Roger F. Uren is in the Department of Medicine, University of Sydney, Sydney, New South Wales, Australia. rogeruren@optushome.com.au
Quantum dots show potential as a tool for imaging sentinel lymph nodes and guiding surgery.
Only the most experienced and adept surgeons can perform sentinel lymph node biopsy (SLNB), an increasingly popular strategy for determining whether a cancer has spread (metastasized). Some help may be at hand to guide the surgeon's scalpel in the form of a paper reported in this iss- ue by Kim and colleagues1, which demonstrates the visualization of sentinel lymph nodes in large animals via optical imaging of near-infrared (NIR) fluorescence emitted by quantum dots. The work represents not only a pioneering medical application of nanocrystals, but also a step forward in the clinical application of SLNB in cancer surgery.
SLNB, which was first described by Morton and colleagues2 in 1990, is a method to stage regional node fields for metastasis. Lymphatic drainage is mapped from a primary tumor site to the draining lymph node or nodes (Fig. 1), and these are then removed for detailed histological examination. If the sentinel node is normal, all of the lymph nodes in the node field can be assumed to be normal. There is thus less surgery for the patient, reduced morbidity and, paradoxically, more certainty in nodal staging. Because of this, SLNB has caused great excitement in surgical oncology and is being applied to an increasing number of solid cancers in humans. It is interesting to recall that the original article by Morton and colleagues describing SLNB in patients with melanoma was rejected by two of the major surgical journals in the United States before being published in 1992 and has since become one of the most frequently cited articles in surgical oncology.
Figure 1. Any lymph node receiving direct lymphatic drainage from a cancer site is a sentinel node with the potential to contain metastatic cancer cells.
SLNB is elegantly simple in concept but quite often very difficult to perform accurately in individual patients. Anything that potentially improves the technique is therefore welcome. With this in mind, Kim and colleagues have taken type II quantum dots tuned to fluoresce in the NIR (while preserving absorption cross section), which were coated in a polydentate phosphine that renders them soluble and stable in serum. Injection of only picomolar amounts of the quantum dots enabled visualization of sentinel lymph nodes 1 cm below the skin using excitation fluence rates of only 5 mW/cm2. The injections were given intradermally first in the paw of a mouse and then in the thigh of a pig. Lymphatic collecting vessels were clearly seen passing to the sentinel nodes in the axilla and groin respectively. These were confirmed to be sentinel nodes by a second intradermal injection of blue dye (the current 'gold standard'), which also flowed to the same nodes.
Optical imaging using the NIR fluorescence of quantum dots would appear to have immediate advantages in SLNB over current methods. Surgeons would not require retraining to apply this method as it is similar to the current intraoperative use of blue dye. The advantage over blue dye is the ability to 'see' through several centimeters of tissue so that there would be real-time visual guidance of the surgery, with resolution being limited only by the visual acuity of the surgeon. Visual inspection would also allow the surgeon to confirm that all sentinel nodes had been removed from the node field. There would be no need for a gamma probe to confirm this and no need for blue dye injection. There is also the exciting potential for the histopathologist to focus exactly on the part of the sentinel node containing the quantum dots by using a fluorescent microscope. This is precisely the part of the sentinel node that would contain any micrometastasis.
For SLNB in melanoma and breast cancer using quantum dots, I would envision preoperative lymphoscintigraphy using a radio-labeled colloid to provide an accurate map of lymph drainage from the tumor site with the exact surface location of the sentinel nodes being marked on the skin. Sometimes lymph drainage is slow and can take up to three hours, an observational period that would be unacceptable in an operating suite. The depth of the node from the skin would also be measured. SLNB could then be performed using NIR optical imaging with quantum dots; this would not need to be performed within 24 hours of the lymphoscintigraphy, as is currently the case when an intraoperative gamma-detecting probe is used (owing to the rapid radioactive decay of the isotope). This would simplify scheduling of operating theater time. One notable caveat for anyone investigating both of these cancers is that the sentinel nodes can be very deep, up to 10 cm from the skin, and sometimes the nodes are inside the body cavities; situations such as these would likely prove problematic for optical imaging using NIR fluorescence.
At present, surgeons attempting SLNB in cancers involving visceral organs such as the gastrointestinal tract, lung, prostate and uterus encounter significant technical difficulties. Performing preoperative lympho-scintigraphy in these patients is extremely difficult, if not impossible, and it is in these patients where I see this exciting new approach having its greatest impact. There would be no need to perform any preoperative mapping, and, with the operative field on view, the surgeon would be able to rapidly detect the sentinel nodes, which in the abdomen and chest usually lie only a centimeter or two below the serosal surface, ideal conditions for optical imaging of NIR fluorescence.
Future research could be directed to examining whether the presence of NIR type II quantum dots in sentinel nodes can be determined retrospectively in a histological specimen. When a SLNB failure occurs (i.e., the tumor recurs in a node field that had a negative SLNB procedure), it is very important to know whether the true sentinel node was removed at the time of surgery, and a measure of the quantity of quantum dots in the node would help this determination. In addition, it will be important to thoroughly assess the potential toxicity of quantum dots.
Overall, the use of quantum dot imaging promises to make an important contribution to the surgical management of cancer patients. It should have a major impact in SLNB of visceral cancers and also has the potential to simplify SLNB in melanoma and breast cancer.
