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Kasr el-aini journal of surgery Volume 14, No.1, January 2013
1
Sentinel lymph node biopsy before neoadjuvant chemotherapy...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
2
SLNB performed before NC in clinically
node-negative breas...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
3
the location and the tumor size, the breast
size and the w...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
4
underwent ALND after NC. An average of
14 additional nodes...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
5
False negative rate of SLNB
The second important aspect of...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
6
allow the detection of micrometastases or
isolated tumoral...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
7
spares breast cancer patients axillary
lymph node dissecti...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
8
management large (> or = 5 cm) invasive
breast cancer. Ann...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
9
Table 1: Patients Characterestics
Patients n=27
Age (Years...
Kasr el-aini journal of surgery Volume 14, No.1, January 2013
11
Table 3: Concordance between histological analysis of SLN...
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Sentinel lymph node biopsy before neoadjuvant chemotherapy for clinical axillary node negative breast cancer impact on staging.

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Ihab S. Fayeka MD; Fouad A. Saleepa MD; Hany F. Habashyb MD; Alfred E. Namourc MD ; Iman G. Farahatd MD ;Magdy Kotbe MD
a: department of surgical oncology - national cancer institute - Cairo university - Egypt.
b: department of surgery - Fayoum university hospital - El Fayoum - Egypt.
c: department of medical oncology - national cancer institute - Cairo university - Egypt.
d: department of surgical pathology - national cancer institute - Cairo university - Egypt.
e: department of nuclear medicine - national cancer institute - Cairo university - Egypt.
For correspondance contact: drihab74@hotmail.com
Kasr el-aini journal of surgery Volume 14, No.1, January 2013

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Sentinel lymph node biopsy before neoadjuvant chemotherapy for clinical axillary node negative breast cancer impact on staging.

  1. 1. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 1 Sentinel lymph node biopsy before neoadjuvant chemotherapy for clinical axillary node negative breast cancer: impact on staging. Ihab S. Fayeka MD; Fouad A. Saleepa MD; Hany F. Habashyb MD; Alfred E. Namourc MD ; Iman G. Farahatd MD ;Magdy Kotbe MD a: department of surgical oncology - national cancer institute - Cairo university - Egypt. b: department of surgery - Fayoum university hospital - El Fayoum - Egypt. c: department of medical oncology - national cancer institute - Cairo university - Egypt. d: department of surgical pathology - national cancer institute - Cairo university - Egypt. e: department of nuclear medicine - national cancer institute - Cairo university - Egypt. For correspondance contact: drihab74@hotmail.com Abstact Background: The ideal timing of sentinel lymph node biopsy (SLNB) is still, by far, a matter of debate. Meanwhile, several authors reported SLNB after neoadjuvant chemotherapy (NC). Methods: We evaluated the accuracy and feasibility of SLNB before NC using a combined procedure (blue dye and radio-labelled detection). Axillary lymph node dissection (ALND) was performed after completion of NC in patients with breast cancer having clinically node- negative axillae. Results: Among the 18 women who had metastatic SLNB (67%) detected before NC, 3 (17%) had additional metastatic node on ALND. While 15 women who had no metastatic SLNB also had no involved nodes in ALND after NC. Conclusion: SLNB done before NC is a reliable and accurate diagnostic tool to stage the clinically negative axillae in breast cancer, permitting to avoid ALND after NC for patients with negative SLNB. Introduction A debate exists as to whether sentinel lymph node biopsy (SLNB) should be performed before or after neoadjuvant chemotherapy (NC) in large breast cancers in order to obtain a down staging allowing for breast conservation.1 However regarding literature review, the accuracy of SLNB performed after NC is controversial because of high false negative rates2 and limited numbers of studies having performed SLNB before NC.3-10 So, we report here a study evaluating the role of
  2. 2. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 2 SLNB performed before NC in clinically node-negative breast cancer patients. All patients underwent a formal ALND following neoadjuvant chemotherapy to validate the SLNB findings. Patients and methods Patients Study candidates were patients referred to the National Cancer Institute (Cairo, Egypt) and University of Fayoum teaching hospital (Fayoum, Egypt) for the treatment of invasive breast cancer. Patients were included in the study if they had tumor more than 4 cm in diameter for which a NC was indicated in order to enhance the likelihood of breast conservation. A proven histopathologic diagnosis of invasive breast cancer was required. Exclusion criteria included: clinically palpable axillary lymph node, distant metastasis, and inflammatory breast cancer, allergy to the isotope used during the sentinel lymph node mapping. The protocol consisted to perform a SLNB before NC and an ALND after NC. All Patients were informed of the protocol and a written informed consent was obtained. Preoperative radioactive colloid mapping of the sentinel node The day before the surgery a combination of intradermal and intraparenchymal radioactive colloid injection and a lymphoscintigraphy of the breast and the axilla were done to determine the position of the sentinel node as previously described.11 Sentinel lymph node biopsy Under general anesthesia and 10 min before incision, 2 ml Patent Blue dye is injected in subareolar area.11 After an axillary skin incision sentinel lymph node dissection was performed by combined intra-operative gamma probe detection (Figure 1). All lymph nodes presenting either blue dye (Figure 2) or radioactive counts (Figure 1) or both were identified as sentinel lymph node(s) and removed. All sentinel lymph nodes were sent individually for histological examination with information concerning blue dye uptake and ex-vivo radioactivity count. Neoadjuvant chemotherapy All the patients were assigned to receive fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , and cyclophosphamide 500 mg/m2 (FEC) intravenously on day 1 every 21 days for four cycles. Clinical response was defined by following criteria: (1) complete response was defined as a total disappearance of the breast tumor (2) partial response a 50% or greater reduction of the product of the two largest perpendicular dimensions of the breast mass (3) minor response a less than 50% reduction of the product of the two largest perpendicular dimensions of the breast mass (4) no change in clinical status (5) progressive disease.12 Axillary lymph node dissection and breast surgery Levels I and II axillary lymph node dissection were systematically performed four weeks after the end of the NC.13 Mastectomy or lumpectomy ( breast- conserving surgery ) was performed according to the clinical response after NC,
  3. 3. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 3 the location and the tumor size, the breast size and the women's wish. Histology No intra-operative evaluation was performed on sentinel lymph node. The sentinel lymph node was analyzed by serial sectioning of the whole node after formalin fixation and paraffin embedding. Every section of 200 µm was stained with haematoxylin-eosin and by antibody to cytokeratin for the detection of micrometastasis (<2 mm) and isolated tumor cells (0.2 mm). Axillary lymph node dissection and tumor were examined according to the standard procedures. Complete pathological response was defined by the complete absence of residual invasive tumor in the breast or axillary lymph nodes even if there was residual carcinoma in situ.14 Statistical analysis The sentinel lymph node identification rate and the false negative rate were used to assess the feasibility of SLNB before NC. The identification rate was defined as the proportion of procedures in which a sentinel lymph node was successfully identified. The false negative rate was defined as the proportion of axillary node dissection-positive cases in which the sentinel lymph node was negative. Results Patients From August 2006 to january 2011, twenty seven women with T2 or T3 invasive breast cancer according to AJCC classification without palpable axillary lymph node underwent SLNB before NC and an ALND after NC.15 The median age of the patients was 48 years (range 29-66 years). The median clinical tumor size was 45 mm (range 40-70 mm). Characteristics of the study population were reported in Table 1. Sentinel lymph node biopsy The sentinel lymph node detection was successfully achieved in all 27 patients. The median number of axillary sentinel node removed was 1 (range 1-3). In 15 cases only one sentinel node was removed (56%); in 7 cases two sentinel nodes were removed (26%). Three sentinel nodes were removed for 5 patients (19%). The sentinel nodes were metastatic in 18 of the 27 patients. All sentinel nodes were macrometastatic, no micrometastatic cases were detected. Neoadjuvant chemotherapy The planned chemotherapy was completed in all 27 patients.Complete clinical response was observed in 11 patients (41%), partial clinical response in 13 patients (48%) and minor clinical response in 3 patients (11%). Complete pathological response was observed in 10 patients (37%) (Table 2). Surgical procedure Fifteen patients (56%) had a mastectomy. In 4 cases, a mastectomy was performed to achieve negative margins after a lumpectomy. Twelve patients (44%) were treated with lumpectomy. All 27 patients
  4. 4. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 4 underwent ALND after NC. An average of 14 additional nodes (range 8-33) were removed. Among the 9 women who had negative sentinel lymph node, the average of additional nodes removed during ALND was 12 (range 8-23). Among the18 women with positive sentinel lymph node, the average of additional nodes removed during ALND was 15 (range 12-33). Three patients had remaining axillary metastatic disease: 1 metastatic node/14 dissected nodes, 1 metastatic node/15 dissected nodes, 2 metastatic nodes/12 dissected nodes,respectively. Feasibility of sentinel lymph node biopsy The identification rate of sentinel lymph node was 100%. Among the 18 patients who had metastatic sentinel nodes (67%) at initial SLNB, 3 (17%) had additional metastatic lymph nodes on ALND after NC. Indeed, all patients who had negative SLNB had also negative ALND (Table 3). The rate of false negative was 0%. Discussion Contrary to the high number of studies reporting SLNB after NC, very few investigators have reported the pertinence of SLNB performed before NC.3-7;9-10 The original idea of this work was to systematically perform a combination procedure for sentinel lymph node detection and an ALND systematically done after NC. This idea has not been systematically performed in previous stud- ies.3-7;9-10 In the present study, we have found a high identification rate as well as no false negative for the application of SLNB before NC. Accuracy of SLNB The major aspect of our study was the achievement of an ALND in all patients following the completion of NC. This attitude may validate the ability of SLNB to identify the axillary status before NC. In most previous studies, ALND was not systematically performed if the SLNB was negative, precluding any conclusion about the false negative rate of such a procedure.3-5,7,9,10 Actually a systematic ALND after NC allows us to report important data about the high accuracy of SLNB in this setting. Among 9 patients who had no metastasis on SLNB (23%) before NC, none had metastasis on the ALND after NC. A potential remark at this stage is that ALND does not allow differentiation between patients with true negative SLNB and those with false negative SLNB sterilized by chemotherapy. However the expected rates of non involved axillary lymph node range from 24% to 41% in large breast cancers.11,16-18 That is approaching our own results (23%). Besides, if NC is known to down stage tumor-involved lymph nodes, more than 74% of axillary node metastases histologically confirmed to persist after NC.3,14,19,20 These arguments are consistent with our low false negative rate (0%) for SLNB. Besides, our data suggest that SLNB performed before NC may spare a significant proportion of ALND (23%). Schrenk et al. 2008 had recently proposed an algorithm for ALND whether SLNB was positive or negative before NC in clinically node-negative axilla.10
  5. 5. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 5 False negative rate of SLNB The second important aspect of our study was the use of a combination procedure (blue dye and radio-labelled) for sentinel lymph node detection in all clinically axillary node-negative breast cancer group. Primarily, it had been said that the combination of blue dye and radio-labelled give the highest sentinel node detection rates with the lowest false negative rates.21 Nevertheless one of the previous trial, on SLNB performed before NC, has reported such lymphatic mapping in one part of the cohort study.6 Then, it had been shown that the unsuccessful axillary mapping during preoperative lymphoscintigraphy was asso- ciated with positive axillary nodes.22 Yet, one previous trial has included women with clinically enlarged axillary lymph nodes at the time of SLNB.6 In fact, to improve sen- tinel node detection and reduce false negative rate, women candidate for SLNB prior NC must be selected with no clinically palpable axillary lymph node and the combination of pre- and intra-operative sentinel node detection must be performed for optimal results.21 Timing of SLNB The ideal time of SLNB in neoadjuvant setting is still a matter of debate. The major disadvantages of SLNB performed before NC are (1) the fact that an additional oper- ative procedure is done may delay the beginning of NC, (2) an ALND is performed after the end of NC for a positive SLNB even if axillary metastases had been sterilized by NC.23 By contrast, the major advantage of post-NC is to provide information that would allow ALND to be avoided if SLNB is negative in a more proportion of women who do axillary staging performed before NC. In fact, NC is known to down staging of tumor-involved lymph nodes. The rate of chemotherapy sterilization of axillary node metastases histologically confirmed by fine-needle aspiration is 20%-26%.3,14,19,20 Nevertheless, if a complete pathologic response to NC in the axilla has improved survival,19 thus far no study has investigated the rate of axillary recurrence following a pathologic complete eradication of axillary node metastase after NC for which no ALND is added. The major limitation of SLNB performed after NC is a technical challenge. A recent meta-analysis including 21 studies report a false negative rate of 12% (IC 10%-15%).2 This rate seems unacceptably high according to the guidelines of the American Society of Breast Surgeons that recommend a false negative rate of 5% or less in order to abandon ALND.21 Lymphatic changes caused by chemotherapy including nodal fibrosis, mucin pools or aggregates of foamy histiocytes may explain the high false negative rate.24 Consequently, the application of SLNB after NC is controversial and does not appear as a robust method to assess the status of the axillary basin. Limitations Our study has some limitations such as the small number of patients included in the analysis. Moreover, the dissected axillary nodes were not analyzed with the same pathological protocol as for SLNB. A recent study has shown that serial sectioning and use of IHC on dissected axillary nodes
  6. 6. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 6 allow the detection of micrometastases or isolated tumoral cells in 21% of patients originally staged as node-negative with the standard procedure.25 Interestingly, such occult metastases have been shown to be prognostically significant.25 Nevertheless this pilot study confirms the pertinence of SLNB performed before NC and might benefit the patient by reducing the morbidity of axillary staging by ALND. These findings remain to be confirmed in a larger cohort before any clinical recommendation can be made. Conclusion Contrary to the limited number of studies that report SLNB before NC, we systematically performed a combination procedure for sentinel lymph node detection before NC and an ALND after NC in a homogeneous cohort study without clinically palpable axillary lymph node. We report a high identification rate and no false negative results. SLNB is a reliable and accurate diagnostic tool to stage the clinically negative axillae in breast cancer before NC and to predict the pre- therapeutic axillary lymph node status. Moreover, SLNB performed before NC may spare a significant proportion of patients with locally advanced breast cancer the morbidity of an axillary lymph node dissection. Further studies with larger patient number are needed to confirm these findings and put them into clinical use. References 1. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672- 85. 2. Xing Y, Foy M, Cox DD, Kuerer HM, Hunt KK, Cormier JN. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg 2006;93:539-46. 3. Cox CE, Cox JM, White LB, Stowell NG, Clark JD, Allred N, Meyers M, Dupont E, Furman B, Minton S. Sentinel node biopsy before neo-adjuvant chemotherapy for determining axillary status and treatment prognosis in locally advanced breast cancer. Ann Surg Oncol 2006; 13:483-90. 4. Ollila DW, Neuman HB, Sartor C, Carey LA, Klauber-Demore N. Lymphatic mapping and sentinel lymphadenectomy prior to neoadju-vant chemotherapy in patients with large breast cancers. Am J Surg 2005;190:371-5. 5. Van Rijk MC, Nieweg OE, Rutgers EJT, Oldenburg HS, Olmos RV, Hoefnagel CA, Kroon BB. Sentinel node biopsy before neoadjuvant chemotherapy
  7. 7. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 7 spares breast cancer patients axillary lymph node dissection. Ann Surg Oncol 2006;13:475-9. 6. Schrenk P, Hochreiner G, Fridrik M, Wayand W. Sentinel node biopsy performed before preoperative chemotherapy for axillary lymph node staging in breast cancer. Breast J 2003;9:282-7. 7. Jones JL, Rhei E, Gadd MA, Howard- Mcnatt, Hughes KS, Lesnikoski BA, Christian RL, Rabban JT, Kaelin C,. Smith BL. Predictive value of sentinel lymph node biopsy prior to neoadjuvant chemotherapy in clinically node negative breast cancer. American Society Clinical Oncology. Annual Meeting. 2004. 8. Jones JL, Zabicki K, Christian RL, Gadd MA, Hughes KS, Lesnikoski BA, Rhei E, Specht MC, Dominguez FJ, Smith BL. A comparison of sentinel node biopsy before and after neoadjuvant chemotherapy: timing is important. Am J Surg 2005;190:517-20. 9. Sabel MS, Schott AF, Kleer CG, Merajver S, Cimmino VM, Diehl KM, Hayes DF, Chang AE, Pierce LJ. Sentinel node biopsy prior to neo-adjuvant chemotherapy. Am J Surg 2003;186:102-5. 10. Schrenk P, Tausch C, Wolfl S, Bogner S, Fridrik M, Wayand W. Sentinel node mapping performed before preoperative chemotherapy may avoid axillary dissection in breast cancer patients with negative or micrometastatic sentinel nodes. Am J Surg 2008;196:176—83. 11. Lelievre L, Houvenaeghel G, Buttarelli M, Brenot-Rossi I, Huiart L, Tallet A, Tarpin C, Jacquemier J. Value of the sentinel lymph node procedure in patients with large size breast cancer. Ann Surg Oncol 2007;14:621-6. 12. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14. 13. Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer 1955;8:776-8. 14. Kuerer HM, Sahin AA, Hunt KK, Newman LA, Breslin TM, Ames FC, Ross MI, Buzdar AU, Hortobagyi GN, Singletary SE. Incidence and impact of documented eradication of breast cancer axillary lymph node metastatses ' before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 1999;230:72-8. 15. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010 Jun;17(6):1471-4. 16. Schule J, Frisell J, Ingvar C, Bergkvist L. Sentinel node biopsy for breast cancer larger than 3 cm in diameter. Br J Surg 2007;94:948-51. 17. Bedrosian I, Reynolds C, Mick R, Callans LS, Grant CS, Donohue JH, Farley DR, Heller R, Conant E, Orel SG, Lawton T, Fraker DL, Czerniecki BJ. Accuracy of sentinel lymph node biopsy in patients with large primary breast tumors. Cancer 2000;88:2540-5. 18. Chung MH, Ye W, Giuliano AE. Role for sentinel lymph node dissection in the
  8. 8. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 8 management large (> or = 5 cm) invasive breast cancer. Ann Surg Oncol 2001;8:688-92. 19. Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, Kau SW, Fornage B, Sahin A, Broglio K, Singletary SE, Valero V. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 2005;23:9304-11. 20. Rouzier R, Extra JM, Klijanienko J, Falcou MC, Asselain B, Vincent- Salomon A, Vielh P, Bourstyn E. Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with Tl to T3 tumors and cytologcally proven axillary metastatic lymph nodes. J Clin Oncol 2002;20: 1304-10. 21. Lyman GH, Giuliano AE, Somerfield MR, Benson AB 3rd, Bodurka DC, Burstein HJ, Cochran AJ, Cody HS 3rd, Edge SB, Galper S, Hayman JA, Kim TY, Perkins CL, Podoloff DA, Sivasubramaniam VH, Turner RR, Wahl R, Weaver DL, Wolff AC, Winer EP. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005 ;23:7703-20. 22. Rossi Brenot, Houvenaeghel G, Jacquemier J, Bardou VJ, Martino M, Hassan-Sebbag N, Pasquier J. Nonvisualization of axillary sentinel node during lymphoscintigraphy: is there a pathologic significance in breast cancer? J Nucl Med 2003;44:1232-7. 23. Newman EK, Sabel MS, Nees AV, Schott A, Diehl KM, Cimmino VM, Chang AE, Kleer C, Hayes DF, Newman LA. Sentinel lymph node biopsy performed after neoadjuvant chemotherapy is accurate in patients with documented node-positive breast cancer at presentation. Ann Surg Oncol 2007;14:2946-52. 24. Newman LA, Pernick NL, Adsay V, Carolin KA, Philip PA, Sipierski S, Bouwman DL, Kosir MA, White M, Visscher DW. Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated preoperative chemotherapy correlates with breast cancer outcome. Ann Surg Oncol 2003;10:734-9. 25. Tan LK, Giri D, Hummer AJ, Panageas KS, Brogi E, Norton L, Hudis C, Borgen PI, Cody HS 3rd. Occult axillary node metastases in breast cancer are prognostically significant: results in 368 node-negative patients with 20-year follow- up..J Clin Oncol 2008;26:1803-9.
  9. 9. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 9 Table 1: Patients Characterestics Patients n=27 Age (Years) ≤50 >50 16 (59%) 11 (41%) Clinical Stage (TNM) c T2 c T3 14 (52%) 13 (48%) Tumor histology Invasive ductal carcinoma Invasive lobular carcinoma Medullary carcinoma 24 (89%) 2 (7.3%) 1 (3.7%) Tumor grade Grade I Grade II Grade III 4 (15%) 17 (63%) 6 (22%) Receptor status ER-PR +ve ER-PR -ve 19 (70%) 8 (30%) HER2/neu overexpression 6 (22%) Table 2: Pathological results (clinical and histological) and types of surgery Patients n=27 SLNB Involved Not involved 18 (67%) 9 (23%) Clinical response to NC Complete Partial Minor or No response 11 (41%) 13 (48%) 3 (11%) ALND Involved Not involved 3 (11%) 24 (89%) Type of breast surgery Mastectomy Consevative 15 (56%) 12 (44%) Histologic response to NC Complete Partial (residual tumor) 9 (33%) 18 (67%)
  10. 10. Kasr el-aini journal of surgery Volume 14, No.1, January 2013 11 Table 3: Concordance between histological analysis of SLNB before NC and ALND after NC Non metastatic SLNB n=9 Metastatic SLNB n=18 Total n=27 Non metastatic ALND 9 (100%) 15 (83%) 24 metastatic ALND 0 3 (17%) 3

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