Intravenous ultrasound contrast agents versus other imaging methods in pediatric patients with neoplastic diseases - a comparison.

The lack of registration of ultrasound contrast agents for use in patients below the age of 18 is a significant limitation of their usage. Despite this, examinations with the use of contrast agents are conducted in numerous centers, mainly as part of the diagnostic process of vesicoureteral reflux. Examinations after an intravenous administration of contrast agents are conducted rarely. The reason for this is not only the lack of registration, but also the lack of studies on their safety profile in paediatric patients or no guidelines concerning the dosage. It seems that imaging with the use of such agents could help solve certain clinical problems when other diagnostic methods fail. The paper presents selected cases of pediatric patients treated in oncological departments, in whom the examination with the use of ultrasound contrast agents had a considerable influence on the diagnostic and therapeutic process.

Introduction

Modern imaging techniques, which have developed intensively in the recent years, have changed the procedure in the diagnostic process of neoplastic diseases. Physicians who diagnose pediatric patients with suspected neo-plasms expect not only a fast assessment of their extensiveness, but also require more and more accurate differential diagnoses. This is why, the advancement of diagnostic methods, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) or ultrasonography (US), not only aims at improving the differentiation between morphological details, but also leads to monitoring tissue functions by assessing the microcirculation or even processes occurring at the cellular level.

The CT perfusion scanning enables a quantitative and qualitative assessment of blood flow within the examined region. However, due to a very large dose of radiation, this technique is limited to certain organs and is not currently used in pediatric patients.

The diffusion MRI and MR spectroscopy are highly promising. Nevertheless, a significant element which limits their usage in the pediatric population is a long duration of the examination which is conducted in a specified position. This entails sedating the youngest patients.

The PET/CT, a method based on ionizing radiation, is an expensive one. The image obtained in this examination is the effect of visualizing the metabolism of fluorinated deoxyglucose. A significant limitation of this method in the pediatric population is its low usefulness in imaging proliferative lesions with low glucose metabolic rate(, but also the necessity to sedate patients and the presence of ionizing radiation.

The most “children-friendly” technique is sonography. Following the introduction of the second-generation ultra-sound contrast agents (UCAs), it became possible to assess vascularity of proliferative lesions in real-time. In adult patients, the position of the UCAs is well-established. In numerous cases, contrast-enhanced ultrasound examination (CEUS) is the last stage of the diagnostic procedure, particularly in the case of focal lesions of the liver(. Due to the off-licence use of the UCAs available on the market in patients below 18 years old, the possibilities of their diagnostic application in the pediatric population are considerably limited(.

Below, based on four medical cases, we present various aspects of using the second-generation UCAs for the assessment of proliferative lesions in pediatric patients.

Case 1

A 5-year-old boy was admitted to hospital with a pathological mass in the right lumbar region. Following a contrast-enhanced US examination, the diagnosis of Wilms tumor was established (fig. 1A) and later confirmed in a CT examination. Four weeks after the initiation of chemotherapy, a follow-up CEUS examination was performed. It was observed that the lesion decreased in size and its vascularity reduced considerably (fig. 1B).

Fig. 1

Nephroblastoma in a 3-year-old boy: A. examination prior to chemotherapy – a strong enhancement of the lesion 17 seconds after the administration of the UCA (arrows); B. examination after the first cycle of chemotherapy – 17 seconds after the UCA administration, a considerably weaker enhancement is observed (arrows) by comparison with the fig. 1A

Comment

In the case of solid lesions in adult patients, the radiological measure of response to treatment is the RECIST scale (response evaluation criteria in solid tumors)(. One of the main response markers in this classification is the assessment of tumor size during treatment. However, the limitations of these criteria are commonly known. We know that the response to treatment may lead to a transient increase in the tumor size. Such an enlargement may be caused by the appearance of fluid spaces as well as by the consequences of bleeding into the lesion. As of today, the RECIST criteria have not been introduced as a means to assess the response to treatment of solid tumors in pediatric patients. This mainly results from the lack of randomized trials among the pediatric population and from the aforementioned limitations(.

In the case presented above, the UCA enabled the assessment of not only the size, but also vascularity of the lesion which underwent a visible reduction in response to the treatment (fig. 1A, B). Perhaps in the future, thanks to the simultaneous assessment of the size and vascularity in a CEUS examination, it will be possible to determine new criteria of the response to treating solid tumor in pediatric patients. This would eliminate the RECIST scale limitations, reduce exposure to ionizing radiation and make it possible to avoid potential sedation of patients for a CT/MRI scan.

Case 2

One year after the therapy for non-Hodgkin lymphoma (NHL), a 14-year old girl was admitted to hospital with severe pain in the left umbilical region. The first examination performed on the day of admission was a US examination. It revealed an area with low echogenicity in the lower pole of the left kidney which was difficult to interpret (fig. 2A) and enlarged lymph nodes with low echogenicity in the region of the axillary fossae and mediastinum (fig. 3A). A contrast-enhanced ultrasound examination was conducted. The UCA was administered twice to assess the mediastinal lymph nodes and the kidney. The examination of the kidney revealed an area of vascularity that was different from the remaining parenchyma (fig. 2B). The course of vessels was not typical of those in the kidney. Moreover, fast contrast washout in this region drew the examiner's attention (fig. 2C, D). Within the mediastinal lymph nodes, intensive enhancement with a subsequent fast contrast washout was observed (fig. 3B–D). Based on a similar behavior of the contrast agent in the kidney and in the examined lymph nodes, the diagnosis of a relapse of NHL and renal involvement was diagnosed.

Fig. 2

Area with low echogenicity in the lower pole of the left kidney (arrows): A. lesion in the lower pole of the kidney in a power Doppler examination (arrows); B. area of intense enhancement visible 4 seconds after the administration of the UCA; the lesion undergoes enhancement earlier than the remaining renal parenchyma (arrows); C, D. area in the lower pole of the kidney with a visibly faster washout than in the remaining renal parenchyma (arrows)

Fig. 3

Nodal lesions within the anterior mediastinum (arrows): A. enlarged lymph nodes within the anterior mediastinum in grey scale; B–D. fast inflow and outflow of the UCA in the nodal lesions; the dynamics of the UCA distribution resembles the lesion of the kidney

In this case, the contrast agent was administered twice. During its first administration, its distribution within the altered area of the left kidney was assessed. After 6 minutes, the UCA was administered again, this time for the assessment of the nodal package within the mediastinum. The key aspect in the assessment was the observation of similar UCA inflow and outflow times in both observed regions. It was therefore decided that the lesions are similar in etiology and based on a previous diagnosis, a relapse of NHL was identified.

Case 3

A focal lesion within the liver was detected in a 16-year-old girl with Nijmegen breakage syndrome (NBS). In the conclusion of the MRI examination, a benign lesion was suspected: angioma or focal nodular hyperplasia (FNH) of the liver. It was stated, however, that a malignant character of the lesion cannot be absolutely ruled out. The diagnostic process was extended to include biopsy which revealed the presence of cells typical of normal hepatic parenchyma. Due to ambiguous findings and oncological concern, a CEUS examination was conducted. The analysis of the examination revealed a typical vascular pattern of focal nodular hyperplasia of the liver (fig. 4A–F).

Fig. 4

Focal lesion of the liver (arrows): A–E. typical centrifugal enhancement of the lesion and faster contrast washout in the delayed phase (arrows); F. grey-scale image with its size

In the case of hepatic lesions, contrast-enhanced sonography is characterized with high sensitivity and specificity, which was proven by numerous studies in the adult population(. A part of these studies, as with the assessment of hepatic focal lesions, may be also interpreted with respect to the pediatric population (particularly to older children).

The syndromes associated with chromosome breakage constitute a contraindication to examinations and procedures with X-rays since they intensify chromosome breakage processes. In such a group of patients, the examination of lesions in parenchymal organs with the use of the UCA may be equivalent or complementary to MRI.

Case 4

A 13-year-old boy underwent a US examination in the regional health care center due to a persisting abdominal pain. The examination revealed a focal lesion in the spleen with unclear etiology (no trauma in the interview). On admission to the oncology department, the examination was repeated. It revealed an isoechoic and round lesion with the size of 23 × 21 mm. An anechoic rim was visible around the lesion, and within it, an area of lower echogenicity was observed. A color Doppler examination showed no signs of flow (fig. 5A). A contrast-enhanced examination was conducted on the same day and revealed a lesion which showed peripheral enhancement that was slightly slower than in the adjacent splenic tissue. The contrast washout from the lesion was moderately fast by comparison with the splenic parenchyma (fig. 5B). Based on the contrast-enhanced examination, it was not possible to unequivocally determine the character of the lesion, but the specificity of the contrast inflow and outflow was typical of benign lesions. CT and MRI also failed to unambiguously determine the character of the lesion. It is currently being monitored with the use of contrast-enhanced sonography; its size and morphology do not change.

Fig. 5

Lesion of the spleen: A. lesion of the spleen in a color Doppler examination (arrows) – see the text for a detailed description; B. lesion of the spleen in the first minute after administration of the UCA (arrows)

It is not always possible to establish an accurate diagnosis using imaging methods. Sometimes, it is sufficient to determine the character of a proliferative lesion to decide about further actions, e.g. monitoring, biopsy or surgical procedure. The possibility to conduct a CEUS examination shortly after the admission or at the patient's bedside, without the necessity to transport the patient, makes it possible to quickly determine the character of the lesion in the majority of cases. Undoubtedly, this is very helpful for the attending physician as well as for the patients and their families.

It is essential to reduce potential complications which may follow the administration of iodine contrast agents for CT or take place during sedation. The shortening of the diagnostic path with the possibility to reduce the number of procedures with ionizing radiation and general sedation are also significant.

Discussion

The low number of publications concerning the administration of the UCAs to pediatric patients, which indirectly results from the limitations of the off-license use, does not enable a reliable assessment of the benefits that such agents carry. However, in the currently available publications, the authors of which administered the UCA to patients below the age of 18, no adverse reactions were noted after their intravenous administration(. The off-license use of medicines is not only permitted, but also common in the majority of European countries. Such a use must, however, be justified(. It is important that the benefits of such a use outweigh the potential risks and that their medicinal properties are proven in a reliable and credible way. The situation is similar in the case of the UCAs. Firstly, it needs to be indicated which groups of pediatric patients will benefit from their use. It appears that these patients are:

patients in whom unambiguous diagnosis cannot be established on the basis of MRI and CT;

patients at risk of repeated follow-up examinations with the use of ionizing radiation after the treatment;

patients with absolute contraindications to examinations using ionizing radiation;

patients with lesions which may be diagnosed in CEUS examinations without the need to conduct a CT scan.

Secondly, it must be determined which organs should be examined by means of contrast-enhanced sonography for the best diagnostic effect. What is more, the sensitivity and specificity of this method should be as high as in the case of CT and MRI. In order to address these issues, it is necessary to analyze a large number of patients examined with the use of the intravenous UCAs, which is feasible only when multicenter studies are conducted. Data collected this way will allow the guidelines for the use of second generation contrast agents to be specified and their genuine safety profile to be determined.