Radioguided Surgery: Novel Applications
A few years ago, the concept of Guided intraOperative Scintigraphic Tumor Targeting (GOSTT) was introduced to encompass the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap for radioguided surgery. This concept included the use of interventional nuclear medicine imaging to depict targets to be resected by radioguided surgery. With the incorporation of SPECT/CT and PET/CT, three-dimensional roadmaps to guide surgical procedures became possible. On the other side, new intraoperative portable imaging devices (gamma cameras and other tools) were added to conventional modalities such as gamma probes and blue dye. More recently, the development of hybrid tracers integrating radioactivity and fluorescence in one single signature has enabled the additional use of near-infrared cameras. All these advances have facilitated the extension of radioguided sentinel lymph node biopsy procedures from the classical applications in cutaneous melanoma and breast cancer to other fields such as oral cavity, gastrointestinal, urological, and gynecological malignancies. At present, three GOSTT working models can be defined in relation to radiotracer administration: intralesional without tracer migration for occult lesion localization, intralesional with tracer migration for occult lesion localization and sentinel lymph node biopsy, and systemic to enable excisional biopsy of primary lesions and recurrences as well as isolated regional and distant metastases. The latter is probably the field with the largest potential due to the continuous introduction of new PET and SPECT tracers. Novel modalities like luminescence detection and tracked image-guided navigation will further reinforce the role of GOSTT and radioguided intervention procedures.
KeywordsGuided intraoperative scintigraphic tumor targeting GOSTT Radioguided surgery Novel applications Sentinel lymph node biopsy Lesion occult localization Interventional SPECT/CT Interventional PET/CT Intraoperative portable imaging technologies
American Joint Committee on Cancer
X-ray computed tomography
Guided intraOperative Scintigraphic Tumor Targeting
Metastasis status according to the AJCC/UICC TNM staging system
Multiple endocrine neoplasm
Maximum intensity projection
Lymph node status according to the AJCC/UICC TNM staging system
Positron emission tomography
Positron emission tomography/Computed tomography
Prostate-specific membrane antigen
Radioguided occult lesion localization
Radioguided 125I seed localization
Sentinel lymph node
Combined sentinel lymph node biopsy and radioguided occult lesion localization
Single-photon emission computed tomography
Single photon emission computed tomography/Computed tomography
Tumor status according to the AJCC/UICC TNM staging system
Union Internationale Contre le Cancer (International Union Against Cancer)
Radioguided surgery is one of the applications of nuclear medicine with more relevant growth in the last quarter-century. Radioguided surgery constitutes a wide range of combined procedures involving close collaboration with other specialties like surgery, pathology, and radiology; correct application of such multidisciplinary procedures ensues obvious immediate and long-term benefits to the patient. In general, radioguided surgical procedures are less invasive than traditional surgical approaches, while they may also result in improved local-regional control of malignant disease .
In 2011 the term GOSTT (Guided intraOperative Scintigraphic Tumour Targeting) was introduced in order to encompass the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap for radioguided surgery . The GOSTT concept was recently further updated incorporating the discussion of novel modalities such as hybrid tracers for simultaneous fluorescence and radioactive signal detection, sophisticated navigation approaches based on mixed-reality protocols, and the use of Cerenkov luminescence related to PET tracers . An extensive overview of the GOSTT procedures is given in a book recently edited by the International Atomic Energy Agency (IAEA) .
Working GOSTT Models in Interventional Imaging and Radioguided Surgery
The basic modality to illustrate and discuss the GOSTT concept is the sentinel lymph node (SLN) procedure. Historically, the term “sentinel lymph node” was introduced to describe a group of lymph nodes retrieved in patients with penile carcinoma under the assumption that they receive direct drainage from the site of the primary lesion . In the last 25 years, radioguided surgical applications have rapidly expanded especially to perform sentinel lymph node (SLN) biopsy. In addition to ongoing applications in patients with breast cancer and cutaneous melanoma, radioguided SLN biopsy has been extended to a wide variety of other solid epithelial malignancies such as head and neck cancers, gynecological cancers (vulvar, cervical, and endometrial), gastrointestinal cancers (esophagus, stomach, colorectal, anus), urological malignancies (prostate cancer, bladder cancer, penile carcinoma, and others), non-small cell lung cancer, differentiated thyroid carcinoma, and others [1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15].
A second field of GOSTT applications is constituted by the excisional biopsy techniques based on direct intralesional injection of 99mTc-MAA, which are expanding from the classical application of “radioguided occult lesion localization” (ROLL) for nonpalpable breast lesions to other tumors, such as solitary pulmonary nodules as well as others [16, 17]. In more recent years, the ROLL technique has been used in breast-conserving surgery combining lumpectomy and SLN biopsy [18, 19].
The model of systemic tracer administration is illustrated by radioguided parathyroid surgery with 99mTc-sestamibi, a radiotracer with preferential uptake and/or accumulation in tumor tissues. This approach has also been described using radiolabeled monoclonal antibodies against tumor-associated antigens. These procedures also include receptor-mediated uptake of radiolabeled agents by tumors such as neuroendocrine tumors or paragangliomas, accumulation of bone-seeking agents for radioguided excision of isolated bone metastasis, and radioiodine uptake in recurrences/metastases from differentiated thyroid carcinoma. The field of applications following systemic administration has been extended to intraoperative radioguidance using [18F]FDG or other positron-emitting radiopharmaceuticals using specific probes able to detect the high-energy gamma photons originated by the annihilation reaction or directly β+ particles . More recently, an intraoperative Cerenkov luminescence device for detection of [18F]FDG-avid malignant lesions has been presented .
This chapter will focus on radioguided surgery in the context of the GOSTT concept, emphasizing the innovative methodological aspects for both novel clinical procedures and the more recent investigational applications.
General Background of SLN Biopsy
The rationale of SLN biopsy in solid epithelial tumors relates to the general concept that initial lymphatic spread of such tumors occurs to locoregional lymph nodes in an orderly way, generally from lower- to higher-echelon levels. Of course, this orderly progress does not exclude the potential of tumors to spread hematogenously, which is associated with most distant metastases. Probably in only few circumstances do distant metastases arise from progression of an initial lymphatic metastasis.
The modern SLN concept [22, 23] concerns not only the first lymph node encountered by lymphatic vessels draining the primary tumor but also all first-echelon lymph nodes upon which a lymph vessel originating in the tumor drains directly. This definition does not always correspond to the lymph node nearest to the tumor, as the route of the lymphatic vessels may be complex and unpredictable with different lymphatic pathways leading to different sentinel lymph nodes (Fig. 1); in practice each lymph node identified as SLN should therefore be investigated for the presence of metastasis. Lymphatic mapping following interstitial radiocolloid injection is essential to precisely visualize sequential lymphatic drainage of the radiopharmaceutical and to provide surgeons an intraoperative roadmap [24, 25].
The presence or absence of SLN metastasis usually has a significant impact on therapeutic strategy. In patients with early cancer, if the SLN does not contain metastasis, the surgical approach should aim at removing the primary tumor and avoiding unnecessary regional node dissection. The likelihood that non-SLNs contain metastasis is extremely low, thus making extensive node dissection unnecessary in case the SLN is free from metastasis. Patients whose SLN contains metastasis usually require dissection of regional lymph nodes .
The Evolution of Intraoperative Instrumentation for SLN Biopsy and Other GOSTT Applications
Gamma probes were incorporated into the procedure of SLN biopsy in the early years of the procedure . These devices were able not only to count radioactivity in the surgical field intraoperatively but also to provide numerical readouts and audible signals proportional to the counting rate. The hand-held probe is connected to a counting unit either with a cable or with a wireless system. The detector is usually limited to a long narrow cylinder with a diameter varying from about 12 mm up to 16–18 mm. It may be slightly angled in order to allow for easier access in specific applications and easier manipulation within the surgical field.
Thanks to the auditory signals and digital readouts, gamma probes enabled the surgeon to localize and remove radioactive tissue like the SLN or tumor tissue. In fact, gamma-probe counting constituted the acoustic component of the SLN identification procedure in the operating room and for surgeons was the complement of the process of visual detection as implemented by the use of blue dyes. This acoustic/visual feature was introduced in the early 1990s as a step forward in comparison with the original approach, which was exclusively based on the injection of blue dyes to visualize lymphatic ducts and SLNs as originally described by Morton et al. .
The combination of gamma-probe counting and blue dies represented the second step in the evolution of the procedure. On the other hand, this possibility to combine visual and acoustic signals during the surgical SLN procedure has become the cornerstone for new portable technologies, which now enable image generation in the operating room reinforcing the visual component in the guidance of surgical excision . These portable imaging technologies include devices like small gamma cameras for high-resolution planar imaging , gamma probe- or small camera-based devices for 3D intraoperative imaging , near-infrared (NIR) cameras used in combination with portable gamma devices when fluorescent detection is added to the SLN procedure , and cameras for Cerenkov luminescence imaging .
Preoperative Imaging: From Planar Images to Hybrid Computed Tomography
Lymphoscintigraphy constitutes the cornerstone of preoperative lymphatic mapping. Its incorporation to the SLN procedure helped to transform the paradigm in radioguided SLN surgery from the original “open and see” approach based on the use of vital dies to visualize lymphatic ducts and SLNs to another “see and open” based on the gamma camera images acquired prior to the surgical procedure. This lymphatic mapping enabled not only to personalize imaging of lymphatic drainage for every individual patient but also made possible to mark with indelible ink the SLN site projection on the skin. This approach gained in popularity in Europe and was highly effective for SLN localization not only in the expected areas of drainage but also in unusual locations . Lymphoscintigraphy was found to be 88–96% reproducible in melanoma [31, 32] and 100% in breast cancer as well as penile cancer [33, 34].
For SLN identification, early images, to depict first draining lymph nodes, and delayed images, to differentiate second-echelon nodes, are required. The visualization of lymphatic ducts, the time of lymph node appearance, the lymph node basin, and the intensity of lymph node uptake are all important factors to take into account. Lymph nodes draining from the site of the primary lesion through their own lymphatic vessel, or a single radioactive lymph node in a basin, are considered as definitely SLN. Lymph nodes appearing between the injection site and a first draining node or nodes with increasing uptake appearing in other lymph node basin may be considered as SLN with a high probability. Higher-echelon lymph nodes in the trunk and extremities or lower-echelon nodes in the head and neck region may be included in the low-probability SLN category .
More than 10 years after planar lymphoscintigraphy, SPECT/CT imaging was introduced in the SLN procedure , thus enabling to incorporate an additional dimension to preoperative mapping. In fact, the functional information on draining lymph nodes provided by SPECT could be combined with the morphological information from CT by acquiring both modalities in one session. The resulting fused SPECT/CT images were able to depict SLNs in an anatomical landscape, thereby providing important reference landmarks to be recognized by surgeons in the operating theater. Lymphatic mapping complemented by SPECT/CT is currently applied both in malignancies with predominantly superficial drainage (e.g., breast cancer and melanoma) and in tumors draining to deep lymphatic basins or areas of complex anatomy such as the head and neck or the pelvis [37, 38, 39, 40, 41, 42, 43, 44, 45, 46]. A specific requirement for SLN localization is that the CT component of SPECT/CT must be of sufficient high quality to provide optimal anatomical landmarks to be recognized by surgeons in the operating room. The CT component is also used to correct the SPECT signal for tissue attenuation and scattering; thanks to such corrections, SPECT/CT may be particularly useful in obese patients to detect SLNs not observed on planar images and additional SLNs in other basins. After these corrections, SPECT can be fused with CT. For fused images a gray scale is used to display the morphology in the background image (CT), whereas a color scale is used to display the SLN in the foreground image (SPECT). Most frequently, a radioactive hot spot corresponds to a single lymph node on CT, but in some cases it correlates with a cluster of lymph nodes .
Simultaneously with the evolution of the SLN procedure, a similar “see and open” approach is catapulting also other applications of radioguided surgery in which preoperative imaging plays an important role leading to surgical intervention. This interventional molecular imaging can be illustrated by the preoperative use of 99mTc-sestamibi scintigraphy for the localization of parathyroid adenomas, where preoperative imaging is used as a roadmap for radioguided surgery of these lesions . Recently, the addition of SPECT/CT to planar imaging did significantly increase the accuracy in correctly identifying a parathyroid adenoma from 75% to 85% .
Radiopharmaceuticals for Interventional Molecular Imaging and Radioguided Surgery
As mentioned earlier, an important aspect in GOSTT possibilities is related to the choice of radiotracers for interventional imaging and radioguided surgery. For lymphoscintigraphy and radioguided SLN biopsy, the tracers most widely used are radiocolloids that, after their interstitial administration, migrate from the injection site allowing the visualization of the lymphatic vessels by lymphoscintigraphy and SPECT/CT . These colloids are preferentially retained by the first lymph nodes encountered along the course of the draining lymphatic vessel(s), enabling their identification as SLN(s). Once within the lymph node, radiocolloids are phagocytized by macrophages lining the lymph node sinusoids. Such retention of radiocolloids in the SLN is a physiological process and does not indicate presence or absence of metastases in the lymph node. Radiocolloids can be constituted by an inorganic substance (198Au-colloid, 99mTc-antimony sulfur, 99mTc-colloidal sulfur, 99mTc-stannous fluoride, 99mTc-rhenium sulfur) or can be derived from biological substances (nano- or micro-colloidal human serum albumin). Radiocolloid particle size, varying from 5 to 1,000 nm, mainly determines the speed of lymphatic drainage from the interstitial injection site and the amount retained in the SLN. In particular, small-size radiocolloids (less than about 100 nm) migrate quite fast from the injection site through the lymphatic system. This factor underlines the need to sequentially perform dynamic images at short time intervals after interstitial injection as well as static early and delayed images in order to differentiate SLNs from secondary lymph nodes. Larger size radiocolloids are retained longer in the SLN, so that lymphoscintigraphy does not generally visualize more than one to two lymph nodes along a single lymphatic draining vessel. However, migration of larger particles from the interstitial administration site is very slow, so that a longer time, even 2 h or more, can be required to complete mapping. In Europe, 99mTc-albumin nanocolloid (which has a quite narrow range of particle size, with over 90% of the particles being smaller than 80 nm) is widely available and employed, while in the USA, 99mTc-sulfur colloid (with a wide range of particle size between about 20 and 400 nm) is the most employed; to overcome the problem of heterogeneous particle size distribution, in some nuclear medicine centers, 99mTc-sulfur colloid is filtered immediately after labeling and prior to administration, in order to remove particles with a diameter bigger than a certain size, usually 220 nm or other sizes [50, 51].
The radiopharmaceutical 99mTc-tilmanocept has recently been introduced for lymphatic mapping and SLN biopsy. This radiotracer accumulates in SLNs after binding the mannose-binding protein receptor expressed on the surface of phagocytes. 99mTc-tilmanocept contains 7 nm particles, which are rapidly cleared from the injection site through lymphatic vessels . In contrast to larger particle radiocolloids, there is also significant diffusion into the blood capillaries. Although diffusion from the injection site via the blood route may limit the amount of lymphatic flow of the tracer, the reduction in signal intensity at the location of the primary lesion may facilitate identification of SLN located close to the injection site. 99mTc-tilmanocept has been used in oral cavity cancer , melanoma , and breast cancer .
More recently, the hybrid tracer indocyanine green-99mTc-nanocolloid (ICG-99mTc-nanocolloid) has been explored for clinical use. Concerning lymphatic drainage pattern and SLN location, this novel tracer showed a 100% reproducibility rate when compared with the parental 99mTc-nanocolloid in patients with different malignancies and lymphatic drainage basins . Based on its radioactive signature, such hybrid tracer preserves the possibilities for perioperative imaging using conventional gamma cameras, SPECT/CT, and portable devices. At the same time, the added fluorescent signature leads to improved visual resolution and SLN detectability during surgery. A further validation of the clinical applicability of ICG-99mTc-nanocolloid has been reported for oral cavity cancer , vulvar cancer , penile cancer , prostate cancer , and more extensively in melanoma .
Intralesional tracer administration enabling excisional biopsy of primary tumors is a GOSTT application known as “radioguided occult lesion localization” (ROLL) , originally validated for breast lesions but with subsequent rapid extension to other malignancies. The first clinical validation of ROLL was based on a direct intralesional injection of 99mTc-MAA in nonpalpable breast lesions guided by ultrasonography or stereotactic mammography . To accomplish concentricity in the distribution of the tracer into the tumor, the radiotracer must be injected as centrally as possible in the lesion. During excision, which can be performed on the same day or on the next day, the gamma probe is introduced through a small skin incision that can ensure an optimal cosmetic outcome without the topographic constraints required by the classical intralesional markers such as the carbon tracer of the hooked wire. Intraoperative gamma-probe counting enables the surgeon to easily localize the focal deposition of 99mTc-MAA, thereby facilitating the procedure. The surgical specimen is checked ex vivo with the gamma probe for further confirmation of radioactivity and can also be x-rayed to ensure complete removal of the area containing the lesion. The technique enabled a 99.5% lesion removal rate in the breast . When used in combination with wire localization in nonpalpable breast cancer, ROLL did significantly reduce reoperation from 21% to 2% . In the last years, radioguided iodine-125 seed localization (RSL) has been introduced for excisional breast lesion . Using similar gamma-probe devices, RSL appears to be comparable with ROLL concerning margin status and re-excision rates, but with significantly lower weight of the resected specimen in patients with nonpalpable ductal carcinoma in situ or invasive carcinoma . In locally advanced breast cancer receiving neoadjuvant chemotherapy, RSL is also comparable with ROLL but with more practical advantages, due to the long halftime of iodine-125 which enables seed implantation before chemotherapy without additional tracer injection for excision of residual tumor . The ROLL principle has been applied in other tumors such as papillary thyroid cancer , solitary pulmonary nodules , and lymph node metastases . On the other hand, RSL has been helpful to localize axillary metastatic lymph nodes after neoadjuvant chemotherapy in breast cancer patients reaching a 97% identification rate .
More recently the ROLL technique has been used in breast-conserving surgery combining lumpectomy and SLN biopsy by means of a single intralesional tracer injection [18, 19]. This approach is known as SNOLL and is based on the use of a radiocolloid with the ability to migrate to the regional lymph nodes. Basic work based on ex vivo lymph node measurements effectuated in the 1990s when validating the SLN procedure demonstrated that when 99mTc-nanocolloid is administered into a breast tumor, only 2–3% migrate to the axillary SLNs, while the remaining predominant fraction remains at the injection site and can thus guide a ROLL procedure simultaneously with the SLN biopsy procedure .
Radioguided surgery related to the systemic administration of a tracer is probably the GOSTT working model with the greatest potential for the future. This potential is based on the detection by either SPECT/CT or PET/CT (depending on the radiopharmaceutical used) of target lesions with subsequent indication for resection for diagnostic or therapeutic purposes. The indication may be closely related to suspected cancer recurrence with elevation of tumor markers during follow-up. For example, PET/CT with [18F]FDG in combination with a hand-held PET probe, suitable to detect 511 KeV gamma emissions, resulted in appropriate tissue sampling by excisional biopsy approach in patients with suspected lymphoma . Also in patients with breast cancer, melanoma, and other malignancies, PET/CT led to the resection of [18F]FDG-avid metastases using a high-energy gamma probe . More recently, an intraoperative device for detection of [18F]FDG-avid malignant lesions based on the detection of the Cerenkov luminescence, which is emitted by emitters of β-particles (both negatrons and positrons), has been used for optical lesion visualization .
Regarding radiopharmaceuticals for SPECT, besides the aforementioned 99mTc-sestamibi [48, 49], another example can be found in radioguided surgery of neuroendocrine tumors (NETs) using 111In-DTPA-pentetreotide; this approach was found to be useful to guide cytoreduction in 29 out of 30 patients with abdominal NETs . Also radiolabeled metaiodobenzylguanidine (MIBG) has been advocated to improve quality of resection in selected NET cases . On the other hand, SPECT/CT led to improve lesion definition and localization with reduction of false-positive results in NET patients . More recently, 68Ga-labeled somatostatin analogues have been incorporated to radioguided surgery of NETs in a “see and open” approach on the basis of preoperative PET/CT and intraoperative gamma-probe guidance .
Interventional SPECT/CT and PET/CT for GOSTT
SPECT/CT is usually performed in addition to lymphoscintigraphy as a preoperative phase of the SLN procedure. SPECT/CT imaging with 99mTc radiocolloids is possible thanks to the prolonged lymph node retention after phagocytosis of such radiocolloids by the macrophages, which often results in an adequate detection window. This facilitates not only the acquisition of delayed planar images and SPECT/CT but also intraoperative gamma ray-guided SLN localization.
For detection of both SLNs (when patient is scheduled for SLN biopsy) and metastatic tumor tissue (when tumor-seeking radiotracers are used), a specific requirement for localization is that the CT component of SPECT/CT needs to be of sufficient quality to provide optimal anatomical information. The second generation of SPECT/CT gamma cameras includes an improved CT component; this enables the identification and evaluation of the lymph nodes corresponding with the radioactive nodes on fused SPECT/CT images by acquiring a low-dose (e.g., 40 mAs) CT. In superficial areas such as the groin and the axilla, 5-mm slices may provide adequate anatomical details. For more complex anatomical areas (head/neck, pelvis, abdomen), 2-mm slices may be necessary. With this approach, SPECT/CT can accurately localize SLNs in relation to the vascular structures in deep anatomical areas.
The CT component is also used to correct the SPECT signal for tissue attenuation and scattering. After these corrections, SPECT can be fused with CT . For fused images a grayscale is used to display the morphology in the background image (CT), whereas a color scale is used to display the SLN in the foreground image (SPECT).
For reading/reporting purposes, SPECT/CT or PET/CT images are mostly displayed in a similar manner as that of conventional tomography. Two-dimensional display of fused images to be correlated with CT and SPECT is facilitated by multiplanar reconstruction (MPR), and the use of cross-reference lines allows for the navigation between axial, coronal, and sagittal views. In the SLN procedure, this tool enables the correlation of radioactive SLNs seen on fused SPECT/CT with lymph nodes seen on CT. Most frequently, a radioactive SLN corresponds to a single lymph node on CT, but in some cases it correlates with a cluster of lymph nodes. This information may be useful for the intraoperative procedure and the post-excision control using portable gamma cameras or probes, as additional radioactive SLNs may be detected with the high-resolution portable gamma camera at the same location, then harvested for analysis.
The use of maximum intensity projection (MIP) to display fused SPECT/CT or PET/CT images may also help surgeons to anatomically recognize and localize SLNs or radiotracer-avid metastases. MIP is a specific type of rendering in which the brightest voxels are projected into a three-dimensional image. A limitation of MIP is that the presence of other high-attenuation voxels on CT may complicate recognition of the vasculature and other anatomical structures. Furthermore, MIP is actually a two-dimensional representation, which cannot accurately depict the actual relationships of the vessels and other structures . Also localization of SLNs or of tracer-avid metastases in a three-dimensional context can be supported by the application of volume rendering. In this modality different colors are assigned to anatomical structures such as vessels, the muscle, bone, and skin. This results in easily recognizable anatomical reference points of the target lesions, for instance, in relation to the vasculature. By incorporating a color display, volume rendering improves visualization of complex anatomy and 3D relationships.
Retrieving SPECT/CT and PET/CT Findings in the Operating Room
Another important possibility to utilize SPECT/CT and PET/CT findings during surgery is the intraoperative real-time generation of virtual elements. These elements can be added to the surgical environment in the context of an augmented reality protocol. Augmented reality approaches can be considered as a part of mixed reality, but it is also an independent modality, which has been applied in radioguided surgery mainly after the introduction of the freehand SPECT technology based on a tracked gamma probe suitable for 3D image generation . This device has been the basis for augmented reality experiences in SLN procedures in breast cancer , oral cancer , and melanoma , as well as for surgery of parathyroid adenomas . The same freehand SPECT technology may be considered a helpful tool in transferring SPECT/CT, and potentially PET/CT, to the operating room using mixed reality protocols. The concept of mixed reality was introduced by Milgram and Kishino in 1994 and concerns the merging of real and virtual elements to produce new environments . More related to the GOSTT approach, with the use of a tracked protocol, it has become possible today to transfer the virtual SPECT/CT images to the operating room, so that a merged environment can be created for adequate surgical navigation. This approach enabled to generate tracked 3D images of a phantom prepared with a reference target (ReT) and simulated SLNs containing ICG-99mTc-nanocolloid. After feeding the SPECT/CT images to the navigation system, optical tracking could be used to position the tip of the fluorescence endoscope relative to the preoperative 3D imaging data allowing accurate identification of the simulated SLNs in the phantom. A similar approach was used to navigate toward the prostate and SLNs in a patient undergoing robot-assisted prostatectomy . This navigation approach has been found to be feasible in areas of rigid anatomy like the retroperitoneal space and the groin . However, more difficulties for SPECT/CT-based mixed reality surgery are to be expected for “non-rigid” anatomical areas. Recently, the use of freehand SPECT in combination with a mobile handheld gamma camera has been validated . The freehand SPECT technology has also been used to generate intraoperative 3D navigation for single or multiple 125I-seeds in RSL l  and ROLL  in breast-preserving cancer surgery.
Novel Clinical GOSTT Applications
The clinical SLN applications in breast cancer, cutaneous melanoma, and head and neck cancer are extensively discussed in other chapters of this book. This chapter mainly concerns novel clinical applications as well as the incorporation of new technologies for both preoperative imaging and intraoperative localization in existing GOSTT applications.
Head and Neck
In a recent study in which SPECT/CT imaging has been performed in a series of 58 patients with oral or oropharyngeal carcinoma, 11 additional SLNs were detected by SPECT/CT; one of these nodes contained metastases . In another study concerning 34 patients, extra SLNs were found by SPECT/CT in 15 patients, and in seven the anatomical level of SLN location was reconsidered . The superior anatomical information of SPECT/CT may lead to adjust surgical approach, as observed for 11 out of 38 patients (29%) with head and neck melanoma; in six patients of this group, SPECT/CT detected additional SLNs (16%) . In another study SPECT/CT modified the surgical approach (more superficial incision or incision at other site) in 9 out of 34 (27%) patients with head and neck malignancies . The surgical adjustment rate due to the additional information provided by SPECT/CT increases when SLNs are located in the periparotid areas; in 8 out of 14 patients (57%) with melanoma and drainage to the parotid region on planar lymphoscintigraphy, SPECT/CT was able to distinguish SLNs in level II of the neck from those located in or around the parotid . In another evaluation in melanoma patients, SPECT/CT caused an increase of the detection rate from 91% (planar scintigraphy) to 98% with a clinical impact of 63.6% . The overall clinical value of the SPECT/CT anatomical information for lymph node mapping was also used to adjust superselective prophylactic irradiation of the neck in a feasibility study including ten patients with squamous cell carcinoma of the head and neck . Further GOSTT developments in the head and neck region include the hybrid tracer ICG-99mTc-nanocolloid that has been reported for oral cavity cancer , the use of high-resolution portable gamma cameras in addition to SPECT/CT , and freehand SPECT probes with 3D display . The incorporation of SPECT/CT and a portable gamma camera in combination with a fluorescence camera to the SLN procedure has led to identify 26% additional SLNs 
Lymphoscintigraphy and SPECT/CT have also been validated for SLN identification in papillary thyroid cancer. In an initial study, SLNs were identified in 19 of 24 patients (79%); the identification rate increased to 96% during surgery using a handheld gamma probe. Multidirectional drainage to both central and laterocervical compartments was observed in 50% of the patients . In another series concerning 23 clinically node-negative patients combined, visualization rate of lymphoscintigraphy and SPECT/CT was 91%. The two patients without drainage presented non-SLN positive for metastases. Most SLNs were located in levels VI (83%) and II (35%) of the neck, whereas in four patients, contralateral drainage was also noted .
The use of systemic administered radiotracers has been helpful to detect local regional recurrences of well-differentiated thyroid cancer; these cases were subsequently managed using radioguided surgical excision with 131I-iodide in eight patients and [18F]FDG in another five patients with a proven loss of iodine avidity . In another study an optically tracked navigation system was used to navigate to suspected persistence or recurrence in seven patients with malignant skull base disease .
Patients with primary hyperparathyroidism and rarely tertiary hyperparathyroidism
Scintigraphic visualization of a single site of tracer uptake
Good uptake of 99mTc-sestamibi by the hyperfunctioning parathyroid gland
Absence of concomitant solid thyroid nodules
Exclusion of the multiple endocrine neoplasm (MEN) syndromes
In general, male and female urogenital malignancies located in the pelvis drain to lymphatic basins in the vicinity of the primary tumor and may follow a similar trajectory in the dissemination of regional metastases. There are different nodal groups receiving lymphatic drainage from the pelvic structures: the external iliac nodes whose medial subgroup includes the obturator nodes, the internal iliac lymph nodes, and the nodes in the trajectory of the common iliac vessels. Lymphatic spread of metastasis from malignancies of the prostate, bladder, cervix, and endometrium may frequently be found in these iliac basins. However, alternative lymphatic drainage to the para-aortic and aortocaval lymph nodes as well as to the proximity of the sacrum and anterior abdominal wall is also possible.
In penile cancer the SLN procedure was one of the first applications of SLN biopsy validated in patients with clinically negative lymph nodes, in order to select patients who can benefit from lymph node dissection. It is usually performed by intradermal peritumoral injection of the radiocolloid, following the recommendation of injecting within 1 cm radius from the primary tumor, or from the surgical scar in case of prior excision of the primary tumor . The SLN procedure has led to a SLN identification rate of 97% with an acceptable false negative rate of 7%  and to increase the 5-year survival to 91% in these patients . SPECT/CT imaging has been used to optimize the procedure and to evaluate the pattern of lymphatic drainage from the malignancy by evaluating the possible implications for the extent of inguinal lymph node dissection. In a study including 50 patients, lymphatic drainage was visualized in 82 of 86 clinically node-negative groins (95%) scheduled for the SLN procedure. All SLNs were located in the inguinal zones medial superior (73%), lateral superior (8.7%), and central superior (18.3%) on SPECT/CT. No lymphatic drainage to the inferior zones of the groin was seen which suggests the possibility to exclude these zones from a subsequent inguinal lymph node dissection in the case of a tumor-positive SLN .
In other urological malignancies, the SLN procedure has been validated only on an investigational basis in limited series of patients. In bladder cancer the imaging protocol, including lymphoscintigraphy and SPECT/CT, is similar to the one recommended for prostate cancer. Radiocolloid injection into the detrusor muscle and around the primary lesion is guided by cystoscopy . Depending on the location of the primary tumor, lymphatic drainage may be unilateral or bilateral. The addition of SPECT/CT to planar lymphoscintigraphy did increase the detection rate from 33% to 83%. The negative predictive value of the SLN procedure has been found to be 92% on the basis of 156 patients reported in the literature . In testicular cancer lymphatic drainage to lymph nodes along the abdominal aorta and vena cava is usually found after tracer administration with a single intratesticular injection; however, in some cases, SLNs are also found alongside the funicular vessels. SPECT/CT identified aortocaval or paracaval SLNs in five patients with right-sided testicular cancer and para-aortic SLNs in five patients with left-sided tumors; in three patients, SLNs along the funicular vessels were detected. All these SLNs were resected using a portable gamma camera . Finally, in renal cell carcinoma, lymphatic drainage was seen in 14/20 patients (70%) and SPECT/CT detected 26 SLNs. The SLNs were most frequently located para-aortically, but also drainage to retrocaval, hilar, celiac trunk, and thoracic (internal mammary chain, mediastinal, and pleural) SLNs was seen . The visualization of lymphatic drainage from renal cell carcinoma along the thoracic duct was further documented using SPECT/CT in 4 out 22 patients (18%) with SLN visualization .
Another important GOSTT application in gynecological surgical oncology concerns SLN biopsy in cervical cancer. A recent meta-analysis evaluating 67 studies resulted in a pooled detection rate of 89.2% and a pooled sensitivity of 90%; both SLN rates were related to mapping method (blue dye, radiotracer, or both) and history of preoperative neoadjuvant chemotherapy. Preoperative lymphatic mapping could also detect SLNs outside of routine lymphadenectomy areas, thus providing additional histological information important to optimize regional staging . A prospective multicenter study evaluated the contribution of lymphoscintigraphy to the SLN procedure in 139 patients and concluded that, although the preoperative detection rate is lower than the intraoperative one (87.8% vs. 97.8%), the substantial proportions of SLNs in unusual drainage territories found by lymphoscintigraphy provide valuable guidance for the surgical exploration . SLN visualization in preoperative lymphatic mapping can be optimized by the addition of SPECT/CT. This approach was evaluated in a meta-analysis including eight studies; the median overall detection rate was 98.6% for SPECT/CT and 85.3% for planar lymphoscintigraphy . Indication for SLN biopsy in cervix cancer concerns patients with early stage (Ia2/Ib1, IIa1) and no clinical evidence of lymph node metastases. Radiocolloid administration is based on injecting peritumoral/periorificial aliquots into the four quadrants of the cervix or pericicatricial in patients with prior conization. It is recommended to perform SPECT/CT after delayed planar imaging of lymphoscintigraphy and is crucial to assess deep lymphatic drainage and anatomical SLN localization in parametrial stations and in unusual locations .
In endometrial cancer a meta-analysis published in 2013  resulted in a pooled SLN detection rate of 77.8% and a pooled sensitivity of 89%. The evaluation was based on 51 studies with enough information for detection rate evaluation and 35 studies providing false negative rates. The combination of blue dye and radiotracer resulted in higher detection rate and sensitivity. However, there are various approaches regarding the injection site: cervical, endometrial peritumoral, and myometrial/subserosal. Although the injection of the tracer into the four quadrants of the cervix is the easiest approach with also the highest detection rates, the other two routes appear to better reflect the drainage of endometrial cancer, with a higher incidence in drainage to the para-aortic lymph node basins . SPECT/CT has been found to be helpful, and in 44 patients with high-risk endometrial cancer, SPECT/CT identified SLNs in 34 of them (77%) with a total of 110 depicted SLNs. The most frequent location was the external iliac chain (71%), but drainage to para-aortic SLNs was also common (44%). SPECT/CT was able to localize the only pelvic metastatic lymph node that was not depicted on planar images . Also recently, in a study of 70 patients with endometrial cancer, SPECT/CT detected SLNs in 64 of them (91.4%). However, SPECT/CT could detect only 88.9% of the SLNs found during surgery; most of these undetected nodes on SPECT/CT had very low activity . SPECT/CT SLN identification rate (94%) was significantly higher than that of planar lymphoscintigraphy (68%) in a series of 31 patients with endometrial cancer investigated after transcervical tracer injection into the isthmocervical myometrium .
Finally, radioguided SLN localization, without preoperative lymphatic mapping, was found to be feasible in a study including 21 patients who were at high risk of ovarian malignancy ; both radiocolloid and blue dye were intraoperatively injected into the proper ovarian ligament and suspensory ligament of the ovary. During open surgery the gamma probe identified SLN locations before retroperitoneal exploration; subsequently SLNs were detected in the para-aortic/paracaval regions only (67%), the pelvic region only (9%), and both the para-aortic/paracaval and the pelvic regions (24%).
Since lymphatic drainage from the gastrointestinal tract is multidirectional and usually follows a random pattern, preoperative lymphatic mapping for SLN biopsy can be very helpful , considering that extensive dissection shows that metastases are found in lymph nodes nearest to the primary tumor site in, e.g., only about 60% of the gastric cancers or 40–50% of esophageal cancers. Also in lower rectal cancers, skip metastases and lateral lymph node metastases are found in a high number of the patients. However, these aggressive surgical procedures are burdened by high morbidity and even mortality.
In esophageal cancer the radiocolloid is administered endoscopically by injecting in the submucosal layer at the four quadrants closer to the primary lesion in the submuscosal layer, often the day before surgery. Lymphoscintigraphy is very useful to localize unexpected patterns of drainage to distant lymph nodes. In fact, in more than 80% of the cases, lymph drainage can be observed in a wide area extending from the cervical to the abdominal region. In a systematic review and meta-analysis including 23 studies of radioguided SLN mapping, the overall detection rate was 93% with a sensitivity of 87% .
In patients with gastric cancer, SLN biopsy aims at identifying clinically undetectable lymph node involvement and is generally reserved to T1 and T2 tumors (with diameter <4 cm), in which the type of resection can be modified toward function-preserving surgery whenever possible. The radiocolloid is injected endoscopically in the submucosal layers around the tumor. In a recent study involving patients with T1N0 or T2N0 operable gastric cancer , gamma probe in combination with blue dye identified SLNs in 372 out of 385 patients (96.6%).
Locoregional lymph node staging is an important prognostic factor for colorectal malignancies. In this regard, lymphatic mapping and SLN biopsy may be very important especially for identifying alternative mesenteric lymphatic drainage patterns and for detecting lymph node micrometastasis. Although at present the most popular technique is based on intraoperative subserosal injection of blue dye at the primary tumor, lymphoscintigraphy has proven definite advantages over the blue dye technique for SLNB . However, evaluation of this approach in large-scale prospective investigations has not been performed. By contrast, in anal cancer radioguided SLN biopsy using preoperative imaging has had more acceptance; in a meta-analysis based on 16 studies including 323 patients, the best approach for SLN identification was found for the combined use of radiotracer and blue dye with a 90% detection rate .
GOSTT Applications in Other Malignancies
In lung cancer the GOSTT approach concerns both radioguided excision of solitary pulmonary nodules and radioguided SLN biopsy . The radioguided excision has been extensively validated, and in 2012 Ambrogi et al.  reported radioguided video-assisted thoracoscopic surgery in 211 patients with pulmonary nodules smaller than 1 cm and/or deeper than 1 cm below the visceral pleura; the procedure was based on preoperative CT-guided administration of 99mTc-MAA into the nodule followed by lesion excision using video-assisted thoracic surgery with gamma ray probe guidance. The procedure was successful in 208 patients (98.6%) leading to histological confirmation of primary lung cancer in 113, metastases in 61, and benign lesions in 98. On the basis of a similar clinical indication and CT-guided radiotracer administration (99mTc-MAA) in or near the nodule, 112 patients underwent thoracoscopy or thoracotomy for lesion resection; in this series histology showed 14 benign lesions, 85 primary lung cancers, and 24 metastases . Recently, 99mTc-sulfur colloid and a metallic clip were introduced into ground-glass opacities to enable resection; radiotracer administration was preceded by injection of cyanoacrylate that polymerizes immediately after injection into the lung parenchyma with the forming of a hard nodule enabling radiotracer retention, confirmed by SPECT/CT and easier identification during operation . Concerning SLN biopsy and despite limited diffusion in surgical oncology, this GOSTT procedure has been evaluated for detection rate and sensitivity in 47 and 43 studies, respectively ; pooled detection was 80.6% and pooled sensitivity 87% with higher rates for the combination of radiotracer and dyes. In a pilot study, SPECT/CT has been found to be helpful in separate draining lymph nodes from the injection site of radiotracers .
Future GOSTT Scenarios
Development of new systemic radiotracers for interventional imaging. The best example for this issue is illustrated by the recent introduction of 68Ga-PSMA for prostate cancer and its interventional use in resection of lymph node metastases. The pairing of this PET tracer to 111In-PSMA  not only enables preoperative SPECT/CT imaging but also radioguided surgery based on the more advantageous properties of 111In. Similarly paired tracer use for interventional imaging and radioguided surgery can be found for iodine-based radiotracers and somatostatine analogues.
SLN-guided lymph node template resection. This model is currently discussed for prostate cancer with high-risk of regional lymph node involvement. The use of radiocolloids to guide SLN identification can help to optimize separate injection of fluorescent agents to guide lymph node resection in the basin of the SLN.
RSL following neoadjuvant chemotherapy. In analogy with the setting for locally advanced breast cancer and based on the practical advantages due to the long halftime of iodine-125, this approach enables seed implantation before chemotherapy and excision of residual tumor or lymph node metastasis after treatment in other local advanced malignancies scheduled for neoadjuvant therapy.
Mixed-reality navigation. Probably the use of new sensor technologies for tracking will help to transfer SPECT/CT, PET/CT, and PET/MRI with improved resolution to operation rooms in order to facilitate image-guided navigation to target regions.
Hybrid detection procedures. Portable imaging devices as gamma cameras probably will be integrated with other modalities as NIR cameras. On the other side, the integration of Cerenkov luminescence devices will extend the intraoperative applicability of PET tracers.
Robot-assisted procedures with integrated radioguided navigation. In a similar approach as the one used for prostate cancer [60, 161], the fluorescence and probably the radioactive imaging will be integrated to robot-assisted procedures in other pelvic malignancies. Development of novel accessory devices like drop-in gamma probes  for insertion and residence inside the abdominal cavity using a robotic gripper will make identification of SLNs and tumor lesions during laparoscopic surgery more flexible by improving detector accessibility and geometry.
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