J Pediatr Endocr Met 2015; aop
Nicoleta C. Arva* and Sarah G. Deitch
Reclassification of cytologically atypical thyroid nodules based on radiologic features in pediatric patients Abstract Aim: In children the percentage of “Atypia of undetermined significance/follicular lesion of undetermined significance” (“AUS/FLUS”) cases is greater and the risk of malignancy is higher than expected. Our study aimed to determine if cytologically atypical nodules can be better characterized using imaging techniques for appropriate management of pediatric patients. Methods: Thyroid fine needle aspiration (FNA) specimens were reclassified using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Cytologic-histologic correlation was performed to determine if the cytopathologic groups had different associations with the surgical outcome. The “AUS/FLUS” lesions were then subdivided based on radiologic features and the outcome was analyzed for each subgroup. Results: Histologically benign follicular nodules showed uniform distribution between the “benign” vs. “AUS/ FLUS” (p = 0.09) or between the “AUS/FLUS” vs. “follicular neoplasm” (“FN”) cytologic groups (p = 0.27). The follicular neoplasms were also evenly distributed between the “FN” vs. “AUS/FLUS” categories (p = 0.31). “Benign”, “AUS/FLUS”, and “FN” designations showed comparable associations with papillary thyroid carcinoma classical variant (PTC-cv). Reclassification of atypical lesions based on ultrasound findings yielded two subcategories with different risk of malignancy: one similar to the “benign” group (11% malignancy rate) and one comparable with the “FN” category (28% risk of malignant neoplasm). Conclusion: “AUS/FLUS” designation does not add significant value in categorization of pediatric thyroid nodules. These lesions can be reclassified based on radiologic features to provide accurate information for follow-up.
*Corresponding author: Nicoleta C. Arva, MD, PhD, Department of Pathology, Ann & Robert H. Lurie Children’s Hospital of Chicago Feinberg School of Medicine, Northwestern University, 225 East Chicago Avenue, Chicago, IL 60611, USA, Phone: +1-312-227-3956, Fax: +1-312-227-9616, E-mail: [email protected] Sarah G. Deitch: Department of Medical Imaging, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Keywords: “Atypia of undetermined significance/Follicular lesion of undetermined significance”; Bethesda System for Reporting Thyroid Cytopathology; follicular neoplasm; hyperplastic/adenomatous nodule; pediatric thyroid nodules. DOI 10.1515/jpem-2014-0427 Received October 11, 2014; accepted February 26, 2015
Introduction The prevalence of thyroid nodules is lower in pediatric population as compared to adults. It has been estimated that 1.8% of children have palpable nodules (whereas in adults the range of incidence is 2%–6% by palpation). With ultrasound exam, thyroid nodules can be found in up to 5.1% of children as opposed to older individuals, whereas sonography can demonstrate thyroid lesions in 35% of the individuals (1). However, the risk of malignancy is increased in young patients (estimated on average at 25%), when compared to adults (where 5% of the nodules are malignant) (2). Fine needle aspiration (FNA) biopsy proved to be an accurate tool in determining the nature (benign vs. malignant) of a thyroid nodule in both adults (3) and children (4). In a meta-analysis including 12 pediatric studies with 183 malignant and 347 benign nodules, the FNA sensitivity was 94% and the negative predictive value was 98.2% (4). In 2007, the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) was developed and includes six diagnostic categories: “non-diagnostic”, “benign” (comprises benign follicular nodules and inflammatory diseases), “atypia of undetermined significance/follicular lesion of undetermined significance” (“AUS/FLUS”), “suspicious for follicular neoplasm/follicular neoplasm” (“FN”), “suspicious for malignancy”, and “malignant” (5). This diagnostic scheme has been applied mostly to aspirates obtained from adult patients. In contrast, in children a nonstandardized four-tier categorization has been used, with the following designations: “non-diagnostic”, “benign”, “indeterminate/ atypical/suspicious”, and “malignant” (6–9).
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2 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children
The “AUS/FLUS” designation of the adult BSRTC is a very heterogeneous group and includes those cases in which the interpretation is hindered by sample preparation artifact, cases that are sparsely cellular with scant colloid and a prominent population of microfollicles (architectural atypia), specimens with a predominant Hurthle cell population, as well as samples showing focal nuclear/cytologic atypia (presence of nuclear grooves, enlarged nuclei with pale chromatin and irregular nuclei) in an otherwise predominantly benign appearing specimen (5). According to BSRTC about 7% of all thyroid FNAs should to be diagnosed as “AUS/FLUS”. The risk of malignancy for a nodule placed into this category ranges between 5% and 15% and the recommended follow-up is repeat FNA. Due to its heterogeneous nature, it is not surprising that “AUS/FLUS” designation has a very high interobserver variability (10). Many studies in adults have tried to reclassify these lesions using additional methodologies. It has been shown that the corresponding histologic outcome highly depends on the nature of atypia: focal nuclear/ cytologic atypia appears to carry a significantly higher risk of malignancy than architectural atypia (11–14). Even more, “AUS/FLUS” aspirates without features of papillary carcinoma from nodules smaller than 1 cm were shown to have the same risk of malignancy as benign aspirates (12), suggesting that ultrasound features (size) can complement cytology offering additional information for proper clinical follow-up. Molecular studies have recently been used to better characterize the indeterminate aspirates. Although their specificity is high, they have poor sensitivity and it still remains unclear whether implementation of such techniques will change clinical management (15). Recently, BSRTC has been applied to pediatric thyroid nodules (16) and revealed that the percentage of cases diagnosed as “AUS/FLUS” was significantly higher (24%) than the recommended 7% and more than half of the patients (58%) underwent surgical follow-up. In addition, the risk of malignancy in this cytologic group was 28%, being comparable with the risk of malignancy seen in the pediatric category “indeterminate” and similar to the adults’ risk when placed in the “FN” group. These results question the usefulness of “AUS/FLUS” designation in children and highlight the need for additional methodologies to better define these lesions even in pediatric population. In this study, we retrospectively categorized all thyroid FNAs performed at our Children’s Hospital using the BSRTC guidelines and performed cytologic-histologic correlation to determine if “AUS/FLUS” designation is different from other categories in predicting the surgical diagnosis. The ultrasound appearance was used to
subclassify the atypical lesions in two subgroups and their risk of malignancy was compared with that seen in other categorizations of the BSRTC.
Materials and methods Cytologny samples Information on patients enrolled in this study was collected under the approval of Ann & Robert H. Lurie Children’s Hospital of Chicago Institutional Review Board. The cytopathology reports of all thyroid FNA samples accessioned in our Department between January 2000 and December 2013 were retrieved by a search into the pathology information system. There were 187 specimens obtained from 180 patients. Seven patients underwent aspiration of two separate thyroid nodules; in these situations, each nodule was followed-up independently. In all cases, the aspiration procedure was performed under ultrasound guidance by an interventional radiologist with immediate on-site assessment of adequacy by a pathologist. The number of passes varied from 2 to 7 for each nodule. From each pass one air-dried Diff-Quick-stained and one ethanol-fixed Papanicolaoustained smears were prepared. Based on the microscopic description of the cytopathology preparation, and in selected cases by reviewing the cytology slides, all 187 specimens were reclassified using the sixtier diagnostic scheme according to BSRTC guidelines.
Surgical resection specimens Patients with available surgical follow-up were identified and based on the surgical pathology diagnosis, the cases were then grouped into the following histopathologic categories: (i) benign NOS (included cases of lymphocytic thyroiditis or colloid nodules); (ii) benign follicular nodule (hyperplastic/adenomatous nodule); (iii) follicular neoplasm (including follicular adenoma/carcinoma, Hurthle cell adenoma/carcinoma, papillary thyroid carcinoma, follicular variant (PTC-fv), and (iv) Papillary thyroid carcinoma, classical variant (PTC-cv). There were four instances of cytologically atypical nodules where patients sought further medical care at different institutions and the follow-up outcome was unavailable.
Radiologic characteristics and reclassification of “AUS/ FLUS” lesions The ultrasound features of the atypical nodules were blindly (without access to the cytology or final surgical pathology diagnosis) reviewed by the radiologist and an ultrasound scoring system was designed in order to objectively evaluate the radiologic aspect of the lesions. Points (0, 1, or 2) were assigned to each of the most common sonographic features used to describe thyroid nodules [(17); Table 1] and the sum was calculated for each individual case. The maximum possible score was 8. Based on the radiologic aspects, the “AUS/FLUS” lesions were subdivided into two groups: the first group was comprised of cases
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Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 3
Table 1: Ultrasound scoring system. Sonographic feature
Characteristics
Points
Echogenicity
Homogenous or mixed echogenicity (heterogenous) Hypoechoic 2 cm No flow detected Increased flow Well-defined Ill-defined Absent Present Almost entirely cystic Mixed cystic/solid Completely solid
0
Vascularity Margins Calcifications Cystic or solid Total maximum score Size
1 0 1 2 0 1 0 1 0 1 0 1 2 8
with an ultrasound score ≤ 4; the second group was composed of lesions with an assigned radiology score > 4.
Statistical analysis Correlation between the cytology and histology diagnosis was performed. Chi-square or Fisher exact tests were used to determine if the cytologic categories of the BSRTC had different associations with the histopathologic diagnosis. A p value ≤ 0.05 was considered statistically significant. Sensitivity, specificity, and predictive values were calculated for the ultrasound scoring system.
Results Reclassification of pediatric thyroid nodules using the BSRTC Our study included 187 thyroid FNA specimens from 180 patients (with seven patients undergoing aspiration of two separate nodules). The patient’s age averaged 13.5 years (range 3–20 years). Three patients were above the age of 18 (a 19-year-old, a 20-year-old, and a 28-year-old) – although not meeting anymore the pediatric age criteria, these patients were still included in the study because they have been followed extensively at our institution for various medical conditions since early childhood. 77% of the patients were female. The size of the nodules ranged from 0.4 cm to 5.5 cm, with an average of 2.14 cm. 52.5% of the nodules were located in the right lobe, 34% in the
left lobe, 7.5% in the isthmus, and in 6% of the cases there were multiple, bilateral nodules. When BSRTC was applied to our cohort, 6% of the cases were considered “non-diagnostic”, 61% were diagnosed as “benign”, 14% of cases were included in the “AUS/FLUS” category, 9.5% were categorized as “FN”, and 10% were “suspicious for malignancy” or overtly “malignant” (Table 2). All “non-diagnostic” aspirates showed cyst content material with limited number of follicular cells and none of the 11 patients receiving this diagnosis were followed-up, most likely because the lesions were predominantly cystic and not clinically worrisome. A total of 37 patients with a cytologically “benign” nodule were followed-up and the majority (29) underwent surgical resection, mostly lobectomy (Table 2). A total of 16 out of the 26 atypical lesions were surgically removed, with total thyroidectomy (nine instances) being the predominant surgical procedure (Table 2). All nodules diagnosed as “FN”, “suspicious for malignancy”, or “malignant” were resected, mainly by total thyroidectomy (Table 2). The rate of malignancy increased with each cytological category: from 10.5% in the “benign” group to 18.75% for the atypical cases, 27.7% in the “FN” designation, and up to 100% for “suspicious” or overtly “malignant” lesions (Table 3).
Cytologic-histologic correlation Histopathologic examination of all resection specimens (n = 81, Table 4) revealed a total of 31 benign follicular nodules: 20 from the “benign” cytologic group, seven diagnosed as atypical on cytology, and four previously designated as “FN” on cytopathology exam. None of the nodules that were cytologically “suspicious” or overtly “malignant” resulted in a benign follicular nodule on histopathologic exam. The χ2 and Fisher exact test revealed no statistically significant difference in the distribution of surgical benign follicular nodules between the “benign” vs. “AUS/ FLUS” cytologic designations (χ2-test, p = 0.09) or between the “AUS/FLUS” and “FN” categories (Fisher test, p = 0.27). However, a statistically significant higher number of histologically benign follicular nodules were included in the “benign” cytopathologic group when compared with the “FN” category (Fisher test, p = 0.002). A total of 24 cases received a surgical pathology diagnosis of follicular neoplasm (Table 4): three diagnosed as “benign” on cytopathology, seven from the “AUS/FLUS” cytology group, 11 previously designated on cytologic
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4 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children Table 2: Classification of thyroid nodules aspirates using the BSRTC and the subsequent follow-up. Category
Number (%) of cases
Number of cases with follow-up
Number (%) of cases with FNA follow-up
“Nondiagnostic” “Benign”
11 (6%)
0
0
114 (61%)
37
8 (21.5%)
“AUS/FLUS”
26 (14%)
17
1 (6%)
“Follicular neoplasm”
18 (9.5%)
18
0
“Suspicious for malignancy” “Positive for malignancy”
6 (3.25%)
6
0
12 (6.5%)
12
0
Table 3: Rate of malignancy for each BSRTC category. Category
“Benign” “AUS/FLUS” “Follicular neoplasm” “Suspicious for malignancy” “Positive for malignancy”
Bethesda-recommended guidelines
0
Repeat FNA with ultrasound guidance Clinical follow-up
29 (78.5%): – 11 total thyroidectomy – 18 partial thyroidectomy 16 (94%) – 9 total thyroidectomy – 7 partial thyroidectomy 18 (100%) – 11 total thyroidectomy – 7 partial thyroidectomy 6 (100%) – All total thyroidectomy 12 (100%) – All total thyroidectomy
Repeat FNA
Lobectomy
Near-total thyroidectomy Near-total thyroidectomy
significant smaller number of histologic follicular neoplasms were diagnosed cytologically as “benign” when compared with the “AUS/FLUS” or “FN” categories (Fisher test, p = 0.02 and p = 0.0003, respectively). PTC-cv was diagnosed in 20 surgical resection specimens: three previously categorized as “benign” on cytology, two included in the “FN” cytologic group, four from “suspicious for malignancy” designation, and 11 diagnosed as “positive for malignancy” on cytopathology exam (Table 4). The distribution of PTC nodules was not statistically different between the “benign”, “AUS/ FLUS”, and “FN” cytologic groups (“benign” vs. “AUS/ FLUS”, Fisher test p = 0.25; “AUS/FLUS” vs. “FN”, Fisher test p = 0.27; “benign” vs. “FN”, Fisher test p = 0.64), but reached statistical significance when each of these categories were compared with “suspicious for malignancy” or ”positive for malignancy” categorizations (data not
Number (%) of Recommended % by malignant cases Bethesda system 10.5% (3/29) 18.75% (3/16) 27.7% (5/18) 100% (6/6) 100% (12/12)
Number (%) of cases with surgical follow-up
0%–3% 5%–15% 15%–30% 60%–75% 97%–99%
exam as “FN”, and three included in the “suspicious for malignancy” or “malignant” categories. Same type of statistical analysis yielded no statistically significant difference in the distribution of histology-proven follicular neoplasms between the “AUS/FLUS” and “FN” cytologic designations (χ2-test, p = 0.31). However, a statistically
Table 4: Cytologic-histologic correlation for cases with surgical follow-up (number of cases). Histologic diagnosis n = 81
Benign, NOS (5 thyroiditis and 1 benign cyst) n = 6 Benign follicular nodule n = 31 Follicular neoplasm n = 24 Follicular adenoma n = 15 Follicular carcinoma n = 4 Hurthle cell carcinoma n = 1 PTC-fv n = 4 PTC-cv n = 20
Bethesda category “Benign”
3 20 3 – – – 3
“AUS/FLUS”
“Follicular neoplasm”
“Suspicious for malignancy”
“Malignant”
2 7 4 1 – 2 –
1 4 8 3 – – 2
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– – – – 1 1 4
– – – – – 1 11
Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 5
shown). All three instances of malignancy within the “benign” cytologic designation were incidental papillary microcarcinomas, classical variant (one case diagnosed as nodular hyperplasia with foci of PTC-cv, a second case showing a predominantly cystic nodule with few papillary structures demonstrating cytological features of PTC, and the third case with multifocal PTC-cv in a background of lymphocytic thyroiditis).
Reclassification of atypical nodules based on their ultrasound appearance The sonographic score allowed us to reclassify the 16 “AUS/ FLUS” nodules with surgical follow-up into two subgroups: nine were considered to have sonographic features suggestive of a benign lesion (ultrasound score ≤ 4), whereas the remaining seven cases had indeterminate radiologic appearance, with an ultrasound score > 4 (Table 5). The “AUS/FLUS” group included one patient above the age of 18 (a 19-year-old female followed at our institution for medulloblastoma and neurofibromatosis type 1) that had a benign surgical outcome (nodular hyperplasia). Surgical follow-up of the nine cases with less worrisome radiologic findings demonstrated malignancy in one instance (minimally invasive follicular carcinoma, Table 5, case # 8), resulting in a rate of malignancy of 11% for this subgroup. Two of the seven cases with high ultrasound score resulted in malignant outcome (both PTC-fv, Table 5, cases # 10 and 14), causing a risk of malignancy of 28.5% for the second subcategory. The ultrasound scoring system had a sensitivity of 66.67%, specificity 61.58%, and a negative predictive value of 88.89% for detecting malignancy (Table 6).
Discussion The BSRTC is a uniform six-tier diagnostic scheme developed in 2007 with the goal of standardizing the practice of thyroid cytopathology. Since then, it was adopted mainly to report aspirates from adult thyroid nodules and data collected after its implementation is based mostly on studies performed on older individuals. In children, a nonstandardized four-tier diagnostic scheme is frequently used (6–9) and more records are needed to determine if adopting the BSRTC system would offer better management for pediatric patients with thyroid nodules. We retrospectively applied the BSRTC to all thyroid FNAs performed at our Children’s Hospital and found that
the risk of malignancy within each diagnostic category was greater than expected, findings consistent with previous results showing an increased rate of malignant neoplasms in pediatric thyroid nodules compared to adults (2). In our cohort of patients, the benign category had a rate of malignancy of ∼10%, significantly higher than the proposed 0% to 3%, with all malignant cases diagnosed as incidental papillary thyroid microcarcinomas, not surprisingly not represented in the FNA material. Similarly, nodules classified as “AUS/FLUS” proved to be malignant in 18.75% cases, which is greater than the suggested 5% to 15%. This rate of malignancy is similar to that anticipated for the “FN” category and also comparable to the risk of malignancy reported for the pediatric designation “indeterminate/suspicious” (7–9), observation revealed also by a recent study by Monaco et al. (16). We also noticed that a higher than recommended percentage of cases were included in the “AUS/FLUS” category (14% in our study vs. 7% according to BSRTC), which is also consistent with prior reports (16). These results raise concern regarding the value of the “AUS/FLUS” designation for guiding further management of pediatric patients with thyroid nodules. In fact, our cytologic-histologic correlation did not highlight any significant differences between the “AUS/FLUS” vs. “benign” or between the “AUS/FLUS” vs. “FN” groups in their ability to predict the histologic diagnosis, exposing a lack of value for the “AUS/FLUS” designation in the categorization of pediatric thyroid lesions. The “AUS/FLUS” is a controversial diagnosis, with poor interobserver agreement. In the study by Harvey et al. (10) comparing the incidence of “AUS/FLUS” at different institutions, the percentage of aspirates receiving this qualification varied from 2.1% to 18% and the rate of malignancy within this designation was between 6% and 48%. A trend for an inverse relationship between the percentage of cases classified as “AUS/FLUS” and the rate of malignancy within this category was noted. Retrospectively, at our pediatric institution the percentage of atypical aspirates resides toward the higher rate; however, the risk of malignancy is also increased within this category, suggesting that atypical lesions in children deserve closer follow-up and more aggressive management. Not surprisingly, the increased rate of malignant neoplasms translates into a more aggressive management of thyroid nodules in children: many of our patients underwent surgical resection, with more extensive procedures. Due to its heterogeneity, many studies proposed reclassification of atypical lesions based on different methodologies. For example, it appears that the histologic outcome depends on atypia qualifier: nuclear/
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6 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children
Table 5: Ultrasound score for all “AUS/FLUS” lesions with surgical follow-up. Case
Age, years
Nodule size, cm
1
18
0.7
2
19
0.9
3
16
1
4 5 6 7
12 14 12 15
1.1 1.6 1.6 1.7
8
16
1.7
9
15
1.9
10
15
2
11
15
3
12
15
3.5
13
18
4.2
14
13
4.4
15
15
5
16
15
5.5
Ultrasound appearance
Radiologic score
Solid hypervascular, heterogenous (moderately hyperechoic) nodule; also other nodules, majority mixed solid-cystic. Single solid hypoechoic nodule with increased vascularity; history of prior radiation. Single solid echogenic nodule with flow, history of radiation.
3
Hyperplastic nodule
4
Nodular hyperplasia
4
Hypoechoic solid nodule; no flow; other nodules present as well. Single mixed solid and cystic nodule; no flow. Single, predominantly cystic nodule without vascularity. Multiple nodules, the largest of which is solid, hypoechoic, with increased blood flow. Single solid heterogeneous nodule with increased vascularity.
4 2 1 5
Adenomatoid nodule with hyperplastic changes Lymphocytic thyroiditis Benign colloid cysts Hyperplastic nodule Follicular adenoma
4
Enlarged multinodular thyroid with heterogeneous echotexture. The largest well-defined nodule is solid and has mild hypervascularity. Solid, hypoechoic nodule with increased flow. Other nodules present as well. Single mixed solid/cystic nodule with heterogenous aspect and thick wall. There is increased vascularity and microcalcifications are present. Single round complex nodule with a sizable irregular clear fluid component. The solid component is heterogeneous, and includes a number of punctate highly echogenic foci, highly suggestive of calcifications; the nodule is well perfused. Single heterogeneous solid nodule that occupies the majority of the right thyroid lobe. Internal vascularity is demonstrated within this nodule. Microcalcifications also seen. Single large well circumscribed mixed echogenicity (mostly hyperechoic) solid nodule within the right lobe with increased flow. Single, partially solid/partially cystic nodule occupying and enlarging the majority of the left lobe, hyperfunctioning. There are microcalcifications as well as increased flow. Single complex nodule occupying much of the left thyroid lobe; the nodule has a thickened wall with multiple septations. There is increased vascularity.
4
Minimally invasive follicular carcinoma Adenomatous nodule
6
PTC follicular variant
5
Follicular adenoma
5
Nodular hyperplasia
6
Hyperplastic nodule
5
Follicular variant PTC
5
Follicular adenoma with Hurthle cells
4
Follicular adenoma
cytologic atypia bears a significantly higher risk of malignancy compared with architectural atypia, trend that has been observed in both children and adults (11–14, 18). It has been proposed to separate specimens that are categorized as “AUS/FLUS” owing to compromised quality or quantity of the sample from those with cytologic atypia.
Histopathologic diagnosis
The former may benefit from a repeated FNA, whereas the latter should prompt more extensive evaluation (19). Recently, molecular studies (BRAF, RAS mutation analysis or RET/PTC, PAX8/PPAR rearrangements) performed on pediatric aspiration material have been used to identify malignant nodules (16, 20). In the study by Monaco et al.
Table 6: Subclassification of “AUS/FLUS” lesions based on the ultrasound score and histologic outcome. “AUS/FLUS” lesions
Ultrasound score
Total number
Benign outcome
Malignant outcome
Rate of malignancy
1 (minimally invasive follicular carcinoma) 2 (both PTC-fv)
11%
≤ 4
9
8
Score > 4
7
5
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28.5%
Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 7
(16), all cases harboring molecular abnormalities turned out to be papillary thyroid carcinomas. However, about half of the nodules that were negative for all the mutations tested were malignant on histological follow-up, revealing a low sensitivity for the molecular tests. In addition, Renshow et al. (12) demonstrated that for nodules smaller than 1 cm, atypical aspirates without features of papillary thyroid carcinoma (nuclear atypia) have the same risk of malignancy as benign aspirates, suggesting that radiologic appearance should also be considered when managing patients with atypical lesions. In a pediatric study, Saavedra et al. (21) demonstrated that 80% of cases with benign cytology but a malignant histologic diagnosis had multiple ultrasound malignancy criteria, concluding that sonography complements FNA and a more aggressive approach is warranted in children with a benign FNA but radiologic findings suggesting malignancy. Our study is the first to reclassify the atypical pediatric thyroid lesions using their ultrasound features to determine if more valuable information can be obtained for better patient care. The “AUS/FLUS” lesions were separated into two subgroups based on ultrasound score: the rate of malignancy for those with less worrisome radiologic findings was 11%, similar to the rate of malignant
neoplasm for the “benign” cytologic group and comparable with that proposed by BSRTC for “AUS/FLUS” category; histologic exam of nodules with high ultrasound score resulted in malignant outcome in 28.5%, rate similar to that seen for the “FN” designation. “AUS/FLUS” diagnosis often imposes difficult clinical decisions – here we offer evidence that sonography can guide future follow-up of pediatric patients with atypical nodules: children with only few ultrasound malignancy criteria should be treated similarly to those with cytologically “benign” lesions, probably by repeat FNA or very close clinical follow-up considering the still high rate of malignancy (10%–11%), whereas those with numerous worrisome radiologic findings could be regarded as “follicular neoplasms” and managed by following the BSRTC for this cytopathologic designation, possibly by surgical resection (Figure 1). In conclusion, our study demonstrates that “AUS/ FLUS” cytologic category does not add valuable information to better characterize pediatric thyroid nodules. Ultrasound exam performed by experienced radiologists using optimal quality equipment can complement the cytopathology findings and help clinicians decide the next best step in patient’s care when dealing with atypical nodules in children.
Figure 1: Proposed algorithm for further work-up of “AUS/FLUS” lesions in children. Ultrasound exam performed by experienced radiologists using optimal equipment can complement the cytopathology findings and help clinicians decide the next best step in patient’s care. Patients with only few ultrasound malignancy criteria should be treated similarly to those with “benign” lesions, probably by repeat FNA or very close clinical follow-up considering the still high rate of malignancy (10%–11%), whereas those with numerous worrisome radiologic findings could be regarded as “follicular neoplasms” and managed by following the BSRTC for this cytopathologic designation, possibly by surgical resection.
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8 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children Acknowledgments: We would like to thank Gang Zhang from the Research Center, Biostatistics Core, Ann & Robert H. Lurie Children’s Hospital of Chicago for significant input regarding the statistical analysis used in our study. Conflict of interest statement: The authors have no conflicts of interest, commercial or financial disclosures.
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10. Harvey AM, Mody DR, Amrikachi M. Thyroid fine-needle aspiration reporting rates and outcomes before and after Bethesda implementation within a combined academic and community hospital system. Arch Pathol Lab Med 2013;137:1664–8. 11. VanderLaan PA, Marqusee E, Krane JF. Usefulness of diagnostic qualifiers for thyroid fine-needle aspirations with atypia of undetermined significance. Am J Clin Pathol 2011;136:572–7. 12. Renshaw AA, Gould EW. Should “indeterminate” diagnoses be used for thyroid fine-needle aspirates of nodules smaller than 1 cm? Arch Pathol Lab Med 2013;137:1627–9. 13. Walts AE, Mirocha J, Bose S. Follicular lesion of undetermined significance in thyroid FNA revisited. Diagn Cytopathol 2014;42:18–22. 14. Wu HH, Inman A, Cramer HM. Subclassification of “atypia of undetermined significance” in thyroid fine-needle aspirates. Diagn Cytopathol 2014;42:23–9. 15. Keutgen XM, Filicori F, Fahey TJ 3rd. Molecular diagnosis for indeterminate thyroid nodules on fine needle aspiration: advances and limitations. Expert Rev Mol Diagn 2013;13:613–23. 16. Monaco SE, Pantanowitz L, Khalbuss WE, Benkovich VA, Ozolek J, et al. Cytomorphological and molecular genetic findings in pediatric thyroid fine-needle aspiration. Cancer Cytopathol 2012;120:342–50. 17. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2009;19:1167–214. 18. Smith M, Pantanowitz L, Khalbuss WE, Benkovich VA, Monaco SE. Indeterminate pediatric thyroid fine needle aspirations: a study of 68 cases. Acta Cytol 2013;57:341–8. 19. Singh RS, Wang HH. Eliminating the “Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance” category from the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2011;136:896–902. 20. Buryk MA, Monaco SE, Witchel SF, Mehta DK, Gurtunca N, et al. Preoperative cytology with molecular analysis to help guide surgery for pediatric thyroid nodules. Int J Pediatr Otorhinolaryngol 2013;77:1697–700. 21. Saavedra J, Deladoëy J, Saint-Vil D, Boivin Y, Alos N, et al. Is ultrasonography useful in predicting thyroid cancer in children with thyroid nodules and apparently benign cytopathologic features? Horm Res Paediatr. 2011;75:269–75.
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Nicoleta C. Arva* and Sarah G. Deitch
Reclassification of cytologically atypical thyroid nodules based on radiologic features in pediatric patients Abstract Aim: In children the percentage of “Atypia of undetermined significance/follicular lesion of undetermined significance” (“AUS/FLUS”) cases is greater and the risk of malignancy is higher than expected. Our study aimed to determine if cytologically atypical nodules can be better characterized using imaging techniques for appropriate management of pediatric patients. Methods: Thyroid fine needle aspiration (FNA) specimens were reclassified using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Cytologic-histologic correlation was performed to determine if the cytopathologic groups had different associations with the surgical outcome. The “AUS/FLUS” lesions were then subdivided based on radiologic features and the outcome was analyzed for each subgroup. Results: Histologically benign follicular nodules showed uniform distribution between the “benign” vs. “AUS/ FLUS” (p = 0.09) or between the “AUS/FLUS” vs. “follicular neoplasm” (“FN”) cytologic groups (p = 0.27). The follicular neoplasms were also evenly distributed between the “FN” vs. “AUS/FLUS” categories (p = 0.31). “Benign”, “AUS/FLUS”, and “FN” designations showed comparable associations with papillary thyroid carcinoma classical variant (PTC-cv). Reclassification of atypical lesions based on ultrasound findings yielded two subcategories with different risk of malignancy: one similar to the “benign” group (11% malignancy rate) and one comparable with the “FN” category (28% risk of malignant neoplasm). Conclusion: “AUS/FLUS” designation does not add significant value in categorization of pediatric thyroid nodules. These lesions can be reclassified based on radiologic features to provide accurate information for follow-up.
*Corresponding author: Nicoleta C. Arva, MD, PhD, Department of Pathology, Ann & Robert H. Lurie Children’s Hospital of Chicago Feinberg School of Medicine, Northwestern University, 225 East Chicago Avenue, Chicago, IL 60611, USA, Phone: +1-312-227-3956, Fax: +1-312-227-9616, E-mail: [email protected] Sarah G. Deitch: Department of Medical Imaging, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Keywords: “Atypia of undetermined significance/Follicular lesion of undetermined significance”; Bethesda System for Reporting Thyroid Cytopathology; follicular neoplasm; hyperplastic/adenomatous nodule; pediatric thyroid nodules. DOI 10.1515/jpem-2014-0427 Received October 11, 2014; accepted February 26, 2015
Introduction The prevalence of thyroid nodules is lower in pediatric population as compared to adults. It has been estimated that 1.8% of children have palpable nodules (whereas in adults the range of incidence is 2%–6% by palpation). With ultrasound exam, thyroid nodules can be found in up to 5.1% of children as opposed to older individuals, whereas sonography can demonstrate thyroid lesions in 35% of the individuals (1). However, the risk of malignancy is increased in young patients (estimated on average at 25%), when compared to adults (where 5% of the nodules are malignant) (2). Fine needle aspiration (FNA) biopsy proved to be an accurate tool in determining the nature (benign vs. malignant) of a thyroid nodule in both adults (3) and children (4). In a meta-analysis including 12 pediatric studies with 183 malignant and 347 benign nodules, the FNA sensitivity was 94% and the negative predictive value was 98.2% (4). In 2007, the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) was developed and includes six diagnostic categories: “non-diagnostic”, “benign” (comprises benign follicular nodules and inflammatory diseases), “atypia of undetermined significance/follicular lesion of undetermined significance” (“AUS/FLUS”), “suspicious for follicular neoplasm/follicular neoplasm” (“FN”), “suspicious for malignancy”, and “malignant” (5). This diagnostic scheme has been applied mostly to aspirates obtained from adult patients. In contrast, in children a nonstandardized four-tier categorization has been used, with the following designations: “non-diagnostic”, “benign”, “indeterminate/ atypical/suspicious”, and “malignant” (6–9).
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2 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children
The “AUS/FLUS” designation of the adult BSRTC is a very heterogeneous group and includes those cases in which the interpretation is hindered by sample preparation artifact, cases that are sparsely cellular with scant colloid and a prominent population of microfollicles (architectural atypia), specimens with a predominant Hurthle cell population, as well as samples showing focal nuclear/cytologic atypia (presence of nuclear grooves, enlarged nuclei with pale chromatin and irregular nuclei) in an otherwise predominantly benign appearing specimen (5). According to BSRTC about 7% of all thyroid FNAs should to be diagnosed as “AUS/FLUS”. The risk of malignancy for a nodule placed into this category ranges between 5% and 15% and the recommended follow-up is repeat FNA. Due to its heterogeneous nature, it is not surprising that “AUS/FLUS” designation has a very high interobserver variability (10). Many studies in adults have tried to reclassify these lesions using additional methodologies. It has been shown that the corresponding histologic outcome highly depends on the nature of atypia: focal nuclear/ cytologic atypia appears to carry a significantly higher risk of malignancy than architectural atypia (11–14). Even more, “AUS/FLUS” aspirates without features of papillary carcinoma from nodules smaller than 1 cm were shown to have the same risk of malignancy as benign aspirates (12), suggesting that ultrasound features (size) can complement cytology offering additional information for proper clinical follow-up. Molecular studies have recently been used to better characterize the indeterminate aspirates. Although their specificity is high, they have poor sensitivity and it still remains unclear whether implementation of such techniques will change clinical management (15). Recently, BSRTC has been applied to pediatric thyroid nodules (16) and revealed that the percentage of cases diagnosed as “AUS/FLUS” was significantly higher (24%) than the recommended 7% and more than half of the patients (58%) underwent surgical follow-up. In addition, the risk of malignancy in this cytologic group was 28%, being comparable with the risk of malignancy seen in the pediatric category “indeterminate” and similar to the adults’ risk when placed in the “FN” group. These results question the usefulness of “AUS/FLUS” designation in children and highlight the need for additional methodologies to better define these lesions even in pediatric population. In this study, we retrospectively categorized all thyroid FNAs performed at our Children’s Hospital using the BSRTC guidelines and performed cytologic-histologic correlation to determine if “AUS/FLUS” designation is different from other categories in predicting the surgical diagnosis. The ultrasound appearance was used to
subclassify the atypical lesions in two subgroups and their risk of malignancy was compared with that seen in other categorizations of the BSRTC.
Materials and methods Cytologny samples Information on patients enrolled in this study was collected under the approval of Ann & Robert H. Lurie Children’s Hospital of Chicago Institutional Review Board. The cytopathology reports of all thyroid FNA samples accessioned in our Department between January 2000 and December 2013 were retrieved by a search into the pathology information system. There were 187 specimens obtained from 180 patients. Seven patients underwent aspiration of two separate thyroid nodules; in these situations, each nodule was followed-up independently. In all cases, the aspiration procedure was performed under ultrasound guidance by an interventional radiologist with immediate on-site assessment of adequacy by a pathologist. The number of passes varied from 2 to 7 for each nodule. From each pass one air-dried Diff-Quick-stained and one ethanol-fixed Papanicolaoustained smears were prepared. Based on the microscopic description of the cytopathology preparation, and in selected cases by reviewing the cytology slides, all 187 specimens were reclassified using the sixtier diagnostic scheme according to BSRTC guidelines.
Surgical resection specimens Patients with available surgical follow-up were identified and based on the surgical pathology diagnosis, the cases were then grouped into the following histopathologic categories: (i) benign NOS (included cases of lymphocytic thyroiditis or colloid nodules); (ii) benign follicular nodule (hyperplastic/adenomatous nodule); (iii) follicular neoplasm (including follicular adenoma/carcinoma, Hurthle cell adenoma/carcinoma, papillary thyroid carcinoma, follicular variant (PTC-fv), and (iv) Papillary thyroid carcinoma, classical variant (PTC-cv). There were four instances of cytologically atypical nodules where patients sought further medical care at different institutions and the follow-up outcome was unavailable.
Radiologic characteristics and reclassification of “AUS/ FLUS” lesions The ultrasound features of the atypical nodules were blindly (without access to the cytology or final surgical pathology diagnosis) reviewed by the radiologist and an ultrasound scoring system was designed in order to objectively evaluate the radiologic aspect of the lesions. Points (0, 1, or 2) were assigned to each of the most common sonographic features used to describe thyroid nodules [(17); Table 1] and the sum was calculated for each individual case. The maximum possible score was 8. Based on the radiologic aspects, the “AUS/FLUS” lesions were subdivided into two groups: the first group was comprised of cases
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Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 3
Table 1: Ultrasound scoring system. Sonographic feature
Characteristics
Points
Echogenicity
Homogenous or mixed echogenicity (heterogenous) Hypoechoic 2 cm No flow detected Increased flow Well-defined Ill-defined Absent Present Almost entirely cystic Mixed cystic/solid Completely solid
0
Vascularity Margins Calcifications Cystic or solid Total maximum score Size
1 0 1 2 0 1 0 1 0 1 0 1 2 8
with an ultrasound score ≤ 4; the second group was composed of lesions with an assigned radiology score > 4.
Statistical analysis Correlation between the cytology and histology diagnosis was performed. Chi-square or Fisher exact tests were used to determine if the cytologic categories of the BSRTC had different associations with the histopathologic diagnosis. A p value ≤ 0.05 was considered statistically significant. Sensitivity, specificity, and predictive values were calculated for the ultrasound scoring system.
Results Reclassification of pediatric thyroid nodules using the BSRTC Our study included 187 thyroid FNA specimens from 180 patients (with seven patients undergoing aspiration of two separate nodules). The patient’s age averaged 13.5 years (range 3–20 years). Three patients were above the age of 18 (a 19-year-old, a 20-year-old, and a 28-year-old) – although not meeting anymore the pediatric age criteria, these patients were still included in the study because they have been followed extensively at our institution for various medical conditions since early childhood. 77% of the patients were female. The size of the nodules ranged from 0.4 cm to 5.5 cm, with an average of 2.14 cm. 52.5% of the nodules were located in the right lobe, 34% in the
left lobe, 7.5% in the isthmus, and in 6% of the cases there were multiple, bilateral nodules. When BSRTC was applied to our cohort, 6% of the cases were considered “non-diagnostic”, 61% were diagnosed as “benign”, 14% of cases were included in the “AUS/FLUS” category, 9.5% were categorized as “FN”, and 10% were “suspicious for malignancy” or overtly “malignant” (Table 2). All “non-diagnostic” aspirates showed cyst content material with limited number of follicular cells and none of the 11 patients receiving this diagnosis were followed-up, most likely because the lesions were predominantly cystic and not clinically worrisome. A total of 37 patients with a cytologically “benign” nodule were followed-up and the majority (29) underwent surgical resection, mostly lobectomy (Table 2). A total of 16 out of the 26 atypical lesions were surgically removed, with total thyroidectomy (nine instances) being the predominant surgical procedure (Table 2). All nodules diagnosed as “FN”, “suspicious for malignancy”, or “malignant” were resected, mainly by total thyroidectomy (Table 2). The rate of malignancy increased with each cytological category: from 10.5% in the “benign” group to 18.75% for the atypical cases, 27.7% in the “FN” designation, and up to 100% for “suspicious” or overtly “malignant” lesions (Table 3).
Cytologic-histologic correlation Histopathologic examination of all resection specimens (n = 81, Table 4) revealed a total of 31 benign follicular nodules: 20 from the “benign” cytologic group, seven diagnosed as atypical on cytology, and four previously designated as “FN” on cytopathology exam. None of the nodules that were cytologically “suspicious” or overtly “malignant” resulted in a benign follicular nodule on histopathologic exam. The χ2 and Fisher exact test revealed no statistically significant difference in the distribution of surgical benign follicular nodules between the “benign” vs. “AUS/ FLUS” cytologic designations (χ2-test, p = 0.09) or between the “AUS/FLUS” and “FN” categories (Fisher test, p = 0.27). However, a statistically significant higher number of histologically benign follicular nodules were included in the “benign” cytopathologic group when compared with the “FN” category (Fisher test, p = 0.002). A total of 24 cases received a surgical pathology diagnosis of follicular neoplasm (Table 4): three diagnosed as “benign” on cytopathology, seven from the “AUS/FLUS” cytology group, 11 previously designated on cytologic
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4 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children Table 2: Classification of thyroid nodules aspirates using the BSRTC and the subsequent follow-up. Category
Number (%) of cases
Number of cases with follow-up
Number (%) of cases with FNA follow-up
“Nondiagnostic” “Benign”
11 (6%)
0
0
114 (61%)
37
8 (21.5%)
“AUS/FLUS”
26 (14%)
17
1 (6%)
“Follicular neoplasm”
18 (9.5%)
18
0
“Suspicious for malignancy” “Positive for malignancy”
6 (3.25%)
6
0
12 (6.5%)
12
0
Table 3: Rate of malignancy for each BSRTC category. Category
“Benign” “AUS/FLUS” “Follicular neoplasm” “Suspicious for malignancy” “Positive for malignancy”
Bethesda-recommended guidelines
0
Repeat FNA with ultrasound guidance Clinical follow-up
29 (78.5%): – 11 total thyroidectomy – 18 partial thyroidectomy 16 (94%) – 9 total thyroidectomy – 7 partial thyroidectomy 18 (100%) – 11 total thyroidectomy – 7 partial thyroidectomy 6 (100%) – All total thyroidectomy 12 (100%) – All total thyroidectomy
Repeat FNA
Lobectomy
Near-total thyroidectomy Near-total thyroidectomy
significant smaller number of histologic follicular neoplasms were diagnosed cytologically as “benign” when compared with the “AUS/FLUS” or “FN” categories (Fisher test, p = 0.02 and p = 0.0003, respectively). PTC-cv was diagnosed in 20 surgical resection specimens: three previously categorized as “benign” on cytology, two included in the “FN” cytologic group, four from “suspicious for malignancy” designation, and 11 diagnosed as “positive for malignancy” on cytopathology exam (Table 4). The distribution of PTC nodules was not statistically different between the “benign”, “AUS/ FLUS”, and “FN” cytologic groups (“benign” vs. “AUS/ FLUS”, Fisher test p = 0.25; “AUS/FLUS” vs. “FN”, Fisher test p = 0.27; “benign” vs. “FN”, Fisher test p = 0.64), but reached statistical significance when each of these categories were compared with “suspicious for malignancy” or ”positive for malignancy” categorizations (data not
Number (%) of Recommended % by malignant cases Bethesda system 10.5% (3/29) 18.75% (3/16) 27.7% (5/18) 100% (6/6) 100% (12/12)
Number (%) of cases with surgical follow-up
0%–3% 5%–15% 15%–30% 60%–75% 97%–99%
exam as “FN”, and three included in the “suspicious for malignancy” or “malignant” categories. Same type of statistical analysis yielded no statistically significant difference in the distribution of histology-proven follicular neoplasms between the “AUS/FLUS” and “FN” cytologic designations (χ2-test, p = 0.31). However, a statistically
Table 4: Cytologic-histologic correlation for cases with surgical follow-up (number of cases). Histologic diagnosis n = 81
Benign, NOS (5 thyroiditis and 1 benign cyst) n = 6 Benign follicular nodule n = 31 Follicular neoplasm n = 24 Follicular adenoma n = 15 Follicular carcinoma n = 4 Hurthle cell carcinoma n = 1 PTC-fv n = 4 PTC-cv n = 20
Bethesda category “Benign”
3 20 3 – – – 3
“AUS/FLUS”
“Follicular neoplasm”
“Suspicious for malignancy”
“Malignant”
2 7 4 1 – 2 –
1 4 8 3 – – 2
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– – – – 1 1 4
– – – – – 1 11
Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 5
shown). All three instances of malignancy within the “benign” cytologic designation were incidental papillary microcarcinomas, classical variant (one case diagnosed as nodular hyperplasia with foci of PTC-cv, a second case showing a predominantly cystic nodule with few papillary structures demonstrating cytological features of PTC, and the third case with multifocal PTC-cv in a background of lymphocytic thyroiditis).
Reclassification of atypical nodules based on their ultrasound appearance The sonographic score allowed us to reclassify the 16 “AUS/ FLUS” nodules with surgical follow-up into two subgroups: nine were considered to have sonographic features suggestive of a benign lesion (ultrasound score ≤ 4), whereas the remaining seven cases had indeterminate radiologic appearance, with an ultrasound score > 4 (Table 5). The “AUS/FLUS” group included one patient above the age of 18 (a 19-year-old female followed at our institution for medulloblastoma and neurofibromatosis type 1) that had a benign surgical outcome (nodular hyperplasia). Surgical follow-up of the nine cases with less worrisome radiologic findings demonstrated malignancy in one instance (minimally invasive follicular carcinoma, Table 5, case # 8), resulting in a rate of malignancy of 11% for this subgroup. Two of the seven cases with high ultrasound score resulted in malignant outcome (both PTC-fv, Table 5, cases # 10 and 14), causing a risk of malignancy of 28.5% for the second subcategory. The ultrasound scoring system had a sensitivity of 66.67%, specificity 61.58%, and a negative predictive value of 88.89% for detecting malignancy (Table 6).
Discussion The BSRTC is a uniform six-tier diagnostic scheme developed in 2007 with the goal of standardizing the practice of thyroid cytopathology. Since then, it was adopted mainly to report aspirates from adult thyroid nodules and data collected after its implementation is based mostly on studies performed on older individuals. In children, a nonstandardized four-tier diagnostic scheme is frequently used (6–9) and more records are needed to determine if adopting the BSRTC system would offer better management for pediatric patients with thyroid nodules. We retrospectively applied the BSRTC to all thyroid FNAs performed at our Children’s Hospital and found that
the risk of malignancy within each diagnostic category was greater than expected, findings consistent with previous results showing an increased rate of malignant neoplasms in pediatric thyroid nodules compared to adults (2). In our cohort of patients, the benign category had a rate of malignancy of ∼10%, significantly higher than the proposed 0% to 3%, with all malignant cases diagnosed as incidental papillary thyroid microcarcinomas, not surprisingly not represented in the FNA material. Similarly, nodules classified as “AUS/FLUS” proved to be malignant in 18.75% cases, which is greater than the suggested 5% to 15%. This rate of malignancy is similar to that anticipated for the “FN” category and also comparable to the risk of malignancy reported for the pediatric designation “indeterminate/suspicious” (7–9), observation revealed also by a recent study by Monaco et al. (16). We also noticed that a higher than recommended percentage of cases were included in the “AUS/FLUS” category (14% in our study vs. 7% according to BSRTC), which is also consistent with prior reports (16). These results raise concern regarding the value of the “AUS/FLUS” designation for guiding further management of pediatric patients with thyroid nodules. In fact, our cytologic-histologic correlation did not highlight any significant differences between the “AUS/FLUS” vs. “benign” or between the “AUS/FLUS” vs. “FN” groups in their ability to predict the histologic diagnosis, exposing a lack of value for the “AUS/FLUS” designation in the categorization of pediatric thyroid lesions. The “AUS/FLUS” is a controversial diagnosis, with poor interobserver agreement. In the study by Harvey et al. (10) comparing the incidence of “AUS/FLUS” at different institutions, the percentage of aspirates receiving this qualification varied from 2.1% to 18% and the rate of malignancy within this designation was between 6% and 48%. A trend for an inverse relationship between the percentage of cases classified as “AUS/FLUS” and the rate of malignancy within this category was noted. Retrospectively, at our pediatric institution the percentage of atypical aspirates resides toward the higher rate; however, the risk of malignancy is also increased within this category, suggesting that atypical lesions in children deserve closer follow-up and more aggressive management. Not surprisingly, the increased rate of malignant neoplasms translates into a more aggressive management of thyroid nodules in children: many of our patients underwent surgical resection, with more extensive procedures. Due to its heterogeneity, many studies proposed reclassification of atypical lesions based on different methodologies. For example, it appears that the histologic outcome depends on atypia qualifier: nuclear/
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6 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children
Table 5: Ultrasound score for all “AUS/FLUS” lesions with surgical follow-up. Case
Age, years
Nodule size, cm
1
18
0.7
2
19
0.9
3
16
1
4 5 6 7
12 14 12 15
1.1 1.6 1.6 1.7
8
16
1.7
9
15
1.9
10
15
2
11
15
3
12
15
3.5
13
18
4.2
14
13
4.4
15
15
5
16
15
5.5
Ultrasound appearance
Radiologic score
Solid hypervascular, heterogenous (moderately hyperechoic) nodule; also other nodules, majority mixed solid-cystic. Single solid hypoechoic nodule with increased vascularity; history of prior radiation. Single solid echogenic nodule with flow, history of radiation.
3
Hyperplastic nodule
4
Nodular hyperplasia
4
Hypoechoic solid nodule; no flow; other nodules present as well. Single mixed solid and cystic nodule; no flow. Single, predominantly cystic nodule without vascularity. Multiple nodules, the largest of which is solid, hypoechoic, with increased blood flow. Single solid heterogeneous nodule with increased vascularity.
4 2 1 5
Adenomatoid nodule with hyperplastic changes Lymphocytic thyroiditis Benign colloid cysts Hyperplastic nodule Follicular adenoma
4
Enlarged multinodular thyroid with heterogeneous echotexture. The largest well-defined nodule is solid and has mild hypervascularity. Solid, hypoechoic nodule with increased flow. Other nodules present as well. Single mixed solid/cystic nodule with heterogenous aspect and thick wall. There is increased vascularity and microcalcifications are present. Single round complex nodule with a sizable irregular clear fluid component. The solid component is heterogeneous, and includes a number of punctate highly echogenic foci, highly suggestive of calcifications; the nodule is well perfused. Single heterogeneous solid nodule that occupies the majority of the right thyroid lobe. Internal vascularity is demonstrated within this nodule. Microcalcifications also seen. Single large well circumscribed mixed echogenicity (mostly hyperechoic) solid nodule within the right lobe with increased flow. Single, partially solid/partially cystic nodule occupying and enlarging the majority of the left lobe, hyperfunctioning. There are microcalcifications as well as increased flow. Single complex nodule occupying much of the left thyroid lobe; the nodule has a thickened wall with multiple septations. There is increased vascularity.
4
Minimally invasive follicular carcinoma Adenomatous nodule
6
PTC follicular variant
5
Follicular adenoma
5
Nodular hyperplasia
6
Hyperplastic nodule
5
Follicular variant PTC
5
Follicular adenoma with Hurthle cells
4
Follicular adenoma
cytologic atypia bears a significantly higher risk of malignancy compared with architectural atypia, trend that has been observed in both children and adults (11–14, 18). It has been proposed to separate specimens that are categorized as “AUS/FLUS” owing to compromised quality or quantity of the sample from those with cytologic atypia.
Histopathologic diagnosis
The former may benefit from a repeated FNA, whereas the latter should prompt more extensive evaluation (19). Recently, molecular studies (BRAF, RAS mutation analysis or RET/PTC, PAX8/PPAR rearrangements) performed on pediatric aspiration material have been used to identify malignant nodules (16, 20). In the study by Monaco et al.
Table 6: Subclassification of “AUS/FLUS” lesions based on the ultrasound score and histologic outcome. “AUS/FLUS” lesions
Ultrasound score
Total number
Benign outcome
Malignant outcome
Rate of malignancy
1 (minimally invasive follicular carcinoma) 2 (both PTC-fv)
11%
≤ 4
9
8
Score > 4
7
5
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28.5%
Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children 7
(16), all cases harboring molecular abnormalities turned out to be papillary thyroid carcinomas. However, about half of the nodules that were negative for all the mutations tested were malignant on histological follow-up, revealing a low sensitivity for the molecular tests. In addition, Renshow et al. (12) demonstrated that for nodules smaller than 1 cm, atypical aspirates without features of papillary thyroid carcinoma (nuclear atypia) have the same risk of malignancy as benign aspirates, suggesting that radiologic appearance should also be considered when managing patients with atypical lesions. In a pediatric study, Saavedra et al. (21) demonstrated that 80% of cases with benign cytology but a malignant histologic diagnosis had multiple ultrasound malignancy criteria, concluding that sonography complements FNA and a more aggressive approach is warranted in children with a benign FNA but radiologic findings suggesting malignancy. Our study is the first to reclassify the atypical pediatric thyroid lesions using their ultrasound features to determine if more valuable information can be obtained for better patient care. The “AUS/FLUS” lesions were separated into two subgroups based on ultrasound score: the rate of malignancy for those with less worrisome radiologic findings was 11%, similar to the rate of malignant
neoplasm for the “benign” cytologic group and comparable with that proposed by BSRTC for “AUS/FLUS” category; histologic exam of nodules with high ultrasound score resulted in malignant outcome in 28.5%, rate similar to that seen for the “FN” designation. “AUS/FLUS” diagnosis often imposes difficult clinical decisions – here we offer evidence that sonography can guide future follow-up of pediatric patients with atypical nodules: children with only few ultrasound malignancy criteria should be treated similarly to those with cytologically “benign” lesions, probably by repeat FNA or very close clinical follow-up considering the still high rate of malignancy (10%–11%), whereas those with numerous worrisome radiologic findings could be regarded as “follicular neoplasms” and managed by following the BSRTC for this cytopathologic designation, possibly by surgical resection (Figure 1). In conclusion, our study demonstrates that “AUS/ FLUS” cytologic category does not add valuable information to better characterize pediatric thyroid nodules. Ultrasound exam performed by experienced radiologists using optimal quality equipment can complement the cytopathology findings and help clinicians decide the next best step in patient’s care when dealing with atypical nodules in children.
Figure 1: Proposed algorithm for further work-up of “AUS/FLUS” lesions in children. Ultrasound exam performed by experienced radiologists using optimal equipment can complement the cytopathology findings and help clinicians decide the next best step in patient’s care. Patients with only few ultrasound malignancy criteria should be treated similarly to those with “benign” lesions, probably by repeat FNA or very close clinical follow-up considering the still high rate of malignancy (10%–11%), whereas those with numerous worrisome radiologic findings could be regarded as “follicular neoplasms” and managed by following the BSRTC for this cytopathologic designation, possibly by surgical resection.
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8 Arva and Deitch: Atypia of undetermined significance/follicular lesion of undetermined significance in children Acknowledgments: We would like to thank Gang Zhang from the Research Center, Biostatistics Core, Ann & Robert H. Lurie Children’s Hospital of Chicago for significant input regarding the statistical analysis used in our study. Conflict of interest statement: The authors have no conflicts of interest, commercial or financial disclosures.
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