This is a secondary data analysis of a study registered to ClinicalTrials.gov with Identifier NCT00571090. The aim of the study was to identify ultrasonographic features that predict malignant thyroid nodules. The primary data from this study has not been published. Data relevant to cost-effectiveness comparison are reported here. FNAs were performed as an outpatient procedure in Gayrettepe and Şişli Florence Nightingale Hospitals, two private hospitals affiliated with Istanbul Science University and authors' private medical office in Şişli, all located in Istanbul. Turkish Cardiology Foundation owns and operates Istanbul Science University and Group Florence Nightingale Hospitals in Istanbul. These health care facilities are secondary care centers for thyroid disorders, not tertiary care referral centers.
The clinical information and cytology results of all consecutive patients who underwent FNA biopsy of thyroid nodules in above-mentioned outpatient endocrinology clinics were instantaneously recorded in a computerized database on the day of the FNA biopsy. This study was not a retrospective chart review. All patients were examined by ASC, an endocrinologist who also performed all thyroid FNA biopsies between April 2003 and May 2008. Thyroid function tests and thyroid ultrasonography were routinely obtained. Subjects were classified into euthyroid, hypothyroid (TSH>4.20 μIU/ml) and hyperthyroid (TSH<0.27 μIU/ml) categories according to the results of thyroid function tests. The location, three dimensional diameters, echo structure (solid, mixed or cystic), echogenecity (hypoechoic, isoechoic or hyperechoic) and other ultrasonographic features of thyroid nodules were recorded. A nodule was classified as cystic, if its area was 90–100% cystic. Thyroid scintigraphy with Technetium99m was obtained for subjects with a low TSH level. All subjects consented to FNA biopsy in accordance with the hospital bylaws. Institutional Review Board approval from Istanbul Science University Ethics Committee was asked and granted in July 2007 (Number 2007/006). As thyroid FNAs were performed in routine clinical care without any investigational procedure, the Ethics Committee did not ask for signed informed consent for subjects enrolled prior to approval of the study. Subjects admitted after July 2007 signed informed consent for the study.
Each thyroid nodule was counted as a case in this report. Three-hundred and thirty-nine FNAs were performed between April 2003 and May 2008. Nineteen FNAs for nonpalpable nodules and 16 FNAs for nodules <10 mm were excluded. There were 19 nodules with a low TSH level but without a thyroid scintigraphy and these were also excluded. ATA designates cystic nodules as an indication for USG-FNA [1
]. AACE recommends USG-FNA for all nodules, including cystic ones [2
]. As there was no disagreement on the utility of ultrasound guidance for cystic nodules between guidelines, 17 cystic nodules were excluded from the analysis. There were 268 thyroid nodules for comparison. One-hundred and ninety USG-FNAs were performed to palpable thyroid nodules with a SonoSite 180 plus hand-carried ultrasound system and a L38/10-5 MHz transducer between March 2004 and May 2008, starting with the acquisition of the ultrasound system. Both the ultrasound system and the transducer were manufactured by SonoSite Incorporation, located in Bothell, WA, USA. A published standard technique was used for USG-FNA [13
]. Seventy-eight P-FNAs were performed to palpable thyroid nodules with a previously published technique [14
] between April 2003 and February 2008, at times when the ultrasound system was not available for FNA biopsy. Allocation to P-FNA and USG-FNA groups was not random. The FNAs were done by palpation-guidance until the ultrasonography system was purchased. Then USG-FNA was routinely performed. P-FNA was still performed after the acquisition of ultrasonography system, at times when the ultrasonography machine was temporarily unavailable in the above-mentioned outpatient endocrinology clinics. On-site microscopic adequacy was not determined. Local anesthesia with 2% lidocaine was routinely administered for both P- and USG-FNAs. All FNA biopsies were performed with either 22 or 26 gauge needles. Twenty-two gauge needles are long; 26 gauge needles are short. If the nodule is located anteriorly or in the isthmus a 26 G needle, if posteriorly a 22 G needle was used. Two needle aspirations were carried out for each nodule. If no material was seen on the slides to plain eye without using an optical instrument, up to four aspirations were performed. Half of the smears were air-dried and stained with May-Grünwald-Giemsa and the other half were alcohol-fixed and stained with Hematoxylene-Eosine or Papanicolaou. Cytological diagnoses were categorized as malignant, benign, indeterminate and inadequate [1
]. Six clusters of benign cells in at least two slides constituted adequate material for cytological diagnosis. Each cluster was composed of at least 15 cells. The smears that do not meet these criteria were assigned into inadequate category. Indeterminate samples included a pattern of follicular or Hurthle cell neoplasm or aspects of atypia suggestive, but not conclusive of the presence of a malignant neoplasm [14
Continuous variables were presented as means ± standard deviations and Student's t test was used for comparison. As maximal nodule diameter had a positively skewed distribution, its logarithmic transformation was used in Student's t test. Categorical variables were presented as percentages and χ2 test was used for comparison. As the expected frequencies of malignant results were less than five in both groups, each cytology category in P-FNA and USG-FNA groups was compared after collapsing the rest of the categories. Fisher's exact test was employed when the expected frequencies were less than five. Benign and inadequate cytology results were categorized into negative tests, as surgery is not recommended for these conditions. Malignant and indeterminate FNA cytology results were categorized into positive tests, as surgery is recommended to patients with such results. Nodules with benign or inadequate cytology and benign surgical histopathology result were classified as true negatives. Nodules with benign or inadequate cytology and malignant surgical histopathology result were classified as false negatives. Nodules with malignant or indeterminate cytology and malignant surgical histopathology result were classified as true positives. Nodules with malignant or indeterminate cytology and benign surgical histopathology result were classified as false positives. The accuracy of the test was calculated by dividing the sum of true positives and true negatives to the sum of true positives, false positives, false negatives and true negatives.
Cost of thyroid fine-needle aspiration strategies
Health care system of Republic of Turkey is dichotomized to state (government) and private sector. According to Turkish Ministry of Health, 10% of the population receives services from private health care sector in Turkey [15
]. This study was performed in a private health care setting. The minimum fee for medical and laboratory procedures in private health care system is determined by the City Chamber of Physicians, a non-governmental organization elected by physicians. Istanbul Chamber of Physicians' minimum fees are used in this study and are shown in table . Private health care sector charges the minimum fee or usually up to two-fold of it. The minimum fee in table is valid for all private health care facilities in Istanbul. These were actual billed and collected fees obtained from Gayrettepe Florence Nightingale Hospital Patients' Accounts Office. Derived from patients' bills, subtotal hemithyroidectomy fee includes all costs including one night hospital stay but excludes the cost of harmonic scalpel, an expensive device that was used by some surgeons in our hospital. ATA and AACE thyroid nodule management guidelines were constructed using actual frequencies from this study and actual costs from Table . The cost of each diagnostic step was summed until a final cytological or pathological diagnosis was made for one hundred nodules. Malignant, benign and indeterminate cytological results were final diagnoses. For inadequate smears, USG-FNA was the next step whether or not initial FNA was palpation- or ultrasound-guided. If two consecutive thyroid FNAs were inadequate, a hemithyroidectomy was the final procedure to reach a diagnosis [16
]. Cost per nodule was calculated by dividing the sum of costs for one hundred nodules to 100. Incremental cost-effectiveness ratio (ICER) was estimated to find the amount of more spending versus more saving to achieve one additional correct diagnosis of benign versus malignant thyroid nodule, if one modality is used over the other. ICER [17
] was calculated with the following formula:
Cost of diagnostic steps recommended by thyroid nodule management guidelines
cUSG-FNA is the cost of ultrasound-guided thyroid FNA strategy according to AACE thyroid nodule management guideline to achieve a diagnosis for one nodule, cP-FNA is the cost of palpation-guided thyroid FNA strategy according to ATA thyroid nodule management guideline to achieve a diagnosis for one nodule, aUSG-FNA is the accuracy of ultrasound-guided thyroid FNA and aP-FNA is the accuracy of palpation-guided FNA.