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Ultrasound ‘microbubbles’ detecting breast cancer

Ali R Sever and Sue E Jones
17 June, 2011  

Dr Ali R Sever
Consultant Radiologist

Mrs Sue E Jones
Consultant Breast and Oncoplastic Surgeon,
Maidstone Breast Unit, Kent, UK

The introduction of breast screening, increased breast awareness and technological advances in breast imaging have led to the diagnosis of patients with smaller breast cancers. There has been a corresponding fall in the number of patients having axillary nodal involvement, with almost two-thirds presenting with an axilla free of tumour.1 Exposing all patients with invasive breast cancer to the complications associated with axillary lymph node dissection (ALND) is no longer justified.2

Sentinel lymph node biopsy (SLNB) has now become a standard staging procedure in breast cancer patients worldwide.3 Giuliano et al used this technique in early-stage breast cancer with blue dye only.4 Krag et al used radio-labelled colloid5 and Albertini et al6 were the first group to use a combination of blue dye and isotope-guided surgery. There have been previous studies published investigating other methods of finding the sentinel lymph node (SLN), but these methods never gained popularity.7,8

Well-accepted technique
Ultrasound (US) examination of the breast is a practical and well-accepted technique for both patients and healthcare providers. It has become an established imaging modality complementing mammography in the diagnoses of breast cancer. It gains its superiority not only because it provides visualisation of the breast abnormalities, but it also serves as practical tool in guiding biopsy of these lesions.

The use of contrast-enhanced US is well established in clinical practice; IV administration of contrast agents has provided enhanced imaging in many organ systems, particularly in the heart and liver. Ultrasound contrast agents are composed of tiny bubbles of an injectable gas in a supporting shell. These microbubbles are smaller than red blood cells and have a short lifetime (<10 minutes).9 In 2004, Goldberg et al10 published their results in a swine melanoma model, where microbubbles injected peritumourally were seen to enter lymphatic channels and SLNs were identified accurately by US in 90% of cases.

Futile tests
Since SLNB has developed into a routine practice in breast cancer treatment, US assessment of the axilla has also become an integral component of breast imaging. SLNB spares many women a full axillary lymph node dissection when the SLN is negative. However, if the sentinel node is positive, the patient has to return for a second surgical procedure to treat the involved axilla, which is called completion ALND. This is the group of patients where the SLNB procedure is accepted as futile. Pre-operative axillary US and biopsy of the abnormal looking lymph nodes may therefore help in selecting patients who truly will benefit the SLNB procedures.

Several papers in literature have described the abnormal features of axillary lymph nodes as an indicator of lymph node biopsy. These criteria are mainly: cortical thickening of more than 2mm, either diffuse or focal, especially if asymmetric, replacement of the fatty hilum and abnormal or increased peripheral rather than centripetal blood flow.11

In Maidstone Breast Unit, we are currently conducting a systemic review of 15 scientific articles that described the results of pre-operative axillary US in SLNB. This review has shown that pre-operative axillary US followed with biopsy of the abnormal axillary nodes is effective in reducing futile SLNB rates by 10%–15%. This review also demonstrated that completion ALND rates in these units are around 25%. Therefore conventional US, albeit effective, will miss some axillary nodal deposits so that one-in-four patients will require a second axillary procedure after SLNB.

Britton et al have pointed out the limitations of conventional axillary US and concluded the need for better methods of identifying, and more adequate sampling of the axillary nodes.12 In their series, completion ALND rate was 30% as the grey-scale US either failed to identify the abnormal nodes or indeed missed the malignant deposits in the biopsied nodes.

The Maidstone study
In 2008 in The Maidstone Breast Unit, a study was undertaken to assess the role of contrast enhanced US in patients prior to SLNB.13 Fifty-four consecutive, consenting patients with breast cancer who had primary surgical treatment were recruited into the study. Patients received between 0.2 and 0.5ml of ultrasound contrast agent injection (SonoVue; Bracco Imaging, Milan, Italy) by an experienced breast radiologist. Up to three consecutive injections were given intradermally in a similar position to the radioisotope and 
blue dye.

All subsequent US examinations were performed with an Acuson Sequoia 512 scanner (Siemens Medical Systems, Issaquah, Washington, USA), providing conventional grey-scale imaging, pulse-inversion harmonic grey-scale, contrast-specific sonographic imaging with live dual images of tissue only and contrast agent image (Cadence contrast pulse sequencing; Siemens). A high-frequency 14-MHz linear-array probe was used (15L8w).

To reduce microbubble destruction, low mechanical index values were applied (0.2–0.4). Lymphatic channels were visualised immediately on contrast pulse sequencing and followed into the axilla. Areas of contrast accumulation were then imaged with grey-scale or live dual images to confirm the presence of an architecturally defined lymph node. In patients when an enhancing node was identified (see Figure 1), this was localised with a guide-wire.

Most procedures were completed in 15 minutes. The next day, these patients underwent conventional SLNB using blue dye and isotope technique. The results of this study showed that, in 89% of cases, an enhancing node was identified and guide-wired and this node was confirmed to be the SLN at operation the following day using conventional blue dye and isotope identification.

Valuable consequences
The practical consequences of this study were valuable. This was the first published clinical study showing that microbubbles can enter breast lymphatics and traffic to axilla, enabling the contrast-enhanced US to identify SLNs before surgery.

We are now currently conducting a second phase of the microbubble study where the enhancing node is biopsied under US control. This work in progress has already proven to be effective and our preliminary results have confirmed a reduction of completion ALND rates by more than 50%. An audit of Maidstone Breast Unit completion ALND rate prior to microbubbles was found to be 21%.14

We have recently presented our post biopsy series in the Radiological Society of North America meeting, revealing that SLNs were successfully identified in 56 of the 59 cases (95%) using microbubbles. Eleven of these 56 cases (20%) were lymph node positive and six of the 11 (55%) patients had a positive US-guided biopsy and therefore were treated with an immediate ALND. The remaining 50 patients had conventional SLNB with blue dye and isotope injection. In five cases a positive lymph node was identified, giving a completion ALND rate of 10%. These preliminary results demonstrated that microbubble injection followed by biopsy of the enhancing node can lead to a reduction in completion ALND rates. Because fine needle aspiration or core biopsy of the enhancing lymph nodes may miss a small malignant focus, patients whose nodes are negative should still undergo conventional SLNB.

Percutaneous biopsy techniques are developing rapidly. Vacuum-assisted devices are effective in sampling and even removing breast lesions. To our knowledge, there are no published studies assessing the use of these devices in the axilla. It may be prudent to investigate the potential role of vacuum-assisted or other devices in the axilla, as this application has the potential to remove the entire lymph node.

We acknowledge that although further robust research in the use of microbubbles is required before reaching any more conclusions, at The Maidstone Breast Unit we believe that percutaneous sentinel lymph node biopsy is on the horizon and may become a reality in the near future.

References    

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Schijven MP et al. Eur J Surg Oncol 2003;29:341-350.
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  6. Albertini JJ et al. JAMA 1996;276:1818-1822.
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Torchia MG et al. Am J Roentgenol 2002;179:1561-1565.
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Cosgrove D. Eur J Radiol 2006; 60: 324-330.
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Goldberg BB et al. Radiology 2004;
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  12. Britton PD et al. Breast 2009;18:13-16.
  13. Sever A et al. Br J Surg 2009;96:1295-1299.
  14. Mills P et al. Breast J. 2010;16:460-463.