is lower – ‘follicular lesions’ correspond more frequently to non-neoplastic hyperplastic nodules or follicular adenoma than to thyroid cancers (3, 4). The introduction of iodine prophylaxis is related to a gradual decline in the occurrence of non-neoplastic nodular goitre as well as of FNs, but this process lasts for many years (5, 6). Thus, the introduction of the new classification of the thyroid FNAB results, which tries to stratify the risk of malignancy of thyroid follicular lesions in regard to features of cytological image, is of special interest in such areas.

Poland is a country of recently corrected iodine supply – iodine prophylaxis (using household salt iodised with 30±10 mg KI/kg) was introduced in 1997 after a long break. The epidemiological studies performed in the early 1990s showed mild/moderate iodine deficiency (7), while present studies confirm the effectiveness of iodine supplementation in Poland. Nowadays, there is no endemic goitre in children and adolescents, but the prevalence of goitre and follicular lesions in the elder population is considerable. The occurrence of chronic thyroiditis features in cytological specimens is also observed (3, 4, 8).

The most recent recommendations for diagnostics of thyroid nodules permit centres with specific experience in thyroid cytology to divide diagnoses of follicular lesions into ‘follicular lesion of undetermined significance’ (FLUS) and ‘FN/suspicious for follicular neoplasm’ (SFN) categories (1, 2, 9). This distinction separates two cytological groups at different risk for thyroid malignancy. At our centre, similar distinction was introduced earlier – in some cases, the cytopathologist tried to determine more precisely the benign character of the lesion by formulating the result as ‘FN probably benign’ (FN-pB) (3). However, the current guidelines of the National Cancer Institute (NCI) assume wider definition of this particular diagnostic category (2). According to NCI, FLUS is a heterogeneous category that reflects the difficulty in the cytological diagnosis of the follicular lesions of the thyroid. It includes specimens in which the cytomorphological findings are not representative of a benign lesion (BL) such as a hyperplastic/adenomatoid nodule, yet the degree of cellular, nuclear and/or architectural atypia is not sufficient to render an interpretation of SFN or lesion suspicious for malignancy. This diagnosis may also be used in thyroid FNAB specimens that are less than optimal due to limited cellularity, poor fixation and obscuring blood.

The aim of the study was to assess the influence of the application of the new thyroid FNAB classification scheme on the frequency of particular categories of cytological diagnoses in respect to follicular lesions in a post-endemic area. Another aim was to determine the risk for cancer in nodules classified into the category of FLUS or SFN as verified by repeat FNABs or post-operative histopathological examinations. An additional aim was to evaluate the specificity of ultrasound (US) imaging features of FLUS and their comparison with such features of SFN and BL.

Materials and methods

The analysis included outcomes of US and FNAB examinations of the thyroid performed at the Department of Ultrasonography and Thyroid Biopsy, University Hospital No. 2 in Lodz in two periods: years 2008–2009 and after introduction of the new classification of FNAB outcomes – January 2010 to July 2012. The examinations were carried out in patients referred by endocrinologists from outpatient clinics.

At the first stage, cytological diagnoses from thyroid follicular lesions with monomorphic TFC (including oxyphillic cells) dominating in smears were identified in both examined periods. The frequency of particular diagnostic categories of FNAB outcomes was compared for such lesions before and after the introduction of new classification of cytological diagnoses.

Next, the frequency of revealing cancer in a lesion diagnosed as FLUS and SFN and their oxyphilic cell type (FLUS oxyphilic cell type (FLUS-O) and SFN oxyphilic cell type (SFN-O)) was assessed by cytological and/or surgical follow-up (surgeries performed between January 2010 and March 2012 were analysed). Moreover, the features of US image of FLUS and FLUS-O were compared to the ones of nodules diagnosed as SFN, SFN-O and BL (control group: 250 nodules found in 154 patients, diagnosed in the examined period as BL).

US examinations were performed in patients with the suspicion of any thyroid disturbance (palpable nodule, goitre, functional disturbances, previous laboratory or US findings) and in patients at risk for thyroid malignancy (history of neck irradiation in childhood or adolescence and thyroid cancer in relatives). All the US examinations were performed by the team of three physicians with at least 10 years' experience, with the use of two high-resolution sonographs with a 7.5–13 MHz linear transducer and power Doppler capability, before September 2011 (Siemens Elegra Advanced, Siemens Medical Systems, Inc., Issaquah, WA, USA and then Aloka Prosound Alpha 7, ALOKA Co. Ltd., Tokyo, Japan). The analysis of US features included all FLUS, FLUS-O, SFN and SFN-O lesions, which were described with enough precision in the US outcomes or cytological reports. The malignancy risk features (MRF) in the US image were classified into high MRF (H-MRF) and low MRF (L-MRF), according to AACE/AME/ETA and Polish recommendations (1, 9). H-MRF included the presence of intranodular microcalcifications, abnormal cervical lymph nodes and extracapsular invasion. And L-MRF included ratio of anterior–posterior dimension (height) to the transverse dimension (width) of lesion ≥1, hypoechogenicity, intranodular vascular pattern, presence of irregular blurred margins and homogeneity (lack of any cystic components). The presence of other lesions in the thyroid (solitary vs multiple nodule) and percentage of nodules with diameter <10 mm were also examined in each cytological category. Finally, it was assessed whether there is a relationship between worrying evolution of US image of FLUS observed during repeat FNAB (occurring of new MRF or at least 30% increase in the lesion volume) and the outcome of that cytological examination.

Focal thyroid lesions revealed in US examination (with diameter of at least 5 mm) were biopsied if malignancy-suspected US features were present (hypoechoic, solid nodules or containing microcalcifications or presenting with irregular, blurred margins or with chaotic intranodular vascular spots or with a more-tall-than-wide shape) or the patient had a history positive for high risk of thyroid malignancy. In the cases with multiple lesions of a similar picture, one or two of the largest lesions were biopsied. All the biopsies were US guided. In order to obtain a sufficient amount of diagnostic material, usually two or three aspirations of each examined lesion were performed. Ten millilitre syringes, mounted in the aspirating syringe holders with 25 gauge (0.5 or 0.42 mm) needles, were used in the process. In the case of cystic lesions, the cytocentrifugation technique was employed for aspirate preparation, enabling the cell condensation from any residual material that was left in the syringe. All smears were fixed in 95% ethanol and stained with haematoxylin and eosin. In the first analysed period (2008–2009), the cytological reports were formulated according to our old FNAB classification. This classification took into account difficulties in the differentiation between follicular adenoma and carcinoma. In cytological reports, the general term of ‘FN/tumour’ or FN/tumour oxyphilic cell type (FN-O) was used to describe such lesions. In some cases, the cytopathologist tried to determine more precisely the benign character of the follicular lesion by formulating the result as FN-pB or, for lesions with predomination of oxyphilic cells, FN-O-pB. Those outcomes were classified as ‘BL’. Smears with monomorphic TFC present but with cytological picture not allowing to formulate diagnostic conclusion were separated.

In the later period (2010–2012), the new classification of thyroid FNAB outcomes was used, which was based on NCI guidelines and was concordant with Polish guidelines ‘Diagnosis and treatment of thyroid cancer’ (2, 9). Aspirates from follicular nodules were classified into one of two categories: FLUS and SFN or FLUS-O and SFN-O respectively. The specimen showing a monotonous population of TFC arranged in three-dimensional groups and microfollicles with nuclear overlapping and crowding in background of scant or no colloid or containing single cell population of oncocytic TFC arranged in sheets and cohesive groups were classified as SFN or SFN-O respectively. A diagnosis of FLUS was made when the specimen showed features of both benign thyroid nodule and FN. Polish recommendations are equivocal in regard to smears with limited cellularity. At our department, the NCI recommendation was adopted to classify as FLUS the specimens with limited cellularity but with nuclear or architectural atypia. If those specimens were classified as nondiagnostic, it would lead to disregarding potentially significant elements of microscopic picture. The smears with monomorphic TFC but without atypia – usually also with limited cellularity – were categorised separately as in our previous classification of FNAB outcomes. In both evaluated periods, when several nodules were examined, the FNAB outcome was classified according to the one related to the highest risk of malignancy.

Surgical thyroidectomy specimens were processed by standard procedures. If necessary, immunohistochemical procedures were applied. Histopathological results were formulated according to the WHO Histological Classification of Thyroid Tumours. All those results were divided into the following groups: non-neoplastic lesion, benign neoplasm and malignant neoplasm (MN). Histopathological outcomes were analysed only for the patients treated surgically within 12 months of FNAB.

Continuous variables (like the age of patients) were analysed with ANOVA and Newman–Keuls test. The comparison of frequency distributions was performed with χ2 test (or with Yates corrected χ2 test). The value of 0.05 was assumed as the level of significance. The study design was approved by the Local Bioethics Committee.

Results

The frequency distribution of cytological outcomes according to diagnostic categories regarding follicular lesions that were used in both examined periods as well as the age and gender of patients subjected to FNAB were shown in Table 1. There were no significant differences between both periods in the age of patients, gender distribution or mean number of biopsied nodules during a single FNAB procedure (1.6 vs 1.5 nodules per patient). It was found that total incidence of follicular lesions with dominating monomorphic TFC in aspirates was similar (4.6 and 4.4% respectively). Similarly, percentage of FNAB outcomes corresponding to thyroid follicular lesions per patient did not differ – 6.7 vs 6.3%. However, the introduction of the subcategory FLUS significantly decreased the percentage of FNAB outcomes from such nodules without diagnostic conclusion (72.3 vs 26.7%, P<0.0001). The introduction of category FLUS-O enabled identification of several cases of lesions of oxyphilic cells with potentially lower risk for thyroid malignancy. The occurrence of FN-O diagnosis was higher than the new one of SFN-O (11.7 vs 6.8%, P<0.01). In the case of FN and SFN categories, the observed differences were insignificant (11.0 vs 8.8%).

Table 1

Comparison of cytological diagnoses from thyroid follicular nodules formulated in two periods: years 2008–2009 and between January 2010 and July 2012.

Cytological resultsn / %
1st period
 Mon-TFC321/72.3%
 FN-pB22/5.0%
 FN-O-pB0/0.0%
 FN49/11.0%
 FN-O52/11.7%
 Number of follicular nodules444/100.0%
 Incidence of follicular nodules per   all nodules444/9684 (4.6%)
 Incidence of follicular nodules per   patients404/6053 (6.7%)
 Mean age of all patients±s.d.52.4±12.3
 Female/male5387/666 (89%/11%)
2nd period
 Mon-TFC157/26.7%
 FLUS337/57.2%
 FLUS-O3/0.5%
 SFN52/8.8%
 SFN-O40/6.8%
 Number of follicular nodules589/100.0%
 Incidence of follicular nodules per   all nodules589/13 304 (4.4%)
 Incidence of follicular nodules per   patients570/8994 (6.3%)
 Mean age of all patients±s.d.51.8±13.8
 Female/male7915/1079 (88%/12%)

Mon-TFC, monomorphic thyroid follicular cells without conclusion; FN, follicular neoplasm; FN-pB, FN probably benign; FN-O-pB, FN oxyphilic cell type probably benign; FLUS, follicular lesion of undetermined significance; FLUS-O, FLUS oxyphilic cell type; SFN, suspicious for follicular neoplasm; SFN-O, SFN oxyphilic cell type.

No significant differences in the age of patients were observed between cytological diagnoses of FLUS (mean±s.d.: 56.8±13.1), SFN (50.5±16.0), SFN-O (59.8±15.5) and BL (53.5±11.6), and in the FLUS-O group there were only three persons (females) aged 58–82 years old. Similarly, there were no significant differences in the gender of patients between those groups, but in the FLUS group, male patients constituted 9.9%, while in the SFN and SFN-O groups, 17.5 and 19.2% respectively. The mean volumes of nodules in the groups of FLUS, SFN and SFN-O were similar (5.3±9.1, 5.5±10.9 and 6.3±9.8 cm3 respectively; mean±s.d.). In the group of surgically treated patients, the mean volume of FLUS nodules (9.7±17.3 cm3) was higher than that of SFN and SFN-O nodules (4.4±9.9 and 5.1±6.9 cm3, P<0.05 each vs FLUS). There were no significant differences in frequency of FNAB outcomes in categories that were defined similarly in both periods: nondiagnostic, 8.7 vs 8.2%; benign, 83.7 vs 84.3% and malignant or suspicious for malignancy, 1.3 vs 1.2%.

Altogether, FLUS diagnosis was formulated in 337 cases in relation to 318 nodules in 306 patients – including twice diagnosis in 17 patients, thrice in one patient, and in 12 patients with two nodules simultaneously. In six cases (1.8%), FLUS diagnosis was made because of the presence of few cell groups with nuclear overlapping and crowding and with nuclear pleomorphism (enlarged nuclei) in the smear. Moreover, in six cases (1.8%) marked anisokaryosis and in 27 cases (8.0%) less marked, anisokaryosis of TFC was observed. In other cases (298–88.4%), FNAB showed monomorphic TFC with features of architectural atypia. Diagnosis of FLUS-O was made in the case of three nodules observed in three patients.

In 123 patients with FLUS or FLUS-O diagnoses, cytological and/or histopathological follow-up was made. Repeat FNAB was carried out in 83 patients with 84 FLUS and two patients with two FLUS-O nodules, 45 patients with 47 nodules were treated surgically; seven patients with eight nodules were followed in both ways. In 15 patients, three or more FNABs were performed (Table 2). Eventually, repeat FNAB of FLUS identified: three papillary cancers or their suspicion (3.5%), two SFN (2.3%); in 20 cases (23.3%), the conclusion FLUS was maintained or control aspirates lacked cellular material; two other results (2.3%) were restricted to the specification of monomorphic TFC; in 59 cases (68.6%), BL were diagnosed, including four cases of chronic thyroiditis. In total, repeat FNABs allow to make more specific cytological diagnosis in 74.4% cases of FLUS or FLUS-O (64 out of 86). The histopathological examination of 47 FLUS showed papillary thyroid cancer (PTC) in three (6.4%) cases (two revealed in repeat FNAB and one without repeat FNAB) and the follicular adenoma in four (8.5%) nodules (two cases of SFN in repeat FNAB and two cases operated without repeat FNAB) (Table 2). In the group of patients with cytological or surgical follow-up, thyroid cancer was diagnosed in 2.4% nodules of FLUS type and in none of the two nodules of FLUS-O type. Moreover, in one patient with FLUS, histopathological examination revealed papillary microcancer in the contralateral lobe.

Table 2

Results of subsequent cytological examinations and post-operative histopathological outcome in patients with diagnosis of FLUS, FLUS-O, SFN and SFN-O.

Cytological diagnosis
FLUSFLUS-OSFNSFN-O
Cytological follow-up
 Control FNABs
  2nd FNAB
   ND101
   BL52211
   Mon-TFC1
   FLUS172
   SFN-O1
   SMN2
   MN2
   Total84242
  3rd FNAB
   ND2
   BL10
   Mon-TFC1
   FLUS1
   SMN1
  4th FNAB
   BL1
   FLUS1
  5th FNAB
   BL1
Histopathological follow-up
 Total number   of cases4702518
  NG40a (85%)22 (88%)13a (72%)
  BN4 (9%)2 (8%)3 (17%)
  MN3 (6%)1 (4%)2 (11%)

ND, nondiagnostic; Mon-TFC, monomorphic thyroid follicular cells without conclusion; FLUS, follicular lesion of undetermined significance; FLUS-O, FLUS oxyphilic cell type; SFN, suspicious for follicular neoplasm; SFN-O, SFN oxyphilic cell type; SMN, suspicious for malignant neoplasm; NG, nodular goitre; BN, benign neoplasm; MN, malignant neoplasm.

Coexistence of nodular goitre and chronic thyroiditis: in FLUS group in six cases and in SFN-O group in two cases.

Diagnosis of SFN was made in 52 patients, in single nodules in all cases, and SFN-O diagnosis was made 40 times in 39 nodules observed in 39 patients – including two repeated diagnoses in one patient. Four patients with SFN and two patients with SFN-O were subjected to repeat FNAB because of contraindications for surgery or lack of consent for such treatment. Surgical treatment was applied in 43 patients: 25 with SFN diagnosis and 18 with SFN-O (Table 2). In post-operative examination, the thyroid cancer (papillary cancer) was revealed in one nodule (4.0%) of SFN type and in two cases (11.1%) of SFN-O (both follicular cancer oxyphilic cell type). Follicular adenoma was identified in five cases: two (8.0%) in the case of SFN and three (16.7%) in the case of SFN-O. Altogether, thyroid carcinoma was diagnosed in 7.0% (three out of 43) of operated patients with cytological diagnosis of SFN or SFN-O (NS vs FLUS).

In 157 cases, FNAB outcome was limited to the description of monomorphic TFC without conclusion. Such outcome was observed in 149 patients, in one of them twice – and related to 156 nodules (in seven patients with two nodules simultaneously). Repeat FNAB was performed in 18 of those patients – eventually in 15 of them (83.3%) BL were diagnosed, in other two (11.1%) FLUS and in one (5.6%) SFN. Surgical treatment was performed in eight patients (ten nodules with monomorphic TFC outcome), and in none of those nodules, thyroid cancer was found (one papillary microcarcinoma was revealed in the contralateral lobe).

The comparison of US features of BL, FLUS, SFN and SFN-O nodules is shown in Table 3. This analysis did not include FLUS-O nodules because of too small a number of cases and nodules without full description of US characteristics. Examples of US images of FLUS were given in Fig. 1A, B, C, D and E. It was found that FLUS nodules showed US features of intermediate values between BL and SFN/SFN-O nodule types. FLUS occurred as solitary nodules two times more often than BL and two times less often than SFN. FLUS were hypoechoic, showed abnormal vascular pattern and blurred margins with similar frequency to BL nodules but were homogenic more frequently than BL (similar to SFN and SFN-O nodules). SFN and SFN-O showed similar US features and were more frequently than BL and FLUS hypoechoic and presenting abnormal vascular pattern and less frequently had blurred margins. Moreover, nodules of SFN or SFN-O type more often than BL and FLUS showed at least two L-MRFs and less often single L-MRF (Table 3). There were no significant differences in the shape of nodules. There were no differences in frequency of H-MRF either: occurrence of microcalcifications did not differ between the examined groups, in none were patient features of cervical lymph node metastasis or extracapsular invasion of nodule observed. The change of cytological diagnostic category by repeat FNAB was not related to any significant change if US image of the nodule. In six of 56 cases (10.7%) of FLUS during repeat FNAB, above 30% enlargement of the nodule was found – in one of them papillary carcinoma was revealed and in others FLUS or BL was confirmed. Nodules that were eventually found to be thyroid cancers (irrespective of the class of the first FNAB diagnosis) showed in five of six cases at least two L-MRFs or the presence of microcalcifications regarded as H-MRF.

Table 3

Ultrasound features of nodules of BL, FLUS, SFN and SFN-O type.

Cytological diagnosis (no. of cases)
Sonographic featureBL (250)FLUS (302)SFN (48)SFN-O (37)Statistical significance
Microcalcifications36 (14.4%)30 (9.9%)6 (12.5%)2 (5.4%)NS
Hypoechogenicity (%)177 (70.8%)198 (65.6%)39 (81.3%)32 (86.5%)P<0.005: SFN/SFN-O vs FLUS
P<0.05: SFN-O vs BL and vs FLUS; SFN vs FLUS; SFN/SFN-O vs BL
Homogeneity (%)34 (13.6%)76 (25.1%)16 (33.3%)14 (37.8%)P<0.0001: SFN/SFN-O vs BL
P<0.001: FLUS, SFN, SFN-O vs BL
Blurred margins (%)36 (14.4%)41 (13.6%)0 (0%)2 (5.4%)P<0.005: SFN/SFN-O vs BL and vs FLUS
P<0.01: SFN vs BL and vs FLUS
Increased internal  vascularity (%)23 (9.2%)42 (13.9%)14 (29.2%)10 (27.0%)P<0.0001: SFN vs BL; SFN/SFN-O vs BL
P<0.005: SFN-O vs BL; SFN–SFN-O vs FLUS
P<0.01: SFN vs FLUS
P<0.05: SFN-O vs FLUS
Height/width ≥124 (9.6%)42 (13.9%)8 (16.7%)4 (10.8%)NS
Lesions <10 mm (%)22 (8.8)27 (8.9)7 (14.6)8 (21.6)P<0.05: SFN-O vs BL and vs FLUS; SFN/SFN-O vs BL and vs FLUS
Solitary (%)14 (5.6%)33 (10.9%)11 (22.9%)5 (13.5%)P<0.0001: SFN vs BL
P<0.0005: SFN/SFN-O vs BL
P<0.05: FLUS vs BL; SFN/SFN-O vs FLUS
>1 L-MRF62 (24.8%)90 (29.8%)23 (47.9%)22 (59.5%)P<0.0001: SFN-O vs BL; SFN/SFN-O vs BL and vs FLUS
P<0.005: SFN vs BL; SFN-O vs FLUS
P<0.05: SFN vs FLUS
1 L-MRF152 (60.8%)182 (60.3%)19 (39.6%)13 (35.1%)P<0.0005: SFN/SFN-O vs BL and vs FLUS
P<0.005: SFN-O vs BL and vs FLUS
P<0.01: SFN vs BL and vs FLUS

BL, benign lesions; FLUS, follicular lesion of undetermined significance; FLUS-O, FLUS oxyphilic cell type; SFN, suspicious for follicular neoplasm; SFN-O, SFN oxyphilic cell type; L-MRF, low malignancy risk features.

Figure 1
Figure 1

Ultrasound images for follicular lesion of undetermined significance: (A) normoechoic nodule, (B) isoechoic, partially spongiform nodule, (C) large, solid and hypoechogenic nodule, (D) nodule in a patient with chronic thyroiditis and (E) nodule in a patient after radioiodine treatment.

Citation: European Journal of Endocrinology 168, 4; 10.1530/EJE-12-0993

Discussion

The areas of normal iodine supply and endemic areas differ significantly in incidence of thyroid nodules as well as in their histopathological types. Higher incidence of multinodular goitre is characteristic of endemic areas, where follicular proliferative lesions (hyperplastic nodules and FNs) predominate (5, 10). Such epidemiological differences have significant impact on effectiveness of selection thyroid nodules for FNAB as well as on potential risk for malignancy in the case of cytological diagnostic categories related to follicular lesions. Our earlier studies showed that the risk for cancer in a lesion classified cytologically as ‘FN’ is relatively low in an endemic area and does not exceed 5–10%, while in iodine-rich regions it reaches 25–30% or even more (4, 10, 11, 12, 13, 14). Introduction of the new category of cytological diagnoses – FLUS – potentially allowing to select from follicular nodules lesions with lower risk for malignancy was therefore particularly welcome. We undertook earlier attempts in this area. Our experienced pathologist, in some cases of follicular lesions, formulated the following outcome: ‘FN – probably adenoma or probably benign’. The risk for cancer in the case of such outcome was similar to that in the case of BL (2 vs 1.9%), but such outcome was relatively rare (3). Also, there was a fair percentage of follicular lesions in which smears were obtained with low cellularity, monomorphic TFC with microfollicular pattern and very scant colloid, and the outcome in such cases was limited to the description of cellular composition without specific diagnostic conclusion. Those outcomes in relation to clinical picture were regarded by physicians as a diagnosis of BL or as nondiagnostic. Such smears, when considered separately, did not satisfy criteria of ‘BL’ or ‘FN’. The current category of FLUS allows to include some of such cases. As a result, in our material, the number of cytological outcomes without any diagnostic conclusion decreased significantly from 72.3 to 26.7% of all follicular lesions. The category of FLUS, although not perfect, brings some relevant information, which helps physicians to find the optimal management.

According to published reports, diagnosis of FLUS constitutes about 1% up to nearly 20% of all cytological outcomes (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). In our material, such diagnosis is made in 3.8% of patients subjected to FNAB and constitutes above 57% of outcomes in the case of follicular lesions. The differences in frequency of making a FLUS diagnosis may result from the above-mentioned epidemiological circumstances that affect the incidence of follicular lesions. But a more important cause seems to be the lack of uniformity of the applied criteria for FLUS diagnosis. It is especially difficult to define demarcations between FLUS and its neighbouring diagnoses (nondiagnostic, benign, SFN and suspicious for malignancy) (15). As a consequence, reproducibility of FLUS diagnoses is as low as 20% (22). There is general consensus that this category should include the cases in which it is impossible to distinguish whether the smear should be classified as BL or SFN. But the border between nondiagnostic smears and FLUS is not so clearly defined (16, 23, 24). According to NCI guidelines, the FLUS category may include smears with predominant microfollicular pattern, but limited cellularity – as at our centre. But some reports suggest that in this group of smears, there are marked differences in the potential risk for malignancy. Nayar & Ivanovic (25) showed that this risk is about 5% in the case of cystic lesions and 21% in other cases (i.e. cases with blood excess and low cellularity with a predominant microfollicular pattern, cases with extensive clotting or other artefacts). In our material, FLUS category did not include predominantly cystic or colloid-rich lesions with rare/absent follicular cells. We placed those cases in the nondiagnostic category or in the benign category if cysts contained colloid only or if complete emptying could be achieved and there were no atypical cytological or imaging findings. Low cellularity aspirates with monomorphic TFC were included into FLUS on the basis of nuclear or architectural atypia. If all the smears with monomorphic TFC and usually low cellularity had been included into FLUS, the percentage of that diagnosis would have been higher. The problem of the degree of nuclear atypia that allows to classify a nodule as FLUS and not as suspicious for malignancy is also debatable. Some authors do not accept including into FLUS the cases with the presence of local features suggestive of PTC (nuclear grooves, enlarged nuclei with pale chromatin and alterations in nuclear contour and shape) in an aspirate that is otherwise benign in microscopic appearance (26). Such cases could represent benign nodules with focal nuclear atypia, follicular carcinomas with nuclear atypia, variants of papillary carcinoma with subtle nuclear changes or a rare variant of PTC arising within a follicular adenoma (27). In our previous classification, such cases were regarded as lesions suspicious for malignancy. Both ‘suspicious for malignancy’ and FLUS categories can show morphologic changes suggestive of PTC. Clear demarcation may not be possible in all cases, what affects not only the frequency of FLUS diagnoses but also the potential risk for malignancy in this category. Our cytopathologists reserve suspicious for malignancy category for cases that show more pronounced atypia and then malignancy risk in this group is several times higher than in the FLUS category (45 vs 6.4% respectively). However, the data from other centres show marked diversity as Table 4 shows. It describes the percentage of MNs found in post-operative histopathological examination of nodules that had been categorised as FLUS. This percentage varies between 4.7 and 48.2%, so in some centres, it is several times higher than that suggested in the NCI guidelines. Thus, there are attempts to distinguish among FLUS category two groups – showing ‘nuclear atypia’ that relates to higher risk for malignancy, and the group with ‘microfollicular architecture’ in which the risk is lower (12, 19, 28, 29, 30). As early as in 2001, Kelman et al. (28) found that in the group of indeterminate specimens, cytological/nuclear atypia confers a higher risk of cancer than microfollicular patterns without atypia – 60 and 7% respectively. The significance of cytological/nuclear atypia in indeterminate thyroid biopsies was confirmed by Kato et al. (31), who showed that the risk is particularly high for patients having both nuclear grooves and inclusions. VanderLaan et al. (30) reported that the rate of malignancy for patients with ‘cytological/nuclear’ atypia in the FLUS group was 50% in contrast with 24% for patients with ‘architectural’ atypia. Similar data were shown by Olson et al. (12) – 48 and 27% respectively. Horne et al. (29) found that malignancy risk was several times higher in the group of FLUS with nuclear atypia (56%) than in the group with low cellularity and predominant microfollicular pattern (7%). In our material, FLUS with nuclear atypia was rare and the lesions with architectural atypia predominated, which may be a consequence of epidemiological situation and still high incidence of non-neoplastic follicular lesions. Thus, we were not able to assess those two groups separately. A low number of cases with nuclear atypia may also attribute to the low percentage of cancers revealed in FLUS nodules at our centre. Faquin & Baloch (11) reported that the presence of few atypical cells showing intranuclear grooves with or without nuclear pleomorphism was a basis for FLUS diagnosis in nearly 30% of cases. Theoharis et al. (19) showed this percentage to be 35%, while in our material significant nuclear atypia was observed in ∼5% cases of FLUS. Our data confirm the rationality of conservative management in the case of FLUS diagnosis.

Table 4

Results of surgical follow-up in patients with cytological diagnosis classified to the category of indeterminate lesions (FLUS or FLUS-O), comparison with the data from other reports.

Surgery follow-up for indeterminate lesionsOur results (2013)Nayar & Ivanovic(25)Theoharis et al.(19)Faquin & Baloch(11)Broome & SolrzanoRenshaw(32)VanderLaan et al.(20)Bongiovanni et al.(17)Jo et al.(18)Nga et al.(38)Teixeira et al.(36)Wu et al.(14)
Non-neoplastic lesions (%)85.151.225.957.154.975c54.3c85.6c83c53.450.856.9
No. of cases47383a27273822041991325313119751
Benign neoplasm (%)8.544.125.923.826.833.633.021.5
Malignant neoplasm (%)6.44.748.219.118.32545.714.41713.016.26b

Without low cellularity cases.

After excluding papillary microcarcinoma.

Includes both non-neoplastic lesions and benign neoplasm.

Another problem is the differentiation of the malignancy risk between FLUS and SFN categories. Olson et al. (12) showed that in the case of indeterminate cytology related to microfollicular architecture, the risk for cancer amounts to 27% and is similar to that observed in SFN (28%). Faquin & Baloch (11) reported that the rate of malignancy in FLUS cases exceeded 19% and was slightly lower than in the SFN category (25%). According to Broome & Solorzano (13), the rate of malignancy for the FLUS category reached 20%, and for SFN, 36%; while Theoharis et al. (19) reported higher risk in the FLUS group than in the SFN group, (48 and 34% respectively), which can be attributed mainly to a high rate of FLUS with nuclear atypia. As a result, the FLUS category interpreted in such a way does not play its main role because it does not separate from follicular nodule lesions with lower risk for malignancy. However, in many centres, the use of the FLUS category allows to successfully distinguish between follicular lesions of higher and lower risk for malignancy: Wu et al. (14) – the rate of malignancy for FLUS diagnosis – 6 vs 22% for SFN category; Bongiovanni et al. (24) – 14.4 vs 32.1% respectively. In our material, post-operative histopathological verifications revealed cancer in 6.4% of FLUS, 4.0% of SFN and 11.1% of SFN-O. The observed differences were not statistically significant, possibly because of too few cases. In the group of monomorphic TFC without conclusion, the risk for malignancy was similar to that observed in BL.

The recommended management of nodules diagnosed as FLUS is to perform repeat FNAB. Our data confirm its advantages. In 75% of cases of FLUS, repeat FNAB led to making a more specific diagnostic conclusion, most often of BL (68% of repeat FNAB for FLUS). Additionally, repeat FNABs allowed to reveal some papillary cancers. Faquin & Baloch (11) also showed the usefulness of repeated FNAB – in patients who underwent repeat FNAB, the malignancy rate was 27% on surgical excision compared with 15% in the cases without repeat FNAB. On the other hand, Broome & Solorzano (13) as well as VanderLaan et al. (20) did not find any differences in the rate of malignancy for patients who had undergone repeated FNAB before surgery and patients going directly to surgery. In our material, the number of resections in the patients who underwent repeat FNAB with FLUS diagnosed in the first examination was too small to allow comparison with the patients operated directly after FLUS was found in FNAB. The majority of our patients were referred to surgical treatment because of large goitre, without delay after the first FNAB. In our material, the mean size of nodules in the FLUS group was nearly twice as large as that reported by Horne et al. (29) as well as by Faquin & Baloch (11). Repeat FNAB seems to be controversial in the cases of FLUS with nuclear atypia. The high risk for malignancy in these cases raises doubts about rationale for delaying surgical treatment. Moreover, Renshaw (32) found that patients with an atypical and then a benign cytological diagnosis have a risk for malignancy significantly higher than those with a single benign diagnosis (16 vs 1.7%). VanderLaan et al. (20) showed that there was no statistically significant difference between the rate of malignancy in patients with a benign aspirate after initial FLUS vs patients with no repeated FNAB or a repeated FLUS diagnosis. According to various reports (including our data), in ∼20–30% of FLUS cases, a repeat FNAB will again be interpreted as FLUS (Table 5). The optimal management of patients with two or more subsequent FLUS diagnoses is equivocal– it is not clear whether repeated FLUS outcome increases the risk for malignancy (11, 25).

Table 5

Results of repeat FNABs in patients with diagnosis classified into category of indeterminate lesions (FLUS or FLUS-O), comparison with other reports.

Our results (2013)Nayar & Ivanovic(25)Faquin & Baloch(11)Nga et al.(38)VanderLaan et al.(20)
Category of cytological diagnoses of repeat FNAB for indeterminate lesions86 cases144 cases203 cases82 cases287 cases
ND (%)7.070.99.84.2
BL (%)68.65461.646.348.4
FLUS/FLUS-O (%)16.3a3122.728.027.9
SFN/SFN-O (%)2.369.915.98.7
SMN (%)1.2<13.49.1
MN (%)2.311.51.7

ND, nondiagnostic; BL, benign lesions; FLUS, follicular lesion of undetermined significance; FLUS-O, FLUS oxyphilic cell type; SFN, suspicious for follicular neoplasm; SFN-O, SFN oxyphilic cell type; SMN, suspicious for malignant neoplasm; MN, malignant neoplasm; Mon-TFC, monomorphic thyroid follicular cells without conclusion.

Additionally 2.3% Mon-TFC.

Our data indicate that in endemic and post-endemic areas, it is justified to adopt conservative management not only in the case of FLUS nodules, with possible exclusion of cases with nuclear atypia, but also in some cases of SFN. In the latter category, the risk for malignancy is lower than in iodine-rich areas. Our earlier reports showed that in the case of FN, diagnosis made in the regions of recently normalised iodine supply indicates that surgical treatment may be safely postponed for small lesions (diameter <10 mm) (4). Other reports also show that the size of a lesion is an important feature in the assessment of probability of thyroid cancer in patients with cytological diagnosis of FN (33, 34, 35). In relation to FLUS category, recent studies indicate no correlation between the size of nodule, age, gender of patients and elevated risk for malignancy (11, 36, 37). Little data exist in the published literature about sonographic risk features for cancer in FLUS. According to our data, FLUS nodules present a US image that is intermediate between that of BL and SFN, and the presence of at least two MRFs is more frequent in SFN nodules than in BL and FLUS. Moreover, 80% of revealed cancers had at least two MRFs. Thus, taking into consideration the presence of at least two MRFs may improve effectiveness of US examination in selection of nodules for FNAB and revealing thyroid cancers in endemic/post-endemic areas.

Summing up, establishing the subgroup of ‘FLUS’ is of particular importance in endemic areas where it significantly decreases the percentage of FNAB outcomes without diagnostic conclusion. The risk of malignancy connected with such diagnosis is dependent on the iodine status of the examined population and on the method of classification of smears into this category – especially of cases with nuclear atypia. In iodine-deficient areas and areas of recently normalised iodine supply, this risk is low – as evaluated on the basis of clinical and surgical follow-up it does not exceed 5%. It is mainly a consequence of a lower percentage of nodules with nuclear atypia among numerous non-neoplastic follicular lesions. In such areas, the proper management of FLUS is to repeat biopsy rather than to refer to surgeon (unless the necessity for surgical treatment results from the size of goitre). Repeat FNAB of FLUS nodules leads to more specific cytological diagnosis in about 3/4 of cases.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by Medical University of Lodz (grant number 502-03-1-153-05-502-14-005).

References

  • 1

    GharibHPapiniEPaschkeRDuickDSValcaviRHegedüsLVittiPAACE/AME/ETA Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules. Endocrine Practice201016 (Suppl 1) 143. (doi:10.4158/10024.GL).

    • Search Google Scholar
    • Export Citation
  • 2

    BalochZWCibasESClarkDPLayfieldLJLjungBMPitmanMBAbatiA. The National Cancer Institute Thyroid fine needle aspiration state of the science conference: a summation. CytoJournal20085117. (doi:10.1186/1742-6413-5-1).

    • Search Google Scholar
    • Export Citation
  • 3

    Słowinska-KlenckaDKlenckiMSpornySLewinskiA. Fine needle aspiration biopsy of the thyroid in an area of endemic goitre: influence of restored sufficient iodine supplementation on the clinical significance of cytological results. European Journal of Endocrinology20021461926. (doi:10.1530/eje.0.1460019).

    • Search Google Scholar
    • Export Citation
  • 4

    Słowińska-KlenckaDPopowiczBLewińskiAKlenckiM. The fine-needle aspiration biopsy efficacy of small thyroid nodules in the area of recently normalized iodine supply. European Journal of Endocrinology2008159747754. (doi:10.1530/EJE-08-0524).

    • Search Google Scholar
    • Export Citation
  • 5

    Feldt-RasmussenU. Prevalence and types of thyroid cancer as a function of iodine intake. In The Thyroid and Environment pp 187192. Eds PeterFWiersingaWHostalekU. Stuttgart, New York: Verlag Schattauer.2000

    • Search Google Scholar
    • Export Citation
  • 6

    LaurbergPCerqueiraCOvesenLRasmussenLBPerrildHAndersenSPedersenIBCarléA. Iodine intake as a determinant of thyroid disorders in populations. Best Practice & Research. Clinical Endocrinology & Metabolism2010241327. (doi:10.1016/j.beem.2009.08.013).

    • Search Google Scholar
    • Export Citation
  • 7

    SzybinskiZZarneckiA. Prevalence of goiter, iodine deficiency and iodine prophylaxis in Poland. The results of the nation-wide study. Endokrynologia Polska199344373388.

    • Search Google Scholar
    • Export Citation
  • 8

    SzybinskiZGolkowskiFBuziak-BerezaMTrofimiukMPrzybylik-MazurekEHusznoBBandurska-StankiewiczEBar-AndziakEDorantBKinalskaI. Effectiveness of the iodine prophylaxis model adopted in Poland. Journal of Endocrinological Investigation200831309313.

    • Search Google Scholar
    • Export Citation
  • 9

    SpornySLangeDSygutJKuligAOlszewskiWSłowińska-KlenckaDJakubowskiWJarzębB. Diagnosis and treatment of thyroid cancer – Polish guidelines. Part I: diagnosis of nodular goiter and fine needle aspiration biopsy. Polish Journal of Endocrinology201061522542.

    • Search Google Scholar
    • Export Citation
  • 10

    FratesMCBensonCBDoubiletPMKunreutherEContrerasMCibasESOrcuttJMooreFDJrLarsenPRMarquseeE. Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. Journal of Clinical Endocrinology and Metabolism20069134113417. (doi:10.1210/jc.2006-0690).

    • Search Google Scholar
    • Export Citation
  • 11

    FaquinWCBalochZW. Fine-needle aspiration of follicular patterned lesions of the thyroid: diagnosis, management, and follow-up according to National Cancer Institute (NCI) recommendations. Diagnostic Cytopathology201038731739.

    • Search Google Scholar
    • Export Citation
  • 12

    OlsonMTClarkDPErozanYSAliSZ. Spectrum of risk of malignancy in subcategories of atypia of undetermined significance. Acta Cytologica201155518525. (doi:10.1159/000333232).

    • Search Google Scholar
    • Export Citation
  • 13

    BroomeJTSolorzanoCC. The impact of atypia/follicular lesion of undetermined significance on the rate of malignancy in thyroid fine-needle aspiration: evaluation of the Bethesda system for reporting thyroid cytopathology. Surgery201115012341241. (doi:10.1016/j.surg.2011.09.006).

    • Search Google Scholar
    • Export Citation
  • 14

    WuHHRoseCElsheikhTM. The Bethesda system for reporting thyroid cytopathology: an experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy. Diagnostic Cytopathology201240399403. (doi:10.1002/dc.21477).

    • Search Google Scholar
    • Export Citation
  • 15

    OhoriNPSchoedelKE. Variability in the atypia of undetermined significance/follicular lesion of undetermined significance diagnosis in the bethesda system for reporting thyroid cytopathology: sources and recommendations. Acta Cytologica201155492498. (doi:10.1159/000334218).

    • Search Google Scholar
    • Export Citation
  • 16

    SinghRSWangHH. Eliminating the “atypia of undetermined significance/follicular lesion of undetermined significance” category from the Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2011136896902. (doi:10.1309/AJCPIX52MBOKTICP).

    • Search Google Scholar
    • Export Citation
  • 17

    BongiovanniMKraneJFCibasESFaquinWC. The atypical thyroid fine-needle aspiration: past, present, and future. Cancer Cytopathology20121207386. (doi:10.1002/cncy.20178).

    • Search Google Scholar
    • Export Citation
  • 18

    JoVYStelowEBDustinSMHanleyKZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2010134450456. (doi:10.1309/AJCP5N4MTHPAFXFB).

    • Search Google Scholar
    • Export Citation
  • 19

    TheoharisCGASchofieldKMHammersLUndelsmanRChhiengDC. The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution. Thyroid20091912151223. (doi:10.1089/thy.2009.0155).

    • Search Google Scholar
    • Export Citation
  • 20

    VanderLaanPAMarquseeEKraneJF. Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations. American Journal of Clinical Pathology2011135770775. (doi:10.1309/AJCP4P2GCCDNHFMY).

    • Search Google Scholar
    • Export Citation
  • 21

    LayfieldLJMortonMJCramerHM. Implications of the proposed thyroid fine-needle aspiration category of ‘follicular lesion of undetermined significance’: a five-year multi-institutional analysis. Diagnostic Cytopathology200937710714. (doi:10.1002/dc.21093).

    • Search Google Scholar
    • Export Citation
  • 22

    Cochand-PriolletBSchmittFCTötschMVielhP. The Bethesda terminology for reporting thyroid cytopathology: from theory to practice in Europe. Acta Cytologica201155507511. (doi:10.1159/000334687).

    • Search Google Scholar
    • Export Citation
  • 23

    VanderLaanPARenshawAAKraneJF. Atypia of undetermined significance and nondiagnostic rates in The Bethesda System for Reporting Thyroid Cytopathology are inversely related. American Journal of Clinical Pathology2012137462465. (doi:10.1309/AJCPI41QOQUSKDGP).

    • Search Google Scholar
    • Export Citation
  • 24

    BongiovanniMCrippaSBalochZPianaSSpitaleAPagniFMazzucchelliLDi BellaCFaquinW. Comparison of 5-tiered and 6-tiered diagnostic systems for the reporting of thyroid cytopathology. Cancer Cytopathology2012120117125. (doi:10.1002/cncy.20195).

    • Search Google Scholar
    • Export Citation
  • 25

    NayarRIvanovicM. The indeterminate thyroid fine-needle aspiration. Cancer Cytopathology200925195202. (doi:10.1002/cncy.20029).

  • 26

    CibasESAliSZ. The Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2009132658665. (doi:10.1309/AJCPPHLWMI3JV4LA).

    • Search Google Scholar
    • Export Citation
  • 27

    OnoJCWilburDCLeeHYangJKraneJFBongiovanniMFaquinWC. Cytologic features of focal papillary thyroid carcinoma arising within follicular adenoma: a masked cytomorphologic analysis of 17 cases. Acta Cytologica201155531538. (doi:10.1159/000333240).

    • Search Google Scholar
    • Export Citation
  • 28

    KelmanASRathanALeibowitzJBursteinDEHaberRS. Thyroid cytology and the risk of malignancy in thyroid nodules: importance of nuclear atypia in indeterminate specimens. Thyroid200111271277. (doi:10.1089/105072501750159714).

    • Search Google Scholar
    • Export Citation
  • 29

    HorneMJChhiengDCTheoharisCSchofieldKKowalskiDPrasadMLHammersLUdelsmanRAdeniranAJ. Thyroid follicular lesion of undetermined significance: evaluation of the risk of malignancy using the two-tier sub-classification. Diagnostic Cytopathology201240410415. (doi:10.1002/dc.21790).

    • Search Google Scholar
    • Export Citation
  • 30

    VanderLaanPAMarquseeEKraneJF. Usefulness of diagnostic qualifiers for thyroid fine-needle aspirations with atypia of undetermined significance. American Journal of Clinical Pathology2011136572577. (doi:10.1309/AJCPO0BQ2YSKPXXP).

    • Search Google Scholar
    • Export Citation
  • 31

    KatoMABuitragoDMooTAKeutgenXMHodaRSRicciJAChristosPJYangGFaheyTJIIIZarnegarR. Predictive value of cytologic atypia in indeterminate thyroid fine-needle aspirate biopsies. Annals of Surgical Oncology20111828932898. (doi:10.1245/s10434-011-1635-1).

    • Search Google Scholar
    • Export Citation
  • 32

    RenshawAA. Does a repeated benign aspirate change the risk of malignancy after an initial atypical thyroid fine-needle aspiration?American Journal of Clinical Pathology2010134788792. (doi:10.1309/AJCPRA9Y2XQVFOFV).

    • Search Google Scholar
    • Export Citation
  • 33

    LubitzCCFaquinWCYangJMekelMGazRDParangiSRandolphGWHodinRAStephenAE. Clinical and cytological features predictive of malignancy in thyroid follicular neoplasms. Thyroid2010202531. (doi:10.1089/thy.2009.0208).

    • Search Google Scholar
    • Export Citation
  • 34

    MihaiRParkerAJRoskellDSadlerGP. One in four patients with follicular thyroid cytology (THY3) has a thyroid carcinoma. Thyroid2009193337. (doi:10.1089/thy.2008.0200).

    • Search Google Scholar
    • Export Citation
  • 35

    BalochZWFleisherSLiVolsiVAGuptaPK. Diagnosis of ‘follicular neoplasm’: a gray zone in thyroid fine-needle aspiration cytology. Diagnostic Cytopathology2002264144. (doi:10.1002/dc.10043).

    • Search Google Scholar
    • Export Citation
  • 36

    TeixeiraGVChikotaHTeixeiraTManfroGPaiSITufanoRP. Incidence of malignancy in thyroid nodules determined to be follicular lesions of undetermined significance on fine-needle aspiration. World Journal of Surgery2012366974. (doi:10.1007/s00268-011-1336-8).

    • Search Google Scholar
    • Export Citation
  • 37

    MoonWBaekJHJungSLKimDWKimEKKimJYKwakJYLeeJHLeeJHNaDG. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean Journal of Radiology201112114. (doi:10.3348/kjr.2011.12.1.1).

    • Search Google Scholar
    • Export Citation
  • 38

    NgaMEKumarasingheMPTieBSterrettGFWoodBWalshJNguyenHWhyteAFrostFA. Experience with standardized thyroid fine-needle aspiration reporting categories: follow-up data from 529 cases with “indeterminate” or “atypical” reports. Cancer Cytopathology2010118423433. (doi:10.1002/cncy.20111).

    • Search Google Scholar
    • Export Citation

*(D Słowińska-Klencka and E Woźniak contributed equally to this work)

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    Ultrasound images for follicular lesion of undetermined significance: (A) normoechoic nodule, (B) isoechoic, partially spongiform nodule, (C) large, solid and hypoechogenic nodule, (D) nodule in a patient with chronic thyroiditis and (E) nodule in a patient after radioiodine treatment.

  • 1

    GharibHPapiniEPaschkeRDuickDSValcaviRHegedüsLVittiPAACE/AME/ETA Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules. Endocrine Practice201016 (Suppl 1) 143. (doi:10.4158/10024.GL).

    • Search Google Scholar
    • Export Citation
  • 2

    BalochZWCibasESClarkDPLayfieldLJLjungBMPitmanMBAbatiA. The National Cancer Institute Thyroid fine needle aspiration state of the science conference: a summation. CytoJournal20085117. (doi:10.1186/1742-6413-5-1).

    • Search Google Scholar
    • Export Citation
  • 3

    Słowinska-KlenckaDKlenckiMSpornySLewinskiA. Fine needle aspiration biopsy of the thyroid in an area of endemic goitre: influence of restored sufficient iodine supplementation on the clinical significance of cytological results. European Journal of Endocrinology20021461926. (doi:10.1530/eje.0.1460019).

    • Search Google Scholar
    • Export Citation
  • 4

    Słowińska-KlenckaDPopowiczBLewińskiAKlenckiM. The fine-needle aspiration biopsy efficacy of small thyroid nodules in the area of recently normalized iodine supply. European Journal of Endocrinology2008159747754. (doi:10.1530/EJE-08-0524).

    • Search Google Scholar
    • Export Citation
  • 5

    Feldt-RasmussenU. Prevalence and types of thyroid cancer as a function of iodine intake. In The Thyroid and Environment pp 187192. Eds PeterFWiersingaWHostalekU. Stuttgart, New York: Verlag Schattauer.2000

    • Search Google Scholar
    • Export Citation
  • 6

    LaurbergPCerqueiraCOvesenLRasmussenLBPerrildHAndersenSPedersenIBCarléA. Iodine intake as a determinant of thyroid disorders in populations. Best Practice & Research. Clinical Endocrinology & Metabolism2010241327. (doi:10.1016/j.beem.2009.08.013).

    • Search Google Scholar
    • Export Citation
  • 7

    SzybinskiZZarneckiA. Prevalence of goiter, iodine deficiency and iodine prophylaxis in Poland. The results of the nation-wide study. Endokrynologia Polska199344373388.

    • Search Google Scholar
    • Export Citation
  • 8

    SzybinskiZGolkowskiFBuziak-BerezaMTrofimiukMPrzybylik-MazurekEHusznoBBandurska-StankiewiczEBar-AndziakEDorantBKinalskaI. Effectiveness of the iodine prophylaxis model adopted in Poland. Journal of Endocrinological Investigation200831309313.

    • Search Google Scholar
    • Export Citation
  • 9

    SpornySLangeDSygutJKuligAOlszewskiWSłowińska-KlenckaDJakubowskiWJarzębB. Diagnosis and treatment of thyroid cancer – Polish guidelines. Part I: diagnosis of nodular goiter and fine needle aspiration biopsy. Polish Journal of Endocrinology201061522542.

    • Search Google Scholar
    • Export Citation
  • 10

    FratesMCBensonCBDoubiletPMKunreutherEContrerasMCibasESOrcuttJMooreFDJrLarsenPRMarquseeE. Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. Journal of Clinical Endocrinology and Metabolism20069134113417. (doi:10.1210/jc.2006-0690).

    • Search Google Scholar
    • Export Citation
  • 11

    FaquinWCBalochZW. Fine-needle aspiration of follicular patterned lesions of the thyroid: diagnosis, management, and follow-up according to National Cancer Institute (NCI) recommendations. Diagnostic Cytopathology201038731739.

    • Search Google Scholar
    • Export Citation
  • 12

    OlsonMTClarkDPErozanYSAliSZ. Spectrum of risk of malignancy in subcategories of atypia of undetermined significance. Acta Cytologica201155518525. (doi:10.1159/000333232).

    • Search Google Scholar
    • Export Citation
  • 13

    BroomeJTSolorzanoCC. The impact of atypia/follicular lesion of undetermined significance on the rate of malignancy in thyroid fine-needle aspiration: evaluation of the Bethesda system for reporting thyroid cytopathology. Surgery201115012341241. (doi:10.1016/j.surg.2011.09.006).

    • Search Google Scholar
    • Export Citation
  • 14

    WuHHRoseCElsheikhTM. The Bethesda system for reporting thyroid cytopathology: an experience of 1,382 cases in a community practice setting with the implication for risk of neoplasm and risk of malignancy. Diagnostic Cytopathology201240399403. (doi:10.1002/dc.21477).

    • Search Google Scholar
    • Export Citation
  • 15

    OhoriNPSchoedelKE. Variability in the atypia of undetermined significance/follicular lesion of undetermined significance diagnosis in the bethesda system for reporting thyroid cytopathology: sources and recommendations. Acta Cytologica201155492498. (doi:10.1159/000334218).

    • Search Google Scholar
    • Export Citation
  • 16

    SinghRSWangHH. Eliminating the “atypia of undetermined significance/follicular lesion of undetermined significance” category from the Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2011136896902. (doi:10.1309/AJCPIX52MBOKTICP).

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    • Export Citation
  • 17

    BongiovanniMKraneJFCibasESFaquinWC. The atypical thyroid fine-needle aspiration: past, present, and future. Cancer Cytopathology20121207386. (doi:10.1002/cncy.20178).

    • Search Google Scholar
    • Export Citation
  • 18

    JoVYStelowEBDustinSMHanleyKZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2010134450456. (doi:10.1309/AJCP5N4MTHPAFXFB).

    • Search Google Scholar
    • Export Citation
  • 19

    TheoharisCGASchofieldKMHammersLUndelsmanRChhiengDC. The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution. Thyroid20091912151223. (doi:10.1089/thy.2009.0155).

    • Search Google Scholar
    • Export Citation
  • 20

    VanderLaanPAMarquseeEKraneJF. Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations. American Journal of Clinical Pathology2011135770775. (doi:10.1309/AJCP4P2GCCDNHFMY).

    • Search Google Scholar
    • Export Citation
  • 21

    LayfieldLJMortonMJCramerHM. Implications of the proposed thyroid fine-needle aspiration category of ‘follicular lesion of undetermined significance’: a five-year multi-institutional analysis. Diagnostic Cytopathology200937710714. (doi:10.1002/dc.21093).

    • Search Google Scholar
    • Export Citation
  • 22

    Cochand-PriolletBSchmittFCTötschMVielhP. The Bethesda terminology for reporting thyroid cytopathology: from theory to practice in Europe. Acta Cytologica201155507511. (doi:10.1159/000334687).

    • Search Google Scholar
    • Export Citation
  • 23

    VanderLaanPARenshawAAKraneJF. Atypia of undetermined significance and nondiagnostic rates in The Bethesda System for Reporting Thyroid Cytopathology are inversely related. American Journal of Clinical Pathology2012137462465. (doi:10.1309/AJCPI41QOQUSKDGP).

    • Search Google Scholar
    • Export Citation
  • 24

    BongiovanniMCrippaSBalochZPianaSSpitaleAPagniFMazzucchelliLDi BellaCFaquinW. Comparison of 5-tiered and 6-tiered diagnostic systems for the reporting of thyroid cytopathology. Cancer Cytopathology2012120117125. (doi:10.1002/cncy.20195).

    • Search Google Scholar
    • Export Citation
  • 25

    NayarRIvanovicM. The indeterminate thyroid fine-needle aspiration. Cancer Cytopathology200925195202. (doi:10.1002/cncy.20029).

  • 26

    CibasESAliSZ. The Bethesda system for reporting thyroid cytopathology. American Journal of Clinical Pathology2009132658665. (doi:10.1309/AJCPPHLWMI3JV4LA).

    • Search Google Scholar
    • Export Citation
  • 27

    OnoJCWilburDCLeeHYangJKraneJFBongiovanniMFaquinWC. Cytologic features of focal papillary thyroid carcinoma arising within follicular adenoma: a masked cytomorphologic analysis of 17 cases. Acta Cytologica201155531538. (doi:10.1159/000333240).

    • Search Google Scholar
    • Export Citation
  • 28

    KelmanASRathanALeibowitzJBursteinDEHaberRS. Thyroid cytology and the risk of malignancy in thyroid nodules: importance of nuclear atypia in indeterminate specimens. Thyroid200111271277. (doi:10.1089/105072501750159714).

    • Search Google Scholar
    • Export Citation
  • 29

    HorneMJChhiengDCTheoharisCSchofieldKKowalskiDPrasadMLHammersLUdelsmanRAdeniranAJ. Thyroid follicular lesion of undetermined significance: evaluation of the risk of malignancy using the two-tier sub-classification. Diagnostic Cytopathology201240410415. (doi:10.1002/dc.21790).

    • Search Google Scholar
    • Export Citation
  • 30

    VanderLaanPAMarquseeEKraneJF. Usefulness of diagnostic qualifiers for thyroid fine-needle aspirations with atypia of undetermined significance. American Journal of Clinical Pathology2011136572577. (doi:10.1309/AJCPO0BQ2YSKPXXP).

    • Search Google Scholar
    • Export Citation
  • 31

    KatoMABuitragoDMooTAKeutgenXMHodaRSRicciJAChristosPJYangGFaheyTJIIIZarnegarR. Predictive value of cytologic atypia in indeterminate thyroid fine-needle aspirate biopsies. Annals of Surgical Oncology20111828932898. (doi:10.1245/s10434-011-1635-1).

    • Search Google Scholar
    • Export Citation
  • 32

    RenshawAA. Does a repeated benign aspirate change the risk of malignancy after an initial atypical thyroid fine-needle aspiration?American Journal of Clinical Pathology2010134788792. (doi:10.1309/AJCPRA9Y2XQVFOFV).

    • Search Google Scholar
    • Export Citation
  • 33

    LubitzCCFaquinWCYangJMekelMGazRDParangiSRandolphGWHodinRAStephenAE. Clinical and cytological features predictive of malignancy in thyroid follicular neoplasms. Thyroid2010202531. (doi:10.1089/thy.2009.0208).

    • Search Google Scholar
    • Export Citation
  • 34

    MihaiRParkerAJRoskellDSadlerGP. One in four patients with follicular thyroid cytology (THY3) has a thyroid carcinoma. Thyroid2009193337. (doi:10.1089/thy.2008.0200).

    • Search Google Scholar
    • Export Citation
  • 35

    BalochZWFleisherSLiVolsiVAGuptaPK. Diagnosis of ‘follicular neoplasm’: a gray zone in thyroid fine-needle aspiration cytology. Diagnostic Cytopathology2002264144. (doi:10.1002/dc.10043).

    • Search Google Scholar
    • Export Citation
  • 36

    TeixeiraGVChikotaHTeixeiraTManfroGPaiSITufanoRP. Incidence of malignancy in thyroid nodules determined to be follicular lesions of undetermined significance on fine-needle aspiration. World Journal of Surgery2012366974. (doi:10.1007/s00268-011-1336-8).

    • Search Google Scholar
    • Export Citation
  • 37

    MoonWBaekJHJungSLKimDWKimEKKimJYKwakJYLeeJHLeeJHNaDG. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean Journal of Radiology201112114. (doi:10.3348/kjr.2011.12.1.1).

    • Search Google Scholar
    • Export Citation
  • 38

    NgaMEKumarasingheMPTieBSterrettGFWoodBWalshJNguyenHWhyteAFrostFA. Experience with standardized thyroid fine-needle aspiration reporting categories: follow-up data from 529 cases with “indeterminate” or “atypical” reports. Cancer Cytopathology2010118423433. (doi:10.1002/cncy.20111).

    • Search Google Scholar
    • Export Citation