Breast cancer is the most common cancer diagnosed in women worldwide.1 The most significant prognostic factor in patients with early stage breast cancer is given by the status of the axillary lymph nodes, which also guides the further treatment management.2,3
Traditional staging requires a complete axillary lymph node dissection (ALND), which, as an invasive procedure, carries several complications such as lymphedema, pain, sensory disturbances. Furthermore, ALND may be unnecessary (overtreatment) because axillary involvement is found in 10% to 30% of T1 and 40% to 45% of T2 patients only.2,4
Sentinel node biopsy (SNB) has been studied and applied as an alternative procedure to ALND: it is a less invasive procedure associated with low risk of complications and allows the pathologist to study less lymph nodes in a more detailed way, therefore obtaining a more accurate staging.5 For these reasons, SNB has emerged as the standard of care in the evaluation of the involvement of the axillary nodes status in patients with early stage breast cancer.6
For the SNB procedure, a radiotracer or blue dye or both can be used.5 In the first case, after the injection of the radiotracer, a preoperative lymphoscintigraphy is usually performed, providing information on the technical integrity of the injection; it identifies preoperatively the drainage pathways, the position and number of the sentinel node(s), which very often are more than one, also recognizing any atypical drainage sites.7,8 However, γ-cameras are not always available, or sometimes, even if available, they are not used because some authors doubt about the usefulness of preoperative lymphoscintigraphy.5,9
Recently, several portable imaging γ-cameras have been developed and proposed in clinical setting, also for SNB in breast cancer patients. The aim of this study was to evaluate the feasibility and the potential usefulness of a new high resolution hand-held imaging γ-camera for intraoperative SNB procedures. A comparison with the preoperative lymphoscintigraphy and the traditional γ-probe approach was obtained.
PATIENTS AND METHODS
Sixteen T1 to T2 breast cancer consecutive female patients were evaluated (mean age, 62 years, range 46–80 years) affected by breast cancer proven by previous core biopsy. Inclusion criteria were unifocal tumor with dimensions less than 2 cm as measured by mammography as well as ultrasonography or MRI and with no clinically palpable axillary lymph nodes (cN0).
The study was performed according to the Helsinki declaration and the ethical rules of our hospital; informed written consensus was obtained from all the patients.
γ-Cameras and γ-Probe
The hand-held imaging γ-camera used in the present study was the IP Guardian2 (Li-Tech; Rome, Italy) shown in Figure 1. It consists on a CsI(Tl) scintillator crystal array with 18 × 18 elements, thickness of 5 mm, coupled with a position-sensitive photomultiplier tube. It is equipped with a tungsten collimator, with parallel squared holes 2.4-cm-long and 0.2-mm-thick septa. The FOV is 4.4 × 4.4 cm. It is fully portable, hand held, relatively light (1.3 kg), and easy to use in the operating room. Physical characteristics and phantom measurements of this portable imaging γ-camera have been previously reported by our group.10
The γ-camera used for preoperative scintigraphy was a dual-head e.CAM (Siemens, Erlangen, Germany). Each detector consists of a NaI(Tl) scintillator crystal, thickness of 9.5 mm, coupled with 59 photomultiplier tubes. The FOV is 53.3 × 38.7 cm. For the present measurements, each detector was equipped with a low-energy high-resolution collimator, with parallel hexagonal holes 2.4-cm-long and 0.36-mm-thick septa.
The γ-probe intraoperatively used by the surgeon was the Europrobe II (EuroMedical Instruments, Le Chesnay, France), equipped with a CdTe detector shielded by a tungsten cylindrical collimator with 4-m aperture diameter. The sentinel lymph node (SLN) localization is based on the increase in count rate, also translated in an acoustic signal.
All patients presented with an ultrasound-guided cutaneous mark on the overlying skin perpendicular to the tumor site. In the nuclear medicine department, human albumin colloidal particles (Nanocoll, GE Healthcare) were labeled with 60 to 70 MBq (1.6–1.9 mCi) of sodium 99mTcO4 (99mTcO4), in a saline volume of 0.1 to 0.2 mL. At least 95% of particles had a diameter of 80 nm or less, as declared by the manufacturer. Before each injection also, radiochemical and radionuclidic purity were checked.
The intradermal injection was performed, perpendicular to the tumor, in the afternoon of the day preceding surgery. All patients were asked to gently massage the site of the injection for several minutes to facilitate lymphatic drainage and were evaluated by lymphoscintigraphy. Lymphoscintigraphy consisted of a standard anterior and oblique anterior (45-degree) planar acquisition of the thorax acquired for 5 minutes (matrix, 256 × 256; zoom, 1.23), starting at 10 to 30 minutes after the injection, covering the injection site during acquisition with a lead shielding; in some cases extraprojections or late images (2–4 hours after injection) were also obtained to better identify the SLNs and to assess their exact number. Anterior projection was routinely obtained to assess radioactive nodes in the internal mammary chain. Body contour was drawn using a small radioactive source (99mTcO4 in a syringe needle) to offer the surgeon with anatomic landmarks. The radioactive lymph node(s) projection on the overlying skin was marked with an indelible pen in the oblique projection, with the patient keeping the arm positioned over the shoulder for the axillary nodes and in anterior projection for nonaxillary nodes. In the final report number, position, activity grade, and, if possible, timing of appearance of the radioactive nodes were described.
Lymphoscintigraphy was interpreted by 3 skilled nuclear medicine physicians (S.C., L.R., and D.R.) and by the surgeon (E.F.). An SLN was interpreted as a focal hot spot visualized in more lymphoscintigraphic projections. Pathway drainages were identified owing to their change in uptake and shape during the scintigraphic acquisition.
Surgery took place the day after (18–20 hours after tracer injection) in a different hospital, where no nuclear medicine unit was present. All operations were performed by the same skilled surgeon who regularly uses the γ-probe for radio-guided surgery and who annually performs more than 200 SNB procedures.
Intraoperative SLN Localization
For intraoperative SLN localization, a hand-held γ-probe was used by a skilled surgeon. A portable imaging γ-camera was also used by the nuclear physician who was present in the operating room. The γ-camera was covered with an appropriate sterile surgical plastic suite, and scans were acquired with the surface of the γ-camera in contact with the patient skin.
The surgery started with lumpectomy. Then, the SLNs were localized by the surgeon and nuclear physician independently and blinded each other. Surgeon used the hand-held γ-probe, whereas the nuclear medicine physician used the hand-held γ-camera. The subsequent SLN resection was divided into 2 steps. First, the surgeon removed each radioactive SLN localized through the γ-probe; in 10 patients (62% of cases), 2 or more radioactive nodes were removed. In the second part, when no further radioactive SLNs were identified by the γ-probe, the nuclear physician evaluated the surgical area with the portable γ-camera searching for possible “missed” radioactive lymph nodes in the axillary region, in the internal mammary chain or elsewhere; if other radioactive nodes were imaged, they were identified and removed by the surgeon. Patients with positive SLN underwent subsequent ALND, whereas patients with negative SLN did not receive further axillary surgery.
In 3 cases, the portable γ-camera’s “help” was asked by the surgeon also during his traditional evaluation (first step) to better localize the radioactive node. Before sending surgical specimens for histological examination, every removed lymph node was checked “ex vivo” both by the γ-probe and the imaging γ-camera to confirm that they were radioactive.
The results of the 3 methods (lymphoscintigraphy, γ-probe, and imaging γ-camera) were compared, and the opinion of the surgeon about the contribute during surgery was obtained.
To compare the spatial resolution of the portable imaging γ-camera with the large-FOV γ-camera used in lymphoscintigraphy, a capillary tube filled with 99mTcO4 (1-mm internal diameter) was imaged by both systems at a distance of 1.5 cm from their collimators. The measurement was repeated also in scattering conditions, inserting different Plexiglas slabs (thickness ranging from 1 to 5 cm, covering an area of 30 × 30 cm2), between the capillary tube and the collimator of each imaging systems, keeping an air gap of 1.5 cm. The spatial resolution values were computed, extracting the line-spread function profile, performing a best-fit with a Gaussian function, and calculating the full width half maximum. Furthermore, we evaluated the hand-held γ-camera’s sensitivity, by imaging a point source of 99mTcO4 (activity 8.5 MBq), positioned at contact with the collimator.
Phantom measurements showed that portable γ-camera was better than large-FOV γ-camera with regard to the spatial resolution, as shown in Figure 2, with and without scattering (ie, interposing or not Plexiglas slabs). Moreover, in clinical settings, the portable γ-camera images can reach even better spatial resolution than preoperative γ-camera images mainly because it is positioned on the patient skin with minimum source-to-detector distance, whereas during lymphoscintigraphy, the large-size detector is quite distant from the skin (range, 3–5 cm). The portable γ-camera sensitivity equaled to 204 cps/MBq, which allowed very short acquisition periods during the intraoperative evaluation (5–10 seconds for each image).
The tumor characteristics of the 16 patients operated on are summarized in Table 1.
In the whole series of 16 patients, both the preoperative lymphoscintigraphy and the γ-probe identified a total of 23 SLN, whereas additional 5 radioactive nodes were identified only using the portable imaging γ-camera. Therefore, a total of 28 radioactive SLNs were removed at surgery and sent for pathologic evaluation: 14 were located in the level I, 8 in the II level, 5 in the level III, and 1 intrapectoral. Of note, all the nodes located in the level I, 6 in the level II, 2 in level III, and 1 intrapectoral were detected by all the 3 imaging techniques, whereas 2 nodes in level II and 3 in the level III were detected by imaging γ-camera only.
The counts rate in the radioactive nodes ranged from 380 to 1200 cps (mean, 670 cps) with the γ-probe. The controlateral shoulder was taken as site to check the background activity, which was less than 30 cps in all cases (ie, negligible), so we did not use these data for correcting the SLN uptake. Each removed radioactive node was also checked ex vivo to confirm the photon emission.
In 11 patients, preoperative lymphoscintigraphy, γ-probe, and portable imaging γ-camera detected the same number of radioactive nodes (Fig. 3). In these patients, 17 radioactive lymph nodes were identified by all 3 procedures, 6 (35%) of which where metastatic in 6 different patients.
In 5 patients, the portable γ-camera depicted 1 node more than lymphoscintigraphy (for a total of 5 radioactive nodes more). One of them was metastatic, and it was the only metastatic node in that patient (Fig. 4).
The initial evaluation of SLNs with the portable γ-camera correctly localized all the radioactive nodes intraoperatively detected by the surgeon with the γ-probe. In 3 cases, the portable imaging γ-camera was used by the surgeon to localize the residual radioactive node with more confidence than the γ-probe.
Of course, it was not possible to calculate sensitivity, specificity, and accuracy with our data because only patients with a positive SLN underwent ALND; however, we can state that in this preliminary experience, imaging γ-camera showed the highest detection rate of SLN (100%), whereas lymphoscintigraphy and γ-probe showed a detection rate of 82%. A greater number of study patients are necessary to confirm these favorable results.
Sentinel lymph node is any lymph node that receives direct lymphatic drainage from a primary tumor site12; therefore, SLNs can be more than one. Sentinel node biopsy in breast cancer is based on the assumption that the malignant cells follow an orderly progression from the tumor site to the lymph nodes of the different levels of the axilla; therefore, it presumes that a negative SLN implicates the absence of metastatic disease in the whole axilla. In this case, no further dissection is needed, avoiding unnecessary ALND and the related complications. On the other hand, an involved SLN would send the patient to ALND. The only weakness of this concept, which could potentially lead to undertreatment, is the false-negative rate of the procedure (patients with a negative sentinel node at biopsy but with positive axillary node dissection). Several trials in which SLN was followed by axillary dissection have recognized this drawback.13 In the larger trials, the SLN identification rates were very high (93.5%–97.2%), with false-negative rates ranging from 5.5% to 16.7%.12,14 Yet, a higher identification rate (proportion of patients with at least one sentinel node found at operation) was associated with a low false-negative rate, which decreases with the number of removed radioactive lymph nodes.12–18
The data from the ALMANAC study on 842 patients suggested that surgeons should not stop intervention just after the finding of one SLN, but they should search thoroughly for other radioactive nodes. This recommendation is important because the false-negative rate in patients who had multiple SLNs removed (3 or more) was 1.1% compared with 10.1% in those with only 1 sentinel node removed.18
In patients with multiple SLNs removed (of which at least 1 metastatic) in nearly 80% of cases, the node with the highest counts was found to be metastatic, whereas in the remaining cases, the positive nodes were the less radioactive ones.19,20 This suggests that we can not rely on the hottest SLN removal only.
In this regard, the portable imaging γ-camera has proven very useful because it can detect a higher number of radioactive nodes compared with preoperative lymphoscintigraphy because of its higher spatial resolution and minimum source-to-detector distance compared with a large-FOV γ-camera.
In our study on 16 patients, the portable imaging γ-camera depicted more radioactive SLNs in 5 patients (31% of the whole series) in comparison with lymphoscintigraphy and γ-probe. Of interest, one of the extra nodes identified by the portable imaging γ-camera was metastatic, and this led the surgeon to perform ALND. Therefore, the use of the imaging γ-camera changed the management in a 55-year-old patient: all lymph nodes removed during ALND were not metastatic; thus, the only metastatic lymph node in that patient was detected by the portable imaging γ-camera. Another interesting observation in this patient is that this additional SLN was the less radioactive one (320 cps were detected in the positive node vs 740 cps in the negative one).
In accordance with our findings, Mathelin et al21 reported a case in which the use of an intraoperative portable γ-camera allowed to identify an SLN not depicted by the lymphoscintigraphy and not recognized by the surgeon, which was metastatic and prevented an underestimation of staging, with potential suboptimal treatment in a 44-year-old patient.
Another interesting aspect of our study was that the portable γ-camera allowed to correctly detect some radioactive lymph nodes (n = 5), which were not identified both at the preoperative lymphoscintigraphy and at γ-probe. Similarly Mathelin et al,22 using a portable γ-camera, reported the intraoperative visualization of radioactive lymph nodes in 11% of patients negative at preoperative lymphoscintigraphy.23
Despite the small number of patients, our preliminary results suggest that the use of the portable imaging γ-camera in SLN detection in breast cancer is feasible and can detect the exact number of radioactive nodes in real time during the operation.
Finally, it is important to point out that in all cases the documentation through saved images of the removal of all radioactive nodes and the confirmation of their ex vivo activity was useful to the surgeon, as suggested also by other authors.24
A strength of our study is that it is the first prospective study comparing lymphoscintigraphy, γ-probe, and γ-camera for SLN in breast cancer, especially regarding a potential additional value of hand-held imaging γ-camera in more carefully performing SLN procedure. On the other hand, the major weakness is that the number of enrolled patients is still limited, without prolonged follow-up results, to establish the effective role of this new imaging device.
The use of a portable high-resolution hand-held imaging γ-camera is a feasible, not-time consuming, noninvasive procedure in intraoperative sentinel node localization, offering extra confidence to the surgeon. In our hands, it was a very useful auxiliary imaging tool especially in the identification of nodes located deep in the axilla, which are difficult to detect at preoperative lymphoscintigraphy. The hand-held imaging γ-camera was very useful in case of nodes with challenging localization, and it could be helpful as an auxiliary imaging device for surgeons with limited experience in radio-guided surgery. Another important role of the portable imaging γ-camera is the confirmation of the dissection of all radioactive nodes and the documentation of their removal through intraoperatively saved images. Lastly, the hand-held imaging γ-camera could be an effective alternative imaging modality for SLN localization in those centers in which lymphoscintigraphy is not available.
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