Multimodality high-frequency ultrasound in the evaluation of cervical malignant lymphoma before biopsy

ABSTRACT

Objective

To investigate the application value of multimodality ultrasound in the evaluation of lymphoma.

Methods

The regression models were performed to determine whether there were differences in differentiating lymphoma from benign lymph nodes. Receiver operator curves were drawn to evaluate the diagnostic performance of three ultrasound modalities.

Results

Multivariate analysis showed statistically significant differences in the long to short axes ratio, visibility of the hilum, Adler grade of blood flow, cortical echo, maximum elasticity, elastic color pattern, enhancement distribution, and Area. The combination of three modalities achieved a sensitivity of 95.6%, specificity of 87.5%, accuracy of 93.5%, positive predicted value of 97.0%, and negative predicted value of 82.4%.

Conclusion

Multimodal ultrasound can provide valuable differential diagnosis and improve the diagnostic performance.

1. Introduction

Malignant lymphomas account for approximately 5% of malignant neoplasms in the head and neck region, [1,2] and some patients usually come to see a doctor because of swollen lymph nodes in the neck. Malignant lymphoma exhibits significant morphological, immunophenotypic, genetic, and clinical heterogeneity, and some cases are refractory or prone to relapse, which has a poor prognosis, and high fatality rate [3,4]. Therefore, timely diagnosis is pivotal for subsequent therapeutic management of lymphoma. Conventional ultrasound(US)plays a crucial role in lymphadenopathy, this approach enables the assessment of lymph node size, morphology, internal architecture (including the absence of hilar architecture, the presence of intranodal necrosis, and calcification), as well as the vascular pattern [5,6]. The existing literature indicates that certain morphological features of cervical lymph nodes, such as a long-to-short axis ratio (L/S) of less than 2, the presence of an anechoic hilum, and uneven echotexture, can serve as discriminating factors between benign and malignant lymphadenopathies [7,8]. However, some studies have reported that conventional ultrasound (US) demonstrates a sensitivity and specificity for distinguishing between benign and malignant lymph nodes that varies from 78% to 96% and 76% to 98%, respectively [9,10]. Malignant lymphoma and benign lymph node diseases are prone to overlap in conventional ultrasound images, especially in cervical lymph nodes. This implies that the prevalence of false-positive outcomes is substantial enough to frequently warrant biopsy, consequently leading to a considerable number of unnecessary biopsies being conducted [11], which, in turn, results in some complications, such as hematoma, bleeding, pain, and so on. Therefore, we try to find a new auxiliary diagnostic method based on conventional US, aiming to enhance diagnostic precision and ensure the precise targeting of biopsy sites.

In recent years, the concept of multimodal ultrasound has become a hot topic, which can provide more diagnostic information for clinicians. Shear-wave elastography (SWE) provides a quantitative assessment of lymph node stiffness and texture, circumventing the limitations associated with strain elastography and theoretically mitigating operator-dependent variability [9]. Malignant lymph nodes exhibit significantly elevated tissue stiffness compared to benign counterparts, as indicated by studies demonstrating increased elasticity and shear wave velocities in the former [12,13]. Contrast-enhanced ultrasonography (CEUS), utilizing an intravenous contrast medium, is a noninvasive imaging modality capable of visualizing the microvascular perfusion within lymph nodes and detecting blood vessels with diameters less than 100 μm or those characterized by low flow velocities. CEUS has demonstrated its distinctive utility in the diagnostic assessment of lymphoma. Previous studies show that CEUS has a good effect on the diagnosis and curative effect evaluation of superficial lymph nodes [14,15]. The pathophysiological basis of different lymphadenopathy varies. Due to the formation of neovascularization, tumor tissue shows a unique pattern of microcirculation. Thus, employing CEUS to elucidate the microcirculatory perfusion significantly enhances the ultrasound’s capacity to differentiate between benign and malignant lymph nodes, aiding in the determination of biopsy necessity [16].

This study aims to provide a basis for accurate localization before biopsy by comparing the differences between benign lymph nodes and lymphoma through multimodal ultrasound, so as to avoid unnecessary biopsy and complications and contribute to more precise and individualized treatment measures for lymphoma.

2. Materials and methods

2.1. Patients

This is a retrospective study including 203 patients with cervical enlarged lymph nodes in our department between October 2020 and June 2022. Inclusion criteria: Lymph nodes exhibiting one or more radiographic abnormalities, including a rounded morphology, absence of a hilum, hypoechoic uniformity, marginal irregularities, and peripheral vascular signals; Patients confirmed by pathology; ③Patients diagnosed for the first time with lymphoma and no other treatment was given. ④All enrolled patients voluntarily underwent the necessary examinations and provided written informed consent. Exclusion criteria: Patients treated at external medical facilities or those who experienced relapse (n = 18); Patients lacking comprehensive ultrasound and clinical data (n = 15). Finally, 136 malignant lymphoma and 34 benign lymph nodes from 170 patients who had undergone US, SWE, and CEUS prior to biopsy. To minimize operator-dependence of US, one experienced radiologist conducted the examination according to standardized institutional protocols and recorded the images. Another two radiologists in our team independently reviewed all ultrasonic images, and if the two radiologists disagreed on the conclusion of a case, the case was ruled out.

The study protocol was granted approval by the Institutional Review Board (IRB) of our hospital, with ethical number 2022-SR-058. Written informed consent was secured from all participants enrolled in the study.

2.2. Ultrasound examination

A Supersonic Aixplorer ultrasound (Aixplorer®, SuperSonic Imagine, Aix-en-Provence, France) was employed in conventional US, with a 4–15 MHz (SuperLinear™ SL15–4) linear probe. The subsequent lymph node parameters were meticulously documented: size and the long-to-short axis ratio (L/S), shape, cortical echo, visibility of the hilum, boundary, presence of fusion tendency, blood flow pattern, Adler grade of blood flow [17]. The specific classification criteria refer to supplementary material 1.

2.3. SWE

SWE uses the same instrument and the same examination conditions as conventional US. The elastogram was concurrently presented alongside the grayscale sonograms in real time on the display, ensuring precise delineation of the region of interest (ROI). The operator froze the images and manually sketched the entire outline of the lesion as the ROI. The measurements for each lesion were repeated three times and averaged, and such parameters as elastic color pattern, mean elasticity (Mean-SWE, Kpa), and maximum elasticity (Max-SWE, Kpa) were recorded. All lesions were categorized using the four-color overlay pattern classification system proposed by Tozaki and Fukuma [18]. The specific Reference standard is shown in supplementary material 1.

2.4. CEUS

For the CEUS examination, a LogiqE9 ultrasound system (GE Healthcare, Milwaukee, WI, USA) equipped with a 15–4 MHz linear transducer (SuperLinear™ SL15–4) was utilized. The mechanical index (MI) was adjusted to 0.14. A mixture was prepared by combining 5 ml of 0.9% saline with the contrast agent (SonoVue, Bracco, Milan, Italy) and vigorously agitating it to create an emulsion containing micro-bubbles. Under real-time ultrasound contrast mode, 2.4 ml of the contrast agent was administered intravenously through the patient’s anterior elbow vein, followed by a flush of 5 ml of 0.9% sodium chloride solution. The real-time images were captured for a duration of 120 s, during which the patient’s well-being was closely monitored for any signs of discomfort.

2.5. CEUS imaging analysis

In the context of CEUS, the characteristics of lymphomas encompassed the patterns of enhancement, the boundaries of enhancement, the intensity of enhancement, and the distribution of enhancement. By means of the quantitative analysis software configured on the machine, a time intensity curve (TIC) was obtained. To reduce errors, the TIC of each lesion was depicted two times, and all quantitative indicators were averaged. Then, the relevant parameter values on the curve were recorded as follow: arrival time (AT), time to peak (TP), basic intensity (BI), peak intensity (PI), area under the curve (AUC), ascending slope (AS), washout time (washout-T), area under the TIC curve (Area) [11]. Supplementary material 1 showed the classification standard of CEUS.

2.6. Pathological acquisition

After the completion of multimodal ultrasound, 170 cases underwent ultrasound-guided core needle biopsy (CNB) or surgical excision biopsy (SEB) to obtain definite pathological results. SEB is not needed unless the results of CNB are uncertain.

2.7. Statistical analysis

Data analysis was conducted using SPSS software (version 25.0; IBM Corporation, NY, USA). Qualitative data were subjected to univariate analysis via chi-square tests, while quantitative parameters were evaluated using t-tests. Receiver operating characteristic (ROC) curves were constructed to determine diagnostic thresholds for the quantitative data obtained from shear-wave elastography (SWE) and CEUS. Variables that demonstrated statistical significance in the univariate analysis and a strong correlation with pathological findings were subsequently entered into a multivariate analysis using a binary logistic regression model. A p-value of ≤ 0.05 was set as the threshold for statistical significance. Inter-rater reliability was assessed using the intra-class correlation coefficient (ICC) for quantitative variables and the Kappa statistic for qualitative parameters. ICC values exceeding 0.75, indicative of near-perfect agreement, were selected for further analysis [19].

3. Results

3.1. ICC

The ICC and kappa values indicated an excellent level of inter-rater agreement (Table 1, in the supplementary material 1).

Table 1.

The multivariate analysis of high-frequency ultrasound between the lymphoma and benign lymph nodes.

Ultrasound-features	B	SE	P value	Exp(B)	95%CI limits
					Lower	upper
L/S	−2.315	0.742	0.002	0.099	0.023	0.422
Hilum	−1.205	0.568	0.034	0.300	0.099	0.912
Cortical echo	1.165	0.527	0.027	3.207	1.142	9.002
boundary	19.912	0.801	0.998	4.811	1.001	23.109
Adler grade of blood flow	1.351	0.342	0.000	3.860	1.974	7.574

L/S: the ratio of the longitudinal diameter to the short axis; Cortical echo: homogenous, reticulate, or striped appearance; Hilum: presence or absence of a central echogenicity – genic hilum in the lymph node; Adler grade of blood flow: grades 0–3; B: constant; SE: standard error; Exp(B): expected values; 95%CI limits: 95% confidence interval.

3.2. Clinical features

This study enrolled a total of 170 patients, comprising 136 cases of malignant lymphoma and 34 cases of benign lymph nodes. The malignant lymphoma group comprised 59 males and 77 females with a mean age of 56 ± 14 years (range, 16–88 years) and a mean longitudinal diameter of 31 ± 12 mm (range, 9–78 mm). The pathological diagnoses within this group were as follows: diffuse large B-cell lymphoma (DLBCL, n = 54), follicular lymphoma (FL, n = 20), marginal zone lymphoma (MZL, n = 12), Hodgkin’s lymphoma (HL, n = 16), and other rare types (n = 34). The benign lymph node group consisted of 31 males and 3 females with a mean age of 49 ± 14 years (range, 21–73 years) and a mean longitudinal diameter of 24 ± 8 mm (range, 10–39 mm) (Table 2, in the supplementary material 1).

Table 2.

The multivariate analysis of SWE results between the lymphoma and benign lymph nodes.

SWE-features	B	SE	P value	Exp(B)	95%CI limits
					Lower	Upper
Max-SWE	1.263	0.563	0.025	3.534	1.173	10.647
Elastic color pattern	1.268	0575	0.027	3.555	1.152	10.970
Mean-SWE	0.140	0.361	0.697	1.151	0.568	2.333

SWE: Shear-wave elastography; Max-SWE: maximum elasticity; B: constant; SE: standard error; Exp(B): expected values; 95%CI limits: 95% confidence interval.

3.3. Diagnostic performance of conventional US features

The univariate results showed that five ultrasonic characteristics were statistically significant between the lymphoma and benign lymph node. Table 1 details the outcomes of the multivariate analysis, revealing statistically significant disparities between the two groups in the long-to-short axis ratio (L/S, p = 0.002), presence of a hilum (p = 0.034), cortical echo intensity (p = 0.027), and Adler grading of blood flow (p < 0.001). The diagnostic threshold for the Adler grade of blood flow, as ascertained by the ROC curve, was identified at a value of 2. Lymphoma represented the following characteristics: L/S＜2, reticulate or striped cortical echo, absence of a central echogenicity – genic hilum, Adler grade of blood flow>2. The discriminatory ability of conventional ultrasound is good with an AUC of 0.875 (95% CI 0.819, 0.931). The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were determined to be 87.3%, 75.0%, 85.9%, 96.3%, and 44.1%, respectively.

3.4. Diagnostic performance of SWE features

The characteristics of elastic color pattern, Mean-SWE, and Max-SWE were found to be statistically significant between the lymphoma and benign lymph nodes in univariate analysis. The multivariate analysis outcomes indicated that the elastic color pattern (p = 0.027) and maximum shear-wave elastography (Max-SWE) values (p = 0.025) between the two groups were statistically significant. The receiver operating characteristic (ROC) curve analysis established a diagnostic threshold of 25.12 kPa for Max-SWE. The diagnostic performance of SWE was found to be moderate, with an area under the curve (AUC) of 0.772 (95% confidence interval, 0.660 to 0.885). The sensitivity, specificity, accuracy，PPV, and NPV are 89.3%, 51.3%, 80.6%, 86.0%, and 55.8%, respectively. Detailed information of the SWE features between two groups is demonstrated in Table 2.

3.5. Diagnostic performance of CEUS features

In the univariate analysis, the qualitative parameters of enhancement distribution and the quantitative parameters including PI, AS, and Area were statistically significant (p < 0.05) between lymphoma and benign lymph node. Table 3 showed the enhancement distribution (p = 0.017), and Area (p = 0.010) were statistically significant in the multivariate analysis. As a result, 60 (44.1%) patients with lymphoma appeared with centripetal enhancement, 44 (32.4%) cases of centrifugal enhancement, and 32 (23.5%) cases of mixed enhancement. The diagnostic efficiency of CEUS was moderate with an AUC of 0.783 (95% CI 0.663, 0.902). The sensitivity, specificity, accuracy, PPV, and NPV are 81.4%, 75.8%, 88.8%, 94.8%, and 64.7%, respectively.

Table 3.

The multivariate analysis of CEUS results between the lymphoma and benign lymph nodes.

CEUS-features	B	SE	P value	Exp(B)	95%CI limits
					Lower	upper
Enhancement distribution	0.433	0.181	0.017	1.514	1.082	2.196
PI	−0.063	0.046	0.171	0.939	0.857	1.028
AS	0.392	0.639	0.540	1.489	0.423	5.181
Area	0.010	0.004	0.010	1.010	1.002	1.017

CEUS: Contrast-enhanced ultrasonography; AS: ascending slops; Area: Area under the gamma curve; B: constant; SE: standard error; Exp(B): expected values; 95% CI limits: 95% confidence interval.

3.6. Diagnostic performance combined conventional US, SWE, and CEUS

The combination of the three methods has the highest diagnostic efficiency with an AUC of 0.933 (95% CI 0.878, 0.988). The sensitivity, specificity, accuracy, PPV, and NPV are 95.6%, 87.5%, 93.5%, 97.0%, and 82.4%, respectively (Figure 1). Figures 2 and 3 showed the application of multimodal ultrasound in differential diagnosis of lymphoma and benign lymph nodes. Table 4 showed the sensitivity, specificity, accuracy, PPV, and NPV of US, SWE, and CEUS in distinguishing DLBCL from benign lymph nodes.

Figure 1.

Receiver operating characteristic (ROC) curve for assessing the diagnostic value of different examination methods in differentiating lymphomas from benign lymph nodes，the area under the curve (AUC) of ultrasound (US), shear-wave elastography (SWE), and contrast-enhanced ultrasonography (CEUS) was 0.875, 0.772, 0.783 respectively. The AUC of ROC curve for the combination of three modalities was 0.933.

Figure 2.

A male, 56 years old, whose lymph node enlargement on the left side of the neck was found 1 month ago, underwent multimodal ultrasound imaging of lymphoma. A conventional showed enlarged lymph nodes in the left neck, the long-to-short axis ratio(l/s) >2, and cortical echo was reticulate. b the shear-wave elastography (SWE) showed maximum elasticity is 81.1 kpa. c the time intensity curve of contrast-enhanced ultrasonography (CEUS) showed area is 467,736. They met the criteria of multimodal ultrasonography for diagnosis of malignant lymph nodes, and the biopsy pathology showed diffuse large B-cell lymphoma (DLBCL).

Figure 3.

A male, 56 years old, lymph node enlargement on the right side of the neck was found 1 month ago, underwent multimodal ultrasound imaging of lymphoma. A conventional ultrasound showed enlarged lymph nodes in the right neck, the long-to-short axis ratio(L/S)>2, and cortical echo was homogeneous. b the shear-wave elastography (SWE) showed maximum elasticity is 24.3 kpa. c the time intensity curve of contrast-enhanced ultrasonography (CEUS) showed area is 285.913. They met the criteria of multimodal ultrasonography for diagnosis of lymphoma, the biopsy pathology showed lymphoid tissue hyperplasia.

Table 4.

Comparison of US, SWE, and CEUS in distinguishing DLBCL from benign lymph nodes.

Groups	Sensitivity	Specificity	Accuracy	PPV	NPV	AUC	95% CI limits
							Lower	upper
Conventional US	0.873	0.750	0.859	0.963	0.441	0.875	0.819	0.931
SWE	0.893	0.513	0.806	0.860	0.558	0.772	0.660	0.885
CEUS	0.814	0.758	0.888	0.948	0.647	0.783	0.663	0.902
US+CDFI+SWE+CEUS	0.956	0.875	0.935	0.970	0.824	0.933	0.878	0.988

US: ultrasound; CDFI: Color Doppler Flow Imaging; SWE: Shear-wave elastography; CEUS: Contrast-enhanced ultrasonography; B: constant; SE: standard error; Exp(B): expected values; 95%CI limits: 95% confidence interval.

3.7. Patients’ follow-up

For patients with malignant findings from multimodal ultrasound, we performed CNB or SEB; while for patients with negative ones from multimodal ultrasound, we should closely observe and follow-up with intervals of 1 month, 3 months, 6 months. If there are changes in the characteristics of multimodal ultrasound, further examination should be carried out timely. Figure 4 is the flow chart of the patient’s clinical treatment.

Figure 4.

The flow chart of the patient’s clinical treatment. For patients with malignant findings of multimodal ultrasound, we perform core needle biopsy (CNB) or surgical excision biopsy (SEB); for patients with negative multimodal ultrasound, we should closely observe and follow up, the interval is 1 month, 3 months, 6 months. If there are changes in the characteristics of multimodal ultrasound, further examination should be carried out in time.

4. Discussion

The present study found that multimodal high-frequency ultrasound held the optimal performance in preoperative diagnosing cervical malignant lymphoma and benign lymph nodes. Compared with conventional US, SWE, CEUS alone, multimodal ultrasound could improve the sensitivity, specificity, accuracy, PPV, and NPV of diagnosis, which could help to accurately select the target lymph nodes for biopsy.

In alignment with the current European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for lymphoma diagnosis, treatment, and follow-up, surgical excision SEB is considered the gold standard for diagnosing lymphoma [20,21]. The diagnostic utility of imaging-guided CNB in malignant lymphoma has been validated across numerous studies [22–25]. Comparative analysis revealed no significant difference in biopsy success rates between the CNB and SEB groups; however, the incidence of grade 3 complications was markedly lower in the CNB group compared to the SEB group.

A low L/T ratio, absence of echogenic hilus, reticular appearance, and higher blood flow have been determined to be significant indicators of malignancy in many studies [17,26], which were consistent with the results of our study, but their specificity (75.0%) and NPV (44.1%) were low. L/S is a dictator for diagnosing benign and malignant cervical lymph nodes. However, disparate studies have proposed a range of threshold values. A high threshold value is associated with reduced specificity and overall accuracy, while a lower threshold value enhances sensitivity but at the expense of specificity [26]. Historically, pseudocystic appearance was considered indicative of lymphomatous lymph nodes, yet with the advent of new-generation high-resolution transducers, a micronodular-reticular pattern has been observed, which is now recognized as a characteristic feature of lymphoma [5]. Rubaltelli et al. and Vassallo et al. [27] have documented that 84–92% of benign lymph nodes exhibit an echogenic hilum, in contrast to 76–96% of malignant lymph nodes where hilum echoes are notably absent. In the malignant lymphoma, the structure of the lymphatic hilum was eccentric or striped and even disappeared when it was under pressure, which was related to the progress of the disease. In the early stages of lymphoma, neoplastic lymphocytes proliferate locally without infiltrating the entire lymph node, preserving the hilum structure. Conversely, in advanced stages, these abnormal lymphocytes permeate the entire lymph node, leading to the obliteration of the lymphatic hilum architecture or its distortion into an eccentric, thin strip under pressure [28]. Malignant lymph nodes typically exhibit higher vascular density compared to benign nodes, with particularly aggressive lymphomas demonstrating elevated micro-vessel density (MVD), a feature that correlates with an unfavorable prognosis [29,30].

Elastography facilitates the measurement of tissue strain, thereby offering insights into tissue stiffness, independent of the lesion’s morphology, margin, or dimensions [31]. The majority of studies report a significant increase in tissue stiffness in malignant LNs compared to their benign counterparts [32,33]. A meta-analysis encompassing eight studies revealed that malignant nodes exhibit higher elasticity and faster wave speeds than benign ones. The pooled results of these studies suggest that shear-wave elastography (SWE) for the diagnosis of malignant cervical LNs possesses a composite sensitivity of 81% and a specificity of 85% [34]. The main reason is that lymphoma refers to the abnormal proliferation of many undifferentiated small lymphocytes and gradually spread to the entire lymph nodes. The abnormally proliferated lymphocytes are confined in the capsule of the lymph nodes, resulting in increased hardness in the lymph nodes and uneven distribution [35,36]. In the data center of this group, these indicators are consistent with previous studies. The multivariate analysis showed that there was significant difference in elastic color pattern and Max-SWE. Max-SWE values of malignant lymphomas were significantly elevated compared to those of benign lymph nodes. Lymphomas exhibited a localized, green-colored region at the lesion’s periphery (pattern 3) or presented with a heterogeneous color distribution within the lesion (pattern 4). Furthermore, benign lymphoid hyperplasia arises from a spectrum of acute and chronic inflammatory conditions. During acute inflammation, the lymph node architecture remains intact, the tissue is soft, and the elasticity grade is low. In contrast, in certain chronic inflammatory states, fibrotic changes within the nodules can result in an elevated elasticity grade [11,37]. These may explain why the false-positive rate of SWE in distinguishing lymphoma from benign lymph nodes in this study is 14.0%. Except for the above reasons, some structures of the neck, such as arteries, bones, trachea, and muscles, are hard, which can reduce the quality of elastic imaging and cause false positive, hence, we manually draw the whole lesion as a ROI (Figure 2b vs Figure 3b) to reduce errors.

CEUS delineates the microvascular architecture of lymph nodes, revealing that peripheral vascularity is infrequently observed in lymphomatous nodes, whereas a mixed vascular pattern is commonly encountered within these nodes. This may be related to the disease progression of lymphoma. In our study, the qualitative measures of enhancement distribution between lymphoma and benign lymphoma nodes have a statistically significant difference. A substantial proportion of malignant lymphomas, specifically 67.6%, exhibited centripetal or mixed enhancement patterns on contrast-enhanced ultrasound, aligning with the findings reported by Francesco et al. [38]. During the initial phases of the disease, lymphomatous involvement often originates within the lymph node parenchyma and may not extend to the subcapsular region. The structure of lymphatic hilum still exists, so the central blood flow can be observed. As the disease progresses, the lymphatic hilum structure disappears, neovascularization is formed, and peripheral blood flow or mixed blood flow occurs [39]. The quantitative indexes of contrast-enhanced ultrasound can also provide a certain value in distinguishing lymphoma from benign lymph nodes, such as AT, TP, PI, Δ I, AS, and Area. PI represents the maximum dose of contrast medium filled with ROI within a certain period. The larger the blood volume is, the more contrast media reach the area after vascular injection, and hence a higher PI. TP represents the time it takes for PI to reach its maximum intensity. Area is determined by the above two parameters: AS is the speed at which the contrast medium reaches its peak [40]. In this study, Multivariate analysis showed that parameters including Area were higher than that of benign lymph nodes, indicating that lymphoma has more abundant blood flow than benign lymph nodes. With the development of lymphoma, the degree of invasion and malignancy becomes higher and higher, which also means that the more abundant the tumor blood vessels are, the faster the blood flow velocity is [41]. Esen. et al. [42] investigation has revealed that in the advanced stages of malignancy, lymphoma cells stimulate the formation of neovascularization, a process that encompasses the destruction of the basement membrane and the migration, proliferation, and lumen formation of endothelial cells. At the same time, abnormal proliferation of lymphocytes can cause neovascularization and occlusion. Therefore, the tumor neovascularization may be narrowed and blocked, which may lead to the prolongation of AT and TP time of lymphoma. However, Yin et al. [43] observed no statistically significant differences in the acoustic texture (AT) between lymphomatous and reactive lymph nodes, a finding that underscores the need for more discriminative diagnostic markers.

In this study, six patients with lymphoma were misdiagnosed as benign lymph nodes, which is because these cases are lymph nodes with initial involvement by lymphoma, and it has been reported that there is no significant difference between early onset of lymphoma and benign lymph nodes in terms of morphological structure, elasticity, and blood flow. Therefore, for patients whose multimodal ultrasound results indicate a benign condition, we recommend close monitoring and regular follow-ups at intervals of 1 month, 3 months, and 6 months. In the follow-up observation, such symptoms appeared on these patients as L/S > 2, blood flow increased, Max-SWE>25.12Kpa. The Area of TIC>206.42, upon detecting these indicators, we performed a percutaneous CNB and pathologically confirmed the presence of lymphoma.

This investigation was conducted retrospectively and thus carries inherent limitations. Initially, the ultrasonographic characteristics of lymphoma were analyzed in a retrospective manner and compared with those of benign lymph nodes. However, the limited sample size precluded a detailed comparison across various lymphoma subtypes. We will continue to collect the multimodal ultrasound findings of each subtype of lymphoma and compare the subtypes. Second, PET-CT is the preferred diagnostic method for lymphoma. In the follow-up work, we should compare the diagnostic effectiveness of multimodal ultrasound and PET-CT.

5. Conclusion

In conclusion, multimodal ultrasonography offers enhanced diagnostic information for the differential diagnosis of enlarged lymph nodes, facilitating the preliminary differentiation between lymphomatous and benign lymph nodes and enabling precise localization for biopsy. Consequently, this approach can prevent unnecessary biopsies and associated complications, thereby facilitating more accurate and personalized therapeutic strategies for lymphoma.

Funding Statement

This paper was not funded.

Article highlights

• Heterogeneity and Prognosis of Malignant Lymphoma: Malignant lymphoma is characterized by significant heterogeneity, with certain cases exhibiting resistance to treatment or a high likelihood of relapse. These factors contribute to a poor prognosis and high mortality rates, underscoring the severity of the condition.

• Urgent Clinical Need for Early Identification: Identifying patients with malignant lymphoma at the earliest possible stage is a critical clinical challenge. Early detection allows for the implementation of personalized treatment plans and the accurate prediction of treatment efficacy and patient prognosis.

• Limitations of Conventional Ultrasound: While conventional ultrasound has been recognized as a significant indicator of malignancy, it suffers from low specificity and negative predictive value, limiting its effectiveness in diagnosing malignant lymphoma.

• Elastography for Tissue Stiffness Assessment: Elastography is a valuable diagnostic tool that assesses tissue strain, providing insights into the stiffness of the tissue composition. This information can be crucial in distinguishing between benign and malignant lymph nodes.

• Contrast-Enhanced Ultrasound for Microvessel Visualization: Contrast-enhanced ultrasound (CEUS) offers the ability to reveal microvessels within lymph nodes, which may correlate with the pathological type of the lymph nodes. This technique enhances the diagnostic capabilities beyond those of conventional ultrasound.

• Multimodal High-Frequency Ultrasound for Optimal Diagnosis: The study highlights that a multimodal approach using high-frequency ultrasound provides the best performance in the preoperative diagnosis of cervical malignant lymphoma and benign lymph nodes. This comprehensive method leverages various ultrasound techniques to achieve higher diagnostic accuracy.

• Biopsy Localization with Multimodal Ultrasound: Multimodal ultrasound can serve as a foundation for accurate localization before biopsy, ensuring that the most suspicious areas are targeted for tissue sampling.

• Avoiding Unnecessary Biopsies and Complications: By utilizing multimodal ultrasound before biopsy, unnecessary procedures and associated complications can be avoided. This approach also aids in formulating more rational treatment strategies tailored to the specific type of malignant lymphoma present.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethical declaration

The study protocol was granted approval by the Institutional Review Board (IRB) of our Jiangsu Province Hospital, with ethical number 2022-SR-058. Written informed consent was secured from all participants enrolled in the study.

Author contributions

Hongyan Deng and Kunpeng Cao contributed equally to this work and should be considered co-first authors. They were responsible for the conception and design of the study, acquisition of data, and drafting the initial manuscript.

Xinhua Ye is the corresponding author and played a significant role in the analysis and interpretation of the data. Dr Ye also provided critical revisions to the manuscript for important intellectual content. Wenjuan Lu and Wenqin Chen were involved in the collection and assembly of data, as well as the execution of the experiments. They also assisted in the analysis of the results.

Ya Yuan and Yasu Zhou contributed to the experimental design and provided technical support throughout the research process.

Hua Shu provided administrative, technical, and material support, ensuring the smooth operation of the research project.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2024.2430168.