European Nuclear Medicine Guide
99mTc-labelled colloid particles
Nanocolloidal albumin: 5-80 nm typical particle size range
Rhenium sulphide: 50-200 nm typical particle size range
Mannosyl-DTPA-dextran or Tilmanocept: 7 nm particle size
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 [5].
The ideal radiotracer should show rapid transit towards SLNs with persistent retention in the lymph 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) [6,7].
Indications for SLN localization and SLN biopsy (SLNB). The appliance of SLNB depends on each cancer’s diagnostic algorithm (see specific guidelines).
Contraindications include poor general health status, grave concurrent disease, poor patient compliance and known systemic spread of disease.
If a lymph node is suspicious for metastasis on physical examination or when imaged, fine-needle aspiration cytology should be attempted to pursue a pathological diagnosis. If fine-needle aspiration cytology does not provide a diagnosis and SLNB is otherwise appropriate, the examination should be performed and the suspicious node should be removed even if not a demonstrable SLN. However, apparent lymph node metastases are a contraindication, because false-negative results may occur due to inhibited tracer accumulation in the SLN and altered lymphatic drainage pattern. SLNB is less sensitive in patients with surgery or trauma (including radiotherapy) in the preceding years, who may have altered lymphatic drainage pathways, but a positive biopsy does have the normal implications. This is equally true after wide local excision of the primary tumour, and SLNB may be contraindicated, because it might not provide a reliable result.
On the radioprotection point of view, SLNB is a safe procedure without known adverse effects even in paediatric population or during pregnancy.
It is not recommended to interrupt breast feeding although an interruption of 4 h during which one meal is discarded can be advised to be on the safe side.
In case of breast SLNB, breast feeding should be interrupted for 24 h following the examination.
Despite the identification rate of SLN being close to 100%, the false-negative rate is substantial. A false-negative SLN occurs when a SLNB fails to identify metastatic disease that is present but remains undetected during the evaluation. To calculate the false-negative rate the number of false-negative procedures is divided by the sum of the true-positive and false-negative procedures [8]’.
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 visualise the afferent lymph vessel, or failure to detect an SLN in an unusual location. Furthermore, large metastases in the SLN may inhibit tracer accumulation in these nodes. Sometimes, if the time between lymphoscintigraphy and the operation is too long, the radioactive node can no longer be traced. If this occurs, reinjection before the surgical procedure is recommended. Surgeons sometimes fail to remove an SLN in a difficult position, even though it has been pointed out by the nuclear medicine physician [9,10].
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. Using a statistical analysis a considerable number of SLN procedures has been estimated [8]. 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.
The suggested activities to administer are [11,12]
[99mTc]Tc-tilmanocept: 37-74 MBq,(superficial or deep injection): 10-150 MBq, depending on the study and on the time to surgery. In pregnant patients, it is recommended one-day protocol with 10-15 MBq.
[99mTc]Tc-tilmanocept: 37-74 MBq, depending on the study and on the time to surgery, although higher doses have been proposed in breast cancer [13,14]
No recommendations are given for paediatric nuclear medicine.
Estimation of the patient’s radiation exposure after administration 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 exposure for the various radiopharmaceuticals used for SLN detection.
The effective dose for small [99mTc]Tc-colloid is typically 1.2 µSv/MBq [15]
The range in effective dose for [99mTc]Tc-colloid 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 [7].
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 emphasised 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 [16]. 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 anatomical SLN localization and attenuation correction.
A sequential imaging approach combining 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 visualised 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:
radiopharmaceutical used;
injection technique (location, depth, number of injections);
activity and volume of injected radiopharmaceutical;
time point of image acquisition;
orientations of images;
name of the responsible nuclear physician.
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 including SLN localization in reference to surgical levels (e.g. head and neck, axilla, groin) or lymph node groups (e.g. pelvis, abdomen, mediastinum). To guide recognition in the operation room SLN localization needs to include anatomical landmarks (muscles, blood vessels etc). 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 (if not present in the operating room) in case any questions arise [17].
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:
Skin contamination arising from the injection or urinary contamination may be misinterpreted as a lymph node. Hot spots attributed to contamination are often very hot and focal. Planar images from different views and SPECT or SPECT/CT help to identify contamination.
Second-echelon nodes might be misinterpreted as SLNs, if no early dynamic or static images are acquired. Acquiring delayed images too soon might also play a role here.
Lymphangioma or lymphatic lakes might be misinterpreted as lymph nodes.
Other tissues containing radioactivity could complicate image interpretation.
Non-visualization of SLN 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 standardised anatomical regions should be performed instead.
Sources of non-visualization of SLN are:
Adjacent nodes may be misinterpreted as one SLN.
The SLN may be masked by the injection site, especially in head and neck cutaneous cancer.
Only a small amount of the radiotracer drains from the injection site. In the event of any alteration in the lymphatic drainage, the SLN may contain little radioactivity.
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 incorrect injection [18].
No special preparation is necessary prior to the examination. However, depending on the site of primary tumour local anaesthesia (spray, injection) is recommended previous to tracer administration; this is particularly the case for areas like the scalp, penis, vulva, oral cavity and pelvis. 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.
Melanoma [19].
SLNB biopsy is a key procedure in staging and managing melanoma, providing crucial prognostic information by identifying the first lymph node likely to harbour metastasis. Indicated for clinically node-negative patients with intermediate to high-risk features.
A significant challenge is the issue of in-transit nodes—lymph nodes or channels located between the primary tumour and the regional nodal basin. These nodes can harbour metastases and may be missed during conventional SLN mapping, leading to false-negative results. In addressing this issue, SPECT/CT has significantly improved SLN mapping accuracy.
As systemic therapies evolve, the role of SLNB and subsequent surgical interventions continues to adapt, ensuring optimal outcomes for melanoma patients.
Breast Cancer [20]
While there is consensus on certain broad aspects of SLN protocols in breast cancer, there remains a lack of agreement on many specific 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). More recently combination of superficial and deep injections in the same session has been successfully reported. 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 deep 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 deep 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.
Oral/oropharyngeal squamous cell carcinoma [21].
SLNB is increasingly used in the staging and management of oral and oropharyngeal squamous cell carcinoma (OSCC) in patients with clinically node-negative necks. Challenges in SLNB for OSCC include the complexity of lymphatic drainage in the head and neck region, which can result in multiple SLNs and unpredictable drainage patterns. Additionally, the proximity of the SLN to vital structures can complicate surgical access. SPECT/CT, is mandatory and improves the accuracy of SLN localization. The technique is at the present well-standardized becoming in numerous specialized centres a minimally invasive alternative to elective neck dissection, optimizing care for OSCC patients.
Gynaecological cancers [22-24]:
In cervical cancer, the radiopharmaceutical is injected peritumourally/periorificially into the four quadrants of the cervix. When previous conization has been performed, peri cicatricial (if possible) injection is preferred. Superficial (submucosal) instillation is preferred in small tumours, while injection into the necrotic part of the tumour should be carefully avoided in bigger ones.
In endometrial cancer, there were three reported injection approaches: cervical injection (the easiest approach), endometrial peritumoural injection assisted by hysteroscopy (usually performed at the beginning of surgery, but if this is the case, the possibility of performing lymphoscintigraphy is lost) or myometrial/sub serosal injection (guided by transvaginal ultrasonography). Currently, cervical injection is widespread used in the majority of specialised centres.
In vulvar cancer three or four intradermal/intramucosal peritumoural injections of radiopharmaceutical should be performed after the application of an anaesthetic cream or spray such as lidocaine or ethyl chloride.
Urological cancers
In penile cancer, SLNB is recommended for high-risk (≥pT1b) cancer with cN0 status. For the procedure 3-4 intradermal/intramucosal peritumoural injections of radiopharmaceutical are administered after the application of an anaesthetic cream or spray such as xylocaine [25].
In prostate cancer, SLNB appears to contain decisive information for the clinical outcome in localized intermediate- and high-risk patients. For the procedure patients receive antibiotic prophylaxis 1 day previous to the administration of 2 injections of the radiotracer in each prostate lobe under endorectal ultrasound guidance [26].