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From the Department of Surgical Oncology, VU Medical Center, Amsterdam, The Netherlands.
Correspondence: Address correspondence and reprint requests to: S. Meijer, MD, PhD, Department of Surgical Oncology, VU Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Fax: 31-2-4444512; E-mail: S.Meijer{at}vumc.nl
ABSTRACT
Since its introduction in the early 1990s, the sentinel node (SN) concept in breast cancer has been validated by many studies. Because SN biopsy in breast cancer enables the identification of node-negative axillae, the potential morbidity of an axillary lymph node dissection (ALND) can be avoided. The SN procedure is still surrounded by many variables and uncertainties, such as the clinical relevance of micrometastases. However, the main goal is to avoid unnecessary ALND in node-negative breast cancer patients. Sufficient clinical data are available to achieve this goal by incorporating the SN procedure into routine clinical practice. The ultimate safety of the applied technique will be determined by the number of axillary recurrences during long-term follow-up. Preoperative lymphoscintigraphy and intraoperative use of both blue dye and a hand-held gamma probe—the triple technique—has been applied at our institute since early 1994.
Key Words: Axillary lymph node dissection • Breast cancer • Sentinel node biopsy • Triple technique
The SN concept of a first draining lymph node has been extensively validated in breast cancer.1–4 As a result, it has become possible to omit axillary lymph node dissection (ALND) in SN-negative breast cancer patients and thereby avoid significant morbidity. Despite growing acceptance of the SN concept, the technique has not been standardized; there are variations in the tracer and the injection site. Since different approaches show similar success rates, it can be concluded that the SN concept is relatively forgiving and robust despite variations in technique. However, ultimately the accuracy of the method used to identify the SN will be proven by the axillary recurrence rate and overall survival after long-term follow-up.
Not only has the SN concept altered the surgical approach for node-negative breast cancer patients but it also has introduced relatively new dilemmas in the treatment of node-positive patients. For example, the SN is reported to be the only positive axillary node in more than 50% of node-positive patients.1,2,5–7 Accurate identification of this subgroup would further reduce the need for ALND. More intensive histopathological workup of the SN can increase the detection of lymph node metastases. This will lead to upstaging in a subset of patients with a minimally involved SN. Whether these patients will benefit from ALND and adjuvant treatments remains uncertain.
Despite all these variables, a new era in the surgical treatment of breast cancer has emerged with the validation of the SN concept. The triple technique combines preoperative lymphoscintigraphy and intraoperative use of blue dye and a hand-held gamma probe to visualize and localize the SN. This triple technique has been applied at our institute since early 1994.
TECHNICAL ASPECTS
The SN concept is based on the orderly progression of tumor cells within the lymphatic system. The SN will be the first lymph node to contain metastases when lymphatic spread has occurred.8 The use of tracers to follow the lymphatic drainage pattern to this lymph node forms the technical basis of the SN biopsy. As first described by Giuliano et al.,3 blue dye stains the lymphatics, making it possible to localize the SN by careful surgical exploration of the axillary lymph node basin. However, this technique has relatively low success rates during the early stages of the learning curve.2 Krag et al.9 identified the SN in 18 of 22 patients (82%) by using a gamma probe after peritumoral injection of technetium-99m sulfur colloid. The triple technique, which combines the advantages of both techniques, has been applied by us in breast cancer patients.1,10 The triple technique allows the surgeon to check performance at various stages of the procedure. Preoperative lymphoscintigraphy provides the surgeon with detailed information on the number and location of focal accumulations of radiocolloid in lymph nodes.
During our implementation study, lymphoscintigraphy revealed axillary focal accumulations in 107 of 115 patients (91%) (Table 1). A negative lymphoscintigram does not always indicate that the SN cannot be located (Table 1). However, in our experience, minimal or absent focal accumulation is associated with grossly involved lymph nodes1,11; we advise complete ALND in these patients. Focal accumulations outside the axilla may indicate altered lymph flow, such as parasternal uptake. Since distinct focal accumulations can always be harvested under hand-held gamma probe guidance, a normal lymphoscintigram is highly predictive of a successful procedure. Moreover, routine preoperative lymphoscintigraphy not only prevents unpleasant surprises in the operating room but also enables surgeons to discuss the procedure in detail with the patient prior to surgery.
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PATHOLOGY
In the ALND era it was customary to obtain a single slide from all lymph nodes in the surgical specimen. With the implementation of the SN biopsy it has become possible for the pathologist to focus on a single lymph node to stage the entire axilla. As a result, more intensive histopathological workup such as serial sectioning and the use of immunohistochemistry (IHC) can be applied. In our institution all SNs smaller than .5 cm are processed intact, those between .5 and 1 cm are halved, and those larger than 1 cm are lamellated into pieces of approximately .5 cm in size. In most cases, intraoperative fresh frozen section analysis of all individual pieces was performed.16 After frozen section analysis the SN was fixed in neutral buffered formaldehyde and completely embedded. One 4-µm-thick hematoxylin and eosin (H&E)-stained section was made per block. When negative, an additional section was done at the first level for IHC and four step ribbons were cut at an interval of 250 µm. From these ribbons one section was stained with H&E and one was used for IHC with the CAM5.2 antibody (Becton Dickinson, San Jose, CA). Serial sectioning and the use of IHC can increase the detection rate of SN metastases by about 10% to 15%.17–20 Multiple step sectioning and IHC have therefore been widely incorporated in the standard histopathological examination of SNs.
Many study reports, including our own, have described the intraoperative examination of the SN by fresh frozen sectioning (FS).16,21–23 FS investigation enables intraoperative selection of patients eligible for ALND, thus avoiding a second operation for these patients. Despite the promising sensitivity while under investigation, in our experience the sensitivity of FS drastically drops when implemented as standard care. Variable expertise among pathologists is a possible explanation for this phenomenon. Furthermore, FS results in a significant loss of tissue available for more sophisticated histopathological workup such as IHC. Therefore, we no longer routinely perform FS analyses, especially since the majority of patients eligible for SN biopsy are found to be node-negative.
FOLLOW-UP AND RECURRENCES
Despite the extensively validated SN concept in breast cancer, many surgeons are reluctant to omit ALND in SN-negative breast cancer patients. We believe that the validation era has ended. The remaining question is which available technique will be the most reliable method to identify the SN. Ultimately, the safety and reliability of the SN procedure will be proven by the number of axillary recurrences and overall survival after long-term follow-up. The few follow-up studies report none to minimal axillary recurrences.24–26 Although these results seem very promising, the majority of axillary recurrences will occur within 3 years after surgery.27 Therefore, we believe that studies with at least 3 years of follow-up will produce reliable results. Giuliano et al. did not observe any relapses in 67 patients after a follow-up of 49 months.28 Using the triple technique, we observed only one axillary recurrence in 100 after a median follow-up of 3.5 years (41 months). Our long-term follow-up results indicate that survival is excellent (98%) and local axillary control is adequate (99%) after omitting ALND in a group of 104 SN-negative breast cancer patients (Table 2).
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FUTURE CONSIDERATIONS
Several studies have shown that the SN appears to be the only positive axillary lymph node in more than 50% of patients.1,2,5–7 Thus, in 50% of SN-positive patients, additional ALND could be omitted. On the basis of this observation, studies have tried to identify this subgroup of patients.14,30–32 All studies, including our own, found a correlation between the tumor load in the SN and the presence of non-SN metastases. Unfortunately, we found additional positive axillary lymph nodes in 27% of patients with micrometastatic involvement of the SN. This was likely caused by rerouting of lymph flow as described before. Therefore, we believe that ALND is routinely indicated even for patients with micrometastatic involvement of the SN.
It remains uncertain whether ALND in node-positive patients is affecting overall survival or is merely an instrument in achieving local control. Some studies confirm a positive effect on survival,33,34 whereas others show no significant improvement.35,36 Moreover, modern chemotherapy has been shown to reduce the number of positive axillary lymph nodes in node-positive breast cancer patients.37 Furthermore, the majority of patients eligible for SN biopsy are treated by breast-conserving therapy that includes radiation of the breast and proximal axillary lymph nodes. Because radiation therapy is as effective in achieving local control as ALND,38 the question is whether adjuvant chemotherapy and local radiation therapy can eradicate tumor cells in the residual axillary lymph nodes in SN-positive patients.
On this rationale, we have designed a randomized trial of immediate vs. delayed ALND in SN-positive patients who have undergone adjuvant radiotherapy and chemotherapy. Unfortunately, the second patient enrolled to the delayed ALND arm showed extensive lymph node involvement despite adjuvant radiotherapy and chemotherapy. Moreover, our only patient with a false-negative SN developed an axillary recurrence despite adjuvant chemotherapy. Our limited experience with this topic shows that the possible downstaging effect of modern chemotherapy must not be overrated.
CONCLUSION
Now that the SN concept has been validated in many studies, the remaining question is which mapping technique should be applied. In our opinion the triple technique is a reliable and simple method to identify the SN because of the incorporated checks. Although others have reported the necessity of a longer training period and more extensive learning curve,39,40 in our experience residents can safely perform the operation after a supervised learning period during which they become familiar with the delicate surgery the SN procedure requires. We believe that the combination of preoperative scintigraphy and intraoperative use of the hand-held gamma probe and blue dye results in a high success rate, whether the procedure is done by a very experienced surgeon or by a surgical resident.
The ultimate safety of the technique will be determined by the number of axillary recurrences during long-term follow-up. Meanwhile, we believe sufficient clinical data are available to safely incorporate the SN procedure into routine clinical practice.
FOOTNOTES
A new era in the surgical treatment of breast cancer has emerged with the validation of the sentinel node (SN) concept. The triple technique combines preoperative lymphoscintigraphy and intraoperative use of blue dye and a hand-held gamma probe to visualize and localize the SN.
Received for publication November 20, 2003. Accepted for publication December 9, 2003.
REFERENCES
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