ORIGINAL RESEARCH Analysis of Contrast-Enhanced Ultrasound Perfusion Patterns and Time-Intensity Curves for Metastatic Lymph Nodes From Lung Cancer Preliminary Results Shanshan Yin, MD, Qiuli Cui, MSc, Song Wang, MSc, Zhihui Fan, MD, Kun Yan, MSc Received March 20, 2017, from the Department of Ultrasound, Key Laboratory of the Ministry of Education for Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China. Manuscript accepted for publication May 8, 2017. This study was funded by a Capital Grant for Featured Clinical Applications (2211-02- 013) and the Capital Health Research and Development Special Fund (2016-2-2153). Address correspondence to Kun Yan, MSc, Department of Ultrasound, Key Laboratory of the Ministry of Education for Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Haidian, 100142 Beijing, China. E-mail: ydbz@vip.sina.com Abbreviations HPF, high-power field; US, ultrasound doi:10.1002/jum.14345 Objectives To retrospectively summarize the similarities and differences in contrast-enhanced ultrasound (US) findings for lymph node metastasis from adenocarcinoma, squamous carcinoma, and small cell lung cancer. Methods Patients who had received contrast-enhanced US examinations and had a histologic diagnosis of supraclavicular lymph node metastasis from lung cancer were included. The perfusion patterns on contrast-enhanced US images and timeintensity curve parameters were analyzed for the different pathologic types. The microvascular density and microvascular diameter were evaluated. Results Totally, 61 patients were enrolled in this study, including 26 cases with lung squamous carcinoma, 26 with lung adenocarcinoma, and 9 with small cell lung cancer. Contrast-enhanced US perfusion showed no significant differences in enhancement uniformity during the arterial phase and in the presence of unenhanced areas of metastatic lymph nodes with the 3 different pathologic origins (P >.05), but fewer unenhanced areas could be seen in metastatic lymph nodes from adenocarcinoma. The analysis of the time-intensity curve parameters showed that there were significant differences in the peak intensity between metastatic lymph nodes from lung squamous carcinoma and lung adenocarcinoma (P <.05). The microvascular density of metastatic lymph nodes from adenocarcinoma was significantly higher than that of metastatic lymph nodes from squamous carcinoma and small cell lung cancer (P <.001; P 5.0444), whereas the microvascular diameter of metastatic lymph nodes from adenocarcinoma was significantly smaller than that from squamous carcinoma and small cell lung cancer (P 5.0277; P <.001). Conclusions Effects of the pathologic diagnosis should be considered when analyzing quantitative parameters of metastatic lymph nodes during contrast-enhanced US examinations, even in the same organ. Key Words contrast agents (clinical); contrast-enhanced ultrasound; metastatic lymph nodes; oncology; time-intensity curve Lung cancer is one of the major tumors that causes human death. 1 Its prognosis is related to tumor pathologic types and sizes and the presence of lymph node metastasis. Accurate evaluation of the clinical stage is the key to selection of the therapeutic regimen, and supraclavicular lymph node metastasis indicates the impossibility of surgical treatment. 2 Two-dimensional ultrasound (US) imaging is an effective inspection method for the diagnosis of VC 2017 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2018; 37:385 395 0278-4297 www.aium.org
supraclavicular lymph node metastasis from lung cancer, but it does not always allow an easy discrimination from lymphoma and tuberculosis. Contrast-enhanced US can better display macrovessels in lymph nodes and can be used to perform a real-time and dynamic observation of lymph node blood perfusion, thereby providing richer diagnostic information for the nature of the lymph nodes. It has been reported that most metastatic lymph nodes are enhanced nonuniformly under contrast-enhanced US, with enhancement from the periphery to the center, with nonperfused areas being visible inside, and then gradual wash-out. 3 However, the contrastenhanced US imaging patterns for metastatic lymph nodes from different primary cancers are different. For example, metastatic lymph nodes from thyroid cancer show nonuniform hyperenhancement, 4 which is different from the appearance of metastatic lymph nodes from lung cancer. Quantitative contrast-enhanced US allows for measurements that reflect fractional blood volume. Compared with subjective evaluations on color Doppler and contrast-enhanced US imaging, quantification analyses diminish the operator dependency and allow for more valid intrapatient and interpatient correlations. Despite many studies published in the literature up to now, there are some factors that influence the time-intensity curve results, such as the size, shape, and depth of the region of interest, the validity of the parameters, the comparability of different software sources, and the different US machines used. 5 7 Local blood perfusion may be very different in different parts of an organ and at different developmental stages of the same organ, which results in different time-intensity curve results and limitations to wide application of time-intensity curves for routine clinical diagnosis. Until now, the effect of the pathologic origin, especially different pathologic types in the same organ, on time-intensity curve parameters has been rarely reported. This study aimed to preliminarily analyze contrast-enhanced US patterns of metastatic lymph nodes from lung cancer and to summarize the similarities and differences in contrast-enhanced US imaging of metastatic lymph nodes from lung adenocarcinoma, lung squamous carcinoma, and small cell lung cancer. Materials and Methods Patients This study was approved by the Ethics Committee of Peking University Cancer Hospital. All patients signed an informed consent form before receiving contrastenhanced US examinations and biopsies. Between April 2015 and March 2016, a total of 202 patients who came to the hospital for supraclavicular lymph node enlargement received both contrast-enhanced US examinations and US-guided lymph node biopsies. Among them, 61 patients with a histologic diagnosis of lymph node metastasis from lung cancer were included in this study. Contrast-Enhanced US Equipment The instrument used was a LOGIQ E9 US system (GE Healthcare,Milwaukee,WI).Thetransducerwasa9L with a 5 9-MHz frequency. The contrast agent was SonoVue (Bracco SpA, Milan, Italy), which consists of sulfur hexafluoride microbubbles. Conventional US Conventional and Doppler US examinations were performed first to observe and record the location, size, border, and morphologic characteristics of the lesion, as well as the internal echo uniformity and blood flow. Ultrasound Elasticity Imaging Ultrasound elastography was performed after lymph node images were stable. The sampling area included the entire lymph nodes and the surrounding tissues on an area greater than twice that of the lymph nodes. The transducer was held with a hand to make tiny vibrations (1 2 times per second) at the lesion sites with or without adding pressure to the skin. The elastic image characteristics were observed. The relative hardness of the lesion was evaluated and classified according to the color coding of the elastic images. For elasticity level 1, the lymph node was green only; for level 2, the lymph node was mainly green; for level 3, the lymph node was mainly blue; and for level 4, greater than 90% of the lymph node was blue. Levels 1 and 2 were considered soft lymph nodes, whereas levels 3 and 4 were considered hard. Contrast-Enhanced US The focus and depth were adjusted to display the lesion clearly, and the biggest section was selected. When patients could breathe smoothly, grayscale contrastenhanced US imaging was performed. The mechanical index was 0.10 to 0.13; the power output was 10%; the totalgainwas27;thetimefrequencywassettores;the dynamic range was 63 db; and the time-gain compensation was adjusted to the middle. In a bolus injection, 386 J Ultrasound Med 2018; 37:385 395
1 ml of the contrast agent was injected into the antecubital vein, followed by a wash with 5 ml of saline. The enhancement within the lesion and the wash-out process were dynamically observed; Digital Imaging and Communications in Medicine dynamic data were stored at 1 minute 30 seconds. Based on the European Federation of Societies for Ultrasound in Medicine and Biology guidelines, the arterial phase started from the first arrival of contrast in the lymph node (usually in 10 20 seconds) until around 30 to 45 seconds, during which the degree of enhancement increased progressively. The delayed phase (or venous phase) started approximately 30 to 45 seconds after contrast agent injection, during which the nearby jugular vein enhanced and the degree of enhancement in the lymph node showed a plateau and then decreased progressively. 8 Analysis of Contrast-Enhanced US Images The data analysis included the enhancement uniformity, enhancement pattern during the arterial phase, including homogeneous enhancement, peripheral to central enhancement, and central to peripheral enhancement, and presence or absence of unenhanced areas. No enhancement area in the lymph node was defined as perfusion defects during the whole contrast-enhanced US procedure. Records were made for comparative analysis. Analysis of Quantitative Parameters Offline processing was performed for the Digital Imaging and Communications in Medicine data, and the time-intensity curve analysis software of the LOGIQ E9 system was used to analyze quantitative parameters of contrast-enhanced US. The region of interest should have contained most of the display area of the lesion. The control area was a cross section of the carotid artery next to the lesion. Based on clinical experiences, published references 6,7 and recommendations from GE Healthcare, the following parameters were analyzed: (1) peak intensity of the lesion; (2) intensity difference (D peak intensity), indicatingthedifferencebetweenthepeakintensitiesof the nearby artery and the lesion; and (3) descending slope of the time-intensity curve (k): decreasing function (k > 0) for wash out. For larger k, the intensity decreased quickly after the peak. Histopathologic Analysis Biopsies were performed with an 18-gauge automatic cutting needle (Magnum; Bard, Inc, Tempe, AZ) after the contrast-enhanced US examinations in less than 2 days. The specimens obtained during the biopsies were fixed in 10% formalin for histopathologic diagnosis. Immunohistochemistry was performed with antibodies to CD34 (Dako, Glostrup, Denmark), a marker of tumor microvasculature, 9 to detect the microvascular density and diameter, using previously described techniques. 10 Stained slides were imaged and analyzed on a microscope (BX43; Olympus Co, Ltd, Tokyo, Japan) with imaging software (Micron; Westover Scientific, Mill Creek, WA). A quantitative analysis was performed by using 2 metrics: the average microvascular diameter and the average microvascular density. The 5 most vascular areas (ie, hot spots) with the highest numbers of microvessel profiles were chosen respectively from each sample under a low-power lens (100), and then the microvascular diameter and microvascular density were counted in 5 random high-power fields (HPFs; 400) within the defined zone. The accuracy of the final data was verified by the senior pathologist. Statistical Analysis SPSS version 21.0 software (IBM Corporation, Armonk, NY)wasusedfordataanalysis.Thecontinuousdata were expressed as means 6 standard deviations. Percentages and composition ratios were used for categorical parameters. The Fisher exact test was used to compare categorical parameters. Analysis of variance was used to compare the differences among the 3 groups. A 2-tailed t test was used for comparisons between 2 groups. P <.05 was considered statistically significant. Results Totally, 61 patients who received both conventional and contrast-enhanced US examinations and had a pathologic diagnosis of supraclavicular lymph node metastasis from lung cancer were analyzed in this study, including 37 male and 24 female patients. The mean age was 58.0 6 10.9 years (range, 31 79 years). The mean size was 2.4 6 0.9 cm (range, 1.2 5.2 cm). Among these patients, 26 had lung squamous carcinoma; 26 had lung adenocarcinoma; and 9 had small cell lung cancer. J Ultrasound Med 2018; 37:385 395 387
Two-Dimensional US Characteristics Conventional US characteristics of metastatic lymph nodes from lung cancer with the 3 different pathologic origins are shown in Table 1. There were no significant differences in 2-dimensional US characteristics of cervical metastatic lymph nodes for lung squamous carcinoma, lung adenocarcinoma, and small cell lung cancer. Contrast-Enhanced US Features The contrast-enhanced US patterns of lymph nodes with different pathologic origins are shown in Table 2. Totally58of61lymphnodes(95.1%)hadcentripetal perfusion (from the periphery to the center), 57 of 61 (93.4%) had nonuniform enhancement; and 44 of 61 (72.1%) had no enhancement areas, indicating necrosis. There were no significant differences in perfusion patterns, enhancement uniformity during the arterial phase, and the presence of unenhanced areas for metastatic lymph nodes with the 3 different pathologic origins (P >.05), but the presence of unenhanced areas was less commonly seen in metastatic lymph nodes from adenocarcinoma (Figures 1 3). Table 1. Conventional US Characteristics of Metastatic Lymph Nodes From Lung Cancer Characteristic Squamous Carcinoma Adenocarcinoma Small Cell Lung Cancer (n 5 9) Lesion size, cm 2.65 6 1.13 2.09 6 0.68 2.30 6 1.45 Boundary Unclear 16 12 3 Clear 10 14 6 Echo Low-level echo 17 18 8 Mixed-level echo 9 8 1 Concentric rings 0 0 0 Calcifications No 15 16 3 Yes 11 10 6 Color Doppler flow imaging No blood flow 4 1 1 Rare blood flow 18 18 8 Rich blood flow 4 5 0 Gate-type blood flow 0 2 0 Elasticity Level 2 11 9 4 Level 3 14 15 5 Level 4 1 2 0 There was no significant difference among the groups (P >.05). Table 2. Contrast-Enhanced US Characteristics of Metastatic Lymph Nodes With Different Pathologic Origins Characteristic Squamous Carcinoma Adenocarcinoma Small Cell Lung Cancer (n 5 9) Perfusion pattern (%) Centripetal 26 (100) 24 (92.3) 8 (88.9) Centrifugal 0 2 1 Enhancement uniformity (%) Uniform 1 2 1 Nonuniform 25 (96.2) 24 (92.3) 8 (88.9) Unenhanced area (%) No 5 11 1 Yes 21 (80.1) 15 (57.7) 8 (88.9) There was no significant difference among the groups (P >.05). 388 J Ultrasound Med 2018; 37:385 395
Figure 1. A 58-year-old male patient had been found to have a lesion on the right lung with multiple swelling lymph nodes in the left supraclavicular region for 1 month. He had a diagnosis of lymph node metastasis from lung adenocarcinoma by US-guided biopsy. A, Traditional US showed a swelling hypoechoic lymph node with an unclear border (star). B, Color Doppler imaging showed a few blood flow signals in the lymph node. C, During the arterial phase of contrast-enhanced US, the lymph node was uniformly hypoenhanced (arrows) without an unenhanced region. D, The time-intensity curve showed that the peak intensity of the metastatic lymph node was about 36 db (arrow and blue curve). The yellow curve is the time-intensity curve of the carotid artery. E, Pathologic examination showed that there was intense and small neovascularization in the lymph node, and the average microvascular density and microvascular diameter were 20.0/HPF and 6.7 mm, respectively (anti-cd34 antibody, original magnification 3 400). J Ultrasound Med 2018; 37:385 395 389
Figure 2. A 52-year-old male patient, who had a history of smoking for up to 30 years, had been found to have multiple swelling lymph nodes in the right supraclavicular region for 2 months. He had a diagnosis of lymph node metastasis from lung squamous carcinoma by US-guided biopsy. A, Traditional US showed a hypoechoic lymph node in the right supraclavicular region with an unclear border (star). B, Color Doppler imaging showed a few blood flow signals in the lymph node. C, During the arterial phase of contrast-enhanced US, the lymph node was nonuniformly hypoenhanced (arrows) with an unenhanced region (heart). D, The time-intensity curve showed that the peak intensity of the metastatic lymph node was about 44 db (arrow and blue curve). The yellow curve is the time-intensity curve of the carotid artery. E, Pathologic examination showed that there was relatively large neovascularization in the lymph node, and the average microvascular density and microvascular diameter were 4.0/HPF and 9.1 mm, respectively (anti-cd34 antibody, original magnification 3 400). 390 J Ultrasound Med 2018; 37:385 395
Figure 3. A 44-year-old male patient had been found to have multiple lung lesions on both sides with swelling lymph nodes in the left supraclavicular region for 2 weeks. He had a diagnosis of lymph node metastasis from small cell lung cancer by US-guided biopsy. A, Traditional US showed multiple hypoechoic lymph nodes in the left supraclavicular region with clear border (star). B, No blood flow signal could be seen in the lymph node on color Doppler imaging. C, During the arterial phase of contrast-enhanced US, the lymph node was nonuniformly hypoenhanced (arrows) with an obvious unenhanced region (heart). D, The time-intensity curve showed that the peak intensity of the metastatic lymph node was about 46 db (arrow and blue curve).the yellow curve is the time-intensity curve of the carotid artery. E, Pathologic examination showed that there was relatively small neovascularization in the lymph node, and the average of microvascular density and microvascular diameter were 12.0/ HPF and 15.1 mm, respectively (anti-cd34 antibody, original magnification 3 400). J Ultrasound Med 2018; 37:385 395 391
Analysis of the Parameters of the Contrast-Enhanced US Intensity Curve As shown in Table 3, the peak intensity of metastatic lymph nodes from adenocarcinoma was higher, and there was a significant difference in the peak intensity between squamous carcinoma and adenocarcinoma (P 5.002). The D peak intensity of metastatic lymph nodes from lung adenocarcinoma was small, but there was no significant difference compared with those from squamous carcinoma and small cell lung cancer. For k values (reflecting the descending branch slope), there were no significant differences among the groups. Microvascular Pathologic Results As shown in Table 4, the results of CD34 staining showed that the microvascular density of metastatic lymph nodes from adenocarcinoma was significantly higher than that of metastatic lymph nodes from squamous carcinoma and small cell lung cancer (P <.001; P 5.0444). On the contrary, the microvascular diameter of metastatic lymph nodes from adenocarcinoma was significantly smaller than that from squamous carcinoma and small cell lung cancer (P 5.0277; P <.001). The microvascular density of metastatic lymph nodes from small cell lung cancer was slightly higher than that from squamous carcinoma, but there was no significant difference between them (P 5.0829); on the other hand, the microvascular diameter of metastatic lymph nodes from small cell lung cancer was markedly bigger than that from squamous carcinoma (P 5.0062). Discussion Two-dimensional and color Doppler US examinations are the first-line diagnostic methods for supraclavicular lymph node metastasis from lung cancer, but the diagnostic specificity is limited. 11,12 Fine-needle aspiration biopsy and cytologic examination is the reference Table 3. Analysis the Contrast-Enhanced US Curve Parameters for Metastatic Lymph Nodes With Different Pathologic Origins Parameter Squamous Carcinoma Adenocarcinoma Small Cell Lung Cancer (n 5 9) P k 0.12 6 0.13 0.15 6 0.13 0.09 6 0.07.517 a.199 b.409 c Peak intensity 244.37 6 4.90 240.47 6 3.93 243.39 6 4.56.602 a.074 b.002 c D Peak intensity 13.98 6 5.56 12.50 6 5.17 13.08 6 5.40.678 a a Comparison between squamous carcinoma and small cell lung cancer. b Comparison between adenocarcinoma and small cell lung cancer. c Comparison between squamous carcinoma and adenocarcinoma..772 b.325 c Table 4. Microvascular Pathologic Results Parameter Squamous Carcinoma Adenocarcinoma Small Cell Lung Cancer (n 5 9) P Microvascular density, n/hpf 7.00 6 3.23 13.73 6 6.28 9.17 6 2.83.0829 a.0444 b <.001 c Microvascular diameter, lm 8.176 2.76 6.80 6 1.37 11.52 6 3.51.0062 a a Comparison between squamous carcinoma and small cell lung cancer. b Comparison between adenocarcinoma and small cell lung cancer. c Comparison between squamous carcinoma and adenocarcinoma. <.001 b.0277 c 392 J Ultrasound Med 2018; 37:385 395
standard for a definite diagnosis of lymph node metastasis, but it is also subject to sampling error and limited by the experience of the physician who takes the samples as well as the pathologist who makes the diagnosis. 13 The second-generation US microbubble contrast agent SonoVue can facilitate the observation of blood perfusion signals within tissues in real time and can help in understanding information related to blood distribution. Various studies indicated that contrast-enhanced US contributes to the diagnoses and differential diagnoses of lymph node diseases. A study by Rubaltelli et al 3 reported that by using noticeable and uniform enhancement as the indication for diagnosis of benign lymph nodes and using perfusion defects and nonuniform enhancement or hypoenhancement as indications for diagnosis of tumor infiltration, the sensitivity of differentiating benign and metastatic lymph nodes was 92%; the specificity was 93%; and the accuracy was 92.8%. Dudau et al 14 observed 17 cervical metastatic lymph nodes from squamous carcinoma and discovered that perfusion defects or nonuniform enhancements were present in 13 metastatic lymph nodes. A meta-analysis 11 found that contrast-enhanced US could differentiate between benign and malignant lymph nodes with relatively high sensitivity and specificity, a relatively high positive likelihood ratio and diagnostic odds ratio, and a relatively low negative likelihood ratio. Therefore, contrast-enhanced US has high clinical value for the diagnosis of malignant lymph nodes. Our study showed that among the metastatic lymph nodes from lung cancer, 58 of 61 (95.1%) had centripetal perfusion (from the periphery to the center);57of61(93.4%)hadnonuniformenhancement; and44of61(72.1%)hadnoenhancementareas,indicating necrosis. These findings were consistent with the perfusion patterns of metastatic lymph nodes reported previously. However, the blood supply of different tissues is associated with the pathologic type, resulting in different perfusion patterns in metastatic lymph nodes originating from different tumors. It has been reported 15 that significant characteristic parameters for the diagnosis of cervical lymphatic metastasis from thyroid papillary carcinoma include centripetal or mixed-type enhancement, a high peak intensity, partial hyperenhancement and partial hypoenhancement, with unclear borders, the presence of a nonperfused area, and a perfusion area that is larger than the grayscale area. The authors also found that the intensity of enhancement of the metastatic lymph nodes from the thyroid was higher than that of the reactive lymph nodes. This finding differed from a previous report 14 that hypoenhancement was common in metastatic lymph nodes from squamous carcinoma. Therefore, it has been suggested that metastatic lymph nodes from different primary tumors have different contrast-enhanced US perfusion patterns. Our study investigated the contrast-enhanced US patterns of metastatic lymph nodes from lung cancers with different pathologic diagnoses. Two-dimensional US images of metastatic lymph nodes from squamous carcinoma, adenocarcinoma, and small cell lung cancer showed no significant differences in the size, boundary, echo, presence of calcification, and blood flow signals. The degree of hardness of the lymph nodes determined by elastography also showed no significant difference. Therefore, we hypothesized that 2-dimensional US cannot provide more diagnostic information for pathologic typing of lymph nodes. Most of the metastatic lymph nodes of the 3 pathological origins showed a nonuniform centripetal enhancement perfusion pattern on contrast-enhanced US images. Nonperfused areas were present in 21 of 26 metastatic lymph nodes from squamous carcinoma, 15 of 26 from adenocarcinoma, and 8 of 9 from small cell lung cancer. Previous studies 16 suggested that the focal hypoperfusion areas and nonperfused areas in metastatic lymph nodes were due to the fact that the blood supply inside the cortex of the metastatic lymph nodes was less than that of the normal lymph nodes, whereas necrosis and liquefaction led to the presence of nonperfused areas, and the whole lymph node showed hypoperfusion whenthewholenodehadbeeninvadedbyatumor. Based on a previous report, 17 on tissue sections, the diagnosis of lung adenocarcinoma is made on the basis of the presence of glands (acini), papillary structures, a lepidic (bronchioloalveolar) pattern, a micropapillary pattern, cellular mucin, or a solid pattern, and fibrosis was rarely found. Histopathologically, lung squamous cell carcinoma cells show keratinization (in the form of keratin pearls or single-cell keratinization), intercellular bridges, or both. The most common pattern of squamous cell carcinoma cells is one of infiltrating nests of malignant squamous cells, with central necrosis, often resulting in cavitation. Lung small cell carcinoma consists of smaller but clearly malignant cells, which may be arranged in sheets. Commonly, there is a spectrum of viability, with necrosis and crushing of tumor cells, as J Ultrasound Med 2018; 37:385 395 393
well as nuclear molding. From the pathologic evidence, we speculated that the unenhanced areas shown on contrast-enhanced US images of metastatic lymph nodes from squamous carcinoma may have been due to fibrosis, whereas for metastatic lymph nodes from adenocarcinoma, the presence of fairly well-defined cellular structures and the low degree of fibrosis may have been the reason for the high peak intensity in our study. We also made the assumption that for metastatic lymph nodes from small cell lung cancer, because of the low degree of differentiation and rapid growth, common necrosis and liquefaction may have been the reasons for the relatively frequent presence of nonperfused areas. Research about the correlation between contrastenhanced US and microvascular density was mostly reported in recent years. 18 These results demonstrated that using contrast-enhanced US could show the information on vascular perfusion inside the tumor, and it also could be a good method for evaluating the microvascular density in malignant tumors. Contrastenhanced US provided an effective assessment of tumor vascularity. 19 Wang et al 20 reported that the peak intensity and area under the curve of contrast-enhanced US could reflect the microvascular density in ovarian tumors. Luo et al 21 also showed that the degree of US contrast enhancement in squamous cell carcinomas was lower than that of adenocarcinomas. In our histopathologic analysis, the microvascular density of metastatic lymph nodes from adenocarcinoma was significantly higher than that of metastatic lymph nodes from squamous carcinoma and small cell lung cancer, whereas the microvascular diameter of metastatic lymph nodes from adenocarcinoma was smaller than that from squamous carcinoma and small cell lung cancer. The higher microvascular density and smaller microvascular diameter may have been the reasons for the high degree of enhancement in adenocarcinoma. Therefore, the results of this study indicated that for metastatic lymph nodes of different pathological origins, the resistance to the microbubbles was different as a result of the different distributions of tumor cells, different compositions of cellular structures, and different neovessels of the lymph nodes examined. These factors resulted in different perfusion parameters. Previous studies 22 showed that there is controversy regarding the use of time-intensity curves to differentiate benign and malignant lymph nodes. Two studies concluded that the intensity difference between areas with a rich versus insufficient blood supply was greater for malignant lymph nodes than for benign lymph nodes, 23,24 whereas Steppan et al 25 reported that malignant lymph nodes showed a longer contrast enhancement duration and higher degree of enhancement compared with benign lymph nodes. These discrepancies might be associated with the pathologic diagnosis of the lymph nodes studied, the settings of the US scanner, the software for time-intensity curve analysis, and the selection of sampling frames. This study preliminarily investigated the contrastenhanced US perfusion patterns and time-intensity curve parameters of metastatic lymph nodes with differentpathologicorigins.ithadthefollowinglimitations: (1) The number of patients was limited, especially for patients with metastatic lymph nodes from small cell lung cancer. (2) Since the biopsy samples were collected by US-guided puncture, there was the possibility of sampling errors and insufficient sampling materials. Removing the whole lymph node instead of a biopsy sample would provide an overall picture of the pathologic morphologic characteristics of metastatic lymph nodes, thereby providing more information in the study of perfusion patterns. (3) The effect of differentiation of lung cancer on the time-intensity curve was not analyzed in this study. (4) The study was retrospective, although the presets of the US machine were prospectively designed. A prospective study with a larger sample size is needed to further investigate the effect of the different pathologic types of metastatic lymph nodes on enhancement modes and the time-intensity curve. In summary, it can be concluded that time-intensity curve parameters of metastatic supraclavicular lymph nodes from lung cancer were different depending on the pathologic origin. It is recommended to consider the effects of the pathologic diagnosis when analyzing quantitative parameters using contrast-enhanced US, even in thesamedisease. References 1. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000; 50:7 33. 2. Kiricuta IC, Mueller G, Stiess J, Bohndorf W. The lymphatic pathways of non small cell lung cancer and their implication in curative irradiation treatment. Lung Cancer 1994; 11:71 82. 3. Rubaltelli L, Khadivi Y, Tregnaghi A, et al. Evaluation of lymph node perfusion using continuous mode harmonic ultrasonography with a 394 J Ultrasound Med 2018; 37:385 395
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