European Nuclear Medicine Guide
The radiopharmaceutical drains from the injection site via lymphatic vessels and is accumulated in the sentinel lymph node (SLN) by phagocytosis of macrophages or retention due to particle size. Often, a fraction of the radiopharmaceutical moves on to second and third echelon nodes downstream. The mannose residues determine the binding of [99mTc]Tc-tilmanocept to CD206 mannose receptors that are expressed on the surface of macrophages.
The ideal radiotracer should show rapid transit towards SLNs with persistent retention in the nodes. In general, the drainage, distribution and clearance of radioactive colloids by the lymphatic system vary and are dependent on the particle size. Smaller particles are drained more quickly to the SLN but also tend to accumulate in non-SLNs. Large particles migrate more slowly and are mainly retained in the SLN. Studies have shown that the success rate in the identification of SLN is not significantly affected by the particle size of the radiotracer used. The selection of the radiotracer is then based more on local availability than on differences in SLN detection. Advantages of [99mTc]Tc-tilmanocept versus the radiocolloid tracers include faster clearance from the site of injection and higher
retention in the SLN (due to specific ligand-receptor binding mechanism) [167].
Despite the identification rate of SLN being close to 100%, the false-negative rate is substantial. There is a learning phase for a lymphatic mapping team. Various durations of learning phases have been recommended, but none have been based on sound scientific data. This is currently less of an issue, because now that the examination is done around the world and young doctors learn it during their specialist training, reductions in the high false-negative rates are being observed. SLNB should be performed by a qualified team of nuclear medicine specialists, surgeons, and pathologists acting in close collaboration. The success of SLNB increases as a centre gains experience.
Analysis of false-negative procedures has revealed that the cause may lie with each of its three elements. Causative factors in lymphoscintigraphy may be imaging of the wrong nodal basin, failure to depict all potential drainage basins, failure to visualize the afferent lymph vessel, or failure to detect an SLN in an unusual location. Furthermore, large metastases in the SLN inhibit tracer accumulation in these nodes. Sometimes, the time between lymphoscintigraphy and the operation is so long, that the radioactive node can no longer be traced. If this occurs, the patient can be reinjected before the surgical procedure is started. Surgeons sometimes fail to remove an SLN in a difficult position, even though it has been pointed out by the nuclear medicine physician.
The suggested activities to administer are
Estimation of the patient’s dosimetry after injection is difficult. Since only a reduced fraction of the tracer is transported, the effective dose is mainly determined by the amount of tracer retained at the injection site. Because the injection depot is usually excised during surgery, shortening the interval to the operation will further decrease the local radiation. In patients, the estimated radiation exposure depends on several variables such as injected activity, retention time, and whether multiple injections were administered. There are minor differences in radiation dosimetry for the various radiopharmaceuticals used for SLN detection.
The effective dose for 99mTc-small colloids is 1.2 µSv/MBq [3] The organ with the highest absorbed dose is the heart wall: 4.1 µGy/MBq
The range in effective dose for 99mTc-colloids is: 0.01-0.18 mSv per procedure.
The effective dose for [99mTc]Tc-tilmanocept is 1.7 µSv/MBq in breast cancer patients and 1.3 µSv/MBq in melanoma patients [168].
Caveat:
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
In recent years, the use of SPECT/CT imaging for SLN detection has increased. Therefore, the additional radiation dose of CT imaging to patients should also be taken into account for dosimetric purposes. The additional absorbed dose from the CT component of SPECT/CT imaging varies and depends mainly on the characteristics of the CT scan, such as whether the procedure is a full-dose CT scan for diagnostic purposes, or, as in most centres, a low-dose CT scan used only for localization and attenuation correction.
Early dynamic, static, and delayed static images identify SLNs in the majority of patients. The strongest criterion for the definition of a lymph node as an SLN is the presence of a lymphatic channel from the primary tumour to the lymph node (usually visualized on dynamic images). Also, the first appearing node is rated as a SLN. The SLN is often the hottest node and the node closest to the injection site, but this is not necessarily the case. The distance from the primary may also contribute to the definition of the SLN. Nodes that appear only on late images, but in a further nodal field, are also SLNs unless dynamic images reveal that they receive lymph channels from an earlier detected node. The results of SLN mapping should be communicated directly to the surgeon, for example, as a brief report in advance of the surgery and including all available and labelled images. This is of particular importance, if lymphatic drainage is ambiguous.
A final report should be sent later and include the following detailed information:
The visualized structures and their location (lymphatic channels, SLNs, second- and third-echelon nodes) should be described and labelled on the images themselves. The number and location of SLNs in each basin must be carefully reported and include depth from the skin. Also, non-SLNs should be described. In particular, errors in the examination procedure, e.g. contamination and unexpected lymphatic drainage, should be described in detail. Information gathered by SPECT and CT should be reported separately. Even additional findings on CT must be mentioned, e.g. pathological lymph nodes without tracer accumulation. All acquired planar images, appropriate co-registered SPECT/CT images, and the final report with a conclusion regarding the results should be available in the operating room. The nuclear physician should be contactable in case any questions arise.
Pitfalls
Some pitfalls may occur in a SLN procedure, and both false-positive and false-negative interpretations of lymphoscintigraphy are possible.
Sources of false-positive interpretation of images:
False-negative interpretation of images.
The majority of patients with preoperative lymphoscintigraphic SLN non-visualization will have at least one SLN detected intraoperatively either by γ probe alone or by γ probe combined with blue dye. In approximately 1-3% of all patients, SLN will not be detected intraoperatively, and the status of the lymphatic basin cannot be determined. This percentage increases to 10-15% in some specific situations (head and neck, cervical, and endometrial cancers). In general, if the SLN is not detected, systematic lymphadenectomy in standardized anatomical regions should be performed instead.
Sources of non-visualization of SLN are:
Other reasons of non-visualization of SLN.
In some patients, lymphatic drainage is slow. If no tracer drainage is observed in dynamic or early static images, massage of the injection site or along the lymphatic vessels can be helpful. Constriction of the lymphatic vessels should also be excluded. Slow lymphatic flow is observed in older patients (>50 years). In some cases, repeated imaging (delayed images up to 24 h) or reinjection of radiotracer may also be helpful if there is any suspicion of false injection.
No special preparation is necessary prior to the examination. The nuclear medicine physician should carefully obtain a history including diagnosis, prior treatment (especially primary resection, including histopathological results), prior surgery or trauma of the affected region, comorbidities, pregnancy/nursing, or prior administration of radiopharmaceuticals. Results of preoperatively performed imaging examinations should be delivered to the responsible nuclear physician. The history should be followed by physical examination of the affected body region. Every suspicion of lymph node metastases has to be excluded before SLNB. In the event of any uncertainty, the responsible nuclear physician should not hesitate to contact the responsible surgeon for further information.
To avoid constriction and occlusion of lymphatic channels, all clothes and jewellery in the region of interest and along the lymphatic vessels should be removed before injecting the radiotracer.
The detailed recommendations regarding SNL in melanoma can be found in the EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma [169].
The detailed recommendations regarding SNL in oral/oropharyngeal squamous cell carcinoma and in breast cancer are available in the EANM Oncology Guidelines [170,171].
Regarding breast cancer: Although there is consensus on some broad aspects of SLN protocols in breast cancer, consensus does not exist on all details. Controversies exist with regard to the particle size of the radiotracer, the optimal route for injection, timing of scintigraphy and intraoperative detection, and whether or not extra-axillary lymph nodes should be considered. The optimal injection technique has been the subject of lively debate. Widely used techniques include superficial tracer injection (periareolar, subareolar, subdermal, intradermal) and deep injection (peritumoural, intratumoural). Results of multiple studies have confirmed that the method of injection does not significantly affect the identification of axillary SLN. One major advantage of superficial injections is that they are easy to perform. The use of peritumoural injections requires careful investigation of a patient’s prior imaging and medical records, particularly if the tumour is nonpalpable. If available, ultrasound guidance to assist with placement of peritumoural injections can be helpful. If a tumour is in the upper outer quadrant, the relatively intense activity at the injection site may make localization of a less-intense nearby SLN difficult. Important advantages of deep injections are improved detection of extra-axillary SLN. Thus, if the goal is axillary staging only, a superficial tracer injection may be preferable to a deep injection. When using superficial injections, large volumes of injectate may interfere with normal lymphatic flow; therefore, volumes of 0.05-0.5 mL are preferred. With peritumoural injections, larger volumes (e.g. 0.5-1.0 mL) are used.
Regarding gynaecological cancers [172]: