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Annals of Surgical Oncology 8:817-820 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

The Problem of the Accuracy of Intraoperative Examination of Axillary Sentinel Nodes in Breast Cancer

Stefano Zurrida, MD, Giovanni Mazzarol, MD, Viviana Galimberti, MD, Giuseppe Renne, MD, Fabio Bassi, MD, Franco Iafrate, MD and Giuseppe Viale, MD,FRCPath

From the Departments of Senology (SZ, VG, FB, FI) and Pathology and Laboratory Medicine (GM, GR, GV) , University of Milan School of Medicine, European Institute of Oncology, Milan, Italy.

Correspondence: Address correspondence and reprint requests to: Stefano Zurrida, MD, Scientific Director’s Office, European Institute of Oncology, Via G. Ripamonti, 435 20141 Milano, Italy; Fax: +29-02-5748-9210; E-mail: stefano.zurrida{at}ieo.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Sentinel node (SN) biopsy has become accepted as a reliable method of predicting the state of the axilla in breast cancer. The key issue, however, is the accuracy of the pathological evaluation of the biopsied node, which should be done intraoperatively whenever possible.

Methods: In our initial experience on 192 patients using a conventional intraoperative frozen section method, the false-negative rate was 6.3%, and the negative predictive value was 93.7%. We devised a new and exhaustive intraoperative method, requiring about 40 minutes, in which pairs of sections are taken every 50 µ for the first 15 sections and every 100 µ thereafter, sampling the entire node. Sentinel node metastases were found in 143 of the 376 T1N0 cases examined (38%).

Results: Metastases were always identified on hematoxylin and eosin sections, although in 4% of cases, cytokeratin immunostaining on adjacent sections was useful for confirming malignancy. In 233 patients the SNs were disease-free; of these patients, 222 had metastasis-free axillary nodes, and 11 (4.7%) had another metastatic node.

Conclusion: Extensive intraoperative examination of frozen sentinel nodes correctly predicts an uninvolved axilla in 95.3% of cases (negative predictive value). This method is, therefore, suitable for identifying patients in whom axillary dissection can be avoided.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel node biopsy (SNB) for breast cancer was developed primarily to provide a minimally invasive method of determining axillary status. However, an almost equally important aspect is that it completes the surgical treatment of the patient in a single session, avoiding a second operation should the biopsied node prove metastatic. In addition to increasing costs, a second operation has a negative psychological effect on the patient, who, having been fully informed of the situation beforehand, now knows her cancer is not in its earliest stages. In particular, she knows she may have to undergo adjuvant chemotherapy, stay longer in the hospital, and also may have in mind the possible sequelae of the dissection, which were described a few days previously during the informed consent procedure.

Many papers on the sentinel node (SN) in breast cancer have been published. Overall, the experience is distinctly positive (Table 1),1–14 and we believe that the method should now be considered an established one for axillary staging. A problem that has emerged with SNB, however, not only in breast cancer but also in melanoma,15 is not the so-called learning phase of the surgical procedure but the pathological evaluation of the removed nodes. This is true for both the blue dye and the radiolabeled methods. The key issue is how to study biopsied nodes intraoperatively, quickly, and with the highest possible accuracy: Conventional frozen section techniques can miss up to 30% of metastases.3


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  		TABLE 1. Summary of principal studies on sentinel node biopsy in breast cancer, with histological method used and false-negative rate
 
In the paper we presented in 2000 at the 53rd Annual Meeting of the Society of Surgical Oncology,16 we offered preliminary data on an exhaustive frozen section method that promised to resolve this problem. We now present our extensive experience with this method, which shows that intraoperative evaluation of the SN in breast cancer can be both practicable and highly accurate.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We have now performed SNB on 1266 women with breast cancer and a clinically negative axilla. The method we use is to inoculate albumin labeled with radioactive technetium close to the tumor. Lymphoscintigraphy is performed subsequently to localize the SN, and a gamma-detecting probe is used to locate and assist removal of this node during surgery.14,17

Of these 1266 women, 371 were subject of our pilot study,14 379 form a special group who specifically asked for SNB, and 516 were included in our recently closed randomized trial. We exclude from discussion the 379 women who chose SNB on their own and also 166 patients of the trial arm (259 cases) who did not undergo axillary dissection because they were randomized to SNB and were found to have negative results.

In the first 60 patients, we sent the excised SN for histological examination along with (but separate from) the other axillary nodes. Histological analysis involved serial sectioning of the whole node after formalin fixation and paraffin embedding. Every 10th section was stained with hematoxylin and eosin (H&E), and the adjacent section was immunostained for cytokeratin. The remaining material was conserved for further investigation in case there was doubt about the diagnosis.

We next started to evaluate the SN intraoperatively using our standard procedure (n = 192). The removed SN was cut in half longitudinally. One half was frozen for immediate intraoperative examination, with two or three contiguous sections observed after H&E staining. The remaining half was conserved for conventional embedding, sectioning, and staining, followed by "definitive" histological analysis.

Because the false-negative rate of this intraoperative examination was unacceptably high, we developed a new intraoperative frozen section method designed to be a definitive examination of the SN. This method was used in 376 patients. The SN was carefully isolated from the surrounding fatty tissue without breaking the node capsule. The node was then bisected along its major axis; both halves were embedded in OCT (Cellpath, England), cut surfaces up, and immediately frozen in isopentane and liquid nitrogen. Fifteen pairs of adjacent frozen sections, 4 µ thick, were cut at 50-µ intervals in each half node, producing a total of 60 sections per node. Whenever residual tissue was left, additional pairs of sections were cut at 100-µ intervals, until the node was completely sampled. One section of each pair was stained with H&E, and the other was immunostained for cytokeratin, using a rapid method with MNF 116 monoclonal anti-cytokeratin antibody/horseradish peroxidase (DAKO, Copenhagen, Denmark).11,18 Later in the study, the immunostaining step was performed only if the H&E examination was inconclusive.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
By standard postoperative examination of paraffin-embedded sections in the first series of 60 patients, the SN was negative in 25 cases. However, in two of these cases, other axillary nodes were metastatic, so that the negative predictive value of SN examination was 92.0%.

Of the 192 cases examined by the routine intraoperative frozen section method, 55 had positive SNs. However, histological examination of permanent sections showed that 26 of the SNs found negative intraoperatively were positive (32.1% of all positive cases) because 7 of the 111 patients with a negative SN in both frozen and permanent sections had metastasis in other axillary nodes, the negative predictive value was 93.7% ([111-7]/111).

Among the 376 patients examined by the new frozen section method, metastases were found in the SN in 143 (38.0%); in 35 of these patients only micrometastases (i.e., metastatic foci < 2 mm in maximum diameter) were found. In all cases, metastatic foci were identified on H&E sections and confirmed by immunostaining; in no case did immunocytochemistry identify metastatic cells that had been overlooked in adjacent H&E sections. However, in nine cases (6% of positive cases), cytokeratin immunoreactivity was very useful for confirming the metastatic nature of cells considered suspicious on purely morphological grounds.

In 65 of the 143 positive cases (45.5%) the SN was the only involved node; in the remaining cases, one or more additional nodes were found to harbor metastases. In 233 patients the SNs were disease-free; of these, 222 had metastasis-free axillary nodes, whereas 11 (4.7%) had another metastatic node—in all cases a single node at the first axillary level. The negative predictive value in this series was, therefore, 95.3% (222 of 233 nodes).

Table 2 shows the negative predictive value in the three series of patients considered in this study, and Table 3 gives a breakdown of the general concordance, which for the entire series of 628 patients is 96.8%.


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  		TABLE 2. Negative predictive value of the sentinel node in our three series of patients
 

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  		TABLE 3. Overall accuracy in the three series of patients combined
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using either the radioguided probe or the blue dye method, an experienced surgeon is able to identify and isolate the SN in almost 100% of cases. Given, however, that the SN should be examined intraoperatively whenever possible, the main problem with SNB is the accuracy of the intraoperative histological examination.

Our use of a standard intraoperative procedure in the second phase of our experience gave a high percentage of false-negative SNs compared to examination of permanent H&E sections of the SN—too high to permit its use to determine whether axillary dissection should be performed.17 Investigations indicated that the main reason for this was inadequate sampling of the frozen node. Only relatively large metastases, or those extending close to the midsagittal plane of the node, were identified by the method; metastases present peripherally or in the unfrozen half of the node were necessarily missed.

For the most recent series of patients in which the new intraoperative method was used, we cannot compare intraoperative and permanent section findings, because no tissue is left for the latter. However, the negative predictive value of the SN in the latest series (95.3%) is higher than in the previous series (93.7%), based on examination of permanent sections, and this suggests that the new method is at least as reliable as permanent section analysis, if not more so. Furthermore, about 38% of patients were found to harbor SN metastases by the new method,14 and this figure is at the high end of the range (27% to 42%) found by other investigators in series of patients with characteristics similar to ours.11,18 19–21

An unexpected finding was that rapid immunostaining for cytokeratins did not increase the rate of detection of SN metastases when the new exhaustive method was used. Metastases were always identified on purely morphological grounds, although in 6% of positive cases immunostaining was useful for confirming the malignant nature of atypical cells seen in H&E sections. This differs from the experience of Turner et al.,12 who reported a 14.3% increase in the detection rate of SN metastases when cytokeratins were detected immunocytochemically.

To conclude, we have found that extensive intraoperative examination of frozen SNs correctly predicts a metastasis-free SN in 95.3% of cases (negative predictive value). The general implication of this finding is that a careful and exhaustive histological examination of SNs (either intraoperatively or on permanent paraffin-embedded material) is necessary to render sentinel node biopsy a safe and reliable procedure for identifying breast cancer patients in whom axillary dissection is not necessary.

The advantages of the intraoperative method were discussed in the introduction. The main disadvantages are the additional surgery time (approximately 40 minutes) required for the diagnosis, and the requirement that experienced technicians and competent pathologists be on hand to examine the SNs as soon as they are removed by the surgeons. If SNB were performed on an outpatient basis, then examination of permanent paraffin sections would be more convenient.

Received for publication May 16, 2000. Accepted for publication July 16, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Viale G, Bosari S, Mazzarol G, et al. Intraoperative examination of axillary sentinel nodes in breast cancer patients. Cancer 1999; 85: 1433–8.
  2. Motomura K, Inaji H, Komoike Y, Kasugai T, Noguchi S, Koyama H. Sentinel node biopsy guided by indocyanine green dye in breast cancer patients. Jpn J Clin Oncol 1999; 29: 604–7.[Abstract/Free Full Text]
  3. Nos C, Bourgeois D, Freneaux P, Zafrani B, Salmon RJ, Clough KB. Identification of sentinel lymph node in breast cancer: experience from the Institut Curie. Bull Cancer 1999; 86: 580–4.[Medline]
  4. Winchester DJ, Sener SF, Winchester DP, et al. Sentinel lymphadenectomy for breast cancer: experience with 180 consecutive patients: efficacy of filtered technetium-99m sulphur colloid with overnight migration time. J Am Coll Surg 1999; 188: 597–603.[CrossRef][Medline]
  5. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer—a multicenter validation study. N Engl J Med 1998; 339: 941–6.[Abstract/Free Full Text]
  6. Rodier JF, Routiot T, Mignotte H, et al. Identification of axillary sentinel node by lymphotropic dye in breast cancer. Feasibility study apropos of 128 cases. Chirurgie 1998; 123: 239–46.[CrossRef][Medline]
  7. Guenther JM, Krishnamoorthy M, Tan LR. Sentinel lymphadenectomy for breast cancer in a community managed care setting. Cancer J Sci Am 1997; 3: 336–40.[Medline]
  8. Kollias J, Gill PG, Chatterton BE, Hall VE, Bochner MA, Coventry BJ, Farshid G. Reliability of sentinel node status in predicting axillary lymph node involvement in breast cancer. Med J Aust 1999; 171: 461–5.[Medline]
  9. Morrow M, Rademaker AW, Bethke KP, Talamonti MS, Dawes LG, Clauson J, Hansen N. Learning sentinel node biopsy: results of a prospective randomized trial of two techniques. Surgery 1999; 126: 714–22.[Medline]
  10. Pendas S, Dauway E, Cox CE, Giuliano R, Ku NN, Schreiber RH, Reintgen DS. Sentinel node biopsy and cytokeratin staining for the accurate staging of 478 breast cancer patients. Am Surg 1999; 65: 500–6.[Medline]
  11. Turner RR, Ollila DW, Krasne DL, Giuliano AE. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997; 226: 271–8.[CrossRef][Medline]
  12. Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 1998; 186: 275–83.[CrossRef][Medline]
  13. Cox CE, Pendas S, Cox JM, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998; 227: 645–53.[CrossRef][Medline]
  14. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999; 91: 368–73.[Abstract/Free Full Text]
  15. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999; 17: 976–83.[Abstract/Free Full Text]
  16. Zurrida S, Galimberti V, Orvieto E, et al. Radioguided sentinel node biopsy to avoid axillary dissection in breast cancer. Ann Surg Oncol 2000; 7: 28–31.[Abstract]
  17. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. The Lancet 1997; 349: 1864–7.[CrossRef][Medline]
  18. Chilosi M, Lestani M, Pedron S, et al. A rapid immunostaining method for frozen sections. Biotech Histochem 1994; 69: 235–9.[Medline]
  19. Albertini JJ, Lyman GH, Cox C, Yeatman T, Balducci L, Ku N. Lymphatic mapping and entinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818–22.[Abstract]
  20. Krag DN, Ashikaga T, Harlow SP, Weaver DL. Development of sentinel node targeting technique in breast cancer patients. Breast J 1998; 4(2): 67–74.
  21. Giuliano AE. Sentinel lymphadenectomy in primary breast carcinoma: an alternative to routine axillary dissection. J Surg Oncol 1996; 62: 75–7.[CrossRef][Medline]



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