Value of CT spectral imaging in the differential diagnosis of sarcoidosis and Hodgkin’s lymphoma based on mediastinal enlarged lymph node: A STARD compliant article

1. Introduction

Mediastinal enlarged lymph node can occur from a wide range of pathologies. Common malignant conditions include metastatic lymph nodes and malignant lymphomas, for example, Hodgkin’s and non-Hodgkin’s disease. Benign causes include sarcoidosis and granulomatous infectious conditions including tuberculosis, coccidioidomycosis, histoplasmosis and others.[1] Among them, it is extremely important for clinicians and radiologists to be able to distinguish metastatic lymph nodes, lymphoma and sarcoidosis in a clinical setting for effective disease management and accurate prognosis.[2–4] Different from sarcoidosis and lymphoma, mediastinal metastatic lymph nodes are common in middle-aged and elderly patients with primary malignant tumors; In addition, the imaging features of metastatic lymph nodes often show asymmetric distribution and heterogeneity, especially uneven enhancement. Hence, for most metastases, diagnosis is not difficult according to clinical and imaging characteristics.[3]

Sarcoidosis is a systemic disorder of unknown etiology with a wide variety of clinical and radiological manifestations. Pathologically, the disease is characterized by presence of widespread non-caseating granulomas.[5] Although, the clinical manifestations of sarcoidosis are widespread, but the lung and intrathoracic lymph nodes are almost universally affected. The most frequent radiological abnormality involves enlarged bilateral hilar and right paratracheal lymph nodes.[6,7] Hodgkin’s lymphoma is a unique type of lymphoma, which is a systemic disease. In the early stage, Hodgkin’s lymphoma is mainly characterized by enlarged lymph nodes with homogeneous enhancement, especially bilateral hilar or mediastinal enlarged lymph node, which are easily confused with sarcoidosis. And then, parenchymal presentations of Hodgkin’s lymphoma and sarcoidosis are similar and indistinguishable as well.[8] Moreover, patients with Hodgkin’s disease also demonstrate a decreased CD41/CD8 ratio in peripheral blood, which occasionally are found in sarcoidosis patients. The last interesting thing is that the age at onset of both also overlaps. As such, the mediastinal enlarged lymph nodes caused by Hodgkin’s lymphoma can be confused with sarcoidosis upon both clinical and imaging information.[9] As is known to all, early and accurate diagnosis of Hodgkin’s lymphoma and sarcoidosis is critical because they require different therapeutic approaches.[10] At present, there is no ideal imaging method and neither functional imaging nor anatomical imaging can accurately characterize lymph nodes. CT and magnetic resonance imaging are the most widely used modalities for evaluation of mediastinal enlarged lymph nodes but both have low sensitivity and specificity in differentiating between Hodgkin’s lymphoma and sarcoidosis.[11] Patients with sarcoidosis and Hodgkin’s lymphoma may undergo invasive diagnostic procedures including transbronchial needle aspirate, transthoracic needle aspirate and endobronchial ultrasound guided, which may lead to some complications.[12–15] There is therefore a need for noninvasive method that can accurately differentiate between sarcoidosis and Hodgkin’s lymphoma.

In recent years, quantitative spectral CT imaging has become a field of intense study. Spectral CT imaging with material decomposition reconstruction has enabled the transformation of conventional attenuation data into effective material densities, such as those of iodine and water.[16] This procedure theoretically allows 2 types of tumor to be differentiated on the basis of tumor iodine density after administering an iodine contrast agent because the amount of neovascularity is unequal.[17] This imaging method has been used in several clinical applications, including differentiating mediastinal lymphoma and thymoma.[18] To the best of authors’ knowledge, a detailed comparison between sarcoidosis and Hodgkin’s lymphoma regarding quantitative analysis of mediastinal enlarged lymph nodes on spectral CT scan has not yet been reported.

The purpose of this study was to investigate the value of CT spectral imaging in differentiating sarcoidosis from Hodgkin’s lymphoma based on mediastinal enlarged lymph node.

2. Materials and methods 2.1. Patients and setting

This retrospective study was approved by Tangshan People’s Hospital Institutional Ethics Committee and all patients provided written informed consent. From January 2018 to August 2020, 21 patients [9 males, 12 females; median age 41.2 (27–65 years)] with untreated sarcoidosis and 39 patients [18 males, 21 females; median age 37.8 (17–62 years)] with untreated Hodgkin’s lymphoma who had undergone non-enhanced CT and dual-phase contrast-enhanced CT in dual-energy spectral mode were enrolled at the CT department, Tangshan People’s Hospital; all the patients were confirmed histologically by bronchoscopic biopsy, surgical biopsy or transthoracic needle aspiration biopsy.

2.2. CT examination

All patients underwent chest contrast-enhanced CT examination craniocaudally in the supine position on GE Discovery CT750 HD spiral CT, including unenhanced and biphasic enhanced scanning. Unenhanced scanning was performed in conventional helical mode and the main scanning parameters were tube voltage 120 kVp, helical pitch 1.375, smart tube current 100 to 500 mA and rotation time 0.7 seconds, respectively. And then, 80 to 100 mL nonionic contrast medium (350 mg iodine mL−1) was injected using a high-pressure injector via antecubital venous at an injection rate of 3.5 mL/second during enhanced scanning, which includes arterial phase (AP) and venous phase (VP). The AP scan started at 25 second after injection of contrast agent, and then the VP scan was performed at an interval of 30 second. The biphasic enhanced scanning was performed in spectral imaging mode. During a single rotation, the fast tube voltage on adjacent views was switched between 80 and 140 kVp. The main scanning parameters were tube current 275 mA, helical pitch 1.375, collimation thickness 1.25 mm, rotation speed 0.7 second and reconstructional standard 30% adaptive statistical iterative reconstruction.

2.3. Criteria and anatomic distribution of mediastinal enlarged lymph nodes

The criterion for significant enlargement of mediastinal lymph nodes was considered to be a short axis dimension ≥10 mm for all zones except for subcarinal lymph nodes (zone 7) were a measurement ≥12 mm was used. For axillary, internal mammary, peridiaphragmatic and retrocrural lymph nodes, short axis cut off points ≥10 mm, 5 mm, 5 mm and 6 mm were used respectively. According to Association for the Study of Lung Cancer,[19] mediastinal lymph nodes were divided into 10 zones. The aforementioned zones were as follows: 1 (low cervical, supraclavicular and sternal notch), 2R (right upper paratracheal), 2L (left upper paratracheal), 3 (prevascular and retrotracheal), 4R (right lower paratracheal), 4L (left lower paratracheal), 5 (subaortic), 6 (paraaortic), 7 (subcarinal), 8 (paraesophageal), 9 (pulmonary ligament), 10R (right hilar), and 10L (left hilar).

2.4. Quantitative analysis

All the measurements were performed on an advanced workstation (AW4.6, Discovery CT 750 HD, GE Healthcare) with the gemstone spectral imaging viewer. Circular regions of interests (ROI) with an area of approximately 20 mm2 were marked on the enlarged lymph node and aorta, with a default of 70 keV for monochromatic images. The ROIs encompassed as much of the high-enhancing areas of the enlarged lymph node as possible. Areas of focal change, such as necrosis, calcification, and large vessels, were carefully avoided. To ensure consistency, all measurements were performed 3 times at different image levels, and the average values were calculated. For all measurements, the size, shape and position of the ROIs were kept consistent between the phases by applying the copy-paste function. The gemstone spectral imaging viewer software package automatically calculated the monochromatic CT values and iodine (water) concentrations for the enlarged lymph node and aorta. Two recently introduced parameters were derived from the iodine concentration (IC) measurements and monochromatic images: NIC, calculated as NIC = IC enlarged lymph node/IC aorta, ICs in the lesions were normalized to those of the aorta in order to minimize variations in patients; HU curve slop (λHU), calculated as λHU = (CT value on 40 keV-CT value on 140 keV)/100.

2.5. Qualitative analysis

Two radiologists who were blinded to the diagnosis of the lesion qualitatively reviewed the CT images in consensus at a workstation. For each patient, characteristics of the enlarged lymph nodes were recorded, including anatomic distribution, border, coalescence, calcification, necrosis, compression, enhancement patterns and degree on 70 keV monochromatic images. The enhancement degree was described as mild-moderate or moderate-severe when the CT value increased by <25 hounsfield units (HU) or >25 HU, respectively. The changes in enhancement pattern between the phases were characterized as gradualness or persistent. Gradualness was defined as a change from low attenuation during the AP to high attenuation during the VP, and persistent was defined as the high attenuation during the AP already and the attenuation during the VP is similar to AP.

2.6. Statistical analysis

The datas were analyzed using SPSS v. 22.0. The 2-sample t test was performed to compare the quantitative parameters of normalized iodine concentrations (NICs), λHU, and the monochromatic CT values between sarcoidosis and Hodgkin’s lymphoma, The differences in anatomical distribution and morphological patterns of mediastinal lymph nodes between sarcoidosis and Hodgkin’s lymphoma were compared with a chi-square test, P < .05 was considered statistically significant. The sensitivity (correct diagnosis of Hodgkin’s lymphomas) and specificity (correct diagnosis of sarcoidosis) of the individual phase were evaluated. The alternative hypothesis was the area under the receiver operating characteristic curve > 0.5.

3. Results 3.1. Quantitative image analysis

Values for the quantitative parameters measured in the patients with Hodgkin’s lymphoma and in those with sarcoidosis are compared in Table 1. The CT values on 40 to 100 keV monochromatic images during the AP, the CT values on 40 to 50 keV monochromatic images during the VP, NICs in AP, λHU-AP and λHU-VP were all lower in Hodgkin’s lymphoma than those in sarcoidosis, and the differences were all statistically significant (P < .05), especially. The monochromatic CT value on 40 keV in AP (mean CT value, 99.54 ± 13.02 HU vs 142.135 ± 25.65 HU; P = .000) (Fig. 1a); The NICs during the AP (mean NIC, 0.13 ± 0.01 mg mL − 1 vs 0.15 ± 0.03 mg mL−1; P = .011) (Fig. 1b); The λHU during the AP (mean λHU-AP, 0.69 ± 0.13 vs 1.09 ± 0.27, P = .000) (Fig. 1c). Two example set of images in a patient with sarcoidosis is shown in Figure 2 and a patient with Hodgkin’s lymphoma in Figure 3.

Table 1 - Quantitative assessment of sarcoidosis and Hodgkin’s lymphoma based on mediastinal enlarged lymph node at CT spectral imaging. Parameter Mediastinal enlarged lymph node of Hodgkin’s lymphoma Mediastinal enlarged lymph node of sarcoidosis t value P value Water concentration(AP) 1028.43 ± 6.40 1032.03 ± 8.73 −1.827 .073 Monochromatic CT value-40 keV(AP) 99.54 ± 13.02 142.13 ± 25.65 −7.131 .000 Monochromatic CT value-50 keV(AP) 76.14 ± 11.88 104.51 ± 15.18 −7.993 .000 Monochromatic CT value-60 keV(AP) 65.36 ± 9.41 79.37 ± 12.45 −4.511 .000 Monochromatic CT value-70 keV(AP) 56.56 ± 6.57 61.35 ± 7.40 −2.576 .013 Monochromatic CT value-80 keV(AP) 45.65 ± 5.59 51.30 ± 5.80 −3.684 .001 Monochromatic CT value-90 keV(AP) 41.04 ± 4.54 45.30 ± 4.28 −3.531 .001 Monochromatic CT value-100 keV(AP) 37.53 ± 3.82 41.15 ± 4.19 −3.378 .001 Monochromatic CT value-110 keV(AP) 36.39 ± 3.76 37.48 ± 3.71 −1.079 .285 Monochromatic CT value-120 keV(AP) 34.33 ± 3.65 36.04 ± 4.89 −1.528 .132 Monochromatic CT value-130 keV(AP) 32.31 ± 3.91 34.49 ± 4.86 −1.895 .063 Monochromatic CT value-140 keV(AP) 31.04 ± 3.89 32.96 ± 5.36 −1.596 .116 NIC (AP) 0.13 ± 0.01 0.15 ± 0.03 −2.784 .011 λHU (AP) 0.69 ± 0.13 1.09 ± 0.27 −7.875 .000 Water concentration (VP) 1032.06 ± 5.61 1036.11 ± 13.28 −1.657 .103 Monochromatic CT value-40 keV(VP) 153.29 ± 9.89 162.47 ± 16.02 −2.392 .024 Monochromatic CT value-50 keV(VP) 111.71 ± 7.09 117.89 ± 11.87 −2.185 .037 Monochromatic CT value-60 keV(VP) 89.77 ± 6.47 88.01 ± 9.24 0.778 .442 Monochromatic CT value-70 keV(VP) 72.99 ± 4.84 72.29 ± 6.74 0.420 .667 Monochromatic CT value-80 keV(VP) 62.89 ± 4.41 64.09 ± 5.45 −0.923 .360 Monochromatic CT value-90 keV(VP) 56.78 ± 4.38 57.83 ± 4.99 −0.849 .399 Monochromatic CT value-100 keV(VP) 51.65 ± 4.35 52.09 ± 5.49 −0.337 .737 Monochromatic CT value-110 keV(VP) 48.41 ± 4.34 48.83 ± 5.16 −0.339 .736 Monochromatic CT value-120 keV(VP) 45.51 ± 4.39 46.40 ± 5.12 −0.710 .481 Monochromatic CT value-130 keV(VP) 43.44 ± 4.31 44.45 ± 5.15 −0.803 .425 Monochromatic CT value-140 keV(VP) 41.69 ± 4.27 42.97 ± 5.10 −1.031 .307 NIC (VP) 0.40 ± 0.06 0.43 ± 0.07 −1.763 .083 λHU (VP) 1.11 ± 0.09 1.19 ± 0.14 −2.532 .014

With exception of t and P values, data are mean values ± standard deviations.

AP = arterial phase, λHU = HU curve slop, NIC = normalized iodine concentrations, VP = venous phase.


F1Figure 1.:

Stem-and leaf plots of (A) the monochromatic CT value on 40 keV in AP, (B) λHU during AP and (C) NIC during AP for sarcoidosis and Hodgkin’s lymphoma. AP = arterial phase, λHU = HU curve slop, NIC = normalized iodine concentration.

F2Figure 2.:

Transverse (a) monochromatic CT image obtained at 40-keV energy level a and (b) monochromatic CT image obtained at 100-keV energy level and (c) iodine-based material decomposition images obtained from spectral CT acquisition in 54-year-old female with sarcoidosis.

F3Figure 3.:

Transverse (a) monochromatic CT image obtained at 40-keV energy level and (b) monochromatic CT image obtained at 100-keV energy level and (c) iodine-based material decomposition images obtained from spectral CT acquisition in 54-year-old male with Hodgkin’s lymphoma.

The area under the receiver operating characteristic curves for all parameters (Fig. 4) can be used to differentiate between sarcoidosis and Hodgkin’s lymphoma, especially the curve of the monochromatic CT value on 40 keV during the AP (0.912).

F4Figure 4.:

ROC curves for the monochromatic CT value on 40 keV in AP (and VP), NIC during the AP and λHU during the AP (and VP) in differentiating sarcoidosis from Hodgkin’s lymphoma based on mediastinal enlarged lymph node. AP = arterial phase, λHU = HU curve slop, NIC = normalized iodine concentration, ROC = receiver operating characteristic curve, VP = venous phase.

By using the receiver operating characteristic curve, we determined the parameter threshold values required to optimize both the sensitivity and specificity for differentiating between sarcoidosis and Hodgkin’s lymphoma (Table 2). For example, during the AP, a threshold monochromatic CT value on 40 keV of 139.89 would yield a sensitivity and specificity of 71.4% (28 of 39 Hodgkin’s lymphoma) and 100% (21 of 21 sarcoidosis), respectively. However, during the VP, the thresholds λHU of 1.11 would increase the sensitivity to 81.0% (32 of 39 Hodgkin’s lymphomas) but decrease the specificity to 56.4% (12 of 21 sarcoidosis).

Table 2 - Thresholds, sensitivities, and specificities for distinguishing sarcoidosis from Hodgkin’s lymphoma based on mediastinal enlarged lymph node. Parameter AUC Threshold Sensitivity Specificity CT value-40 keV-AP 0.912 139.89 71.4% (28) 100% (21) CT value-40 keV-VP 0.653 167.26 52.4% (20) 92.3% (19) NIC-AP 0.746 0.14 57.1% (23) 92.3% (19) λHU-AP 0.871 1.10 71.4% (28) 98.7% (20) λHU-VP 0.689 1.11 81.0% (32) 56.4% (12)

Sensitivity values are cited as percentages. Data in parentheses are numbers of Hodgkin’s lymphoma (n = 39) used to calculate percentages. Specificity values are cited as percentages. Data in parentheses are numbers of sarcoidosis (n = 21) used to calculate percentages.

AP = arterial phase, AUC = area under the curve, λHU = HU curve slop, NICs = normalized iodine concentrations, VP = venous phase.


3.2. Qualitative image analysis

The results of the qualitative analysis of 70 keV monochromatic images are provided in Table 3. The anatomic distribution, coalescence, calcification, compression, enhancement patterns and degree differed between sarcoidosis and Hodgkin’s lymphoma based on mediastinal enlarged lymph node (P < .05). The border and necrosis between the 2 groups were similar (P > .05).

Table 3 - Qualitative CT assessment of mediastinal enlarged lymph node between 2 groups. CT signs Sarcoidosis (21) Hodgkin’s Lymphoma (39) χ 2 value P value n % n % Anatomic distribution 1 7 33.3 25 64.1 5.192 .023 2 16 76.2 30 76.9 0.004 .949 3 8 38.1 28 71.8 6.459 .011 4 19 90.5 31 79.5 1.569 .210 5 15 71.4 25 64.1 0.330 .566 6 11 52.4 21 53.8 0.012 .914 7 16 76.2 28 71.8 0.135 .713 8 7 33.3 12 30.8 0.041 .839 9 3 14.2 4 10.3 0.215 .643 10* 19 90.5 26 66.7 4.127 .042  10R 2 9.5 8 20.5 1.187 .276  10L 0 0.0 8 20.5 4.970 .026  10B 17 81.0 10 25.7 16.873 .000 Axillary 1 4.8 11 28.2 4.689 .030 Peridiaphracgmatic 1 4.8 9 23.1 3.297 .069 Internal mammary 2 9.5 11 28.2 2.807 .094 Retrocrural 0 0.0 6 15.4 3.590 .058 Border Clear 20 95.2 35 89.7 0.539 .463 Fuzzy 1 4.8 4 10.3 Coalescence Yes 1 4.8 29 74.4 26.447 .000 No 20 95.2 10 25.6 Calcification Yes 5 23.8 1 2.6 6.846 .009 No 16 76.2 38 97.4 Necrosis Yes 0 0 3 7.7 1.700 .192 No 21 100 36 92.3 compression Yes 1 4.8 19 48.7 11.868 .001 No 20 95.2 20 51.3 Enhancement pattern Mild-moderate 5 23.8 27 69.2 11.315 .001 Moderate-severe 16 76.2 12 30.8 Enhancement degree Gradualness 2 9.5 30 76.9 24.914 .000 Persistent 19 90.5 9 23.1

*10R (Right unilateral hilar), 10L (Left unilateral hilar), 10B (Bilateral hilar); according to the International Association for the Study of Lung Cancer lymph node map.


4. Discussion

Sarcoidosis is one of the most important lung diseases, mainly manifested as mediastinal lymph node enlargement, with a typical pattern of involvement, including the bilateral hilar and right paratracheal zones.[20] However, this mode of participation is not specific and can be found in Hodgkin’s lymphoma, especially the nodularsclerosis type.[21,22] In addition, parenchymal presentations and the age at onset of both also overlap. Moreover, the treatments of sarcoidosis and Hodgkin’s lymphoma are very different. Therefore, it is of great significance to correctly differentiate lymphoma from sarcoidosis before operation.

CT is the most preferred imaging method for assessing sarcoidosis and can help differential diagnosis of sarcoidosis and other mediastinal abnormalities based on mediastinal enlarged lymph node.[23] Previous study[11] has discussed the important role of CT in the diagnosis of sarcoidosis and Hodgkin’s lymphoma based on mediastinal enlarged lymph node. However, it mainly focused on the qualitative analysis of the imaging characteristics of enlarged lymph nodes, rather than quantitative analysis.

The photon-integrating detector was used by traditional X-ray CT system to collect photons in the entire X-ray spectrum, ignoring the spectral response of the material. Therefore, for biological soft tissues, conventional CT usually does not have high enough contrast resolution.[24–26] But the monochromatic images generated by spectral CT describes the appearance of the imaging object if the X-ray source only generates single energy X-ray photons. The attenuation of different tissues varies with the change of X-ray energy. Lower monochromatic energy can improve the image density resolution and help to display the lesions. According to our study results, based on mediastinal enlarged lymph node, the CT values on 40 to 100 keV monochromatic images in AP and 40 to 50 keV in VP were higher in sarcoidosis than those in Hodgkin’s lymphoma, which confirms that lower monochromatic energy can improve contrast resolution for lesions.

The IC of the lesions obtained from the decomposition images of iodine-based materials is quantitative, so it may be a useful parameter.[24] NIC is the indirect reflection of the iodine content in the lesion, wh

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