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Keywords:

  • thyroid;
  • fine-needle aspiration;
  • needle tracts;
  • repeat aspiration;
  • cytology

Abstract

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

BACKGROUND:

Fine-needle aspiration (FNA) is a screening and diagnostic tool used in the evaluation of thyroid nodules. Its use has resulted in an increase in the ratio of malignant versus benign thyroid nodules undergoing surgical excision. However, the FNA procedure produces some histological and cytologic alterations, which may lead to misinterpretation on repeat FNA. The goal of the current study was to characterize FNA-induced morphological alterations and their potential influence on interpretations in repeat FNA specimens.

METHOD:

Thyroidectomy specimens that had benign histological diagnoses and for which previous FNA specimens were available were retrieved. The FNA-induced histological alterations were evaluated and grouped based on the interval between the FNA procedure and surgical excision. Repeat thyroid FNA specimens with a cytologic diagnosis of “atypical cells/follicular lesion” were reviewed. Worrisome cytologic features that might occur after the previous FNA procedure were discussed.

RESULTS:

Needle tracts were identified in 68 of the 96 thyroidectomy specimens studied. FNA-induced histological alterations included hemorrhage, granulation, exuberant fibroblastic reaction, reactive follicular cells, infarction, and scarring. The presence of plump endothelial cells, myofibroblasts, and, particularly, reactive follicular cells with nuclear grooving and nuclear clearing are potential pitfalls in repeat FNA and these changes are reported to peak within 20 to 40 days after the FNA procedure. Sixteen of 152 repeat FNA cases were diagnosed as atypical cells/follicular lesion, and FNA-induced changes might have contributed to the diagnosis in 2 of these 16 cases.

CONCLUSIONS:

Cytologists should be aware of atypical cellular changes caused by previous FNA procedures. Although uncommon, these changes may become potential pitfalls in the cytologic diagnosis of repeat thyroid FNA specimens. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.


INTRODUCTION

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

The incidence of thyroid cancer has been soaring since the mid-1990s and it is now the fastest increasing cancer in both men and women in the United States.1 Fine-needle aspiration (FNA) has been used increasingly as a screening and diagnostic tool for evaluating thyroid nodules. It has been proven to be safe and accurate, and is generally well tolerated by patients. The reported sensitivity and specificity of thyroid FNA are 65% to 98% and 72% to 100%, respectively.2-4

According to the recently published guidelines for the management of thyroid nodules, patients with a thyroid nodule that is cytologically either nondiagnostic or falls into the category of “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS) should undergo a repeat thyroid FNA to obtain a more definitive diagnosis.5, 6 These would account for approximately 10% to 25% of all thyroid FNA cases. In addition, many of the thyroid nodules with a benign cytologic diagnosis also have been followed up with repeat FNA, although its benefits are still controversial.7-9 Considering the total number of thyroid FNA procedures performed, the cases that require repeat thyroid FNA are expected to increase significantly. The histological alterations resulting from previous thyroid FNA procedures, also referred to as needle tract effects, have been described in the literature, and included post-FNA necrosis, infarction, and capsular and vascular changes on histological diagnosis.10, 11 The potential influences of these changes on the cytologic diagnosis in repeat thyroid FNA have been anticipated, but to our knowledge have not been well studied to date. We recently encountered several cases of thyroid FNA with atypical cytological features that we believe might represent reactive changes in response to the previous thyroid FNA procedure. These cytological changes presented in repeat FNAs could potentially be misinterpreted, resulting in an increase in the number of surgical resections of benign thyroid nodules. The purpose of the current study was to characterize the morphologic features of needle tract effects and their potential influence on the interpretation of repeat thyroid FNA specimens.

MATERIALS AND METHODS

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

Thyroidectomy cases obtained between 2007 and 2009 that had a benign histological diagnosis and for which previous FNA specimens were available were retrieved from the Department of Pathology at the Medical University of South Carolina in Charleston. The cases were grouped based on the interval between the FNA procedure and surgery as follows: group 1: 0 days to 10 days; group 2: 11 days to 20 days; group 3: 21 days to 30 days; group 4: 31 days to 40 days; group 5: 41 days to 80 days; and group 6: > 81 days. All original slides from each case were reviewed to identify the needle tract(s) and morphological alterations caused by the previous FNA procedure. There was no further effort made in those cases in which an obvious needle tract could not be found in the original slides, assuming the area of the needle tract was not sampled in these sections. Repeat thyroid FNA cases from 2009 to 2011 were also retrieved. The cases with a cytologic diagnosis of AUS/FLUS were reviewed and correlated with histological findings whenever available. The atypical cytologic features that might contribute to the previous FNA procedure were discussed.

RESULTS

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

The original histological sections from 96 thyroidectomy cases were reviewed and obvious needle tracts were identified in 68 cases (71%). The interval between the previous FNA procedure and surgery ranged from 1 day to 729 days, with the majority of cases having an interval of within 90 days. Table 1 demonstrates the major morphological changes in response to the previous FNA procedure, which are grouped based on the time interval between the FNA procedure and surgery. The most common histological alteration found within 10 days after FNA (group 1) is the presence of hemorrhage, which was observed in 9 of 13 cases (69%). The number of cases with this feature significantly decreased after 20 days after FNA. In group 2 (interval of 11 days-20 days), the major findings were significant fibrin deposition and granulation tissue formation (6 of 9 cases; 67%) in addition to hemorrhage (7 of 9 cases; 78%). The most remarkable cytological changes were found in group 3 (interval of 21 days-30 days), which were characterized by the presence of exuberant fibroblastic reaction (7 of 14 cases; 50%), reactive endothelial cells, and follicular cells (8 of 14 cases; 57%). There were many myofibroblasts with enlarged nuclei and prominent nucleoli noted (Fig. 1). Both plump endothelial cells and follicular cells adjacent to the needle tract demonstrated enlarged nuclei with significant nuclear clearing, which may potentially be mistaken for papillary thyroid carcinoma in cytologic specimens (Figs. 2 and 3). Cases in group 4 (interval of 31 days-40 days) and group 5 (interval of 41 days-80 days) tended to demonstrate more mature granulation tissue and the presence of scarring. In group 6 (interval of > 81 days), scar tissue was the most common finding (20 of 36 cases; 56%).

Table 1. Histological Alterations After FNA in Thyroidectomy Specimens
 DaysNo. of CasesHemorrhageGranulationReactive SCReactive FCScarringInfarctionNo Needle Tract Found
  1. Abbreviations: FC, follicular cells; FNA, fine-needle aspiration; SC, stromal cells.

Group 10-10139300003
Group 211-2097611001
Group 321-30142878104
Group 431-40112421305
Group 541-80130611512
Group 6>8136031120113
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Figure 1. Granulation tissue with exuberant reactive myofibroblasts and plump endothelial cells is present in a histological section from day 15 after fine-needle aspiration (H & E, × 400).

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Figure 2. Reactive endothelial cells with enlarged nuclei, nuclear clearing, and prominent nucleoli are present in a histological section from day 40 after fine-needle aspiration (H & E, × 800).

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Figure 3. Follicular cells with nuclear clearing and prominent, eccentrically located nucleoli are present in a histological section from day 14 after fine-needle aspiration (H & E, × 400).

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A total of 152 cases of repeat thyroid FNA were identified, accounting for 5.3% of 2843 cases of thyroid FNA performed within the study period. These included 61 cases classified as previously unsatisfactory, 77 cases classified as benign thyroid nodules, and 14 cases of AUS/FLUS. The interval between 2 FNA procedures ranged from 5 days to 25 months, with the majority of repeat FNA procedures performed within 3 months to 6 months. The cytologic diagnoses of these repeat FNA cases were 15 (9.9%) classified as unsatisfactory, 112 (73.7%) classified as benign thyroid nodules, 16 (10.5%) classified as AUS/FLUS, 3 (2.0%) classified as follicular/hurthle cell neoplasms (FN/HN), 3 (2.0%) classified as suspicious for malignant cells, and 3 (2.0 %) classified as positive for malignant cells. The rate in each cytologic diagnostic category was similar to that of all thyroid FNA cases performed within the same period except that there was a higher rate of AUS/FLUS and unsatisfactory cases in the repeat FNA specimens (Table 2). In reviewing the slides from these 16 AUS/FLUS cases, atypical cytologic features that might result from previous FNA procedures were identified in 2 cases, in which the interval between the 2 FNAs was 29 days and 45 days, respectively. The atypical cytologic features included the presence of reactive stromal cells, endothelial cells, follicular cells, and metaplastic cells. The reactive stromal cells (ie, myofibroblasts) often demonstrated significantly enlarged nuclei, prominent nucleoli, and characteristic delicate cytoplasm (Fig. 4). They were scattered and usually embedded in blood or blood clots. The main worrisome features were noted in reactive follicular cells and endothelial cells with enlarged nuclei and nuclear clearing, which overlap with the cytologic features of papillary carcinoma of thyroid (Fig. 5). These atypical changes were not present in the previous FNA samples that were cytologically diagnosed as benign thyroid nodules in both cases. In addition, atypical squamous cells were also noted in 1 case (Fig. 6). Although these atypical squamous cells were not observed in the previous FNA sample, their relation with the previous FNA procedure was unknown because the histological sample that was diagnosed as a benign thyroid nodule was not available for review. These squamous cells may also represent a manifestation of spectrum changes in cystic lining cells. It is interesting to note that all of the above-mentioned changes were focal in cytologic smears, and they did not cause a cytologic diagnosis greater than AUS/FLUS in the current study. The remaining 14 cases of AUS/FLUS demonstrated cellular smears comprised of follicular/Hurthle cells in both a microfollicular and macrofollicular pattern, which are apparently not related to the previous FNA procedure. Among 16 cases of patients with AUS/FLUS, 9 patients underwent thyroidectomy, which revealed 1 case of Hurthle cell carcinoma, 1 case of papillary thyroid carcinoma, 2 cases of follicular adenoma, and 5 cases of nodular hyperplasia. Two patients were followed up again with FNA, both of whom were diagnosed as having a benign thyroid nodule. Two additional patients were followed up with ultrasonography, which demonstrated either no change or a decrease in the size of the nodules. There was no follow-up information obtained for the remaining 3 cases. All cases with a cytologic diagnosis of FN/HN, suspicious for malignancy, and positive for malignancy were followed up with surgical excision; the histological diagnoses of these cases are listed in Table 3. The cases cytologically diagnosed as unsatisfactory and benign thyroid nodules were not reviewed because they were apparently not affected by the previous FNA procedure.

Table 2. Comparison of Cytologic Diagnosis in the Repeat Thyroid FNA Cases Versus All Thyroid FNA Cases Performed in the Same Period
 No. of CasesUnsatisfactoryBenignAUS/FLUSFN/HNSuspiciousMalignant
  1. Abbreviations: AUS, atypia of undermined significance; FLUS, follicular lesion of undermined significance; FN, follicular neoplasm; FNA, fine-needle aspiration; HN, Hurthle cell neoplasm.

Repeat thyroid FNA15215 (9.9%)112 (73.7%)16 (10.5%)3 (2.0%)3 (2.0%)3 (2.0%)
All thyroid FNA2843159 (5.6%)2353 (82.8%)176 (6.2%)44 (1.5%)30 (1.1%)81 (2.8%)
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Figure 4. Atypical cells with enlarged nuclei, nuclear clearing, and prominent nucleoli are present in a cytology smear from day 29 after the previous fine-needle aspiration (Diff-Quik stain, × 800).

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Figure 5. Atypical follicular cells with enlarged nuclei, nuclear crowding, nuclear clearing, and prominent nucleoli are present in a cytology smear from day 45 after the previous fine-needle aspiration (Papanicolaou stain, × 800).

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Figure 6. An atypical squamous cell and background of macrophages are present in a cytology smear from day 150 after the previous fine-needle aspiration (Papanicolaou stain, × 800).

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Table 3. Cytologic–Histological Correlation in Repeat FNA Cases With Surgical Follow-Up
Cytologic DiagnosisNo. of CasesHistological Diagnosis
HyperplasiaFollicular/ Hurthle Cell AdenomaFollicular/ Hurthle Cell CarcinomaPapillary CarcinomaOther
  1. Abbreviations: AUS, atypia of undermined significance; FLUS, follicular lesion of undermined significance; FN, follicular neoplasm; FNA, fine-needle aspiration; HN, Hurthle cell neoplasm.

  2. a

    Ectopic parathyroid.

AUS/FLUS952110
FN/HN311100
Suspicious300111a
Malignant300030

DISCUSSION

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

FNA is considered to be part of the standard of care in evaluating thyroid nodules. It is safe and accurate and can be performed by palpation or under ultrasonographic guidance.1, 12, 13 In the majority of cases, FNA can distinguish benign nodules that can be managed conservatively from potential thyroid neoplasms that require surgical excision. In conjunction with the clinical findings, FNA cytology has played an important role in the clinical management of patients with thyroid nodules.6, 14 However, it is also recognized that there are limitations of thyroid FNA. There exist approximately 10% to 25% of thyroid FNA cases in which a definitive cytologic diagnosis cannot be made either because of insufficient material or the presence of cells with subtle atypical cytologic changes for which the significance cannot be determined. These cases, classified as nondiagnostic/unsatisfactory and AUS/FLUS, respectively, in the Bethesda System for reporting thyroid cytopathology, carry a 5% to 15% risk of harboring malignant neoplasms and therefore it is recommended that they be followed up with repeat FNA if it is clinically indicated.5, 6, 14 With soaring numbers of thyroid FNA procedures being performed in recent years, it is expected that the number of cases requiring repeat FNA will increase as well. At the study institution, the number of thyroid FNA cases has increased from 60 in 1992 to 1047 in 2008, and > 200 cases of repeat thyroid FNA have been encountered within the past 3 years (2009-2011). Currently, the majority of repeat thyroid FNAs in the study institution are performed on thyroid nodules that were previously classified as either nondiagnostic or cytologically benign. The number of repeat FNA cases will further increase as clinicians gradually adopt the recommendations from the National Cancer Institute regarding the management of thyroid nodules that include repeating FNA in patients with a previous cytologic diagnosis of AUS/FLUS.6

We recently observed several repeat FNA cases in which a few atypical cells with large nuclei and nuclear clearing were noted but the follow-up surgical specimens demonstrated benign histology. We believe that some cytologic atypia noted in the repeat FNA specimens might be rooted in the reactive changes that occurred in response to the previous needle tracts.

The worrisome histologic alterations after FNA of the thyroid were first described by LiVolsi and Merino10 and later by other authors.11, 15, 16 The histologic alterations include hemorrhage, necrosis/infarction, reactive stromal and follicular cells, mitosis, squamous cell and Hurthle cell metaplasia, and pseudocapsular and vascular invasion. The extent and type of the alterations are affected by many factors, including the size and type of nodule, the number of needle passes, and the time from FNA to surgery.10 Histologically, much attention has been paid to capsular and vascular alteration caused by the previous FNA procedure because evaluation of capsular and vascular invasion is one of the key elements in distinguishing a follicular adenoma from carcinoma. However, in cytology, the major concerns would be reactive atypia occurring in stromal and follicular cells, which demonstrated significantly enlarged nuclei, prominent nucleoli, mitosis, and nuclear clearing. These cytologic features overlap with those of papillary carcinoma of the thyroid, which is the most common malignancy of the thyroid gland. It is interesting to note that these features are not unique to post-FNA changes and are actually more commonly noted in cases of lymphocytic (Hashimoto) thyroiditis. However, these changes were very focal and there was less significant lymphocyte infiltration and Hurthle cell changes and, more importantly, intranuclear pseudoinclusion was not found among the post-FNA changes. In addition, these changes were cytologically different from those of follicular neoplasms, in which a microfollicular pattern is key for the diagnosis. Similar histological alterations after FNA also have been described in other organs, including the salivary glands and parathyroid gland.17, 18 Because repeat FNA is rarely applied to those organs, the post-FNA changes are much less concerning compared with those in the thyroid.

To the best of our knowledge, the relation between histological changes and length of time from FNA to surgical excision of the thyroid lesion has not been well studied. In the article by LiVolsi and Merino, the changes were divided into acute and chronic groups based on the type of reaction and the interval between the FNA procedure and surgery.10 The acute changes, predominantly hemorrhage and granulation, were found when the interval was ≤ 3 weeks. The chronic changes, dominated by fibrosis and distortion of the capsule, were noted when the interval exceeded 3 weeks, often within the range of 1 month to 6 months. In anticipating the effects of these changes on the interpretation of repeat FNA specimens, it has been recommended that the interval between 2 FNA procedures should be at least 3 months and an interval of 6 months to 18 months appears to be reasonable.19 In the current study, the exuberant reactive changes that might affect cytologic diagnosis in repeat FNA specimens occurred more frequently between 10 days to 40 days after the FNA procedure. There would be an increased chance that these reactive components appear and lead to inconclusive or more aggressive cytologic diagnoses if repeat FNA is performed during this period. The frequencies of these worrisome reactive changes were found to decrease after 40 days, but could still be noted in some cases even beyond 3 months.

In summary, pathologists should be aware of the potential pitfalls of atypical cellular changes caused by a previous FNA procedure, even though they appear to be uncommon. These changes can mimic cytologic features of papillary carcinoma of thyroid. It is advised that a longer interval should take place before FNA is repeated in the same thyroid nodule to reduce needle tract-induced atypical cellular changes in cytology specimens. It should be emphasized that whether or when to repeat FNA is dictated by the combination of both clinical manifestations and the previous cytology of the nodule, with the former being vitally important.

FUNDING SUPPORT

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

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES
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    GharibH, PapiniE, PaschkeR, et al; AACE/AME/ETA Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules. Endocr Pract. 2010; 16(suppl 1): 1-43.
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    PintoRG, CoutoF, MandrekerS. Infarction after fine needle aspiration. A report of four cases. Acta Cytol. 1996; 40: 739-741.
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    PolyzosSA, PatsiaouraK, ZachouK. Histological alterations following thyroid fine needle biopsy: a systematic review. Diagn Cytopathol. 2009; 37: 455-465.
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    LiS, BalochZW, TomaszewskiJE, LiVolsiVA. Worrisome histologic alterations following fine-needle aspiration of benign parotid lesions. Arch Pathol Lab Med. 2000; 124: 87-91.
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    AlwaheebS, RambaldiniG, BoernerS, CoireC, FiserJ, AsaSL. Worrisome histologic alterations following fine-needle aspiration of the parathyroid. J Clin Pathol. 2006; 59: 1094-1096.
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    LayfieldLJ, AbramsJ, Cochand-PriolletB, et al. Post-thyroid FNA testing and treatment options: a synopsis of the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008; 36: 442-448.