|Year : 2012 | Volume
| Issue : 2 | Page : 32-39
Fine-needle aspiration of the thyroid: A cytohistologic correlation with critical evaluation of discordant cases
Pinki Pandey1, Alok Dixit2, Nanak C Mahajan1
1 Department of Pathology, M M Institute of Medical Sciences and Research, M M University, Mullana, Ambala, Haryana, India
2 Department of Pharmacology, M M Institute of Medical Sciences and Research, M M University, Mullana, Ambala, Haryana, India
|Date of Web Publication||12-May-2012|
E-15, MMIMSR Campus, M M University, Mullana- 133 203, Ambala, Haryana
Source of Support: None, Conflict of Interest: None
Background: There is some "gray zone" of thyroid cytology, where the diagnostic efficacy declines sharply rendering it difficult to exactly categorize the lesion resulting in discrepancy. The aim of the study is to assess the accuracy of fine needle aspiration of the thyroid and critically evaluate the cytohistological discordant cases. Materials and Methods: A total of 447 patients with thyroid swelling were aspirated during a seven-year study period. Cases showing cytohistologic disparity were reevaluated for the detection of possible causes of failure. Results: In our study, cytohistologic concordance was achieved in 80.28% of the cases. Of the discordant cases, false positives accounted for 11.60% and false negatives for 9.8%. Suboptimal material and underdiagnosis of papillary carcinoma due to cystic degeneration were recognized as common pitfalls. Too much emphasis on cellularity and architectural pattern led to the erroneous false positive diagnoses. Conclusion: Strict adherence to adequacy criterion and meticulous examination of all the smears are of paramount importance in reducing discrepant cases.
Keywords: Discordance, fine-needle aspiration cytology, thyroid lesions, thyroid neoplasms
|How to cite this article:|
Pandey P, Dixit A, Mahajan NC. Fine-needle aspiration of the thyroid: A cytohistologic correlation with critical evaluation of discordant cases. Thyroid Res Pract 2012;9:32-9
|How to cite this URL:|
Pandey P, Dixit A, Mahajan NC. Fine-needle aspiration of the thyroid: A cytohistologic correlation with critical evaluation of discordant cases. Thyroid Res Pract [serial online] 2012 [cited 2017 Mar 22];9:32-9. Available from: http://www.thetrp.net/text.asp?2012/9/2/32/96026
| Introduction|| |
Fine needle aspiration cytology (FNAC), being reliable, minimally invasive, cost effective, having high sensitivity and specificity, has been applied routinely as a useful and indispensable method to diagnose thyroid lesions. FNAC has allowed a dramatic decrease in unnecessary surgeries with thyroid nodular disease, enhancing the percentage of malignant operated nodules over 50%.  It is relied upon to distinguish benign from neoplastic/malignant thyroid nodules, thus, influencing therapeutic decisions. However, there is some "gray zone" of thyroid cytology where the diagnostic efficacy of FNA declines sharply,  rendering it difficult to exactly categorize the nature of the lesion leading to discrepant cases.
There is increasing concern that like any other test, FNAC has its limitations. The reported pitfalls are those related to specimen adequacy, sampling techniques, the skill of the aspirator performing the aspirations, the experience of the cytopathologist interpreting the aspirate and overlapping cytological features between benign and malignant follicular neoplasms.  Further inadequate, indeterminate FNA, in addition to false positive and false negative diagnosis, are the major limitations of thyroid FNA. The present study is undertaken to evaluate the accuracy of thyroid FNA and determine the reasons for the cytohistological discrepancies. We critically evaluated all the discordant cases and attempted to ascertain ways of minimizing false positive and false negative diagnoses in thyroid FNAC.
| Materials and Methods|| |
This retrospective study was conducted in the Department of Pathology at our tertiary care institute. A total of 447 patients with thyroid swelling were aspirated during a period of seven years using a 23-gauge needle and a 20-ml syringe. The slides were both air-dried and wet-fixed for May-Grünwald Giemsa and Papanicolaou stains, respectively. A concise clinical history, examination and details of relevant investigations were also obtained. Surgical follow-up was available for 112 aspirations. The concordance between cytological and histological diagnoses was determined. Cases with cytohistological discrepancy were selected and cytological smears of these cases were reevaluated for the detection of possible causes of failure.
| Results|| |
Among the 447 patients, females far outnumbered males in the ratio of 5.8:1 and age ranged from 18 to 76 years (median 39 years).
The cytological diagnoses were divided into 4 categories: benign, indeterminate, malignant and inadequate [Table 1]. Benign category encompassed colloid goiter, adenomatous goiter and different cases of thyroiditis. All malignant lesions without any overt follicular architecture were included in the malignant category. The indeterminate category encompassed diagnoses of follicular neoplasm, Hürthle cell neoplasm and suspicious of malignancy.
The cytological diagnoses were then compared with 112 available histopathological diagnoses. Among the benign lesions, histopathology was available in 54 cases. Cyto-histo concordance was obtained in 45 cases, whereas remaining nine showed malignant histology [Table 2]. Conversely, among the malignant category, histopathology was available for 17, of which complete cyto-histo concordance was obtained in 12 (70.58%) cases. Of the five discordant cases, two were diagnosed as colloid goiter and one as Hashimoto's thyroiditis. Evaluation of 24 discordant cases identified, 13 false positive and 11 false negative cases, which were missed on cytological examination [Table 3]. Twenty cytological specimens (4.47%) were deemed inadequate for the study because of insufficient cellularity or poor quality smear due to delayed or inadequate fixation.
|Table 2: Correlation of cytological and histopathological diagnoses (n=112)|
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In the present study, FNAC achieved a sensitivity, specificity, diagnostic accuracy, positive predictive value and negative predictive value of 57.14, 90, 80.28, 70.58 and 83.33%, respectively. Overall cytohistological concordance in all categories was 80.28% and discordance 19.71%. Of the discordant cases, false positives accounted for 11.60% and false negatives for 9.8%.
| Discussion|| |
Over the past two decades, FNA has become a primary diagnostic tool for evaluating thyroid nodules and a correct cytologic diagnosis obviates unnecessary thyroid surgeries. The important steps in FNA thyroid are careful sample procurement, appropriate sample preparation and accurate interpretation by cytopathologists. An appropriate diagnosis can only be offered when all these steps are taken into consideration. Improper sampling and overinterpretation can lead to discrepant cytologic diagnoses. Prudence is recommended to meticulously and carefully scrutinize for various cytologic features so as to reduce the number of discrepant cases. In the present study, we made an effort to ascertain the possible reasons for discrepancies and ways to minimize them.
The value of any diagnostic test lies in its ability to detect the presence of disease when it is present (sensitivity) and reliably verify the absence of disease when it is not present (specificity). As reported earlier, the sensitivity and specificity of the thyroid FNAC ranges from 43 to 99% and 72 to 100% respectively. , Our findings are in line with those reported in other series. ,,
In the present study, indeterminate category accounted for 18.79% of the cytology cases. Histopathological samples were available in 41 of the 84 cases. Of the 27 cases reported as follicular neoplasm on cytology, 22 were confirmed as follicular adenoma, 2 as follicular variant of papillary thyroid carcinoma (FVPTC) and 3 as adenomatous goiter. Of the nine cytologically reported cases of Hürthle cell neoplasm, four were Hürthle cell carcinoma, three showed features of Hashimoto's thyroiditis and two of colloid goiter. Five cases were reported as suspicious of malignancy. On further histopathological examination, three were confirmed to be FVPTC, one papillary carcinoma and one as medullary carcinoma.
It is difficult to differentiate follicular/Hürthle cell adenoma from carcinoma on cytological assessment because cytology cannot evaluate the criteria of vascular or capsular invasion or of intrathyroid spread. Greaves et al found that in 63 out of 92 cases of follicular lesions, there were no distinguishing cytologic features predictive of the histologic outcome. They concluded that this is a gray area in cytologic diagnosis due to the presence of various overlapping cytologic features at the light microscopic level. There is a high possibility of suspicious or indeterminate cases to be neoplastic and a good chance to be malignant. In our study, 80.48% of cases from indeterminate group were confirmed as carcinoma on subsequent histology. In an another study, it was reported for 57-70% of thyroid aspirates  and in the study done by Eva et al nine out of forty cases of indeterminate group were malignant. So, based on this fact, it is reasonable to consider patients with indeterminate or suspicious FNA results for either repeat aspiration or surgical intervention.
False positive diagnoses involve misinterpretation of aspirates from benign non-neoplastic diseases of the thyroid as malignant neoplasms. The higher number of false positive cases (11.60%) in our series was comparable with that reported by previous study.  For our convenience to critically evaluate the causes of discrepancy and possible remedies to minimize them, we grouped false positive cases into four categories on the basis of cytoarchitectural pattern of smears as papillary patterned,follicular patterned, Hürthle cell rich and lymphoid cell rich smears, summarized in [Table 4].
Among papillary patterned smears, in two of our cases cytological diagnosis of papillary carcinoma was made, on the basis of excess of cellularity with plenty of sheets of papillae, few of the cells contained round nucleus, pale open chromatin and intranuclear inclusion. Also in one of the case there was presence of psammoma body. But subsequent histology of both the cases showed papillary hyperplasia in nodular colloid goiter [Figure 1]a, possibly due to too much stress on cellularity and architectural pattern. Cytomorphological features of papillary carcinoma were lacking. Furthermore, inspissated colloid within follicles simulated psammoma body (pseudopsammoma body). Likewise cytological diagnosis of papillary carcinoma was suggested in two cases based on the papillary configuration of many tissue fragments and discrete cells with intranuclear inclusions. The histology though showed features of Hashimoto's thyroiditis [Figure 1]b. Too much emphasis on papillary architecture and intranuclear inclusions led to over diagnosis in these cases. The minimal criteria for cytodiagnosis of papillary carcinoma include, a syncytial-type tissue fragment regardless of architectural pattern, typical nuclear features i.e. pale enlarged nuclei with fine dusty, powdery chromatin; chromatin bar or ridge; single or multiple micro-and/or macro nucleoli; and intranuclear cytoplasmic inclusion.  Although these typical nuclear alterations help define papillary carcinoma, none of them are diagnostic of papillary carcinoma in isolation or low frequency. They are diagnostic of papillary carcinoma in an FNA, when they are relatively widespread and in combination. , Most often errors are committed when too much emphasis is placed on a single cytologic feature.  Multiple aspirations from different parts of the lesion could give a clear picture of cytologic features, reduce over interpretation and help in proper diagnosis.
|Figure 1a: Cytodiagnosis of papillary carcinoma was made based on marked cellular aspirate exhibiting many papillae, discrete cells with pale open chromatin and intranuclear inclusion (MGG, ×100). Inset: subsequent histopathology showed papillary hyperplasia in nodular goiter (Inset; H and E, ×100)|
Figure 1b: Too much stress on papillary architecture and intranuclear inclusions led to erroneous diagnosis of papillary carcinoma on cytology (MGG, ×100). Inset showing the follow up histology of Hashimoto's thyroiditis (Inset; H and E, ×40)
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Papillary hyperplasia in adenomatous goiter can reveal excess of cellularity with plenty of sheets of benign follicular cells. Papillary hyperplasia and hyperplastic nodules are well known to occur in adenomatous goiters  and could have been responsible for an incorrect diagnosis of follicular neoplasm in three of the cases among Follicular patterned smears. Aspiration was probably done from the hyper cellular area of adenomatous goiter which led to over diagnosis in these cases [Figure 2]. Cytological distinction between these two conditions is often difficult due to the presence of various overlapping cytologic features. Both show increased cellularity and scant or absent colloid. Architectural pattern of regular follicles and honeycomb sheets of adenomatous goiter versus syncytial-type fragments with crowding and overlapping of nuclei and irregular follicles of follicular neoplasms is an important criterion that distinguishes the two entities.  This has been highlighted as the reason for false positive diagnoses in other studies also. ,,
|Figure 2: Histological section showing papillary hyperplasia in adenomatous goiter (H and E, ×100). Inset: aspiration done from hypercellular area led to over diagnosis of follicular neoplasm showing syncytial-type fragments with crowding and overlapping of mildly enlarged nuclei (Inset; MGG, ×200)|
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Among Hürthle cell rich smears, an erroneous diagnosis of Hürthle cell neoplasm, was made in two cases as a result of extensive oxyphilic change in a case of nodular goiter [Figure 3]a. This is a known pitfall in diagnosis and has been reported in literature.  A mixture of flat, cohesive sheets of Hürthle cells admixed with non-oncocytic follicular cells and a moderate to abundant amount of colloid is more indicative of a colloid goiter with prominent Hürthle cell metaplasia in contrast to single cells and three-dimensional clusters in Hürthle cell neoplasm.  In addition, cytological smears of three cases showed large population of Hürthle cells with very few lymphocytes and scanty colloid, but were histologically diagnosed as Hürthle cell nodule in Hashimoto's thyroiditis [Figure 3]b. Aspirations were probably done from the Hürthle cell nodule which led to over diagnosis. Failure to demonstrate the lymphocytes and to appreciate the non-neoplastic nature of Hürthle cells were the reasons behind misdiagnosis in these cases. Similar problems of misinterpretation have been reported by others. ,, Tight small cohesive clusters of 3-10 cells, containing large nuclei and smudgy glassy chromatin lacking the prominent macronucleolus of neoplastic Hürthle cells are cytological features favoring a diagnosis of Hürthle cell nodule in Hashimoto's thyroiditis. Hürthle cell metaplasia with nodule formation is a routine histologic feature of Hashimoto's thyroiditis  and should not be overlooked while reporting Hürthle cell rich cytological smears. Multiple aspirations from various parts of the lesion could be helpful to get an appropriate cytological diagnosis.
|Figure 3a: Cytological aspirate revealing flat cohesive sheets of Hürthle cells with mild nuclear pleomorphism led to diagnosis of Hürthle cell neoplasm (MGG, ×400). Inset: follow up histology showed extensive oxyphilic change in colloid goiter (Inset; H and E, ×100)|
Figure 3b: False positive case of Hashimoto's thyroiditis misdiagnosed as Hürthle cell neoplasm on cytology exhibiting syncytial clusters of oxyphilic cells showing mild nuclear pleomorphism. (MGG, ×100) Inset showing histological diagnosis of Hürthle cell nodule in Hashimoto's thyroiditis. Aspiration probably done from the Hürthle cell nodule led to the overdiagnosis (Inset; H and E, ×40)
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In Lymphoid cell rich smears, cytological smears showed dense population of lymphoid cells with occasional epithelial cells, pointing to a diagnosis of lymphoma. Cytologic identification of both the disease is certainly a challenge to the cytopathologist because of the heterogenous population of lymphocytes in each. Cytologic differences between these two can be very subtle, but presence of a combination of lymphocytes in all stages of maturation with a predominant population of small mature lymphocytes admixed with plasma cells and polymorphic germinal centre cells favors the diagnosis of Hashimoto's thyroiditis. , Multiple aspirations from various parts of the lesion could be helpful to get a correct cytological diagnosis. It may be appropriate to inform the clinician about the limitation of FNAC in such situations.
The false negative FNAC results may occur because of sampling error or misinterpretation of cytology, and are of great concern because they indicate the potential to miss malignant lesion.  Since only a small percentage of patients with benign cytological findings undergo surgery, it is difficult to state the true frequency of false negative results.  False negative rates in our series accords with the reports that suggest a range in literature from 1 to 11%. , This high rate of failure to diagnose cancer could be attributed to the failure of aspiration from precise locations. Also false negative cytology results in a delay in treatment and hence adversely affects the outcome in patients with thyroid cancer. 
A false negative cytological diagnosis of colloid goiter was rendered in 6 cases which turned out to be neoplasm on histology, four being follicular adenomas while two cases were diagnosed as cystic papillary carcinomas. Cytological smears of all the four cases revealed moderate colloid with small groups of poorly cohesive thyroid follicular cells, favoring the diagnosis of a nodular colloid goiter. The histology though, showed features of follicular adenoma. Cytologically it is difficult to differentiate colloid-rich macrofollicular adenoma from nodular goiter due to the presence of various overlapping cytologic features.  Cytological features like increased cellularity with repetitive uniform cell patterns, uniformly enlarged nuclei with nuclear crowding and overlapping, syncytial clusters, microfollicular structures, scanty or no colloid may be helpful in distinguishing follicular adenomas from nodular goiters, although none of them is conclusive.  Poor cellularity of the aspirated samples in cystic lesions and suboptimal preparations is often misinterpreted as benign lesions. Sampling errors were responsible for the under diagnosis of papillary neoplasm in two of our cases [Figure 4]. An accurate diagnosis could not be rendered because of sampling of areas of cystic change rather than cellular areas. Occurrence of cystic change in thyroid lesions is a common diagnostic pitfall in cytology.  Aspiration from multiple sites and from solid areas may be useful in preventing sampling error. Most authors recommend preparation of 4-6 smears from different areas of the nodule. Strict criteria for specimen adequacy could help to reduce markedly the erroneous diagnosis in such cases. , Ultrasound-guided FNAC in cystic thyroid nodule results in better sample acquisition leading to low rate of non-diagnostic smears and high overall accuracy. 
|Figure 4: Cytology smear demonstrated follicular cells and numerous colloidophages, interpreted as colloid goiter with cystic degeneration (MGG, ×200). Inset: histologically diagnosed as cystic papillary carcinoma exhibiting nuclear features like clearing and nuclear grooves, also numerous macrophages. (Inset; H and E, ×200)|
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Cytological diagnosis of Hashimoto's thyroiditis was obtained in three cases, on the basis of clumps of Hürthle cells with presence of lymphocytes focally, which turned out to be Hürthle cell carcinoma on histology. The under diagnosis was as a result of failure to appreciate the absence of follicular cells, Hürthle cell with high nuclear cytoplasmic ratio, nucleoli, dissociation and focal presence of lymphocytes and has been reported in earlier study.  It is recommended, when >75% of the cells show Hürthle cell morphology with high nuclear cytoplasmic ratio and dissociation, possibility of Hürthle cell neoplasm should be considered.  Hürthle cell change can be seen in other lesions as well, and strict adherence to this criterion can obviate the false diagnosis of Hürthle cell neoplasm.
One of the most common and clinically significant pitfalls in the assessment of an aspirate from a follicular lesion is the failure to recognize the nuclear features of the FVPTC, the most common variant of papillary carcinoma.  Cytological diagnosis is difficult because of the paucity of nuclear changes of papillary carcinoma and overlapping features with benign and malignant follicular lesion. FVPTC can pose a diagnostic challenge due to the abundance of monolayered sheets and/or microfollicles with subtle nuclear features mimicking a follicular neoplasm [Figure 5]. Contrasting hyperchromatic chromatin of follicular neoplasm, FVPTC exhibits oval/round monomorphic nuclei, pale, powdery chromatin with scarce nuclear grooves and intranuclear pseudoinclusions in addition to dense globular colloid in the background and lack of papillary pattern.  Increased cellularity with presence of follicular structures led to misinterpretation in two of our cases. Similar misinterpretations have been encountered by others. , Prudence is recommended to evaluate the nuclear features of the cells to avoid the pitfall of the FVPTC. In addition to the cytologic features, due importance should be given to various clinical features, such as age, sex and diameter of the nodules. It is reported that though 70% of follicular lesions are benign; male sex, age 40 years and nodule diameter >3cm are associated with an increased risk of malignancy. 
|Figure 5: Marked cellular aspirate exhibiting microfollicular pattern with crowding and overlapping of nuclei and absence of colloid, interpreted as follicular adenoma (MGG, ×200). Inset: the follow up histology showed follicular variant of papillary thyroid carcinoma exhibiting exclusive follicular growth pattern displaying nuclear features of papillary thyroid carcinoma (Inset; H and E, ×400)|
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An adequate cellular aspirate is indispensable for an accurate diagnosis. Smear adequacy does not only refer to the cell yield but also takes into consideration primary fixation and the quality of the smear. Presence of 8-10 tissue fragments of well preserved follicular epithelium on at least two slides as recommended seems to be a fairly reasonable criterion for adequacy.  Inadequate FNA specimen can occur as a result of sampling error, faulty technique and highly vascular or focal lesions. Thyroid nodules that are sclerotic or calcified and those with large areas of cystic degeneration or necrosis are extremely difficult to aspirate. The inadequacy rate of 4.47% of the current study is comparable with those in other series, which range from 0 to 25%.  Our overall opinion on the false negative category is that accurate sampling is of utmost importance. Ultrasound-guided FNAC results in better sample acquisition, especially in patients with small thyroid nodules, solid-cystic lesions or difficult-to-palpate lesions. Therefore in case of difficulty, a repeat guided aspirate with multiple aspirations from various parts of the lesions, correlation with USG findings and awareness of the standard pitfalls will facilitate the correct cytological diagnosis.  A repeat FNA should be performed by experienced operator, and pathologists should be aware of changes occurring in thyroid following FNA procedure which are labeled as WHAFF (worrisome histologic alterations following fine-needle aspiration).
Essential to the success of FNAC is an experienced and competent cytopathologist who is prepared to give an opinion. While interpretation is not always easy, it can always be learnt. Our surgeons find that the cytopathologic information is very useful for scheduling patient's visits and making their surgical plans. To summarize, FNAC as such is an expedient, effective and safe diagnostic method for defining thyroid disorders, but inadequate, indeterminate FNA in addition to false positive and negative diagnosis are the major limitations of thyroid FNA. Also follicular patterned lesions and Hürthle cell rich smear offer diagnostic challenge perpetually. An attempt was made by us to find the level of cytohistologic concordance, critically evaluate the discrepant cases and possible methods in which it could be minimized. Thus, strict adherence to adequacy criterion and meticulous examination of all the smears are of paramount importance in reducing the discrepant cases.
| Acknowledgement|| |
I acknowledge the immense help of Mr Sanjiv Mittal, senior technician, of our department.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]