Lymphatic Metastasis and Sentinel Lymphonodectomy

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Topics from this paper. Anatomic Node Set of regional lymph nodes lymph node metastases. Citations Publications citing this paper. Real-time imaging of lymphogenic metastasis in orthotopic human breast cancer. Accuracy of computed tomography perfusion in assessing metastatic involvement of enlarged axillary lymph nodes in patients with breast cancer Yun Liu , Massimo Bellomi , Giovanna Gatti , Xuejun Ping. Tumor-lymphatic interactions in an activated stromal microenvironment. Sunny Y. Wong , Richard O Hynes. The relationship between tumors and the lymphatics: what more is there to know? Jonathan P Sleeman.

Lymphangiogenesis and its role in cancer. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. CRKII overexpression promotes the in vitro proliferation, migration and invasion potential of murine hepatocarcinoma Hca-P cells.


A history of exploring cancer in context Shelly Maman , Isaac P. Radiocolloids injected intradermally over mammary gland drain to subcutaneous plexus, which is also terminal pathway of predominant lymph drainage from mammary gland. B Schematic representation of pathways of lymphatic drainage from mammary gland modified from Most lymph produced in mammary gland surfaces at subareolar plexus, then merges with subcutaneous plexus of overlying skin, and flows with centrifugal pattern mostly toward axilla.

Lymph from deeper portion of gland drains either through same pathway or through deep lymphatics to reach parasternal, internal mammary chain and even contralateral side. Under physiologic conditions of lymph flow and pressure, unidirectional valves in the communicating vessels drive lymph from the deep fascial plexus toward the subcutaneous plexus A minor component of lymph drainage almost exclusively for the deeper portion of the mammary occurs through the deep fascial plexus located within the fascia overlying the pectoral muscles.

This lymph can drain either through the periductal plexus as described or directly to lymph nodes of the internal mammary chain or both through the deep lymphatic collectors Complex architecture deriving from common embryologic origin explains why most of the mammary gland and of overlying skin can be considered as a single biologic unit sharing a common centrifugal lymphatic pathway to the same axillary nodes 80 Fig.

However, certain lymphatic vessels from the lateral portion of the gland drain to lymph nodes of the pectoral group, whereas part of the medial portion of the breast drains to nodes of the internal mammary chain and to lymphatics of the opposite gland , part of the lower portion of the breast drains to the lymphatic system of the abdominal wall, and, finally, part of the upper portion of the gland drains to the apical axillary lymph nodes and to the deep cervical nodes.

These patterns of lymphatic drainage are very variable and it is impossible to predict the route of drainage of any particular tumor on the basis of the location of the tumor within the breast. In general, epithelial cancers do not have an efficient lymphatic system of their own. Tumor lymphangiogenesis is grossly dysplastic, exhibiting some or all of the following patterns: Prelymphatics do not link with lymphatics, basal lamina and flattened endothelium are inconsistent and often incongruous, and interconnection of stroma with blood vessels and lymphatic structures is often abnormal This makes the use of intratumoral injections less logical than that of peritumoral or subdermal injections.

Although tumor-produced angiogenic factors have definitely been linked to tumor growth 81 — 83 , to our knowledge, no similar growth factors have been identified for the lymphatic system. Debate is still open on some lymphangiogenic activity of the vascular endothelial growth factor in tumors 84 — The origin and drainage of lymphatics in the breast are relevant to the technique of injection of the radiopharmaceutical for lymphoscintigraphy and for radioguided biopsy of the sentinel lymph node.

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Experimental evidence emphasizes either the absence or inefficiency of structured lymphatic drainage from most solid tumors, including breast cancer. The interstitial fluid leaving the tumor bed has to follow the lymphatic spaces and pathways of the normal tissues surrounding the tumor. In particular, radiolabeled colloids injected intratumorally will drain through lymphatic channels encountered after percolating out from the tumor space to the surrounding parenchyma; obviously, such percolation is facilitated when the volume of the injectate is relatively large with respect to the tumor volume.

In radioguided surgery for sentinel lymph node biopsy, the radiopharmaceutical should fulfill at least the following criteria: visualize the lymphatic channels leading from the site of interstitial administration to the corresponding lymph node and be preferentially retained in the first lymph node s encountered. Intranodal retention is associated with the macrophages lining the sinusoid spaces of lymph nodes, whose main function is to clear the affluent lymph of particulate matter, based on active, saturable phagocytosis 87 Fig.

Left Red dots symbolize radiocolloids migrating with afferent lymph from site of interstitial injection to lymph node, where they are entrapped by macrophages lining sinusoid spaces red area. Right Low-magnification histoautoradiograph of sentinel node removed about 20 h after injection of 99m Tc-HSA nanocolloid. Black dots silver grains show retention of radioactive agent in sinusoid spaces. When there is massive nodal metastatic involvement, few normal cells remain in the node, the biologic clearing mechanism is lost, and the node is not visualized during lymphoscintigraphy.

Interstitial injections of specific tumor-seeking radioactive tracers to overcome this problem have shown disappointing results For colloidal particles ranging in size from 2. These properties are shared by several formulations, either inorganic Au-colloid, 99m Tc-antimony sulfide, 99m Tc-sulfur colloid, 99m Tc-stannous fluoride, 99m Tc-rhenium sulfide or derived from biologic substances nano- or microcolloid of human serum albumin [HSA]. Opsonization may occur in plasma or in the lymph, as is the case when the tracer is injected interstitially.

The opsonized material activates a membrane-bound receptor on macrophages, leading to phagocytosis. Efficiency of this clearing process varies with several factors besides the net surface charge and degree of opsonization, such as antigenic properties, size and number of the particles, specific anatomic region, and so forth. After interstitial injection, radioactive colloids are cleared by lymphatic drainage with a speed that is inversely proportional to the particle size. Distribution of the particle size within each radioactive colloid preparation is in general rather disperse not always with a gaussian-type curve 92 , 96 around the mean values indicated by the manufacturers Table 1.

Inconsistencies observed in the reported ranges of particle sizes 11 , 92 , 96 — 98 are associated with several factors, including the method used for the measurement, determination performed before or after radiolabeling, poor stability of the agent after labeling, incubation with serum, and use of regularly eluted high concentration of 99m Tc as a fraction of the total technetium in the eluate versus technetium eluted after a long interval of ingrowth low concentration of 99m Tc as a fraction of the total technetium in the eluate for labeling.

Other factors can include the pore size of any filters used as in the case of 99m Tc-sulfur colloid , in-house modifications of the reconstitution procedures versus those recommended by the manufacturers, and so forth. Lymphatic drainage of radiocolloids injected interstitially proceeds over several hours, as small particles are drained first, followed by intermediate-size particles, whereas large particles may be retained virtually indefinitely at the injection site Fig.

Thus, distribution of the particle size within each radiocolloid preparation is a major determinant of the kinetics of tracer clearance through lymphatic drainage for the different agents.

1. Introduction

Detailed information on the exact distribution in relation to the particle size range is scanty or not available at all, except perhaps for 99m Tc-HSA nanocolloid and 99m Tc-sulfur colloid Table 1 because these 2 tracers including various in-house modifications of sulfur colloid are currently the most widely used radiocolloids for sentinel node biopsy. Injection site shows minimal reduction over 60 min, barely discernible from physical decay.

Tracer appears in sentinel node starting few minutes after injection, with quasiplateau maintained over 60 min. Lymphatic channel shows early passage of radioactivity, continuing with quasipulsatile pattern. Direct supply of radiocolloid draining from injection site continuing over several hours keeps radioactivity content of sentinel node at relatively higher level than that of second- or third-tier nodes, even if active retention of tracer by macrophages is saturated.

The amount of radioactivity retained in the sentinel lymph node s 15—18 h after interstitial injection of radiocolloid of intermediate particle size colloidal albumin is in general quite low. These figures compare well with data obtained similarly after intradermal administration in patients with cutaneous melanoma 0. When radioactive agents for lymphoscintigraphic imaging were originally developed, emphasis was on fast visualization of lymphatic vessels rather than lymph nodes.

In a series of patients evaluated with different injection techniques and tracers, the average number of lymph nodes visualized by radiocolloids with particle size reported between 15 and 50 nm was 2. Scintigraphs obtained in right anterior oblique view 15 min after subdermal injection of radiocolloids with different particle size: 99m Tc-sulfide left , 99m Tc-HSA nanocolloid center , and special formulation of 99m Tc-HSA microcolloid, not available commercially right.

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Even on early imaging, radiocolloids with small and intermediate particle size visualize several nodes in addition to sentinel node, whereas only sentinel node is visualized by radiocolloid with relatively large particles. Different pore sizes or nm have been proposed, with the goal of obtaining particles in the range of about 50— or 50— nm. Although some authors still claim the superiority of the unfiltered versus the filtered preparation , , the prevailing trend now favors the routine use of filtered 99m Tc-sulfur colloid for sentinel lymph node studies.

At present, this radiopharmaceutical offers the best range of particle size, approaching the ideal range, and offers the additional benefits of instant labeling at room temperature and stability in vitro and in vivo. The number of particles injected is another important parameter in radioguided sentinel node procedures. Only a small fraction of the colloidal particles is actually radiolabeled in the tracers prepared by current standard methods.

Franceschini, Nycomed-Amersham-Sorin, Saluggia, Italy; personal communication, March : Refining the radiolabeling technique to increase considerably this fraction should be a priority of radiochemistry in this field. In fact, the clearing function of lymph nodes is not based on mere mechanical filtration depending on size of the particles; rather, it is a biologic trap mechanism based on active phagocytosis by macrophages.

Because it can be assumed that the clearing capacity of each node is saturated rather quickly, the higher is the number of particles arriving to the draining lymph node, the sooner macrophages are saturated and particles progress to serially visualize subsequent echelon nodes. In this regard, radioguided identification of the sentinel node requires administration of a radioactive dose high enough to allow detection based on counting rates, for external imaging and intraoperative localization.

The specific activity of the preparation is important to administer a preparation with the fewest particles. Therefore, methods of high specific activity labeling should be sought. At least 3 main parameters define the optimal technique s of administering the radiopharmaceutical for lymphatic mapping and sentinel node biopsy in breast cancer surgery: site of injection, volume of the injectate, and dose injected. An additional parameter is timing of injection relative to surgery, though with lesser importance in the overall procedure.

Criteria for defining the optimal combination of these parameters partly overlap each other; site of injection is the most crucial parameter, which heavily affects the final choice of the other 2 main parameters, volume and dose. Advocates of intratumoral injection an extension of the technique developed earlier for intraoperative lymphatic mapping with vital blue dye argue that this is the best site to inject to visualize lymph drainage from the tumor.

Common corollaries of the intratumoral route are a relatively large volume of the injectate at least 4 mL, which easily percolates out of the tumor mass especially for T1 breast cancers and a relatively high injected dose of radiocolloid about 37— MBq [1—10 mCi]. The purpose of injecting a large volume is to increase intratumoral pressure which is higher than in the surrounding normal tissues because of the abnormal lymphatic system in the tumor to force lymph flow from the tumor, thereby enhancing the likelihood of visualizing the lymphatic pathways and draining node s.

A high dose is required because the fraction of radiocolloid injected intratumorally that leaves the tumor through this paraphysiologic lymphatic drainage is minimal because of the virtual absence of a lymphatic system within the tumor. The introduction of a large volume can lead to distortion of tissues and lymphatics and, therefore, have an unpredictable effect on radiocolloid clearance.

Drawbacks of direct intratumoral injection include the following: a The tumor is intrinsically devoid of an organized lymphatic system of its own. Most investigators currently favor interstitial administration of radiocolloids through the extratumoral route for sentinel node biopsy. At this time, 2 approaches to extratumoral radiocolloid administration are used: the peritumoral, intraparenchymal injection technique and the intradermal—subdermal injection technique. With intraparenchymal administration, the tracer is injected in a site immediately adjacent to the tumor, in the space with a supposedly normal lymphatic system that is the only possible drainage pathway for fluids, particles, and cells leaving the tumor through the extravascular route.

In this approach, the radiocolloid is given in 4—6 deposits around the tumor circumference. Each aliquot is about 0. Although injections are directed simply by palpation in most centers, it is advisable to inject the tracer under sonographic guidance or stereotactic devices within about 2 mm from the tumor periphery. As with the other 2 approaches intratumoral and subdermal—intradermal , gauge or even gauge needles are commonly used for injection, the only difference being the length of the needle bore according to depth of the injection. Radiocolloids injected in the mammary parenchyma tend to visualize the lymphatic drainage pathway and nodes faster than radiocolloids injected intratumorally.

Nonetheless, although this is not the norm, completing a lymphoscintigraphic study can still require up to 3—4 h, especially on patients with large breasts or on postmenopausal women; slow lymphatic clearance in the latter condition possibly reflects the physiologically reduced lymph flow in the aging mammary parenchyma. The use of gentle massage for 2—3 min after injection may aid clearance of radiocolloids, possibly by breaking up the injected bolus. Although the long-term clinical impact of identifying pathways of lymphatic drainage to the internal mammary chain in patients with early breast cancer is still unclear, this finding is a definite plus of the peritumoral administration route when one compares its merits with those of the subdermal—intradermal injection technique.

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Some sentinel nodes can also be detected within the breast parenchyma, in between the pectoralis muscles, and in the supraclavicular fossa. The likelihood of visualizing a lymphatic duct and a draining node increases when the radiocolloid is injected in the skin overlying the mammary gland; as a matter of fact, vast experience acquired with hundreds of lymphoscintigraphic studies G.

Paganelli, unpublished data, December clearly indicates that lymphatic drainage of radiocolloids from the skin is richer and faster than drainage from the resting breast parenchyma Therefore, axillary sentinel lymph nodes can be efficiently visualized as early as 20—30 min after intradermal injection of radiocolloid, thus making the entire lymphoscintigraphic procedure highly practicable. Nevertheless, convenient timing is not the only factor that makes the intradermal administration route such an attractive option for sentinel lymph node biopsy in early breast cancer.

Reliability of this approach for sentinel node identification has a sound anatomic and physiologic basis. Because of the common embryologic origin in the ectoderm, the mammary gland and the overlying skin can be regarded as a single biologic unit whose pathways of lymphatic drainage are intimately embedded in each other Fig.

In particular, the subcutaneous plexus is the common draining system for lymph produced in the dermis which is the site where radiocolloid is injected and for most of the lymph produced in the mammary gland. Lymph collected by the periductal plexus converges in the subareolar plexus, which in turn merges in a centrifugal manner with the subcutaneous plexus.

Clearly, a radiocolloid injected intradermally or subdermally will less likely drain toward the deep fascial lymphatic collectors to visualize the internal mammary chain, unless the regional pattern of lymph flow is disrupted by some paraphysiologic mechanism s , such as change of flow direction associated with, for instance, metastatic involvement of the more superficial pathways of lymphatic drainage or prior surgery that may have altered the pathways of lymph flow.

Using this administration approach, a small volume of tracer 0. On the basis of how deep injection is performed, tracer administration is defined as intradermal when the needle is almost tangent to the skin surface and a classical urticarial pomphus develops; when, instead, injection is a little deeper this occurrence is signaled by reduced resistance to penetration of the needle , the pomphus is less obvious and administration is defined as subdermal.

Some overlap occurs between these 2 modalities and the 2 terms are often used interchangeably, also because of wide variations in thickness of the skin overlying the breast. Some investigators perform periareolar tracer injection usually 4 aliquots as a modification of the subdermal route; however sound its pathophysiologic basis may be because of rich connections of the subareolar plexus with the general subcutaneous plexus , we do not favor this technique, also because it causes some discomfort to patients.

This approach may also reveal sites of drainage of the breast per se against specific drainage of the tumor. Advantages of the intradermal—subdermal injection technique are represented by its high practicability with minimum training, small volume administered as a single injection, fast visualization of lymphatic drainage pathways, and low dose administered. Some studies have compared the lymphoscintigraphic pattern and performance of sentinel node identification by adopting the intradermal approach and the peritumoral, intraparenchymal approach in the same patients 11 , — Although the 2 techniques are reported to yield virtually equivalent results in the vast majority of patients , , , some authors report a sizable proportion of discordant results concerning sentinel nodes either in the axilla or in the internal mammary chain or both 11 , Perfect equivalence between the 2 approaches requires further comparative studies and better understanding of the role of tumor status of the internal mammary chain nodes on therapy planning and on long-term outcome of patients.

It is reasonable to assume that the 2 injection techniques, intradermal and peritumoral, are complementary 11 Fig. Intradermal injection ensures visualization of single sentinel lymph node between breast and axilla, whereas intraparenchymal injection visualizes lymphatic drainage toward internal mammary chain at least 3 sequential lymph nodes.

It is particularly helpful when visualizing more than a single sentinel node in the axilla to distinguish true additional sentinel nodes on different lymphatic pathways from second- and third-tier nodes Fig. Moreover, by providing accurate topographic coordinates preoperatively, lymphoscintigraphy enables the surgeon to focus attention on the correct spot in the axilla, thus shortening the surgical procedure and increasing the overall accuracy of sentinel node biopsy.

Imaging times were between 30 and 60 min after intradermal injection of 99m Tc-HSA nanocolloid. A Right anterior oblique RAO view shows single lymphatic vessel leading to single sentinel lymph node, with serial visualization of subsequent-tier nodes. B Left anterior oblique LAO view shows 2 separate lymphatics leading, through widely diverging pathways, to 2 separate but adjacent sentinel nodes with serial visualization of subsequent-tier nodes.

C LAO view shows 3 separate lymphatics leading, through widely diverging pathways, to 2 separate but very close sentinel nodes 2 of vessels, originating at opposite poles of injection site, merge in single channel before crossing path of third vessel. D RAO view shows multiple lymphatics leading from site of injection in outer upper quadrant to at least 3 separate sentinel nodes with serial visualization of subsequent-tier nodes. Performing lymphoscintigraphy in the afternoon before surgery 15—18 h preoperatively is logistically convenient for the routine in the nuclear medicine department and consistent with the pathophysiology of lymphatic drainage for radiocolloids In this case, tracer injection in the early morning with surgery at 4—6 h may be more ideal.

Whichever technical approach is followed in the choice of tracer and modality of injection, there is more general consensus on how to perform lymphoscintigraphic acquisitions for sentinel lymph node identification. In this regard, doses injected intratumorally are usually at least fold higher than those injected intradermally, thus resulting in scatter artifacts that are particularly inconvenient when they affect visualization of a sentinel node that is located a few centimeters away from the injection site.

Intermediate effects are observed with intraparenchymal injection, which involves doses about 5-fold higher than those of intradermal injection. Large-field-of-view gamma cameras are useful to obtain the lymphoscintigraphic pattern of the entire lymphatic basin in a single picture. However, in some cases, small-field-of-view gamma cameras are especially helpful for accurate topographic localization because they can be placed closer to the axilla.

The patient should be positioned supine, with the arm abducted completely to allow the head of the gamma camera to be placed as close as possible to the axilla. An anterior scintigraphic view is frequently used initially, but it is usually changed to oblique anterior views, with some craniocaudal tilting, during visualization of radiocolloid drainage. The angles are modified as needed to distinguish between the injection site and focal accumulations corresponding to the draining nodes.

Timing of the sequential spot views reflects the variable combination of tracer used and modality of injection: Radiocolloids with small particle size migrate faster than large radiocolloids and, conversely, radiocolloids injected intradermally migrate faster than those injected intratumorally or intraparenchymally. The entire procedure is usually completed with good visualization of the sentinel node s within about 50—60 min after tracer injection. After intratumoral or intraparenchymal injection of the same tracer, images can be acquired every 30 min or so because the lymphoscintigraphic study can take as long as 2 or 3 h to complete.

Finally, completion of lymphoscintigraphy can take even longer 15—18 h when radiocolloids with larger particle size are injected intratumorally or intraparenchymally. Nonetheless, recording dynamic lymphoscintigraphy can be useful in the learning phase of the procedure, to gain confidence, and to become acquainted with the technique. It is helpful to define the outline of the body in the area under the head of the gamma camera to localize the sites of tracer accumulation. The body silhouette is easily represented either through a transmission scan obtained with a 57 Co flood source or simply by moving a radioactive point source along the contour of the body while recording the scan.

Marking the skin projection of the sentinel node and having the images available may assist the surgeon in reducing the operating time to find the sentinel node and in keeping the surgical incision to a minimum. Minor variations in the sequence of operating procedures exist: Some surgeons remove the primary tumor first and then proceed to perform the biopsy of the sentinel node, whereas other surgeons perform the sentinel node biopsy first and then proceed to remove the tumor while waiting for the results of intraoperative frozen section histopathology.

Occasionally, a single surgical incision is extended to expose the tumor and the location of the sentinel node in the axilla when the tumor is located in the outer upper quadrant. Many surgeons combine the 2 techniques using the blue dye in the lymphatics as a road map to help find the radioactive sentinel node. This can be important because a noninvolved lymph node may be only few millimeters in diameter and very soft to palpation. The probe is now in direct contact with the hot spot and is adequately shielded from radiation scattered from the injection site.

Reexamination of the operative site should then be performed to ensure that the area of radioactivity has been removed and that a second node is not also active; if it is, it should be removed and the axilla should be reexamined until no areas of increased counts are found. Complete removal of the sentinel node s is confirmed by reduction of the counting rate in the axilla to background levels. To have real impact in the management of breast cancer patients, histologic examination of the sentinel lymph node s must be extremely careful and extensive.

The nodes must be entirely and serially sectioned at reduced intervals. Viale, unpublished data, December ; after all, tumor cell clusters giving rise to metastases nest initially in the most peripheral sinusoid spaces of the lymph node. Histologic examination of axillary sentinel nodes can be performed either on permanent sections of formalin-fixed, paraffin-embedded tissue or intraoperatively on frozen sections.

This latter procedure enables surgical treatment of the primary tumor and, when indicated, axillary node dissection in a single session. Even in the case of intraoperative examination, the sentinel nodes must be entirely and serially sectioned because examination of a few frozen sections from only one half of the node as routinely done for other purposes will lead to an unacceptably high number of false-negative results. The general trend toward extensive intraoperative histologic examination of the sentinel lymph node has generated a recommended protocol that can be summarized as follows The nodes are bisected starting at the hilus, and both halves are frozen in isopentane chilled by liquid nitrogen.

Sentinel Lymph Node Biopsy

One section of each pair is routinely stained with hematoxylin—eosin; the other section is left unstained for possible immunocytochemistry with anticytokeratin antibodies to assess the nature of questionable cells detected in the corresponding stained sections. In the experience of a well-trained, harmonized multidisciplinary team focused on breast cancer surgery, the time required for such an extensive examination of the sentinel nodes is approximately 40 min—that is, the time normally spent by the surgeon to complete removal of the tumor, having performed sentinel lymph node biopsy first.

Recent reports have emphasized the role of immunocytochemistry in the accurate identification of micrometastases in sentinel nodes, suggesting that immunoreactions for cytokeratins epithelial markers should be performed for all sentinel nodes — However, the use of immunocytochemistry does not overcome the need for extensive sectioning of the lymph node, which must be sampled entirely.

To keep the time required and the costs of the examination of the sentinel nodes as low as possible, the use of immunocytochemistry should be limited to those cases for which diagnosis cannot be made confidently on purely morphologic grounds hematoxylin—eosin staining. This is particularly true for single-cell metastases, commonly occurring in invasive lobular carcinomas. Thus, the proportion of cases to process with immunocytochemical examination depends on the training and expertise of the examining pathologist on the one hand and the quality of the tissue sections on the other hand.

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The potential of amplification of specific messenger RNA molecules by the polymerase chain reaction to detect metastases in sentinel nodes has also been explored , In these procedures, RNA molecules are extracted from fresh or frozen nodes, and complementary DNA is synthesized by reverse transcription.

Epithelial-specific markers cytokeratin 19, carcinoembryonic antigen, mucine-1, maspin, mammaglobin, and so forth are then amplified by the polymerase chain reaction. In vitro experiments have shown that these techniques are effective in identifying a single metastatic cell among 1,, normal lymphoid cells. However, results obtained in vivo have thus far been less impressive.

Viale, unpublished data, December When one considers the high number of variables involved in the procedure of radioguided sentinel node biopsy, the success rate of the technique reported by different groups is amazingly consistent. Nevertheless, these figures refer only to the easiest, immediate parameter available for assessment—that is, success rate defined as the fraction of patients in whom the sentinel node is identified.

This definition cannot automatically imply that the node identified is the true or the only sentinel node. It also appears that injection of radiocolloid deeper in the breast parenchyma usually entails visualization of additional lymphatic drainage to nodes of the internal mammary chain, although the pathophysiologic and clinical significance of this finding is at present unclear and, therefore, remains to be explored further.

Thus, the very high success rate reported for radioguided localization of the sentinel node in patients with breast cancer must be considered with a word of caution. Further careful investigations, which should also consider the long-term outcome of patients submitted to sentinel node biopsy, are necessary to confirm that the true sentinel node or nodes has been localized.

Another important parameter in sentinel node biopsy is classification of tumor status of the node by intraoperative frozen section histopathology. The occurrence of such false-negative sentinel nodes has been documented in most studies that also involved complete axillary node dissection and extensive histopathologic evaluation of the axilla. The lowest values for the incidence of a false-negative sentinel node are reported when the technique outlined earlier is used for extensive histopathology.

The final, crucial parameter concerning the accuracy of sentinel node biopsy in breast cancer surgery is the impact of this procedure on the long-term clinical outcome of patients. This issue is currently unresolved and hopefully will be clarified by ongoing long-term investigations, involving 2 arms, to which patients who are eligible for the study are randomly assigned.

Axillary node dissection is routinely performed on 1 arm irrespective of the tumor status of the sentinel lymph node; it is performed on the other arm only if the sentinel node is metastatic on intraoperative frozen section histopathologic examination. In a 2- to 4-y follow-up encompassing at present about 1, patients who underwent surgery in the period —, none of the patients with T1 breast cancer and a negative sentinel node has so far developed tumor recurrence G. Paganelli, V.

Galimberti, U. Veronesi, unpublished data. Although systematic analysis is still missing, this observation is in line with similar data derived from a prospective study performed on a small group of patients with a median follow-up of 39 mo Therefore, within any center performing sentinel node biopsy without subsequent axillary clearance, a strategy must be developed for adequate follow-up of these patients. Regular restaging should be considered probably for a minimum of 5 y. This should include not just palpation of the axilla by a trained surgeon but also imaging with sensitive techniques, possibly on an annual basis.

Conflicting results have been reported concerning the accuracy of sentinel lymph node biopsy in patients who previously underwent excisional biopsy of their breast cancer , or neoadjuvant chemotherapy — Therefore, under these conditions, the potential benefit deriving from sentinel lymph node biopsy should be carefully evaluated for each patient on the basis of a strict case-by-case approach.

Some surgeons now consider that enough experience has accumulated indicating that it is safe for the patients to omit axillary lymph node dissection when intraoperative histopathology shows that the sentinel node is free from metastases. In this case, we strongly recommend that the procedure be considered as safe with a high level of certainty only in patients with T1a-b tumors, while keeping in mind the validity of the other exclusion criteria indicated above.

source url Sentinel node biopsy is a combined effort involving at least 3 different specialties: nuclear medicine, surgical oncology, and pathology possibly health physics. The learning curve depends on how quickly the different operators develop the attitude to work as a single team. According to Orr et al. Cody et al. Obviously, full axillary lymph node dissection must be performed on all patients during the learning phase, irrespective of whether histology of the sentinel node shows metastatic disease.

Having instructed nuclear medicine and surgical oncology personnel at several institutions on how to perform radioguided sentinel node biopsy, we believe that the learning phase can be considered as complete after performing about 40—60 radioguided sentinel node biopsies. This range depends on how frequently the procedures are performed, an indirect parameter of the level of motivation of the entire team involved. Besides sentinel node biopsy, additional applications of radioguided surgery can involve radionuclides other than 99m Tc, even including positron emitters. Sensitivity can be measured by moving radioactive point sources at various distances along the central axis of the probe, in air or in water or both.

Rather than being considered an absolute parameter per se, this parameter should be considered in terms of target-to-background ratios, the main factor affecting surgical strategy in the operating room. This specific property is also called contrast and is jointly correlated with the detector sensitivity, energy resolution, and spatial resolution. Energy resolution is related to the statistical uncertainty intrinsic in the radioactive detection process and is inversely related to the number of electrons produced by a radiation in the detector.

Energy resolution is particularly important for rejection of scatter radiation, so that probes with higher energy resolution will eliminate more counts corresponding to scatter radiation while discarding fewer counts corresponding to the primary radiation. Spatial resolution is critical for accurately localizing the radioactive source within the volume being explored and is evaluated by determining the detected counting rates as a function of the lateral distance from the central axis of the detector. Heavier shielding provides better spatial resolution but also reduces sensitivity and increases the weight of the probe.

Adequate shielding on the back and the sides enables the probe to be used for directional counting in the surgical field. Spatial resolution is especially important for sentinel node biopsy in breast cancer surgery because the spot of interest has a counting rate at least 2 logarithms lower than that of the injection site, which can be very close to the sentinel lymph node.

Linearity of the counting rate with increasing amounts of radioactivity is also important. High-quality probes exhibit a linear response up to about 4,—5, cps, well over the maximum counting rates commonly found in sentinel lymph nodes in vivo and ex vivo. The possibility of changing the collimation angle without changing the probe is a definite advantage versus more rigid systems that require additional devices for different uses. Interstitial injection of 99m Tc-labeled colloids for lymphoscintigraphy and radioguided surgery does not entail any relevant radiation burden to patients 98 , The real issue about radiation protection in radioguided surgery concerns the personnel involved in the procedure besides the nuclear medicine personnel.

Two main factors keep the radiation burden to such personnel at virtually negligible levels in radioguided procedures that are performed according to the protocol described above: Very low doses are injected into patients and 2 or 3 physical half-lives elapse between tracer injection and the surgical procedure. The radioactivity counted in operating room materials possibly contaminated during surgery was also minimal and did not require any special handling procedure.

The simple precaution of letting radioactivity decay for some hours was sufficient for tissue specimens in the pathology department, with the hottest material being the injection site. The above data are consistent with those obtained by other groups after normalization to radioactivity unit and timing of surgery relative to tracer administration — Protocols implying the injection of radioactive doses that are higher than those described above up to and shorter time elapsed between tracer injection and surgery result in radiation exposure per procedure correspondingly higher than the above figures.

Identification of the sentinel lymph node draining a small tumor without palpable metastases is becoming the standard of practice in patients with breast cancer. To optimize sentinel node detection, 99m Tc-sulfur colloid or antimony sulfide or albumin nanocolloid should be injected several hours before surgery.

Radiocolloid has been administered directly into the tumor, in 4 quadrants adjacent to the tumor, intradermally, subcutaneously, or subareolar; in our opinion, either intradermal or peritumoral injection or both is preferred. Different volumes of injectate have been advocated, ranging from 0. Images should be recorded after radiocolloid administration to determine if lymph drains to the sentinel node located medially rather than in the axilla.

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At the time of sentinel lymph node surgery, blue dye should be administered around the tumor. Once identified, the sentinel node is removed and evaluated by detailed histologic evaluation, including immune staining, for the presence of neoplastic cells. The remaining lymph nodes in the axilla are untouched, thereby reducing the morbidity associated with axillary node dissection. Although sentinel lymph node identification is valuable in patients with small tumors, it is not recommended in all breast cancer patients.

Indication for sentinel lymph node biopsy should also be evaluated carefully for patients who have had prior neoadjuvant chemotherapy or excisional biopsy or both. Finally, sentinel node detection and biopsy require some experience on the part of the surgeon. Patients are beginning to read about this procedure and to perceive the advantages of a technique that can avoid the potential morbidity of axillary dissection; thus, they may put pressure on surgical teams to opt for sentinel node localization. Like nothing else in nuclear medicine, sentinel lymph node localization has great potential for benefiting patients, but care must be taken to ensure that fair and accurate information is available to all.

The authors are indebted to and thank all coworkers and colleagues who, at various institutions, have contributed greatly to develop the programs of radioguided sentinel lymph node biopsy and to accumulate the expertise that constitutes the basis for this work. In particular, thanks are due to Drs. Previous Section Next Section.

View this table: In this window In a new window. Tracer Injection At least 3 main parameters define the optimal technique s of administering the radiopharmaceutical for lymphatic mapping and sentinel node biopsy in breast cancer surgery: site of injection, volume of the injectate, and dose injected.

Histopathologic Examination of Axillary Sentinel Lymph Nodes To have real impact in the management of breast cancer patients, histologic examination of the sentinel lymph node s must be extremely careful and extensive. Previous Section. Lectures on the lymphatic system of the stomach. Google Scholar. CrossRef Medline Google Scholar. Cabanas RM. An approach to the treatment of penile carcinoma.

Cancer ; 39 : — A rational approach to the surgical management of melanoma. Ann Surg. Medline Google Scholar. Ege G. Internal mammary lymphoscintigraphy in breast carcinoma: a study of patients. Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers.

Semin Nucl Med. Borgstein P, Meijier S. Historical perspective of lymphatic tumour spread and the emergence of the sentinel node concept. Eur J Surg Oncol. Lymphatic mapping and sentinel lymph node biopsy in breast cancer. Eur J Nucl Med. Sentinel lymph node detection and imaging.

The concept of sentinel node localization: how it started. Sentinel node staging of early breast cancer using lymphoscintigraphy and the intraoperative gamma-detecting probe. Levenback C. Intraoperative lymphatic mapping and sentinel node identification: gynecologic applications. Lymphatic Metastasis and Sentinel Lymphonodectomy. Berlin, Germany: Springer Verlag; — Veronesi U, Zurrida S. Present and future of sentinel node lymphadenectomy in breast cancer.

Lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer. Annu Rev Med. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. Gamma probe guided lymph node localization in malignant melanoma. Surg Oncol. Gamma-probe-guided lymph node localization in malignant melanoma. Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining lymphatic channels and locating the sentinel node. J Nucl Med. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe.

Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Willis RA. Metastasis via the lymphatics. London, U.

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