Thyroid nodules are a common clinical problem, and 1–10% are malignant [
Fine needle aspiration cytology (FNAC) has been routinely used as the baseline investigation for diagnosis of nodular thyroid disease. Its advantages include minimal invasion and high sensitivity, specificity, and accuracy [
In an attempt to overcome these problems, fine needle nonaspiration cytology (FNNAC) was developed in France in 1982 by Briffod et al. [
There are many conflicting studies regarding the superiority of FNNAC to FNAC [
Hence, we have conducted a systematic review and meta-analysis to evaluate the performance of FNAC and FNNAC in diagnosing nodular thyroid disease. We also aim to clarify the diagnostic performance of both techniques, which will provide physicians with a theoretical reference and guidelines to properly select between these two techniques.
Relevant publications were collected from PubMed, EBSCO, Google Scholar, OALib, and Cochrane databases. The search keywords used were fine needle, aspiration, capillary, nonaspiration, sampling without aspiration, thyroid, and cytology. There was no restriction on the publication date or language. We removed duplicated publications that were identified in multiple databases.
All relevant titles, abstracts, and full papers identified by the prespecified search strategy were independently screened by two authors (Hongming Song and Chuankui Wei), and irrelevant articles were excluded. Search results were compared, and disagreements were resolved by discussion with the third reviewer (Kaiyao Hua).
The included studies reported comparison of performance between FNAC and FNNAC. Studies that did not refer to thyroid nodules and those that did not compare the cytological findings with histological results were excluded from this study. Letters, reviews, abstracts, editorial materials, and animal trials were also excluded from this study.
The scoring system invented by Mair et al. has been widely used to compare the smear quality obtained by FNAC and FNNAC in numerous studies [ Category 1 (scores 0–2): smear unsuitable for diagnosis. Category 2 (scores 3–6): smear adequate for cytological diagnosis. Category 3 (scores 7–10): diagnostically superior smear [
The Mair et al. scoring system [
Criteria | Quantitative description | Point score |
---|---|---|
Background blood/clot | Large amount, great compromise of diagnosis | 0 |
Moderate amount, diagnosis possible | 1 | |
Minimal amount, diagnosis | 2 | |
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Amount of cellular material | Minimal to absent, diagnosis not possible | 0 |
Sufficient for cytodiagnosis | 1 | |
Abundant, diagnosis possible | 2 | |
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Degree of cellular degeneration | Marked, diagnosis impossible | 0 |
Moderate, diagnosis possible | 1 | |
Minimal, diagnosis easy | 2 | |
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Degree of cellular trauma | Marked, diagnosis impossible | 0 |
Moderate, diagnosis possible | 1 | |
Minimal, diagnosis obvious | 2 | |
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Retention of appropriate architecture | Minimal to absent nondiagnostic | 0 |
Moderate, some preservation of, for example, follicle, papillae, and acini | 1 | |
Excellent architectural display closely reflecting histology, diagnosis obvious | 2 |
We also calculated the diagnostic performance of FNAC and FNNAC by comparing the cytological diagnosis of thyroid nodules with the histological results, regardless of whether the included studies adopted Mair et al. scoring system.
We extracted the following data from the included studies: the number of Categories 1 and 3 smears, the average score (mean ± SD) of each of the five objective parameters (background blood or clot, amount of cellular material, degree of cellular degeneration, degree of cellular trauma, and retention of appropriate architecture), and the average total score of the five parameters (mean ± SD). The numbers of true positive, false positive, false negative, and true negative results were evaluated. The diagnostic performance (accuracy, sensitivity, specificity, NPV, and PPV) of both techniques was extracted. The name of the first author, year of publication, study design, number of patients, number of lesions, and needle gauge were also reviewed and recorded (Table
Characteristics of studies included in this meta-analysis.
First author’s name | Year of |
Number of patients |
Number of nodules |
Histopathological diagnosis |
Study design | Needle gauge | Mair et al. scoring system [ |
Patient’s age and gender |
---|---|---|---|---|---|---|---|---|
de Carvalho [ |
2009 | 260/260 | 520/520 | 58/58 | Prospective | 23 | Yes | 238 females, 22 males, and age of 43.2 ± 12.6 |
Schoedel [ |
2008 | 122/122 | 180/180 | 23/23 | Prospective | 25 | No | The ratio of female to male was about 6 : 1, with average age of 57.3 |
Raghuveer [ |
2002 | 68/68 | 68/68 | 36/36 | Prospective | 23 or 24 | Yes | — |
McElvanna [ |
2009 | 65/65 | 65/65 | 65/65 | Retrospective | 23 | No | 58 females, 7 males, and average age of 49 |
Tauro [ |
2012 | 50/50 | 50/50 | 38/38 | Prospective | 23 | No | 47 females, 3 males, and age of 39.16 ± 11.47 |
Maurya [ |
2010 | 50/50 | 50/50 | — | Prospective | 23 | Yes | — |
Kamal [ |
2002 | 200/200 | 200/200 | — | Prospective | 23 or 24 | Yes | 173 females, 27 males |
Mahajan and Sharma [ |
2010 | 50/50 | 50/50 | — | Prospective | — | Yes | — |
Pinki [ |
2015 | 100/100 | 100/100 | — | Prospective | 22 | Yes | — |
Ibrahim [ |
2012 | 50/50 | 50/50 | — | Prospective | 25 | Yes | — |
Kashi [ |
2011 | 302/302 | 302/302 | — | Prospective | 25 | Yes | 289 females, 13 males, and age of 43.83 ± 12.9 |
Chowhan [ |
2014 | 200/200 | 200/200 | — | Prospective | 24 | Yes | 26 males, 174 females |
Torabizadeh [ |
2008 | 200/200 | 200/200 | — | Prospective | / | Yes | 189 females, 11 males, and age of 43.36 ± 12.3 |
Kaur [ |
2014 | 50/50 | 50/50 | — | Prospective | 23 | Yes | — |
Torres [ |
2003 | 61/61 | 122/122 | — | Prospective | 22 | Yes | 61 females (100%), age of 49.2 ± 15.3 |
Ghosh [ |
2000 | 14/14 | 14/14 | — | Prospective | 23–25 | Yes | — |
FNAC: fine needle aspiration cytology, FNNAC: fine needle nonaspiration cytology, and —: not available.
Risk of bias was independently assessed by the two main authors using Review Manager software (RevMan, version 5.3, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) to evaluate the methodological quality of all included studies. The following six aspects were evaluated: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. All studies were classified as “unclear,” “yes,” or “no” to indicate “uncertain bias,” “low-risk bias,” or “high-risk bias,” respectively. The assessment of risk of bias is described in Table
Risk of bias assessment of included studies.
Study | Sequence |
Allocation |
Blinding | Incomplete |
Selective |
Other |
---|---|---|---|---|---|---|
de Carvalho et al. [ |
Low | Low | Low | Low | Low | Low |
Schoedel et al. [ |
Low | Low | Low | Low | Low | Low |
Raghuveer et al. [ |
High | Low | Low | Low | Low | Low |
McElvanna et al. [ |
Low | Low | Low | Low | Low | Low |
Tauro et al. [ |
Low | Low | Low | Low | Low | Low |
Maurya et al. [ |
Low | Unclear | Low | Low | Low | Low |
Kamal et al. [ |
Low | Unclear | Low | Low | Low | Low |
Mahajan and Sharma [ |
Low | Unclear | Unclear | Low | Low | Low |
Pinki et al. [ |
High | Low | Low | Low | Low | Low |
Ibrahim et al. [ |
Low | Low | Low | Low | Low | Low |
Kashi et al. [ |
Low | Unclear | Low | Low | Low | Low |
Chowhan et al. [ |
High | Low | Low | Low | Low | Low |
Torabizadeh et al. [ |
Low | Low | Low | Low | Low | Low |
Kaur et al. [ |
Low | Low | Low | Low | Low | Low |
Torres et al. [ |
Low | Low | Low | Low | Low | Low |
Ghosh et al. [ |
Low | Unclear | Low | Low | Low | Low |
The data from included studies were analyzed using Review Manager software (RevMan, version 5.3, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Each study was weighted by its sample size. For dichotomous variables such as the smear quality and accuracy of FNAC and FNNAC, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. The weighted mean difference and standardized mean difference were computed for continuous variables that had the same or different units in the assessing system, respectively. The mean difference (MD) and 95% CI were computed for the average score of each parameter and the average total score of the five parameters. Heterogeneity among the studies was assessed using the
A total of 527 records were identified from the databases. Among them, 30 full-text articles were assessed for potential eligibility. Seven articles were excluded because they did not use the Mair et al. scoring system or did not report the diagnostic performance of FNAC and FNNAC [
Flow chart of selection of eligible studies.
In this meta-analysis, the 16 included studies involved 1,842 individual patients and 2,221 samples collected by FNAC and FNNAC. Of these studies, 15 were prospective and only one was retrospective in design. The studies have great differences in the number of patients and samples, needle gauge, sex ratio, and mean age of patients. The results included diagnostically inadequate and superior smears, diagnostic performance (accuracy, sensitivity, specificity, NPV, and PPV), average scores of each parameter, and average total scores of the five parameters of the Mair et al. scoring system. Diagnostically inadequate smears collected using both techniques were reported in 12 studies [
The number of diagnostically superior smears collected via FNAC compared with FNNAC was assessed in 11 studies [
Forest plots showing the quality of specimens obtained by FNAC and FNNAC. (a) Unsuitable for diagnosis, (b) diagnostically superior.
A complete histopathological analysis is essential to make a definite diagnosis for thyroid lesions. Cytological findings obtained by FNAC and FNNAC were confirmed by histopathological analysis in five studies [
Analysis of the results.
Results | Number of studies |
Sample size |
Overall effect size | 95% CI |
|
Heterogeneity | |
---|---|---|---|---|---|---|---|
|
| ||||||
Unsuitable for diagnosis | 12 [ |
1912/1912 | OR = 1.09 | (0.91, 1.30) | 0.36 | 40% | 0.07 |
Diagnostically superior | 11 [ |
1844/1844 | OR = 0.81 | (0.60, 1.09) | 0.16 | 73% | <0.0001 |
Background blood or clot | 5 [ |
986/986 | MD = −0.41 | (−0.84, 0.02) | 0.06 | 98% | <0.0001 |
Degree of cellular trauma | 5 [ |
986/986 | MD = 0.06 | (−0.14, 0.26) | 0.56 | 90% | <0.00001 |
Amount of cellular material | 5 [ |
986/986 | MD = −0.11 | (−0.35, 0.13) | 0.35 | 92% | <0.00001 |
Degree of cellular degeneration | 5 [ |
986/986 | MD = 0.05 | (−0.10, 0.21) | 0.51 | 81% | 0.0003 |
Retention of appropriate architecture | 5 [ |
986/986 | MD = −0.27 | (−0.69, 0.15) | 0.21 | 97% | <0.00001 |
Total score of five parameters | 5 [ |
1172/1172 | MD = −0.36 | (−1.03, 0.30) | 0.29 | 90% | <0.00001 |
Accuracy | 5 [ |
182/192 | OR = 0.96 | (0.56, 1.65) | 0.89 | 12% | 0.34 |
Sensitivity | 4 [ |
146/154 | OR = 1.35 | (0.35, 5.19) | 0.66 | 0% | 0.74 |
Specificity | 4 [ |
146/154 | OR = 1.13 | (0.56, 2.29) | 0.73 | 20% | 0.26 |
Negative predictive value (NPV) | 4 [ |
146/154 | OR = 1.20 | (0.35, 4.11) | 0.78 | 0% | 0.78 |
Positive predictive value (PPV) | 4 [ |
146/154 | OR = 1.17 | (0.50, 2.76) | 0.71 | 0% | 0.46 |
OR: odds ratios, MD: mean difference.
Performance of the four diagnostic studies.
Study | FNAC/FNNAC | ||||||||
---|---|---|---|---|---|---|---|---|---|
Histopathological diagnosis | TP | FP | FN | TP | Performance in diagnosis | Diagnostic criteria for malignancy | Notes | ||
Sensitivity (%) | Specificity (%) | ||||||||
de Carvalho et al. 2009 [ |
53/52 | 14/13 | 10/8 | 1/0 | 28/31 | 93.3/100 | 73.7/79.5 | Suspicious or positive | Excluded ND |
McElvanna et al. 2009 [ |
41/48 | 8/8 | 11/18 | 1/1 | 21/21 | 88.9/88.9 | 65.6/53.8 | Not specified | Excluded inadequate cytology specimens |
Schoedel et al. 2008 [ |
14/16 | 4/4 | 0/0 | 2/4 | 8/10 | 66.7/50 | 100/100 | Suspicious or positive | Excluded I and ND |
Tauro et al. 2012 [ |
38/38 | 2/1 | 0/0 | 0/1 | 36/36 | 100/50 | 100/100 | Not specified |
TP: true positive, TN: true negative, FP: false positive, and FN: false negative. Sensitivity (%) = TP/(TP + FN)
Forest plot showing the diagnostic accuracy of FNNAC and FNAC techniques.
The summary receiver operating characteristic (SROC) curves for FNAC and FNNAC. The areas under the curve (AUCs) for FNAC and FNNAC were
The average score for each parameter of the samples obtained by FNAC and FNNAC was reported in five included studies [
Forest plots showing average scores of the five evaluation parameters for FNNAC and FNAC. (a) Background blood or clot, (b) degree of cellular trauma, (c) amount of cellular material, (d) degree of cellular degeneration, and (e) retention of appropriate architecture.
Forest plot showing the mean of the total scores of FNNAC and FNAC techniques.
Although many studies have compared the efficiency of FNAC and FNNAC techniques in evaluating thyroid nodules, there is no clear agreement as to which method performs better. To the best of our knowledge, this is the first meta-analysis to evaluate the smear quality and diagnostic performance of FNAC and FNNAC. The five parameters used for performance evaluation may interfere with each other; hence, if the scoring system excluding one or more parameters is used, the average score and total score may not accurately reflect each parameter and the smear quality, respectively. Therefore, we strictly selected studies that used the scoring system of Mair et al. to assess the quality of smears obtained by FNAC and FNNAC.
It is well known that the smear quality may affect the cytological diagnosis of thyroid nodules. In this meta-analysis, we compared the quality of smears collected by FNAC and FNNAC using the Mair et al. scoring system and found no statistically significant difference between the quality of smears obtained by FNNAC and FNAC. A larger number of smears collected by FNNAC tended to be superior smears compared with those collected by FNAC; however, this was not statistically significant. We also observed a similar rate of smears unsuitable for diagnosis between FNNAC and FNAC groups.
“Background blood or clot” and “amount of cellular material” are two important criteria in assessing the quality of smears [
The objective of fine needle biopsy is to investigate thyroid nodules. The diagnostic accuracy is important in determining whether patients with suspicious thyroid nodules need surgery. Five included studies reported the diagnostic accuracies of both techniques [
Some studies reported that the execution order of FNNAC and FNAC techniques plays an important role in affecting the quality of smears. Although the order of FNNAC and FNAC sampling was preplanned in most of the included studies (FNAC followed by FNNAC was performed on patients in group A, FNNAC followed by FNAC was conducted in group B, or the technique used for biopsy was alternated sequentially for each patient), three studies had a high risk of bias based on low-quality data. One study conducted FNAC followed by FNNAC sampling for all cases, and two studies reversed the order of FNNAC and FNAC techniques for all patients. This might have led to the differences in results caused by the order of FNNAC and FNAC sampling. However, when we excluded these three studies, the execution order of FNNAC and FNAC made no difference to the quality of smears.
This meta-analysis had some potential limitations. First, numerous factors may have affected the consistency of results, as the included studies used various fine needle biopsy protocols (such as varying needle gauge and size of syringe volume). Moreover, there were differences in the level of suction pressure applied and the insertion depth of fine needles. These factors might have caused a small but possible risk of bias. Second, the sample size of included studies was small, especially for comparing the diagnostic accuracy of both techniques with the histological results; this might lead to the small-study effect; thus, the results obtained should be considered with caution. Third, we did not assess other complications such as nerve damage, tissue trauma, tumor seeding, or vascular injury associated with both techniques, owing to a lack of data in the included studies. Finally, some studies reported that FNNAC combined with FNAC can obtain better quality cellular material [
FNNAC and FNAC techniques are equally useful in the assessment of thyroid nodules. The selection of technique may be dependent on the personal preference of the operator.
The authors declare no conflict of interests regarding the publication of this paper.
Hongming Song, Chuankui Wei, and Lin Fang contributed to the study design and conducted data collection. Hongming Song, Chuankui Wei, Dengfeng Li, Kaiyao Hua, Jialu Song, and Lin Fang conducted data analysis and interpretation of results. Hongming Song, Chuankui Wei, and Niraj Maskey wrote the paper.
This project was supported by the National Natural Science Foundation of China (no. 81272240). The authors thank all authors of the publications included in this study for contributing information as required.