2015 EANM Practice Guidelines for Lymphoscintigraphy and Sentinel Lymph Node Biopsy in Melanoma PDF

Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 DOI 10.1007/s00259-015-3135-1 GUIDELINES EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma Christina Bluemel 1 & Ken Herrmann 1 & Francesco Giammarile 2 & Omgo E. Nieweg 3 & Julien Dubreuil 2 & Alessandro T...

Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 DOI 10.1007/s00259-015-3135-1 GUIDELINES EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma Christina Bluemel 1 & Ken Herrmann 1 & Francesco Giammarile 2 & Omgo E. Nieweg 3 & Julien Dubreuil 2 & Alessandro Testori 4 & Riccardo A. Audisio 5 & Odysseas Zoras 6 & Michael Lassmann 1 & Annette H. Chakera 3 & Roger Uren 7,8 & Sotirios Chondrogiannis 9 & Patrick M. Colletti 10 & Domenico Rubello 9 Received: 2 July 2015 / Accepted: 7 July 2015 / Published online: 25 July 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract (EANM) to promote high-quality lymphoscintigraphy. The Purpose Sentinel lymph node biopsy is an essential staging final result has been discussed by distinguished experts from tool in patients with clinically localized melanoma. The har- the EANM Oncology Committee, national nuclear medicine vesting of a sentinel lymph node entails a sequence of proce- societies, the European Society of Surgical Oncology (ESSO) dures with participation of specialists in nuclear medicine, and the European Association for Research and Treatment of radiology, surgery and pathology. The aim of this document Cancer (EORTC) melanoma group. The document has been is to provide guidelines for nuclear medicine physicians endorsed by the Society of Nuclear Medicine and Molecular performing lymphoscintigraphy for sentinel lymph node de- Imaging (SNMMI). tection in patients with melanoma. Conclusion The present practice guidelines will help nuclear Methods These practice guidelines were written and have been medicine practitioners play their essential role in providing approved by the European Association of Nuclear Medicine high-quality lymphatic mapping for the care of melanoma patients. * Domenico Rubello Keywords Sentinel lymph node. Melanoma. [email protected] Lymphoscintigraphy. Radioguided surgery 1 Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany Preamble 2 Médecine Nucléaire, Hospices Civils de Lyon and EA 3738, Université Claude Bernard Lyon 1, Lyon, France These practice guidelines for sentinel lymph node biopsy 3 Melanoma Institute Australia, The Poche Centre, North (SLNB) in melanoma approved by the European Association Sydney, Australia of Nuclear Medicine (EANM) and the Society of Nuclear 4 European Institute of Oncology, Milan, Italy Medicine and Molecular Imaging (SNMMI) aim to promote 5 St Helens Teaching Hospital, University of Liverpool, St Helens, UK the use of nuclear medicine procedures of high quality. These 6 Department of Surgical Oncology, University Hospital of Heraklion, guidelines are intended to assist practitioners in providing ap- Heraklion, Greece propriate nuclear medicine care for patients. These guide- 7 Sydney Medical School, The University of Sydney, Sydney, NSW, lines are not inflexible rules or requirements of prac- Australia tice and are not intended, nor should they be used, to 8 Alfred Nuclear Medicine and Ultrasound, RPAH Medical Centre, establish a legal standard of care. For these reasons Newtown, NSW, Australia and those set forth below, the SNMMI and EANM 9 Department of Nuclear Medicine, PET/CT Centre, Radiology, caution against the use of these guidelines in litigation NeuroRadiology, Medical Physics, ‘Santa Maria della Misericordia’ in which the clinical decisions of a practitioner are Hospital, Rovigo, Italy called into question. 10 Department of Radiology, University of Southern California, The ultimate judgment regarding the propriety of any spe- Los Angeles, CA, USA cific procedure or course of action must be made by medical Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 1751 professionals taking into account the unique circumstances of Goals each case. Thus, an approach that differs from the guidelines does not necessarily imply that the approach is below the The aim of these practice guidelines is to provide general standard of care. To the contrary, a conscientious practitioner information about the SLN procedure in patients with mela- may responsibly adopt a course of action different from the noma. The guidelines describe protocols currently used rou- one set forth in the guidelines when, in the reasonable judg- tinely, but do not include all existing procedures. They should ment of the practitioner, such course of action is indicated by therefore not be taken as excluding other nuclear medicine the condition of the patient, limitations of available resources modalities that can be used to obtain comparable results. or advances in knowledge or technology subsequent to publi- The present guidelines for nuclear medicine practitioners cation of the guidelines. offer assistance in optimizing nuclear medicine imaging The practice of medicine involves not only the science but prior to SLNB to improve the diagnostic and staging in- also the art of dealing with the prevention, diagnosis, allevia- formation from the SLN procedure. The final result has tion and treatment of disease. The variety and complexity of been discussed by distinguished experts from the EANM human conditions make it impossible at times to identify the Oncology Committee, national nuclear medicine societies, most appropriate diagnosis or to predict with certainty a par- the European Society of Surgical Oncology (ESSO) and ticular response to treatment. Therefore, it should be recog- the European Association for Research and Treatment of nized that adherence to these guidelines will not assure an Cancer (EORTC) melanoma group. The present document accurate diagnosis or a successful outcome. All that should has been endorsed by the SNMMI board. The resources be expected is that the practitioner will follow a reasonable and facilities available for patient care may vary from one course of action based on current knowledge, available re- country to another and from one medical institution to sources and the needs of the patient to deliver effective and another. safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving these objectives. Background and definitions Melanoma is a global health problem and the incidence is Introduction rising worldwide [1, 2]. Important risk factors for the devel- opment of melanoma are a history of sunburn, intermittent The accurate harvesting of a sentinel lymph node (SLN) in high UV exposure, red or blond hair and a family history melanoma entails a sequence of procedures with components of melanoma. The prognosis of localized melanoma is from different medical specialties, including nuclear medi- generally good and worsens in the presence of regional or cine, radiology, surgery and pathology. The topics covered distant metastases. The stage of the disease provides are presented under the headings: prognostic information and guides treatment. Approximate- ly 20 % of patients with a melanoma of greater than 1. Goals 1 mm Breslow thickness have clinically occult lymph 2. Background and definitions node metastases and the risk generally increases with in- 3. Indications creasing thickness of the melanoma. Physical examination 4. Procedure success rate, and qualifications and responsi- of lymph nodes is inaccurate and small metastases elude bilities of personnel detection with imaging modalities. Therefore, histopatho- 5. Procedures in nuclear medicine logical evaluation is important. 6. Procedures in the surgical suite From the late 1800s onwards, elective lymph node dissec- 7. Radiation dosimetry tion (ELND) was performed to detect and treat clinically oc- 8. Issues requiring further clarification cult lymph node metastases. ELND became controversial when randomized studies did not show a survival benefit in The present practice guidelines have been prepared patients without palpable lymph nodes, but a 20 % better for nuclear medicine practitioners. The intention is to survival was noted in the subgroup of patients with involved offer assistance in optimizing the diagnostic information nodes. In order to exploit this potential survival benefit, yet that can be obtained from SLN procedures. If specific without exposing patients unnecessarily to the morbidity of recommendations cannot be based on evidence from ELND, a diagnostic test was needed to detect lymph node original scientific studies, referral is made to “general metastases at this early stage. opinion” and similar expressions. The recommendations In 1992 Morton et al. described the concept of orderly are designed to assist in the referral, performance, inter- progression of lymphatic dissemination and SLNB in 223 pretation and reporting of the SLN procedure. patients with melanoma. Melanoma first drains to a 1752 Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 specific regional lymph node before involving other nodes. Indications This is the SLN, which is defined as a node receiving lymphatic drainage directly from the primary tumour. Indications for SLNB in patients with melanoma include, but Tumour cells are present in the SLN before subsequent are not limited to, the following. SLNB should preferably be nodes in the regional basin become involved. Therefore, performed after diagnostic excision of the primary lesion with the tumour status of the SLN indicates the overall nodal a narrow margin and histological confirmation of the diagno- status. So, the aim of SLNB is to identify patients sis, and should be combined with therapeutic wide excision. with lymph node metastases at an early stage. The SLN is SLNB can be considered in patients with a clinically localized usually located in a regional lymph node basin, but sub- invasive melanoma of Breslow thickness >1 mm and in se- stantial interindividual differences exist [11, 12]. SLNs lected patients with a melanoma of Breslow thickness 0, and regression with documented thick- [13–15]. A melanoma may directly drain to several lymph ness of ≥1 mm or regression of more than 50 – 75 % of the nodes in one or several nodal basins, which is often the whole pigmented lesion [30–33]. SLNB in patients with a case when it is located on the midline of the trunk or melanoma of Breslow thickness between 0.75 and 1 mm is head and neck area. also accepted in some institutions. Lymphoscintigraphy has been shown to be an accurate Breslow thickness is the most important factor determining technique detecting at least one SLN in almost all patients the indication for SLNB. Based on the survival benefit that [17, 18], and can identify the number of SLNs and determine MSLT-1 revealed, the procedure is recommended in patients their location [16, 19]. The lymphoscintigrams provide a with a melanoma of intermediate Breslow thickness, defined roadmap for the surgeon. Blue dye injected at the mel- here as 1.2 – 3.5 mm. National societies differ slightly in anoma site visualizes the afferent lymph channel that their recommendations and the appropriate course of action in leads to the SLN and radionuclide-based detection using the case of melanomas of 200 nm move slowly pared at a minimum activity concentration of 100 MBq/ml and remain predominantly at the injection site. Therefore, (i.e. to deliver 20 MBq in 0.2 ml) at the time of injection 99m Tc-sulphur colloid, with a maximum size of 350 – 5, and, wherever possible, the maximum reconstitution vol- 000 nm, should be filtered with a 100- to 200-nm membrane ume be used (e.g. ≥500 MBq in 5 ml). More information filter after preparation of the radiopharmaceutical to select about good manufacturing practice can be found in Guid- smaller particles. ance on current good radiopharmacy practice (cGRPP) for A further radiotracer was approved by the US Food and the small-scale preparation of radiopharmaceuticals. Drug Administration (FDA) in 2013 and received a positive Colloids are suspensions and may therefore settle by grav- statement from the European Medicines Agency in 2014: ity if the syringe is not moved for more than a few minutes. 99m Tc-tilmanocept (Lymphoseek®), which is a mannosyl Before injecting the radiopharmaceutical, the syringe there- diethylene triamine penta-acetate (DTPA) dextran that targets fore has to be tilted, but not shaken, to distribute the tracer in the CD206 receptor. The molecular size is 7 nm, but accumu- the suspension homogeneously. Until now, no consensus on lation in SLNs is not dependent on particle size as with the the injected activity has been reached. The administered ac- other colloids. Tilmanocept binds to mannose receptors tivity depends on the time between lymphoscintigraphy and expressed by reticuloendothelial tissue including macro- operation (1-day or 2-day protocol) and varies among pub- phages and dendritic cells in lymph nodes, which present it lished studies (from approximately 5 MBq up to 120 MBq). to T-cell lymphocytes in lymph nodes. The advantages of this The injected activity should be adjusted according to the time 1756 Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 point of surgery, the physical decay and the intended residual injection may help to identify lymph nodes next to the injec- activity in the operating room, determined by results of previ- tion site and to differentiate SLNs from second-echelon nodes. ous studies to achieve high detection rates (>10 MBq) , Lymphatic channels can be visualized in dynamic series and but also legal regulations concerning radiation safety of staff. direct drainage pathway(s) can be identified. Furthermore, in- transit nodes can be detected reliably. Dynamic imaging Image acquisition (10 – 20 min, one frame per minute in a 128×128 matrix in word mode) during the first 10 min after injection is recom- Imaging system mended for detection of SLNs in head and neck melanoma. Although dynamic images are time consuming, dynamic se- All possible drainage regions have to be covered during image ries should be acquired whenever possible because this facil- acquisition. Therefore, a dual-head gamma camera with large itates image interpretation. In melanoma of the field of view detectors is preferred to reduce the examination hand/forearm or foot/leg, dynamic imaging should start over time. However, a single-head gamma camera is also suitable. the injection site and follow the lymphatic drainage to the knee Low-energy, high-resolution or ultrahigh-resolution collima- or elbow and axilla or groin to reveal ectopic basins and in- tors are recommended to better distinguish individual SLNs. transit lymph nodes (popliteal, epitrochlear). Using 99mTc, the energy window should be 15 % or 20 % centred on the 140-keV photopeak. Technical details of gam- Early static images ma probes for detection of SLNs preoperatively and in the operating room can be found below. After dynamic series, static planar 5-min images Body contouring facilitates the localization of hot spots. (anteroposterior and lateral) should be acquired with a 256× Therefore, a 99mTc or 57Co flood source should be positioned 256 matrix over the lymph node basin in which the SLN is on the opposite side of the camera head for transmission im- expected. Early images help to discriminate true SLNs from aging. Because faint uptake in SLNs may be missed using a 57 the second-echelon nodes that are often observed. In melano- Co flood source, imaging may be repeated without body mas of the trunk, usually bilateral static images of the axilla, contouring. If no flood source is available, a point source trunk and groin are necessary [84, 85]. Alternatively, body can also be used to trace the outline of the body. In some scanning from the neck to the groin can be performed. gamma cameras a 153Gd source is already integrated for atten- A dual-head gamma camera is helpful because images in uation correction of SPECT images; this enables acquisition different views can be acquired simultaneously, facilitating of simultaneous emission and transmission images at any differentiation of superficial and deep nodes (e.g. iliac, angle. paravertebral, retroperitoneal). Quality control Delayed static images Appropriate quality control of the imaging system should be routinely performed and image display should be used in SLN Late 3- to 5-min anteroposterior and lateral static images procedures. Quality control also should be routinely per- (1 – 3 h after tracer injection) are acquired to identify all formed on the gamma probe used in the nuclear medicine relevant SLNs and to mark them on the skin surface. The department and the operating room for SLN procedures. views according to the location of melanoma are summarized The reader is referred to the EANM guidelines Routine in Table 2. To reduce scattering artefact from the injection site, quality control recommendations of nuclear medicine images with lead shielding of the primary tumour can be instrumentation for additional information and the SNMMI guidelines Procedure guideline for SPECT/CT Table 2 Recommended regions covered by static images and/or imaging 1.0. SPECT/CT according to the location of the primary tumour Dynamic imaging Tumour location Static images Trunk Axilla + trunk + groin; or body scanning Dynamic imaging immediately following tracer injection is from neck to groin important since a lymph collector directly draining to a lymph Hand/forearm Elbow + axilla + neck node clearly identifies this node as a sentinel node wherever it Upper arm Axilla + neck is located. For dynamic imaging the tracer is injected when the Foot/lower leg Knee + groin patient is already lying in a supine or prone position on the bed Head neck Neck in multiple projections of the imaging system, depending on the location of the pri- Thigh Groin mary tumour. Starting image acquisition immediately after the Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 1757 added. This may be helpful especially if the primary tumour is lymphatic channel from the primary tumour to the lymph node located next to the nodal basin. (usually visualized on dynamic images). Also, the first appearing node is rated as an SLN. The SLN is often the SPECT/CT hottest node and the node closest to the injection site, but this is not necessarily the case. The distance from the primary may Often no exact localization of hot nodes is obtained by planar also contribute to the definition of the SLN. Nodes that appear imaging. Hybrid imaging with SPECT and CT including ana- only on late images, but in a further nodal field, are also SLNs tomical information improves the localization of SLNs and unless dynamic images reveal that they receive lymph chan- reduces misinterpretation of images (see below) [83, 86]. Im- nels from an earlier detected node. The results of SLN map- ages obtained by SPECT/CT are three-dimensional and have ping should be communicated directly to the surgeon, for better contrast and spatial resolution than planar images. For example as a brief report in advance of the surgery, including SPECT/CT, a higher overall SLN detection rate and better all available and labelled images. This is of particular impor- detection of SLNs located next to the injection site have been tance if lymphatic drainage is ambiguous. reported , and in addition there is a significant cost reduc- A final report should be sent later, including the following tion. SPECT/CT should be performed in head and neck detailed information: radiopharmaceutical used, injection melanoma owing to the complex anatomy. Moreover, technique (location, depth, number of injections), activity SPECT/CT is highly recommended for the groin area and and volume of injected radiopharmaceutical, time point of recommended for the axillary area because it facilitates the image acquisition, orientations of images and the name of detection of in-transit nodes and aberrant lymphatic drainage the responsible nuclear physician. The visualized structures stasis in lymph vessels and consequently facilitates the surgi- and their location (lymphatic channels, SLNs, second- and cal procedure. In pregnant patients, SPECT without a CT third-echelon nodes) should be described and labelled on the scan should be performed if an inguinal or axillary nodal base images themselves. The number and location of SLNs in each is to be imaged. However, for the head and neck area a low- basin must be carefully reported, including depth from the dose CT scan is justified because of the relative distance from skin. Also, non-SLNs should be described. In particular, the uterus and the intrinsic body shielding for scatter. The errors in the examination procedure (e.g. contamination), added diagnostic value in this specific area justifies the very unexpected lymphatic drainage or in-transit nodes should low added dosage to the foetus contributed by the low-dose be described in detail. Information gathered by SPECT CT scan. SPECT acquisition parameters may include a 360° and CT should be reported separately. Even additional orbit with 180° or 90° detector geometry, 128×128 matrix findings on CT have to be mentioned (e.g. pathological size, and 3° angle step with 20 – 25 s/frame with iterative lymph nodes without tracer accumulation). All acquired reconstruction algorithms. planar images, appropriate coregistered SPECT/CT images CT is usually performed as a low-dose scan without con- and the final report with a conclusion regarding the results trast enhancement, which provides rough anatomical informa- should be available in the operating room. The nuclear tion and can be used for attenuation correction of SPECT physician should be contactable in case any questions images. For depiction of soft tissue, a corresponding CT ker- arise. nel is preferred, such as a B30 kernel. Also to enable 3D viewing, transaxial, coronal and sagittal CT series with fusion Pitfalls series should be processed. Alternatively, one transaxial series with a small increment (1 – 2 mm) should be processed and Some pitfalls may occur in an SLN procedure, including in viewed with modern 3D viewing software capable of both patients with melanoma, and both false-positive and false- rendering multiplanar reconstruction views and displaying negative interpretations of lymphoscintigraphy are possible. fused images with SPECT reconstruction. The small incre- ment limits step artefacts in the z-axis and is also relevant for delineation of small lymph nodes. Display of high- Sources of false-positive interpretation of images resolution images with a 3D viewer is of great benefit, espe- cially in the head and neck area. All acquired images should 1. Skin contamination arising from the injection or urinary be stored in a permanent form. contamination may be misinterpreted as a lymph node. Hot spots attributed to contamination are often very hot Image interpretation and report and focal. Planar images from different views and SPECT or SPECT/CT help to identify contamination. Early dynamic, static and delayed static images identify SLNs 2. Second-echelon nodes may be misinterpreted as SLNs if in the majority of patients. The strongest criterion for the def- no early dynamic or static images are acquired. Acquiring inition of a lymph node as an SLN is the presence of a delayed images too soon may also play a role here. 1758 Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 3. Lymphangioma or lymphatic lakes may be misinterpreted tip or a tracer source (e.g. a 57Co ‘pencil’ marker source) can as lymph nodes. be used. The depth of the node should be described or indi- 4. Other tissues containing radioactivity may complicate cated using SPECT/CT or an orthogonal view. To allow for image interpretation. orthogonal depth measurements using electronic callipers a small amount of tracer in the needle hub or tracer source can be placed on the skin mark. Sources of false-negative interpretation of images To avoid confusion it is recommended that lymph nodes that can be clearly identified as second-echelon nodes should 1. Adjacent nodes may be misinterpreted as one SLN. not be marked, otherwise unnecessary resection of second-tier 2. The SLN may be masked by the injection site, especially nodes may be performed, increasing the risk of morbidity in head and neck cutaneous cancer.. The presence of more than one SLN within a nodal basin 3. Only a small amount of the radiotracer drains from the should be described in detail in the report. In the operating injection site. In the event of any alteration in the lymphatic room, the surgeon should not only rely on skin marking but drainage, the SLN may contain little radioactivity. Imaging read the images acquired prior to the operation carefully. Es- without a transmission source for body contouring or lead pecially in cases of aberrant lymphatic drainage, the responsi- shielding of the injection site may help. ble nuclear physician and surgeon should discuss the results of lymphoscintigraphy. In summary, these pitfalls occur more often if only a single view and late static images are acquired. Images in multiple projections (ventral, dorsal, lateral, oblique) and SPECT or Procedures in the surgical suite SPECT/CT can improve image interpretation and overcome some limitations. For correct intraoperative localization of the SLN, the ac- In some patients lymphatic drainage is slow. If no tracer quired images should be available in the operating room either drainage is observed in dynamic or early static images, mas- as hard copy or in electronic form, depending on local sage of the injection site or along the lymphatic vessels can be conditions. helpful. To avoid contamination, the patient or nuclear tech- nologist should wear gloves. Furthermore, the injection site The operation may be warmed with a hot-water bag to improve drainage of tracer. Constriction of the lymphatic vessels should also be The operation is typically performed as a 1-day admission excluded. Slow lymphatic flow is observed in older patients procedure under general anaesthesia but can if necessary be (>50 years). In extremity melanoma, passive exercise of the performed under local anaesthesia. The surgeon’s repertoire limb may be helpful. In some cases, repeated imaging includes both detection techniques; 13 % of the SLNs are only (delayed images up to 24 h) or reinjection of radiotracer, if radioactive, 1 % are only blue, while the remaining 86 % are there is any suspicion of false injection, may also be helpful. both radioactive and blue. If a blue dye procedure is performed in addition to radioguided surgery, 0.5 – 1 ml pat- Skin marking ent blue V or isosulfan blue is injected intradermally around the melanoma or the biopsy site at the beginning of the oper- A skin mark directly over the location of the SLN is helpful to ation. Massage of the injection site will accelerate lym- define the region of interest in the operating room and to assist phatic drainage. The dynamic lymphoscintigrams indicate the surgeon in intraoperative localization of SLNs. The SLN where the afferent lymph vessel is to be found and guide, in in each basin should be marked accurately on the skin using combination with the skin marking, the site of the incision. indelible ink or tattoo since this is valuable information for This vessel is typically identified underneath the subcutaneous follow up if the SLN is not removed for some unexpected fascia. The blue vessel is dissected until it drains into the SLN. reason. In some patients a pair of skin marks from an anterior The node is freed from the surrounding tissue and afferent and and a lateral view may be helpful. Good communication be- efferent blood and lymph vessels are ligated and divided. The tween the surgeon and the nuclear medicine imaging team is basin is examined for other afferent lymph vessels and important here to ensure that the operating position for the scanned for additional radioactive SLNs. surgical procedure is known before imaging is performed, Using only radionuclides, preoperative lymphoscintigraphy otherwise the skin marks could be misleading. The patient and skin marks are used as a “road map” for moving the positioning has to be noted and if possible the patient should gamma probe and identifying the region with the highest lie in the same position as in the operating room. In order to count rate. To reduce scattering artefacts, the probe has to define the surface location of the SLN, a gamma probe, a be pointed away from the injection site. The probe is then syringe with a small amount of radiopharmaceutical in the used for guidance in an iterative process, as the surgeon Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 1759 proceeds to progressively expose the overlying tissue in Radioactive waste order to identify precisely the location of the radioactive nodes in the surgical bed (in vivo measurement). After The radioactive waste should be collected according to local excision, the probe is placed over the resected tissue to conditions. Personnel working with radioactive material confirm the successful dissection of the SLN (ex vivo mea- should be trained. The staff of the surgical department and surement). Subsequently, the surgical bed is measured the institute of pathology involved in SLNB should be edu- again and checked for remaining activity, which may be cated in safe handling of contaminated material. present especially in cluster nodes. The information from preoperative SPECT/CT is helpful in identifying these clus- Histopathology ter nodes. The surgeon should also palpate the region of interest to identify enlarged hard nonradioactive or nonblue Histopathological assessment of SLNs is the “gold standard” nodes full of metastases and no longer receiving lymphatic to determine the presence of lymph node metastases. Proce- drainage. These nodes should also be removed. dures for pathological examination vary among centres and The advantage of the blue dye technique is that identifica- countries. Frozen sections have a poor (47 %) sensitivity and tion of the node on a direct lymphatic drainage pathway is are no longer used. Serial sections are obtained and certain, but this approach requires finesse and a delicate sur- stained with haematoxylin and eosin and immunohistochem- gical technique. The probe-guided operation is more straight- ical stains, usually S-100 antibodies, MART-1/Melan-A and forward but it can be difficult to identify the correct node when HMB-45 [104, 105]. The EORTC Melanoma Group has pro- multiple nodes have accumulated the radiopharmaceutical. vided dedicated guidelines on how the SLN should be divided Allergic reactions to the blue dye are rare and usually mild and analysed (e.g. [106–108]). but anaphylactic shock has been described. Pregnancy is listed as a contraindication to blue dye due to the risk of Completion lymph node dissection anaphylaxis [29, 61, 96]; however, specific adverse events due to the radioactive and blue tracers in pregnant women Patients with a positive SLN are offered completion lymph are not known to have been reported. node dissection and 12 – 25 % of them are found to have involvement of additional lymph nodes [109–112]. The re- sults of the MSLT-1 study show that this management pro- Gamma probe longs disease-free survival in patients with tumours thicker than 1.2 mm and improves melanoma-specific survival in pa- The gamma probe used should be designed for intraoperative tients with nodal metastases from tumours of intermediate application. The probe should be placed in a sterile sheet. The Breslow thickness. The ongoing MSLT-2 and EORTC probe should provide instantaneous and cumulative counts. Minitub trial have been designed to assess the role of comple- Conversion of count rate into an acoustic signal with a vari- tion lymph node dissection in patients with a positive SLN able pitch facilitates SLN localization. Many different systems [113, 114]. are commercially available, and users are advised to evaluate a number of probe systems prior to purchase to ensure their suitability. All medical devices used need CE certification. Radiation dosimetry Quality control should be routinely performed on the probe used in the nuclear medicine department and the operating The use of radioactive colloids for SLNB requires the room for SLN procedures. optimization of radiation safety issues, including issues regarding patients, staff in nuclear medicine departments, the operating room, pathology laboratories and the dis- Gamma cameras posal of radioactive waste. The following sections on patient and staff dosimetry were taken almost entirely The resolution of a hand-held gamma probe is lower than that from the previous EANM-EORTC general recommenda- of conventional gamma cameras. Deeply located SLNs may tions for sentinel node diagnostics in melanoma, which be difficult to localize because of attenuation due to overlying were published in 2009. tissue. Also, SLNs may be hidden by the injection site, as is often observed in malignancies in the head and neck region Patients (shine-through phenomenon). In these challenging settings, using three-dimensional imaging and navigation [97–99] or For a regular nuclear medicine department, lymphoscintigraphy a portable gamma camera [100–102] may improve intraoper- is a procedure involving low activities. The estimated local ative detection of SLNs. radiation dose varies depending on the administered activity, 1760 Eur J Nucl Med Mol Imaging (2015) 42:1750–1766 injection site, volume of tracer, the use of multiple injections, protocol should be used, with a short interval from injection to and retention time. However, melanoma originates operation to minimize decay [116, 125, 126]. To compensate from skin tissue that is relatively less radiosensitive than for this lower injected dose, image acquisition should be many other tissues. The tissue weighting factor defined twice the normal duration. In pregnant women, by the International Committee of Radiation Protection SPECT/CT of the thorax and the abdomen/pelvis is con- (ICRP) for the determination of effective dose is 0.01 traindicated – in the former because too little diagnostic for skin compared with 0.12 for breast. Therefore, in gain is to be expected for axillary nodal basins and in the patients with melanoma the local radiation dose contributes latter because of the significant foetal dose associated with little to the effective dose. these scan areas. In these cases SPECT alone is preferred. The different radiopharmaceuticals used for SLN imaging However, in single cases a low-dose CT scan in addition show minor differences in dosimetry. The local absorbed dose to SPECT might be performed after interdisciplinary dis- at the injection site with respect to the most common cussion of risks versus benefits. radiocolloids is less than 50 mGy/MBq [116, 118, 119]. In determining the effective dose, it should be taken into account Lactating women that the radiolabelled colloid migrates minimally throughout the bloodstream or reticuloendothelial system (RES) or be- The presence of 99mTc in breast milk has not been reported, yond the SLN and second-echelon lymph nodes. Assuming but it has been recommended that breast feeding should be that 20 % of the administered activity is absorbed in the RES suspended in nursing mothers for at least 4 h and pref- systemically, the effective dose is calculated as 2 μSv/MBq in erably for 24 h after radiopharmaceutical administration , a ‘worst-case’ calculation for melanoma. This corre- since the radiopharmaceutical will be excreted from the breast sponds to 0.04 mSv after an injection of 20 MBq of 99mTc- milk during this period. labelled small colloid. It should be noted that adoption of SPECT/CT imaging Staff dosimetry protocols for SLN in melanoma will increase both local radi- ation dose and effective dose due to inclusion of the CT pro- Within the EU, national implementations of EU Directives cedure, the dosimetry being dependent upon both the site of apply with respect to radiation protection aspects of the the melanoma and the CT acquisition parameters selected. A clinical practice of nuclear medicine. In applying the low-dose CT scan with a field of view limited to avoid radio- 1990 recommendations of the ICRP , the Basic Safe- sensitive tissues can help to keep the effective dose to a min- ty Standards Directive enforces a general radiation imum. For a low-dose CT scan for attenuation correction, an protection framework to ensure the safety of employees effective dose of 2.4 mSv has been reported. The total and the public. The Medical Exposures Directive rein- exposure in such cases is the emission-generated dose plus the forces the need for justification, optimization and transmission-generated dose. limitation of all exposures, and places additional specific requirements on stated duty holders, especially with re- Pregnancy spect to the practical aspects of a medical exposure – referral, individual justification and execution – including Pregnant patients may be offered SLNB after careful counsel- the training and competence of all staff whose actions ling regarding the safety and efficacy of the procedure. Ac- contribute to the procedure(s) performed. cording to ICRP publications, the risk to the foetus is consid- ered negligible for investigations exposing a foetus to