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Keywords:

  • thyroid;
  • thyroid nodule;
  • fine-needle aspiration;
  • Bethesda system;
  • papillary carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

BACKGROUND:

Most malignancies identified by thyroid fine-needle aspiration (FNA) are papillary thyroid carcinoma (PTC). This study sought to determine if clinically adverse features of PTC correlate with the preceding cytologic diagnosis.

METHODS:

Thyroid FNA diagnoses were correlated with subsequent histopathologic findings.

RESULTS:

From 6175 thyroid FNAs, histologic follow-up confirmed PTC in 52 of 184 (28%) FNAs with atypia of undetermined significance (AUS), 52 of 190 (27%) FNAs suspicious for follicular neoplasm, 182 of 229 (79%) FNAs that were suspicious for malignancy, and 188 of 198 (95%) FNAs that were malignant (M). Sex, age, and disease multifocality did not differ among FNA diagnosis groups. However, PTCs following an M FNA were more likely to have a higher American Joint Committee on Cancer T and N stage, and have lymphovascular invasion and/or extrathyroidal extension. Two patients had distant metastasis at initial surgery, whereas 16 developed subsequent recurrence and/or metastasis; all had a preceding M FNA. High-risk histologic subtypes of PTC also stratify to the M category, accounting at least partly for the association of cytologic diagnosis with adverse pathological parameters. Conversely, follicular variants of PTC predominate in non-M categories.

CONCLUSIONS:

The Bethesda System for Reporting Thyroid Cytopathology conveys malignancy risk, but also predicts the presence of pathological risk factors and disease progression when the malignancy is PTC. M diagnoses identify higher risk PTCs, whereas AUS diagnoses identify low-risk PTCs, mostly follicular variants. These findings support the concept of conservative clinical management for some patients with AUS, while suggesting that a central neck dissection may be routinely justified in some patients with a M FNA. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society.

The Bethesda System for Reporting Thyroid Cytopathology (TBS) provides a 6-tiered diagnostic framework that uses defined criteria to promote uniformity in the reporting of thyroid aspirates.1 One of the major advantages of this scheme is that the individual diagnostic categories are associated with defined risks of malignancy, allowing for standardized management algorithms for each diagnosis.

As pointed out by others,2, 3 the low mortality associated with thyroid cancer means that treatment is largely directed at preventing locoregional morbidity rather than averting death. Ideally, therefore, disease detection via fine-needle aspiration (FNA) would also be directed at identifying those cancers posing significant risk for locoregional spread in addition to the small subset of tumors (such as medullary, poorly differentiated, and undifferentiated carcinomas) that carry substantial risk of death.

The vast majority of malignancies identified by thyroid FNA are papillary thyroid carcinoma (PTC), a type of cancer with an overall excellent prognosis. Factors that have been associated with higher risk for adverse outcomes with PTC include male sex, older age (>45 years) at the time of diagnosis, large tumor size, extrathyroidal extension of tumor, and certain histologic subtypes.4, 5 We recently noted that histologic follow-up of atypia of undetermined significance (AUS) diagnoses at our institution yielded a disproportionate number of malignancies classified as the follicular variant of PTC (FVPTC),6 an observation also made by other investigators.7-9 FVPTC is a controversial entity notable for the poor reproducibility of its histologic diagnosis10, 11 as well as the indolent behavior of encapsulated variants with borderline cytologic features12, 13 that has led some authors to suggest that a subset of FVPTC should be reclassified.14, 15 The association of AUS with FVPTC led us to theorize that malignancies detected by AUS may largely represent borderline FVPTCs with minimal potential for malignant behavior. Moreover, we theorized that those cytologic diagnoses most associated with PTC in TBS, progressing in severity from AUS to suspicious for malignancy (SUS) and malignant (M), might correlate both with histologic subtype as well as with features of PTC associated with disease progression. If such a correlation exists, it could have implications for clinical management algorithms within TBS. To address this question, we compared surgical outcome with the preceding cytologic diagnosis for thyroid FNAs performed at our institution over a period greater than 5 years, using TBS terminology.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Following approval by the institutional review board, a retrospective analysis was conducted of all thyroid FNAs performed at the Brigham and Women's Hospital, Boston, Mass., from January 2005 through May 2010. Over this period, 6175 thyroid FNAs were performed under ultrasound guidance by staff endocrinologists, without routine on-site evaluation. Aspirates from 3 to 4 passes using a 25-gauge needle were collected immediately in CytoLyt (Hologic, Inc, Marlborough, Mass.), and Papanicolaou-stained ThinPrep slides were prepared using the ThinPrep 2000 (Hologic). Cell block preparations were not routinely made, but at the discretion of the cytologist were attempted in a small percentage of cases when adequate material was present. All cases were reported by a staff cytopathologist using a 6-tiered diagnostic system and criteria essentially identical to TBS, as previously described.6

Outcome data were collected for those thyroid nodules with the cytologic diagnoses posing the greatest clinical concern for PTC: malignant (M), suspicious for malignancy (SUS), atypia of undetermined significance/follicular lesion of undetermined significance (AUS), or suspicious for a follicular (or Hürthle cell) neoplasm (FOL). Data compiled from the original surgical pathology reports of resected specimens included patient sex, age, size of the targeted nodule, the histopathologic diagnosis, and for malignant cases, prognostic indicators including multifocality, lymphovascular invasion, extrathyroidal extension, the total number of resected lymph nodes at the time of surgery, along with the number of positive nodes. Pathologic subtypes of PTC were combined into 3 groups for analysis purposes: 1) pure follicular variants (including macrofollicular variants); 2) tumors with any high-risk features noted (as per the World Health Organization classification of PTCs,16 including diffuse sclerosing, tall cell, poorly differentiated, and columnar features); and 3) conventional risk types (predominantly classical-type PTC as well as infrequent oncocytic, clear cell, unspecified, and cribriform morular variants considered to represent comparable clinical risk to classical-type PTC).16 The tumor–node–metastasis (TNM) stage of the tumor was determined using criteria from the most current (7th) edition of the American Joint Committee on Cancer staging manual.17 After primary surgical resection, any tumor recurrence or distant metastasis was recorded. The cases in this series had a median of 51 months clinical follow-up after the initial thyroid FNA (range of 18-83 months).

Data processing and statistics were performed using SPSS Statistics software, version 20 (IBM, Armonk, NY). Categorical analysis was performed using a chi-squared likelihood ratio test, whereas mean tumor size was analyzed using a 1-way analysis of variance test. A predetermined level of significance was set at a P value of .05. Post hoc pairwise categorical comparisons (Bonferroni test) were performed when statistical significance was observed across all categories.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

During this nearly 5.5-year period, 6175 thyroid FNAs were performed, with the distribution of diagnoses rendered using TBS criteria and nomenclature provided in Table 1. From this cohort, 192 thyroid nodules were resected following an M diagnosis on FNA, 202 nodules for an SUS diagnosis on FNA, 163 nodules for an FOL diagnosis on FNA, and 168 nodules following a single or repeat diagnosis of AUS. In addition to these cases, 6 nodules were resected after an AUS and follow-up M FNA, 27 nodules were resected after an AUS and follow-up SUS FNA, 27 nodules were resected after an AUS and follow-up FOL FNA, 12 nodules were resected after an AUS and follow-up benign FNA, and 4 nodules were resected after an AUS and follow-up nondiagnostic FNA. These cases were grouped according to the worst (most severe) FNA diagnosis (either M, SUS, FOL, or AUS), giving a total of 198 M nodules, 229 SUS nodules, 190 FOL, and 184 AUS nodules.

Table 1. Distribution of Thyroid Fine-Needle Aspirate Diagnoses Between January 1, 2005, and May 31, 2010
Fine-Needle Aspirate DiagnosisNo. (%)a
  • a

    Values are expressed as number with percent of total following in parentheses.

Nondiagnostic795 (12.9)
Benign3876 (62.8)
Atypia of undetermined significance692 (11.2)
Suspicious for follicular/Hürthle cell neoplasm242 (3.9)
Suspicious for malignancy260 (4.2)
Malignant305 (4.9)
Neoplastic cells present5 (0.1)
Total6175 (100)

The overall distribution of histologic outcomes for these thyroid nodules after surgery is delineated in Table 2. The small numbers of non-PTC epithelial malignancies with significant risk of progression (medullary, anaplastic, and poorly differentiated carcinomas) appear to stratify by severity of the preceding cytologic diagnosis with the exception of the FOL category, accounting both for most follicular carcinomas as well as the majority of poorly differentiated carcinomas. However, PTC accounted for the majority of the malignant surgical outcomes for all 4 groups and composed 90.1% (474 of 526) of all thyroid carcinomas. Because we were only concerned with outcomes for PTC, other malignancies were eliminated from the subsequent analyses.

Table 2. Histologic Outcome Based on Worst Preceding Fine-Needle Aspirate Diagnosisa
DiagnosisMalignantSuspicious for MalignancyFollicular NeoplasmAUSTotal
  • a

    Values are expressed as number with percent of total following in parentheses.

  • ANA indicates anaplastic/undifferentiated thyroid carcinoma; AUS, atypia of undetermined significance; FNUMP, follicular neoplasm of uncertain malignant potential; FTC, follicular thyroid carcinoma; HTT, hyalinizing trabecular tumor; MTC, medullary thyroid carcinoma; PDCar, poorly differentiated carcinoma; PTC, papillary thyroid carcinoma.

PTC188 (94.9)182 (79.5)52 (27.4)52 (28.3)474 (59.2)
FTC0 (0.0)2 (0.9)27 (14.2)8 (4.3)37 (4.6)
MTC6 (3.0)0 (0.0)1 (0.5)0 (0.0)7 (0.9)
PDCar1 (0.5)2 (0.9)4 (2.1)0 (0.0)7 (0.9)
ANA1 (0.5)0 (0.0)0 (0.0)0 (0.0)1 (0.1)
Benign2 (1.0)40 (17.5)104 (54.7)123 (66.8)269 (33.6)
FNUMP0 (0.0)0 (0.0)2 (1.1)0 (0.0)2 (0.2)
HTT0 (0.0)1 (0.4)0 (0.0)0 (0.0)1 (0.1)
Lymphoma0 (0.0)2 (0.9)0 (0.0)1 (0.5)3 (0.4)
Total198 (100)229 (100)190 (100)184 (100)801 (100)

The breakdown of histologic subtypes for the PTC cases is shown in Table 3. Relative to the other categories, the M category had higher proportions of high-risk and conventional subtypes, whereas follicular variants accounted for most PTCs in the SUS, FOL, and AUS groups. The distribution of PTC subtypes showed statistically significant differences across cytologic diagnoses (P < .001) with pairwise comparisons of the M group with the AUS, FOL, and SUS diagnoses also achieving statistical significance (P < .001).

Table 3. Papillary Thyroid Carcinoma Subtype Based on Worst Preceding Fine-Needle Aspirate Diagnosisa
SubtypeMalignantSuspicious for MalignancyFollicular NeoplasmAUS
  • a

    AUS indicates atypia of undetermined significance; CV, conventional variant; FV, follicular variant.

    Values are expressed as number with percent of total following in parentheses.

  • b

    24 diffuse sclerosing, 26 tall cell, and 11 with mixed diffuse sclerosing and tall cell variant/features.

  • c

    10 diffuse sclerosing and 6 tall cell variant/features; 2 with focal poorly differentiated areas.

  • d

    2 follicular variants with poorly differentiated areas.

  • P > .001; post hoc pairwise comparisons: AUS vs M, P < .001, FOL vs M, P < .001, SUS vs M, P < .001. All others not significant.

FV46 (24.5)136 (74.7)38 (73.1)44 (84.6)
CV81 (43.1)28 (15.4)12 (23.1)8 (15.4)
High-risk61 (32.4)b18 (9.9)c2 (3.8)d0 (0.0)
Total188 (100)182 (100)52 (100)52 (100)

There were no significant differences across diagnostic categories with regard to sex or age (Table 4). The difference in mean tumor size was statistically significant (P < .04) across all categories; the only pairwise statistically significant difference in size was PTC associated with M being significantly smaller than PTC associated with FOL (P < .02). Although the M group had a slightly higher proportion of multifocal disease as well as the only 2 cases with metastasis at the initial time of surgery, these differences were not statistically significant compared with the other groups. However, clear differences in other pathologic features were apparent between FNA-diagnosis groups (Table 4). The distribution of cases according to cytologic diagnoses for T stage, N stage, lymphovascular invasion, extrathyroidal extension, and recurrence/metastasis was statistically significant (P < .001). Each of these parameters was statistically significant when comparing M to SUS, M to AUS, and M to FOL (except T stage for M to FOL). Although no statistically significant differences were noted between the AUS and SUS categories, a trend was observed with higher percentages of cases with higher T stage, lymph node metastasis, lymphovascular invasion, and extrathyroidal extension observed in the SUS category compared with AUS. All 5 T3 PTCs associated with AUS were >4 cm in greatest dimension. Only 1 of the 5 T3 PTCs following an AUS would have been classified as T3 based on the presence of extrathyroidal extension, but this tumor also would have been categorized as T3 based on size because it exceeded 4 cm. Only 2 PTCs had distant metastasis at the time of surgery, and 16 patients later went on to develop recurrence and/or distant lymph node metastasis after surgery; all these cases had an M FNA diagnosis preceding surgery.

Table 4. Papillary Thyroid Carcinoma Properties Based on Worst Preceding Fine-Needle Aspirate Diagnosisa
CharacteristicMalignantSuspicious for MalignancyFollicular NeoplasmAUS
  • a

    AUS indicates atypia of undetermined significance; SD, standard deviation. Values are expressed as number with percent of total following in parentheses.

  • b

    Not significant.

  • c

    P < .04. Post hoc pairwise comparison: FOL vs M, P < .02; all others not significant.

  • d

    P < .001. Post hoc pairwise comparison: AUS vs M, P = .001; SUS vs M, P < .001; all others not significant.

  • e

    P < .001. Post hoc pairwise comparison: AUS vs M, P < .001; FOL vs M, P < .001; SUS vs M, P < .001; all others not significant.

  • f

    P < .001. Post hoc pairwise comparison: AUS vs M, P < .02; FOL vs M, P < .02; SUS vs M, P < .001; all others not significant.

Sexb    
 Male:female41:14732:1509:4313:39
Age, yb    
 ≤4585 (45.2)72 (39.6)18 (34.6)16 (30.8)
 >45103 (54.8)110 (60.4)34 (65.4)36 (69.2)
Mean tumor size, cmSD)c1.9 ± 1.12.0 ± 1.32.5 ± 1.62.1 ± 1.3
     
Tumor staged
 T1a25 (13.3)39 (21.4)5 (9.6)11 (21.2)
 T1b58 (30.9)67 (36.8)18 (34.6)24 (46.2)
 T239 (20.7)54 (29.7)23 (44.2)12 (23.1)
 T362 (33.0)19 (10.4)6 (11.5)5 (9.6)
 T44 (2.1)3 (1.6)0 (0.0)0 (0.0)
Lymph node metastasise
 N164 (34.0)9 (4.9)1 (1.9)1 (1.9)
 N078 (41.5)96 (52.7)21 (40.4)26 (50.0)
 NX46 (24.5)77 (42.3)30 (57.7)25 (48.1)
Distant metastasis (time of surgery)b
 M12 (1.1)0 (0.0)0 (0.0)0 (0.0)
 MX186 (98.9)182 (100)52 (100)52 (100)
Lymphovascular invasione
 Present93 (49.5)26 (14.3)8 (15.4)1 (1.9)
 Absent95 (50.5)156 (85.7)44 (84.6)51 (98.1)
Extrathyroidal extensione
 Present63 (33.5)10 (5.5)0 (0.0)1 (1.9)
 Absent125 (66.5)172 (94.5)52 (100)51 (98.1)
Multifocal diseaseb
 Present119 (63.3)96 (52.7)25 (48.1)29 (55.8)
 Absent69 (36.7)86 (47.3)27 (51.9)23 (44.2)
Local recurrence or late metastasisf
 Yes16 (8.5)0 (0.0)0 (0.0)0 (0.0)
 No172 (91.5)182 (100)52 (100)52 (100)
Totals188 (100)182 (100)52 (100)52 (100)
     

None of the statistically significant parameters of T stage, N stage, lymphovascular invasion, extrathyroidal extension, and recurrence/metastasis can be directly evaluated on an initial thyroid FNA; therefore, we theorized that the stratification of these parameters may in turn be dependent on the differential distribution of PTC subtypes across cytologic diagnostic categories. To assess this possibility, we stratified these parameters both by cytologic diagnosis and PTC subtype. Statistically significant differences were noted for N stage, lymphovascular invasion, and extrathyroidal extension according to 1 or more subtypes of PTC (Table 5), while nearly reaching statistical significance for T stage and recurrence/metastasis, thus supporting the conclusion that the stratification of markers of aggressive behavior by FNA category is at least in part dependent on PTC subtype.

Table 5. Pathologic Features Stratified by Cytologic Diagnosis and Papillary Carcinoma Subtypea
Papillary SubtypeCharacteristicCytologic DiagnosisTotal
MalignantSuspicious for MalignancyFollicular NeoplasmAUS
  • a

    AUS indicates atypia of undetermined significance; CV, conventional variant; ETE, extrathyroidal extension; FV, follicular variant; LVI, lymphovascular invasion; NS, not significant; Recur/Met?, local recurrence and/or metastasis.

  • b

    Denotes statistical significance.

  • T stage: FV (P = .58, NS), CV (P = .37, NS), high-risk (P = .08, NS).

  • N stage: FV (P = .15, NS), CV (P < .001), high-risk (P = .13, NS).

  • LVI: FV (P = .05), CV (P = .002), high-risk (P = .001).

  • ETE: FV (P = .13, NS), CV (P = .008), high-risk (P = .001).

  • Recur/Met?: FV (P = .32, NS), CV (P = .08, NS), high-risk (P = .09, NS).

FVT stageT126801628150
T21444181187
T36114526
T401001
 Total461363844264
CVT stageT142167772
T21994133
T31931023
T410001
 Total8128128129
High-riskT stageT115100025
T261108
T33751043
T432005
 Total61182081
FVN stageN024671423128
N144109
 Total28711523137
CVbN stageN031206360
N13110133
 Total62216493
High-riskN stageN02391033
N12940033
 Total52131066
FVbLVIAbsent371223443236
Present9144128
 Total461363844264
CVbLVIAbsent46248886
Present3544043
 Total8128128129
High-riskbLVIAbsent12102024
Present4980057
 Total61182081
FVETEAbsent421323843255
Present44019
 Total461363844264
CVbETEAbsent6226128108
Present1920021
 Total8128128129
High-riskbETEAbsent21142037
Present4040044
 Total61182081
FVRecur/Met?No451363844263
Yes10001
 Total461363844264
CVRecur/Met?No7428128122
Yes70007
 Total8128128129
High-riskRecur/Met?No53182073
Yes80008
 Total61182081

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Our findings confirm a distinct stratification of histologic subtype of PTC according to the preceding cytologic diagnosis. Almost all PTCs identified in association with AUS were FVPTC, whereas M FNA diagnoses encompassed most classical variants as well as aggressive variants such as tall cell and diffuse sclerosing types of PTC. Not surprisingly, the SUS category had intermediate properties, mostly comprising FVPTC but with small numbers of high-risk variants not observed following an AUS diagnosis, whereas PTC associated with the FOL category is predominantly FVPTC with infrequent tumors having a poorly differentiated component. This stratification according to cytologic diagnosis is not surprising in that a significant proportion of tumors diagnosed as FVPTC have marginal nuclear features of PTC18 that would be a logical histologic counterpart to the lesser degrees of atypia encountered in the non-M categories, most notably the mild cytologic atypia responsible for some AUS diagnoses. Perhaps more surprising is how clearly the other PTC subtypes stratify between the AUS and M categories. This implies that AUS diagnoses suggestive of PTC are mostly classified as AUS because of the inherent borderline nuclear features of PTC in the lesional cells rather than representing suboptimal sampling of PTC possessing well-developed cytologic features, as would be typical of classical variants. Those lesions with readily recognizable cytologic features of PTC, such as frequent intranuclear pseudoinclusions, will be diagnosed as M when well sampled by FNA and, as our data indicates, are more likely to be classified as SUS than AUS (or perhaps FOL) if the lesion is suboptimally represented.

The severity of the preceding cytologic diagnosis in TBS was also predictive of histologic parameters associated with more aggressive clinical behavior. Yet, the only parameter that could potentially be directly assessed by cytologic evaluation of the original lesion is the histologic subtype of the tumor. Even this parameter, however, is not routinely assessed on FNA and in most instances may only be suggested by the cytologic features of the specimen. The implication of this finding is that more definitive features of PTC indirectly predict the likelihood of encountering features associated with more worrisome clinical behavior, such as extrathyroidal extension, even though these parameters cannot be directly assessed by cytologic methods. Our data further indicate that the M category is particularly sensitive for detecting more commonly encountered high-risk subtypes of PTC, such as the tall cell type. This stratification of subtype within the TBS framework in turn accounts at least in part for the ability of TBS classification to stratify risk for other parameters associated with more aggressive behavior.

Greater degrees of atypia detected within TBS have been known to predict the risk of malignancy within the TBS framework. In fact, this risk stratification is one of the major benefits of using TBS. Our findings indicate that the severity of the diagnosis within TBS also predicts risk for locoregional complications with PTC. These observations further validate the current definitions of individual categories in TBS as well as the concept of having differing management for each diagnostic category. More significantly, if verified by others, these findings could potentially alter currently recommended clinical management algorithms. Current American Thyroid Association guidelines state that “prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with PTC with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4).”19 In patients with an M FNA diagnosis in our study, lymph node metastases were encountered in 45% (64 of 142) of patients having any lymph nodes removed at the time of surgery, but were infrequently observed following a SUS diagnosis and present in only single cases in the AUS or FOL categories. Consequently, our findings indicate that consideration should be given to routine central compartment lymph node sampling in patients with a preceding M FNA diagnosis.

The potential clinical implications of our data for management of patients with an AUS diagnosis are intriguing. Our previously published data, as well as that of some other investigators,7, 20, 21 have indicated that the overall risk of malignancy associated with the AUS diagnosis may be higher than the 5% to 15% rate that had been anticipated by TBS. A higher malignancy rate potentially argues for earlier surgical intervention rather than the TBS recommended approach of repeating the FNA after an initial AUS diagnosis. The data in the present study, however, indicate that the low clinical risk of locoregional spread associated with the indolent malignancies detected by AUS justifies consideration of both short-term and long-term nonsurgical management in appropriately selected patients within the AUS group. Of the 5 T3 PTCs identified in our study, only 1 exhibited extrathyroidal extension, and all could be identified preoperatively based on their large size. Thus, consideration should be given to stratifying management of an initial AUS based on size (as well as other potentially worrisome clinical and/or radiologic parameters).19 A potential approach would be to send patients with larger nodules (at least those in the T3 size range exceeding 4 cm) to surgery after a single AUS diagnosis, while initially managing patients who have smaller nodules with repeat FNA. Serial ultrasound examination, possibly accompanied by repeat FNA, could represent a viable long-term management option for patients with small nodules lacking worrisome clinical or ultrasound properties. Surgery would be reserved for those individuals whose nodules progress in size, develop other concerning clinical/ultrasound features, or progress in the severity of any repeat FNA cytologic diagnosis. Because of the likely indolent behavior of such PTCs, an approach of “watchful waiting” would pose minimal risk should later surgical intervention prove necessary. At the same time, the major risks of thyroid surgery, including vocal cord paralysis and hypocalcemia, the need for lifetime thyroid hormone replacement therapy, and the potential stigma and anxiety associated with a diagnosis of cancer would be avoided in a significant subset of patients.

The difficulty in diagnosing the FVPTC subtype both through cytologic and histologic means remains a vexing problem. We had previously observed that malignancies detected in our laboratory after an AUS FNA diagnosis are largely FVPTCs.6 Other authors have made similar observations,7-9 and descriptions of FVPTC preceding implementation of TBS have also noted that FVPTCs are often not definitively malignant on FNA.22, 23 Histologically, the diagnosis of FVPTC is known to be notoriously poorly reproducible.10, 11 Some authors have argued that lesions with borderline histological features of FVPTC should be reclassified into existing diagnostic categories, such as follicular adenoma, or alternative nomenclature should be adopted that sets these lesions apart from uniformly recognizable PTCs.14, 15 These proposals have not been widely accepted to date.

Because FVPTC constitutes a larger percentage of malignancies identified with lesser degrees of cytologic atypia on FNA, the corresponding malignancy rates identified for AUS (and to a lesser degree the FOL and SUS categories) would be expected to show greater fluctuations among laboratories, in accordance with local practice regarding the histologic threshold for diagnosing FVPTC. The consequences of such variations in practice regarding classification of FVPTC will not be readily identified because clinical outcome will be almost uniformly excellent. Nevertheless, rare instances have been reported where seemingly banal FVPTC behaved aggressive clinically.24 Such rare cases, along with medicolegal concerns, make it easier to overdiagnose and overtreat patients than to manage them conservatively.18, 25 Mindful that other categories in TBS will account for those malignancies associated with significant mortality as well as those PTCs associated with locoregional morbidity (as shown in our study), overtreatment of the low-risk lesions commonly associated with the AUS diagnosis should be avoided.

Some laboratories have reported notably low rates of AUS as well as low AUS:M ratios.2, 21, 26, 27 These low rates may be achieved at the expense of diagnostic sensitivity.28 Laboratories that practice in this fashion may be avoiding the potential overtreatment of AUS by simply avoiding the diagnosis altogether. This approach may have merit because lesions that could be theoretically missed are unlikely to prove harmful to the patient, at least in the short-term. Whether greater sensitivity to low-risk lesions is beneficial to long-term outcome by intervening in disease progression to more aggressive (poorly differentiated or anaplastic) carcinomas is unclear, but is unlikely to be significant in most instances. Nevertheless, it will prove difficult for many cytopathologists to feel comfortable calling the subtle cytologic features associated with these lesions “benign” rather than AUS unless the histologic practice of diagnosing encapsulated follicular lesions with borderline cytologic features as FVPTC is significantly altered.

Our data demonstrate similar properties for PTCs detected by either the FOL or AUS diagnoses, whereas the FOL category, in addition, accounts for most follicular carcinomas detected by FNA. Nevertheless, in our population, a FOL diagnosis was almost twice as likely to result in a histologic diagnosis of PTC as follicular carcinoma. As was the case with the AUS category, we observed a malignancy rate (44.2%; 84 of 190 cases) higher for the FOL category than anticipated by TBS. Also, as with AUS, however, this increased malignancy rate is largely accounted for by the presence of low-risk FVPTCs. Although the overall higher rates of malignancy for AUS and FOL could argue for more aggressive management than recommended by TBS, the clinically indolent behavior of this large subset of tumors detected with both AUS and FOL diagnoses justifies the more conservative management approach advocated by TBS.

Ideally, molecular testing would provide guidance as to which indeterminate lesions might represent malignancies with the potential for significant clinical risk, and this is an area of intensive research interest at present.29-31 As the FVPTC is currently defined, such lesions are more likely to be associated with RAS mutations, whereas the BRAF V600E mutation is more frequently identified with PTCs with more aggressive clinical behavior.32 If the goal of molecular testing is to detect aggressive tumors rather than maximizing sensitivity for malignancy, then testing for BRAF V600E rather than a panel of markers also including RAS, RET/PTC, and PAX8/PPARγ may be desirable. Here, too, a consensus has not yet been achieved as to how to best use ancillary molecular testing data for indeterminate thyroid FNA specimens.

In conclusion, we have shown that the diagnostic categories in TBS (particularly the M category) not only stratify risk of malignancy, but also correlate with the subtype of PTC as well as the presence of adverse histopathologic features. These findings may have implications for refining clinical management algorithms for patients with AUS or M diagnoses on FNA.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosure.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES