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Lymphatic mapping and tumour localisation

The surgical management of many pathologies, especially, carcinoma-related diseases have been transformed with the introduction of radioguided surgery and its supplementary technologies. Nowadays, radioguided surgery is an expanded multidisciplinary procedure and an established discipline in different clinical centres.

This approach allows adopting less aggressive and invasive options, offering relevant and real time information to the surgeon concerning the location and extent of the disease. The information obtained minimises the surgical invasiveness of many diagnostic and therapeutic procedures. The possibility of identifying, with higher accuracy, patients who can be spared unnecessary lymph node dissection or a better and reliable tumoural excision constitutes a crucial improvement in clinical practice brought about by radioguided surgery and lymphathic mapping.1

The detection and excision of tumours with the aid of such a technique has been described to have excellent results. The use of radioguided occult lesion localisation (ROLL) in non-palpable invasive breast cancer is a surgical technique with a high rate of radical excision compared with wireguided localisation. It was first described nearly 20 years ago in the IEO of Milano and many groups have introduced it in clinical practice. It is based on the intratumoural/peritumoural deposit of a large particle size radiotracer and its localisation with the aid of a handheld gamma probe. This easy-to-do approach has demonstrated a good excision rate, with free-involvement margins and less second surgical re-excisions in comparison with hook-wire approach. Some technical modifications/alternatives have been adopted throughout the years. Thus, the use of radiotracers with a smaller particle size allowed the tumour and the sentinel lymph node (SLN) localisation in the same procedure (SNOLL). The introduction of radioactive seeds gave a nice alternative and refinement to ROLL technique.2 Recently, Lombardi et al. included a cohort of patients with breast cancer to radioguided conservative surgery using a standard gamma probe and a high-resolution handheld camera. They concluded that the combination of these procedures represent an improvement in the surgical management of occult breast carcinomas and is the method of choice for accurate tumour localisation. Handheld cameras have the potential to become highly useful intraoperative aids.3

“Radioguided surgery involves less aggressive surgical procedures and offers real-time information to the surgeon”

Furthermore, the detection of other targeted tissues is used in several fields. Thus, the radiolocalisation of benign endocrine tumours is a demonstrated useful technique. Goldestein et al. evaluated the results of a large series of patients with hyperparathyroidism that underwent minimally invasive radioguided parathyroidectomy without routine intraoperative serum parathyroid hormone (PTH) measurement. The results showed an excellent cure rate for primary hyperparathyroidism with a low rate of surgical complications.4 Currently this technique is usually performed with the intraoperative PTH determination for better results.5 Another example to be mentioned is the use of somatostatin analogues (such as 111In-pentetreotide) or other molecules for the localisation and surgical resection of neuroendocrine tumours (NETs).
Radioguided surgery detects more and smaller lesions compared to pre-surgical imaging and intraoperative digital palpation by the surgeon. It detects residual lesions and also indicates the shortest access route to the lesion. Nevertheless, its use has not become a standard because of technical difficulties.6

Nowadays, the most widespread radioguided surgery technique is the SLN localisation and biopsy. It is indicated for accurate staging of several solid cancers. It was first described in melanoma by using dyes; however, in recent clinical practice, the SLN approach with the aid of radiotracers is extended to other tumours like breast, oropharynx, gynaecologic and urogenital cancers.

The concept of SLN biopsy in oncologic surgery is related to the fact that any solid tumour drains in an orderly fashion via the lymphatic system, from the lower to the upper levels. Therefore, the SLN, namely the first lymph node encountered by lymph draining from the tumour site, is most likely to be the first one to be affected by metastasis, while a negative SLN makes it highly unlikely that other lymph nodes along the same lymphatic pathway will be affected. The main objectives of SLN biopsy is to avoid unnecessary lymphadenectomies and to identify the 20–25% of patients with occult regional metastatic involvement. This technique reduces the associated morbidity from lymphadenectomy and increases the occult lymphatic metastases identification rate by offering the pathologist a few lymph nodes with highest probability of containing metastatic cells.

Based on the use of radiocolloids, preoperative imaging using lymphoscintigraphy became possible and, principally in Europe, this approach was incorporated into daily practice by performing radiotracer injection and skin marking of the identified SNs the day before surgery. Therefore, lymphoscintigraphy may be considered as the first roadmap for surgeons enabling the preoperative determination of lymphatic drainage and SLN localisation. Preoperative imaging is the best procedure to identify relevant nodes. The tracers are administered in the tumour area and it migrates through lymphatic system to finally remain in the SLN. Radiocolloids (such as 99mTc-nanocolloidal albumin) are mostly used in Europe. A preoperative accurate localisation is the goal for offering an optimal surgical planning and the optimum images should be performed in order to identify the number, location and amount of activity of the lymph nodes (Figure 1). Lymphoscintigraphy is crucial to recognise the SLN and it is a standard procedure in most of European countries. The protocol of acquisition of planar images varies between centres and the type of carcinoma disease, although it is recommended to perform three different views to increase the active lymph node visualisation. The SLN visualisation is usually observed (>95% cases) within two hours after radiotracer injection and surgery can be scheduled from this time point to 24 hours later. This is an important issue for surgical planning and it varies through institutions (one or two-day approach).7

Figure 1: Planar Lymphoscintigraphy in-patient with right flank melanoma. Anterior and Lateral of thorax (A–B) and abdomen area. The images demonstrate lymphatic drainage to several right paracostal nodes and right inguinal nodes.

There are cases where the localisation of radioactive nodes remains unclear with planar images; in those cases, fusion images obtained with single photon emission computed tomography with CT (SPECT/CT) improve SLN identification allowing anatomical and functional imaging data information (Figure 2). SPECT/CT is a more sensitive technique than conventional lymphoscintigraphy. The use of SPECT/CT depends on the complexity of lymphatic drainage. In malignancies with predominantly superficial drainage (for example, melanoma and breast cancer) validation of SPECT/CT has been based on specific indications as for instance when SNs in the axilla are not depicted on planar images or when the overlying injection site masks lymph nodes that are located in its vicinity. In a recent review, Vermeeren et al. conclude that current indications for SPECT/CT in patients with breast cancer appear to be nonvisualisation when conventional imaging is performed, obesity and presence of extra-axillary sentinel nodes or otherwise unusual drainage and it might also be performed if the conventional images are difficult to interpret. For the patients with melanoma, it is suggested that SPECT/CT adds relevant information in areas with a complex anatomy like head and neck and the scapular region, or when an unexpected drainage pattern is observed.8

In tumours with complex lymphatic drainage like gynaecological and urological malignancies SPECT/CT is becoming mandatory to localise SNs in anatomically difficult areas such as the pelvis and abdomen. Also in patients with oral cavity cancer and papillary thyroid carcinoma, SPECT/CT contributes to SN identification in the neck basins.9 SPECT/CT should be considered as a complementary modality to planar images of lymphoscintigraphy.

Interpretation of SPECT/CT requires to be performed in combination with the findings of planar images. The acquisition of early and delayed planar images enables lymphoscintigraphy to identify SNs in a majority of cases. In most current protocols, SPECT/CT is performed following delayed planar images (mostly two to four hours after tracer administration). This sequential acquisition helps to clarify the role of both modalities.10

Intraoperative approach
Perioperative imaging employing conventional and hybrid equipment (SPECT/CT) maximises the information on which the surgeon can plan the best approach. The location of a SLN can be marked on the patient’s skin after the late images by positioning an external radioactive point source over the sentinel node during real-time imaging or with the aid of a gamma ray detection probe.

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However, the use of dyes (methylene, patent or isosulfan blues), injected just before surgery, may assist in visual confirmation of the afferent lymphatics from the primary tumour site to the SN. The blue dye travels through the lymph nodes without being trapped. The combination of scintigraphy, gamma probe and blue dye yields the highest accuracy in SN identification. This combining of information is an excellent method for decreasing false-negative findings and increasing sensitivity. In cases of a primary melanoma in close proximity to its regional nodal basin, where the injection depots of the radiocolloid can cause a high background radioactivity interfering with the gamma probe location of SLNs, blue dye is especially useful.

Figure 2: Anterior planar image in a cervical cancer patient showing lymphatic drainage to right common iliac nodes as well as paracaval nodes (A). Maximum intensity projection (MIP) and 3D volume rendering obtained from SPECT/CT data (B and C, respectively).

Figure 3: Sentinel Lymph node localisation by using a handheld gamma probe in a patient with oral cavity tumour. Intraoperative localisation (A), Sentinel node excision in right level II cervical area (B) and surgical field checking with probe for asses remaining activity (C).

“SPECT/CT and intraoperative imaging devices offer the possibility to refine and modify surgery planning”

Intraoperative detection of SLN with a gamma ray detection probe should be performed for over 24 hours after injection of the radiolabelled agent. Radioguided surgery using a gamma probe is an established practice.11 The detector is usually of limited size, basically a long narrow cylinder with a diameter of 12–18mm, sometimes slightly angled in order to allow easier handling within the surgical field. The gamma probe can be utilised in the surgical area because it is made of a material that can be sterilised or it can simply be covered with a sterilised wrapping (such as those used for intraoperative ultrasound probes). Gamma probes provide count rate display and variable-pitch audio output based on the local activity concentration. Through the digital readout and acoustic signal, the gamma probe enables the surgeon to precisely localise areas of maximum radioactivity accumulation, thus guiding identification and removal of the target tissue. Using the preoperative images and the skin marks, the gamma probe could guide the dissection of the hot lymph nodes and explore the surgical bed with the probe after node excision to confirm removal of the hot nodes or remaining activity (Figure 3). SLNs with ex vivo counting rates that are 10% or more of the counting rate of the hottest node may contain metastases even when the hotter nodes are negative. However, this standard of care approach can be cumbersome in patients with a high body mass index or areas with complex anatomy where the intraoperative localisation by means of the gamma probe only may be very challenging.12

To overcome these difficulties, several new approaches have recently been developed. Small gamma cameras for intraoperative imaging assessment are rapidly growing. These devices provide real-time imaging with a global overview of all radioactive hot spots in the whole surgical field. Intraoperative imaging with portable gamma cameras can be used during either open surgery or laparoscopic procedures; the information gained can be combined with data obtained with conventional or laparoscopic gamma probe counting. The introduction of intraoperative imaging technology into the surgical theatre holds great promise for patients undergoing radioguided surgery. Overall, the expansion of intraoperative detection may allow the surgeon to alter his/her intraoperative decision-making (Figure 4). Thus, it may also lead to improved patient management, decreased patient morbidity, improved long-term patient outcomes and healthcare system cost-savings.13

New developments and future perspectives
The concept of radioguided surgery has been modified through the years, with the emerging technology. The popularity gained by the SLN procedure in the last two decades increased the interest of the surgical disciplines for other applications of radioguided surgery. An example is the gamma probe guided localisation of occult or difficult to locate neoplastic lesions. Such guidance can be achieved by intralesional delivery of a radiolabelled agent that remains accumulated at the site of the injection. Another possibility rested on the use of systemic administration of a tumour-seeking radiopharmaceutical with favourable tumour accumulation and retention. In 2011 it was described the concept of guided intraoperative scintigraphic tumour targeting (GOSTT) to include the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap that would optimise surgery. Almost parallel to the introduction of the GOSTT concept, some advances appeared in this field.14

Figure 4: Lymphatic drainage for a lower lobe thyroid cancer. Anterior planar image (A). 3D volume rendering reconstruction (B). Intraoperative image obtained by a portable gamma camera, showing the most craneal sentinel nodes (C). Simultaneous optical and scintigraphy fused images obtained with a hybrid portable camera (D).

“GOSTT involves the whole spectrum offered by radioguided procedures to optimise the surgical approach”

Besides dyes and radiocolloids, fluorescent tracers in the near-infrared spectrum were increasingly being used for lymphatic mapping. Indocyanine green (ICG) is being introduced in routine clinical practice of SLN and even nanocolloidal radiotracer has been combined with ICG providing an hybrid, bimodal tracer, which allows the surgeon to integrate the standard approach based on radioguided detection with a portable gamma camera with a new optical modality based on fluorescent signal detection. This approach is being successfully applied in different malignancies (head and neck, urological, melanoma, breast cancer).15

Currently, there are new possibilities to explore and to be possibly integrated in the radioguided surgery approach. An interesting development based on the handheld probes is the combination of these intraoperative devices with position and orientation tracking systems. This results in a 3D visualisation of the traditional acoustic signal of the gamma probe.

Another area of expansion of the GOSTT concept is constituted by the transference of SPECT/CT imaging to the operating room using mixed reality protocols. With the use of a tracked protocol it has become possible to transfer the virtual SPECT/CT images to the operating room providing intraoperative virtual navigation. This approach will also lead to the requirement for further integration of nuclear physicians and technologists to the surgical act. Real-time image interpretation and decision-making in the operating room to support surgical specialists will obviously demand necessary adjustments in the daily schedules of nuclear medicine departments. The future in this field will be undoubtedly bright.


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