Improved Diagnostic Accuracy Using Arterial Phase CT for Lateral Cervical Lymph Node Metastasis from Papillary Thyroid Cancer

Patient Selection

This study was approved by our institutional review board. Data were collected retrospectively and were de-identified in compliance with the regulations of the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients before undergoing neck CT, US-guided biopsy, and/or an operation.

Among the patients who underwent CT between February 2013 and March 2015 found in the data base of our institution, 151 patients were identified as having primary or recurrent PTC with LN metastasis. Patients with recurrent PTC were those who had been treated with an operation alone and were later diagnosed as having a recurrence. The inclusion criteria were as follows: 1) patients with lateral cervical LN metastasis from PTC confirmed by US-guided aspiration/biopsy, 2) those who subsequently underwent selective neck dissection or excisional biopsy for metastatic lateral cervical LNs, and 3) those having available final histopathologic results. The exclusion criteria were as follows: 1) patients with histopathologic results that lacked information on the cervical level of the aspirated/biopsied LN (10 of 151 patients [6.6%]), and 2) those with poor CT image quality because of motion or beam-hardening artifacts (10 of 151 patients [6.6%]). Finally, 131 patients were included in this study.

CT Protocols

Imaging was performed by using a 128-channel CT scanner (Somatom Definition Flash; Siemens, Erlangen, Germany) with tube voltages of 80 and 140 kVp. CT scanning began at the aorticopulmonary window and continued toward the skull base. CT was performed with the following parameters used consistently in all patients: 32 × 0.6 mm detector collimation; 0.5-second gantry rotation time; 1.0 pitch; 0.75-mm-thick sections; 0.7-mm-thick section increments; and a 256 × 256 matrix. An automated dose-reduction technique (CARE Dose4D; Siemens) was used. The volume CT dose index (CTDI_vol) and dose-length product (DLP) were evaluated to assess radiation exposure.

Three different protocols for contrast-injection strategy and image-acquisition timing were used during CT. The protocols for patients with PTC at our institution were updated following a consensus among radiologists based on a literature review^15⇓–17; the change was from a 70-second delay protocol to a 35- and 25-second scan delay. Protocol A consisted of a 70-second scan delay after IV injection of 100-mL of iodinated contrast agent (February 2013 to September 2013; n = 42, 35 initially diagnosed and 7 with recurrent disease). Protocol B used a 35-second scan delay after IV injection of 100 mL of iodinated contrast agent (October 2013 to October 2014; n = 47, 40 initially diagnosed and 7 with recurrent disease). Protocol C consisted of a 25-second scan delay after injection of 75 mL of iodinated contrast agent, followed by 50 mL of normal saline at the same rate to compensate for the small volume of contrast medium and to improve contrast medium use¹⁸ (November 2014 to March 2015; n = 42, 32 initially diagnosed and 10 with recurrent disease). For all scan delays, the same iodinated contrast agent, Ultravist (iopromide; Bayer HealthCare, Berlin, Germany), was injected at the same rate of 3.5 mL/s. The flowchart of patient enrollment is shown in Fig 1.

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Fig 1.

Flowchart of patient enrollment.

Reference Standard and Histopathologic Assignment

The final histopathologic reports of the US-guided aspiration/biopsy or surgical neck dissection samples served as the reference standard for nodal metastasis. All cervical levels in a neck dissection specimen were labeled on the basis of the American Joint Committee on Cancer cervical regional lymph node level system¹⁹; cervical LN levels were assigned as benign, metastatic, or mixed after correlation with the histopathologic reports. For example, if all the LNs in 1 level were histologically positive for metastasis, the cervical level was assigned as metastatic. If all the LNs in 1 level were histologically negative, the level was assigned as benign. If a level had both benign and metastatic LNs, the level was assigned as mixed. The results of the histopathologic assignment were subsequently used for LN matching and labeling on CT.

LN Matching and Labeling on CT

Lymph node matching and labeling on CT were performed on a PACS by a radiologist (J.H.L., with 14 years of experience in head and neck imaging), either by site-specific matching or surgical-level matching. A LN confirmed by US-guided aspiration/biopsy was chosen and labeled on CT images by matching the images and reports of CT, US, and the final pathologic examination (“site-specific matching”). When there was no site-specific information, LNs measuring >5 mm in the minimum axis diameter and those assigned as benign or metastatic according to the previous histopathologic assignment were chosen and labeled on the CT images (“surgical-level matching”). All cervical-level LNs assigned as mixed were excluded from the final analysis.

Measurement of LN Tissue Attenuation

CT images with labeled LNs were transferred to ImageJ software (National Institutes of Health, Bethesda, Maryland) for assessment of LNTA (Hounsfield unit). Two readers (J.E.P. and K.H.R., with 2 years and 1 year of experience in head and neck imaging, respectively) were blinded to the clinicopathologic results and independently measured the LNTA of the labeled LNs and adjacent anatomic structures, including the common carotid artery (CCA), internal jugular vein (IJV), and paraspinal muscles. The ROI for the labeled LN was drawn to encompass the entire cortex, except for cystic change, necrosis, hilar fat/vessels, and calcification. A 60-mm² circular ROI was also drawn on the ipsilateral CCA, IJV, and paraspinal muscles at the same level as the labeled LN (Fig 2). In addition, normalized LNTAs were calculated as the Hounsfield unit value of the entire LN divided by the Hounsfield unit value of the CCA, IJV, or paraspinal muscles.

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Fig 2.

A, Contrast-enhanced CT scans obtained with protocol C, B, and A (from left to right) in different patients with papillary thyroid cancer. Note the enhancing metastatic lymph node in the right level III. B, A hyperenhancing lymph node in the right level III is shown in protocol C. The ROI (ROI area, 23.8 mm²; mean tissue attenuation, 172 HU) is drawn for a labeled metastatic lymph node. For normalization, a 60-mm² circular ROI was drawn on the ipsilateral CCA (mean CT value, 389 HU), IJV (mean CT value, 370 HU), and paraspinal muscle (mean CT value, 71.5 HU) on the same image. Lymph node tissue attenuation normalized to CCA, IJV, and paraspinal muscle was 0.44, 0.46, and 2.4, respectively.

Qualitative CT features (ie, calcification, cystic or necrotic change, and extranodal extension^9,14) of the labeled LNs were assessed by an independent radiologist (Y.J.C., with 8 years of experience in head and neck imaging) who was blinded to the clinicopathologic results. An LN was categorized as positive when at least 1 of the qualitative CT features was present. We did not include the size criterion because LN size alone is an inaccurate criterion in young patients, who often have hyperplastic LNs, particularly at cervical levels I and II.²⁰

Statistical Analysis

One-way analysis of variance or the Kruskal-Wallis test was performed to compare the characteristics of patients, LNs, and radiation exposure (CTDI_vol and DLP) among the 3 protocols. All parameters were initially assessed for normality by using the Kolmogorov-Smirnov test. The Student t test was used to compare the parameters between benign and metastatic LNs.

Interreader agreement was assessed by using the intraclass correlation coefficient (ICC) with 95% confidence intervals and by applying a 2-way ICC with a random rater's assumption. On the basis of common criteria, measurement reliability was classified as excellent (ICC > 0.75), fair-to-good (ICC = 0.40–0.75), and poor (ICC ≤ 0.40).²¹

A receiver operating characteristic curve analysis was performed for each parameter to calculate the area under the receiver operating characteristic curve (AUC) and to determine the optimal cutoff for differentiating benign and metastatic LNs by each reader. To eliminate possible correlations from multiple measurements in the same patient, we used a logistic regression model with a generalized estimating equation model.²² We estimated the predicted probabilities of metastatic or benign LNs, and the estimated probability was then used as a marker for constructing the receiver operating characteristic curve and computing the area under the curve. We determined the cutoff values that maximized the sum of the sensitivity plus specificity as the points in the upper left-hand area for the receiver operating characteristic curve analysis for each parameter. For comparison of AUCs among protocols in different patient populations, a 2-sample Z-test for comparing 2 means was used. For cross-validation of each AUC, we used leave-one-out cross-validation with bootstrap resampling on R statistical and computing software (http://www.r-project.org/) and analyzed the results by using the package pROC in R.

To assess the diagnostic performance of qualitative LN CT findings, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy by level-by-level analysis.

Statistical analyses were performed by using statistical software (MedCalc, Version 10.2.0.0; MedCalc Software, Mariakerke, Belgium). All tests were 2-sided. A P value < .05 was considered significant.