Abstract
Fine needle aspiration cytology (FNAC) is possibly the most useful investigation for the thyroid. However, conventional FNAC (C-FNAC) is limited by a high rate of inadequate samples. Ultrasound guided FNAC (US-FNAC) has been proposed as an alternative. This study aims to estimate the measures of diagnostic accuracy of FNAC as well as to compare US-FNAC against C-FNAC. Patients who underwent FNAC at our for a period of 5 years were selected. This comprised of 237 C-FNAC cases and 173 US-FNAC cases. Out of these 410 cases, 129 cases had cyto-histological correlation. The proportion of inadequate samples, malignant cases as well as indeterminate cases were compared between US-FNAC and C-FNAC. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratios for positive and negative results and odds ratio were estimated for overall FNAC as well as US-FNAC and C-FNAC patients. US-FNAC has a significantly lower proportion of inadequate samples (0.58 vs. 15.19%), as well as a lower proportion of indeterminate samples (1.7 vs. 7.6%) and a higher proportion of malignant cases (6.4 vs. 2.1%). When the inadequate samples were excluded, the results for tests of diagnostic effectiveness for overall FNAC, US-FNAC and C-FNAC respectively ranged between 66.67 and 80% for sensitivity, between 86.05 and 100% for specificity, between 45.45 and 100% for PPV and between 97.37 and 98.7% for NPV. FNAC is a useful test for differentiating malignant from benign lesions. When inadequate samples are excluded, both US-FNAC and C-FNAC are accurate diagnostic tests. However, US-FNAC is a more useful test since it results in a lower number of inadequate samples. Also, US-FNAC results in a greater yield of malignancy and a lower percentage of indeterminates, possibly due to additional information received from ultrasound examination.
Keywords: Fine needle aspiration, Cytodiagnosis, Thyroid diseases, Thyroid nodules, Sensitivity and specificity
Introduction
Fine needle aspiration cytology (FNAC) is possibly the most important initial diagnostic test for sweilings of the thyroid [1–8]. However, it is limited by inadequate samples in a significant proportion of patients [9]. Ultrasound guided FNAC (US-FNAC) has been described as a superior sampling method compared to conventional FNAC (C-FNAC), with studies mainly finding a far higher adequacy rate [10–15] as also a higher sensitivity and specificity in detecting thyroid cancers.
The present study is an attempt to confirm the diagnostic efficiency of fine needle aspiration cytology of thyroid swellings as well as comparing the diagnostic ability of US-FNAC versus C-FNAC. To do this, we will use both conventional widely used statistical tests as well as some novel tests of diagnostic usefulness.
Materials and Methods
The present study was carried out in a tertiary care hospital in central India over a period of 5 years from June 2004 to May 2009. All patients in this period presenting with palpable thyroid lesions (comprising of outpatient department as well as admitted patients) who were referred for FNAC and had subsequent histopathological confirmation were included in this study. All the cases from June 2004 to June 2007 were subjected to conventional FNAC, while for all the cases from July 2007 to May 2009 FNAC was done under ultrasound guidance where ever possible. Detailed clinical examination and routine investigations were carried out in each patient.
The following diagnostic categories were used for both Conventional as well as Ultrasound guided FNAC
Inadequate
Benign
Indeterminate (follicular neoplasms)
Suspicious of malignancy
Malignant.
Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratios for positive and negative tests and diagnostic odds ratio were estimated using Stats Direct Software version 2.8.0 [16] for the overall FNAC (pooling both conventional as well as ultrasound guided FNAC) as well as conventional and ultrasound guided FNAC. The histopathology report was treated as the “Reference Standard”. These measures of diagnostic effectiveness were calculated after removing the inadequate group. The diagnostic categories of FNAC form an ordered categorical variable, with the presence of an indeterminate group comprising mainly of follicular neoplasms which cannot be categorized further by FNAC and which has an intermediate risk of being diagnosed as malignant on histopathology as compared to those diagnosed as unequivocally benign or malignant on FNAC. For calculating sensitivity, specificity, PPV and NPV, we need to decide whether to include the indeterminate category as benign or malignant. To overcome this problem, two different sets of estimates for the tests of diagnostic effectiveness were done. In the first set of calculations, the indeterminate group was grouped with the benign lesions. In the second set of calculations, the indeterminate group was grouped with the malignant category. A further complication was an undefined estimate of the Lilelihhod ratios and diagnostic odds ratios in some cases due to no false positive or false negative results occuring in some categories. In these cases, the results were reported as undefined and the confidence interval as estimated by the statistical software was reported. We did not need to do add further analysis of including the “suspicious for malignancy group” as these patients were lost to follow up and did not have histopathological investigation for the thyroid in the hospital where the present study was conducted.
The proportions of the inadequate results were also calulated for both the C-FNAC and US-FNAC groups, and the poportion of the inadequate results were compared between patients undergoing C-FNAC and US-FNAC.
Results
A total of 410 cases underwent FNAC. Of these, 237 FNACs were done without guidance and 173 FNACs were done under USG guidance. Out of the total of 410 patients who underwent FNAC, 129 patients had cytohistological correlation. Of the129 patients who had cyto-histological correlation, 49 underwent C-FNAC and 80 patients underwent US-FNAC. The description of the age, gender and diagnostic category distribution of all the cases is given in Table 1. The description of the cases which had cyto-histological correlation after exclusion of inadequate cases and which was used for estimation of diagnostic accuracy statistics are given in Table 2.
Table 1.
Showing the distribution of the age, gender and diagnostic categories for all the patients on whom FNAC was done (Total = overall FNAC (combining both ultrasound guided as well as conventional FNAC), US-FNAC = ultrasound guided FNAC and C-FNAC = conventional FNAC)
| Total | US-FNAC | C-FNAC | |
|---|---|---|---|
| Age (yrs) | |||
| Mean | 36.2 | 36.0 | 36.4 |
| Standard deviation | 12.9 | 13.3 | 12.7 |
| Median | 35 | 35 | 35 |
| Lower quartile | 27 | 26 | 27.5 |
| Upper quartile | 45 | 45 | 43 |
| Minimum | 10 | 10 | 10 |
| Maximum | 75 | 66 | 75 |
| Gender | |||
| M:F | 62:348 | 33:140 | 29:208 |
| Diagnostic categories | |||
| Inadequate | 37 | 1 | 36 |
| Benign | 334 | 156 | 178 |
| Indeterminate | 21 | 3 | 18 |
| Suspicious | 2 | 2 | 0 |
| Malignant | 16 | 11 | 5 |
Table 2.
Showing the distribution of the age, gender and diagnostic categories for all the patients on whom FNAC was done and which had cyto-histological correlation (Total = overall FNAC (combining both ultrasound guided as well as conventional FNAC), US-FNAC = ultrasound guided FNAC and C-FNAC = conventional FNAC)
| Total | US-FNAC | C-FNAC | |
|---|---|---|---|
| Age (yrs) | |||
| Mean | 36.15 | 35.00 | 38.10 |
| Standard deviation | 11.93 | 12.34 | 11.07 |
| Median | 35 | 35 | 36 |
| Lower quartile | 29 | 25 | 30 |
| Upper quartile | 44 | 45 | 42 |
| Minimum | 10 | 10 | 18 |
| Maximum | 67 | 60 | 67 |
| Gender | |||
| M:F | 23:106 | 15:65 | 8:41 |
| Diagnostic categories | |||
| Benign | 112 | 74 | 38 |
| Indeterminate | 10 | 3 | 7 |
| Suspicious | 0 | 0 | 0 |
| Malignant | 7 | 3 | 4 |
Inadequate cases were excluded
Out of the 237 cases that underwent C-FNAC, 36 (15.19%)were given an inadequate report. In contrast, only 1 out of 173 patients (0.58%) were given an indequate report when US-FNAC was done. The difference between these were highly significant (exact two-sided (mid) P < 0.001). The proportion of patients classified as malignant was also higher on US-FNAC (6.4%) as compared to C-FNAC (2.1%), and the proportion of indeterminate samples was lower on US-FNAC (1.7%) as compared to C-FNAC (7.6%). The difference between the proportions of malignant cases in US-FNAC versus C-FNAC was significant (Exact two sided (mid) P = 0.023) as was the difference between the proportions of indeterminate samples in US-FNAC versus C-FNAC (Exact two sided (mid) P = 0.007).
The tests for diagnostic categories are given in Table 3. It can be seen that both US-FNAC, C-FNAC, and overall, the specificity and negative predictive value is high. The Likelihood ratios for both the positive as well as negative tests and the diagnostic odds ratio are also raised (or decreased in the case of Likelihood ratio for negative test). However, due to there being no false negatives in some of the tests, an undefined result was obtained. In the cases where an undefined result was obtained, the lower end of the confidence interval obtained for the likelihood ratio and the diagnostic odds ratio was high, strongly suggesting that the test was useful. The sensitivity of FNAC was also acceptable in most cases, but was limited by a wide confidence interval.
Table 3.
Showing the estimates with 95% confidence intervals of diagnostic efficiency for FNAC (taking histopathology as the gold standard)
| Overall FNAC | US-FNAC | C-FNAC | ||||
|---|---|---|---|---|---|---|
| Classifying the indeterminates as positive | Classifying the indeterminates as negative | Classifying the indeterminates as positive | Classifying the indeterminates as negative | Classifying the indeterminates as positive | Classifying the indeterminates as negative | |
| Sensitivity | 80% (44.39–97.48%) | 70% (34.75–93.33%) | 75% (19.41–99.37%) | 75% (19.41–99.37%) | 83.33% (35.88–99.58%) | 66.67% (22.28–95.67%) |
| Specificity | 92.44% (86.13–96.48%) | 100% (96.95–100%) | 96.05% (88.89–99.18%) | 100% (95.26–100%) | 86.05% (72.07–94.7%) | 100% (91.78–100%) |
| PPV | 47.06% (22.98–72.19%) | 100% (59.04–100%) | 50% (11.81–88.19%) | 100% (29.24–100%) | 45.45% (16.75–76.62%) | 100% (39.76–100%) |
| NPV | 98.21% (93.7–99.78%) | 97.54% (92.98–99.49%) | 98.65% (92.7–99.97%) | 98.7% (92.98–99.97%) | 97.37% (86.19–99.93%) | 95.56% (84.85–99.46%) |
| LR (+ve) | 10.58 (5.02–20.82) | Undefined (22.25 to infinity) | 19 (5.06–60.05) | Undefined (15.27 to infinity) | 5.97 (2.41–13.33) | Undefined (7.89 to infinity) |
| LR (−ve) | 0.22 (0.06–0.55) | 0.3 (0.11–0.61) | 0.26 (0.05–0.73) | 0.25 (0.05–0.70) | 0.19 (0.03–0.66) | 0.33 (0.10–0.71) |
| OR | 48.89 (7.65–501.22) | Undefined (33.90 to infinity) | 73 (3.76–3875.25) | Undefined (12.07 to infinity) | 30.83 (2.52–1495.15) | Undefined (7.41 to infinity) |
Estimates for overall FNAC (combining both Ultrasound guided as well as conventional FNAC), Ultrasound guided FNAC (US-FNAC) and Conventional FNAC (C-FNAC) have been given
PPV positive predictive value; NPV negative predictive value; LR likelihood ratio; +ve positive cases; −ve negative cases; OR diagnostic odds ratio)
Discussion
Fine needle aspiration cytology is accepted as one of the most important tests for pre-operative dianosis of thyroid lesions [4, 5, 7, 8, 17, 18]. It has been shown to have an acceptable sensitivity and specificity in multiple studies. However, the usefulness of conventional FNAC is limited by a relatively high number of inadequate aspirates [9] which causes a dilemma in surgical decision making.
US-FNAC is increasingly being adopted as an alternative to C-FNACs. US-FNAC has been reported to have a lower inadequacy rate [10, 11, 14] as well as higher sensitivity and specificity [11, 14], besides detecting a higher number of malignant lesions [11, 12]. Most reports of US-FNAC have found that US-FNAC is an accurate procedure for the diagnosis of thyroid lesions though there have been discordant voices [19]. The role of cytopathologist experience has been emphasized if FNAC is to give useful results, and may explain the discrepant findings about the usefulness of US-FNAC in diagnosing thyroid lesions.
Our study supported the contention that US-FNACs have a far lower percent of inadequate aspirates (0.58% in case of US-FNAC compared to 15.19% in case of C-FNAC). In addition, the proportion of malignant cases detected on US-FNAC was higher, echoing the findings of some other studies [11, 12]. Also, the proportion of indeterminate cases was lower compared to C-FNAC. This is likely due to the direct visualization of the lesion with a higher likelihood of proper sampling from the lesion in the case of US-FNAC as compared to C-FNAC. Increased information about the lesion is also likely to have an influence of the more favourable (and low) proportion of indeterminate diagnosis in the case of US-FNAC. Ultrasound examination has been shown to have value as an imaging investigation of the thyroid gland [20–22]. Ultrasonography done along with FNAC has also been shown in a previous study to result in a high accuracy of cytological diagnosis [23, 24].
The tests for diagnostic accuracy confirmed the importance of FNAC as a diagnostic modality in differentiating malignant from benign cases in our setting. FNAC was found to be useful not only as a guided procedure, but also when it was done under no guidance. The sensitivities and specificities of US-FNAC and C-FNAC were similar, suggesting that both modalities were useful in differentiating benign from malignant conditions once inadequate samples were excluded.
Therefore, we would like to conclude that both US-FNAC as well as C-FNAC are useful in diagnosing thyroid lesions. However, US-FNAC is more useful as a diagnostic tool because it has an added advantage of a low inadequacy rate. A higher yield of malignancy as well as a lower proportion of indeterminate category are additional advantages of US-FNAC, possibly reflecting additional information from the ultrasound procedure.
Compliance with Ethical Standards
Conflict of interest
Dr. Manoj Sharma and Dr. Sadhana Mahore declare they have no conflict of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained for the procedure from all individual participants included in the study.
Contributor Information
Manoj Sharma, Email: drsharma_manoj@outlook.com.
Sadhana Mahore, Email: mahore.devenmahore@gmail.com.
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