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Indian Journal of Cancer, Vol. 40, No. 2, (April - June 2003) , pp.60-66 Review Article Sentinel Lymph Node Biopsy in the Management of Breast Cancer Kumar R, Bozkurt MF, Zhuang H, Alavi A
Division of Nuclear Medicine, Department of Radiology, Hospital of the University
of Pennsylvania, 110 Donner Bldg. 3400 Spruce Street, Philadelphia, PA, 19104,
USA.
Code Number: cn03009 ABSTRACT Sentinel node localization is the second most important development in this century after conservative lumpectomy for the treatment of early breast cancer. The sentinel node mapping is a new multidisciplinary approach for staging of axilla in an accurate and less morbid way as compared to axillary node dissection. Sentinel lymph node biopsy in patients with breast cancer has been adopted rapidly into clinical practice. The accuracy of sentinel lymph node biopsy is more than 95%, when performed meticulously (by an experienced multidisciplinary team) with proper patient selection. Sentinel lymph node biopsy is most widely used for both palpable and non-palpable T1 and T2 tumors. Recent studies show application of sentinel lymph node technique in patients with locally advanced breast cancer and after neoadjuvant chemotherapy. Therefore, sentinel lymph node biopsy technique has application in developing countries and other countries where screening for breast cancer is not common and most patients present relatively in advanced stage of the disease. Several aspects of the sentinel lymph node biopsy including technique, case selection, pathologic analysis and accuracy with supportive important studies published in the literature will be discussed in this review. Key Words: Sentinel node biopsy, Breast cancer, Blue dye, Radio colloid, Neoadjuvant chemotherapy. Introduction Breast cancer is the most common cancer in the United States and is the second commonest cancer in India in women.1 Approximately 1 in 9 women will have breast cancer during her lifetime. Breast cancer is the commonest cause of deaths due to cancer in females through out the world.2 The incidence of breast cancer is increasing. This increase in incidence may be due to increased detection by regular screening and self-examination. Staging is very important for the management of all cancer patients and breast cancer is not an exception. Staging of axilla in breast cancer is the single most important prognostic factor for selection of appropriate adjuvant therapy, locoregional recurrence and long-term survival. Exact staging of axillary lymph nodes can be obtained in 2 ways, directly by axillary lymph node dissection (ALND) or indirectly by sentinel node biopsy (SLNB). The ALND is drastic and associated with debilitating complications of the ipsilateral arm like lymphedema, seroma, parasthesia etc. Whereas, sentinel node biopsy is less drastic and devoid of above mentioned complications.3-5 The evidences from recent studies that showed benefits from neoadjuvant therapy regardless of axillary lymph node involvement also challenge ALND.6,7 For adopting SLNB technique, it is well-recognized accepted fact that a multidisciplinary team, which includes surgery, nuclear medicine and surgical pathology departments, is required to work in a close cooperation. Each of these disciplines plays a crucial role in achieving success, and the surgeon cannot embark upon a successful SLNB program without cooperation from other disciplines. What is Sentinel Lymph Node? The first lymph node in the lymphatic basin draining the primary tumor is called the sentinel lymph node (SLN). When it is identified, removed and biopsied, it reflects the histological characteristics of the rest of the nodes in the basin. It is well-understood phenomenon that metastases to lymph node are not a random phenomenon and can be determined by identifying the lymph flow from tumor to primary lymph draining node. If there is lymphatic spread of cancer it should involve the sentinel node first and then the other nodes. In case of breast cancer, most of the times SLN node exists in axillary lymph nodes of central group of level I, level II or Level III. The incidence of sentinel lymph node in internal mammary lymph nodes is less than 5% and internal mammary nodes alone harboring metastases are very rare.8 The concept of `sentinel lymph node' was first described by Cabanas in 1977 in patients with carcinoma of penis.9 Sentinel lymphdectomy in 22 breast cancer patients using Tc99m-sulphur colloid and gamma probe was first described in 1993 by Krag et al.10 Giuliano et al in 1994 published the first study in breast cancer patients using blue dye method.11 After that, a large number of studies have been published in the literature on different aspects of this technique. Anatomy and Physiology of Lymphatic System of Breast Since the breast is originally an ectodermal tissue, its lymphatic drainage mostly parallels lymph flow of the overlying skin. Lymphatic flow from the skin finds its way to the diffuse subcutaneous plexus between the skin and the superficial fascia. Each lobule of the breast tissue has an extensive lymphatic plexus, that are merged to form Sappey`s subareolar plexus. Sappey`s subareolar plexus and deep fascial plexus are in connection with each other through fibrous strands traversing the breast tissue. Most part of the breast tissue and the overlying skin can be accepted as a single unit sharing a common lymphatic pathway draining to axillary lymph nodes, because of the common embryologic origin. But there are some exceptional breast areas such as lateral portion of the breast tissue draining to the lymph nodes of the pectoral group and the medial portion that drains to the internal mammarian lymph nodes.12 In general, most of the lymph of the breast tissue drains to the axillary nodes, whereas approximately 3% drains to internal mammarian lymph nodes and parasternal nodes and very small portion of lymph drains to posterior intercostal nodes.13 The drainage pattern of lymphatics in breast tissue plays an important role in choosing different radiocolloid injection techniques. Technical aspects of Sentinel Node Biopsy The sentinel lymph node can be identified by a number of ways. SLNB is a robust procedure as satisfactory results are obtained despite significant variations in the methodology. Some centers use blue dye only, others use radiocolloid (Tc99-sulphur colloid) only but most of the center use combination of two for detection of SLNB. All three methods had reliable results in experienced hands. Though theoretically SLN should be one node, in practice there is often more than one node in the axilla which is positive by either blue dye method or radiocolloid method and they all are labeled as SLN. Since most of the time, there is more than one sentinel lymph node as demonstrated by multi-institutional study of 1436 patients, false negative rates fall from 14.3% to 4.3% if multiple nodes were removed instead of single node.14 McMasters et al also obtained similar results in a large multicentric trial.15 Therefore, combination technique appears to be more accurate than radiocolloid or blue dye alone. Many authors demonstrated best results with combination techniques proving that this hypothesis is true. Of 39 studies, using radioisotopes (16 studies) or blue dye (11 studies) or a combination of both (12 studies) identified SLN in 92%, 81% and 93% respectively, while false negative rates were 7%, 9% and 5% respectively.16 All these studies showed that there is higher identification of SLN and lower false negative rate of SLNB for combined method. In a recent study, we also demonstrated higher success rate of SLN identification with combined method than that of radiocolloid or blue dye method alone.17 Based on our experience and the published data in the literature, we suggest that combined radiocolloid and blue dye method yields the best result of SLN identification and less false negative cases. Injection Techniques Different injection techniques are applied for injection of radiotracer and blue dye in patients with primary breast lesion for SLNB. Initial studies of SLNB involved the multiple peritumoral or intratumoral injection of lymphatic markers because of following reasons; firstly, lymphatic drainage of the skin of the breast and glandular tissue were thought to be significantly different, secondly, the injection distant from tumor may not represent true sentinel lymph node.18,19 However, many recent studies used intradermal (ID), subdermal (SD) and subareolar (SA) injection techniques.20-22 By simultaneous PT injection of blue dye and ID or SD or SA injection of radiocolloid on the same patient and finding the same SLN as hot and blue they demonstrated that these alternate injection sites also detect the SLN correctly. Several authors demonstrated that visualisation of axillary lymph nodes by ID or SA injection is faster than with PT injection.22-25 On the basis of current literature and our own experience, we feel that single SA or ID/SD injection will map SLN as multiple (4-6 sites) peritumoral injection in majority of patients. SA or ID/SD injections are also much simpler. Pre-op Lymphoscintigraphy for localization of SLN Lymphatic mapping demonstrates the draining lymph node of primary breast cancer. Lymph node image acquisition and localization is done with the help of gamma camera after injection of radiotracer. The biggest advantage of pre-operative lymphoscintigraphy is identification of unexpected drainage route especially non-axillary lymph nodes which can be seen in up to 20% patients.26-28 The other advantages include determining the exact number of sentinel nodes and distinguishing first from second-tier nodes. Surgeons at the Netherlands Cancer Institute have stated that the lymphoscintigram can act "as a road map in a strange city".29 However, many researchers feel that pre-operative lymphoscintigraphy does not improve the detection rate of SLN.27,28 McMasters et al in their non-randomized multi-institutional study failed to demonstrate any advantage of pre-operative lymphoscintigraphy in 588 patients.15 In 85% patients in whom SLN was not seen on lymphoscintigraphy initially, it was found intraoperatively. Localization of SLN during Surgery SLN biopsy is usually a straightforward and simple operation. Usually 5 to 10 minutes before the procedure on the breast (excision or mastectomy), 1-2 ml blue dye is injected intraparenchymally at four to six sites around the breast lump or skin-overlying tumor. A gentle massage is given for 10-15 minutes to facilitate the drainage of blue dye to lymph nodes. Isotope counts are taken from the axilla and the injection site in the breast using a hand-held gamma probe with audible guidance system. At the time of surgery, blue lymphatic tract is followed till blue node is identified. Gamma probe is used during surgery to localize isotope positive sentinel lymph nodes. All lymph nodes having counts > 10 times of background count (`hot') are considered as sentinel lymph nodes irrespective of the status of blue dye. As well as all blue dye positive nodes (`blue') are also considered as sentinel node irrespective of radioactive counts. All `hot' and `blue' sentinel nodes should be sent for frozen section, H&E staining as well as for immunohistological (Cytokeratin) staining for detection of micro-metastasis. Learning Curves Learning curves are well known in SLNB training of surgeons.30,32 It takes longer time and more cases are needed for identification of SLN and to achieve reasonable accuracy using blue dye alone than combined blue dye and radiocolloid method.32,33 Cox et al, described results amongst 700 cases operated on by 5 surgeons using combined blue dye and radiocolloid.30 They described a rapid decrease in failure in identification of SLN after first 20 cases. The overall learning curves indicated that 23 and 53 cases were required by 5 surgeons to achieve 90 and 95% accuracy respectively. Similarly, in a large multi-institutional study of 2148 patients, McMasters demonstrated that individual surgeon needs to perform at least 20 SLNB with accompanying complete axillary dissection before the surgeon is likely to reach an acceptable level of identification and accuracy.33 Accuracy of Sentinel Lymph Node Biopsy Sentinel lymph node biopsy can replace axillary dissection for staging and diagnosis in T1 and T2 breast cancer after appropriate and adequate training of surgeons and management team. These were highlights of Philadelphia consensus conference on the role of sentinel node biopsy in breast cancer in 2001.34 Fraile et al conducted a meta analysis of 18 studies on 2500 SLNB plus axillary dissection for assessment of accuracy of SLNB.35 They reported a sensitivity ranging from 83% to 100% and concluded that SLNB is a safe substitute of axillary node dissection. Most of the studies reported > 95% identification of sentinel lymph node in appropriately selected patients.3,15,36,37 The false negative rates of SLNB are <5% and these numbers are comparable to the failure to detect a metastatic focus in nodes recovered from axillary dissection. Tumor Size and SLNB Till recently, tumor size more than T2 was considered as a contraindication. Therefore, most of the studies undertaken included patients having T1 and T2 tumors, though, it is well known fact that incidence of axillary lymph node metastases increases with tumor size.38 But axillary dissection can be avoided in patients who have negative SLNB in patients with larger tumors. Two recent studies showed that there is no significant difference in identification of SLN and false negative rate in T3 tumors when compared to T1 tumors.39,40 Therefore, tumor size should not preclude the use of SLNB in those patients who otherwise are candidates for the procedure. Bedrosian et al concluded that SLN biopsy for patients with large breast tumors is technically feasible and highly accurate. SLN biopsy should be considered for the staging of clinically negative axilla in patients scheduled to receive neoadjuvant chemotherapy.41 Therefore, SLNB is not a contraindication in patients with larger breast malignant tumors and clinically negative axillary lymph nodes. SLNB after Neoadjuvant Therapy The patients with large primary breast tumors are considered poor candidates for breast conservation therapy; however, recent success of chemotherapy has allowed lumpectomy. Besides, SLNB has emerged as a possible alternative to axillary node dissection in patients with operable breast cancer, this procedure is also emerging as a possible alternative in patients who have received prior neoadjuvant chemotherapy. Therefore, it is important to know how safe it is to perform SLNB in these patients. Initial smaller, single-institution series with the SLNB have shown significant variability in the identification rates and false negative rates up to 33% resulting in inconsistent conclusions regarding the appropriateness of this technique in this group of patients.42-46 Subsequent larger, multicenter series have shown that the identification rates and false negative rates with sentinel node biopsy after neoadjuvant chemotherapy is similar to those when sentinel node biopsy is performed after breast cancer diagnosis47-56 (Table 1). Recently, Sabel et al and Schrenk et al demonstrated 100% identification rate of SLN in patients before neo-adjuvant chemotherapy.57,58 There were no false negative results in either of studies. Thus, it appears that the sentinel node concept is also applicable in patients who have undergone neoadjuvant chemotherapy. This observation has the potential to expand the utility of neoadjuvant chemotherapy in patients with operable breast cancer.59 SLNB for Multicentric Cancer Most of the studies available in the literature have excluded patients who had multicentric breast masses with the assumption that it is difficult to localize true sentinel lymph node or there may be multiple lymph nodes representing different tumor lesions. Only few studies tried to answer the question if SLNB is safe procedure in patients with multicentric breast cancer. Schrenk et al identified SLN in all 19 patients with multicentric breast cancer with no false negative study.60 In a study of 48 patients with multicentric breast cancer, we identified SLN in 93% patients.17 There was no false negative result in this series. Fernandez et al had similar experience of identification rate of 98% with no false negative patient.61 All these studies evidenced that lymphatic mapping and SLNB is possible in the patients with multicentric and multifocal breast cancer without increased false negative results. However, large studies are required to validate the utility of SLNB in these patients. Inaccuracy of Frozen Section It is well known fact that micrometastases are missed by routine frozen section of lymph nodes. The serial sectioning with H&E staining and immunohistochemistry methods have found additional micrometastases in 7%-33% cases.62,63 Therefore, these patients need second operation to perform a complete ALND once micrometastases are detected on more extensive serial section and/or immunohistochemistry (IHC) staining leading to increase in morbidity and financial burden. There is enough data in the literature suggesting that frozen section analysis is not as sensitive as routine pathological assessment of paraffin section and IHC.62,64 Intra-operative lymph node involvement can be assessed by imprint cytology.65,66 However this technique has variable results and is operator dependent. Further large studies are required to draw further conclusions. Safety, Contraindications and Limitations There are many specific safety issues in SLNB. Allergic reaction to blue dye and radiocolloid are rare but have been reported. Efron et al reported a case anaphylactic shock in response to injection of isosulfan blue for the purpose of localizing the sentinel node and review the medical literature.67 The urticaria from blue dye may take the form of striking blue colored wheals and should be treated like any other allergic reaction during perioperative situation. Second important safety issue is radiation exposure to patient and staff involved in SLNB. This issue has been undertaken by many authors and it has been demonstrated that risks are negligible and radiation levels are much lower than permissible limits.67-71 The radiation risks to the administered doses are much low relative to many other imaging modalities.68 The list of specific contraindications is becoming short and short with the experience in SLNB. Krontiras et al reviewed the current data regarding contraindications for the use of sentinel lymph node biopsy and lymphatic mapping.72 At present, there are very few contraindications, such as the patient with clinically positive axillary lymph nodes. In these patients with clinically positive lymph nodes, radiocolloid and blue dye may be blocked by infiltration of lymphatic channels by tumour and can lead to identification of non-sentinel lymph node as well as the patient may require axillary dissection as a part of the treatment. Locally advanced breast cancer is also considered as one of the contraindications. Although, recent few studies showed that SLNB can be considered if axillary lymph nodes are negative for metastases even in locally advanced disease. Allergies to blue dye or the radiocolloid should also be considered another contraindication to that material although it is very rare. However there is no cross reactivity among two. The risks of blue dye and radio colloid in pregnancy are not known, and considered as a contraindication till data is available. Prior axillary procedures like augmentation mammoplasty through axillary incision, prior axillary dissection are relative contraindications. However, the important point in this regard is the consideration of intact lymphatic channels between tumor and lymph node. A small data of SLNB after surgery from Port et al study is noteworthy, but more data is required.73 Conclusions Sentinel lymph node biopsy is an exciting new tool for staging the axilla in an accurate and less morbid way in breast cancer patients. Proof of SLN is well established and has success rate of more than 95% with multidisciplinary team work. The combined method of radiocolloid and blue dye yields best results of sentinel node identification. The eligibility criteria for SLNB are increasing and contraindications are decreasing with experience. It is becoming more apparent that SLNB is appropriate in a variety of settings including properly selected patients undergoing neoadjuvant chemotherapy and those with locally advanced breast cancer. The absolute contraindications are palpable metastatic lymphadenopathy and pregnancy. References
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