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10.1245/ASO.2005.01.024
Annals of Surgical Oncology 13:31-35 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Ultrasonography and Fine-Needle Aspiration Cytology Can Spare Breast Cancer Patients Unnecessary Sentinel Lymph Node Biopsy

Maartje C. van Rijk, MD1, Eline E. Deurloo, MD, PhD2, Omgo E. Nieweg, MD, PhD1, Kenneth G. A. Gilhuijs, MD, PhD3, Johannes L. Peterse, MD4, Emiel J. T. Rutgers, MD, PhD, FRCS1, Robert Kröger, MD4 and Bin B. R. Kroon, MD, PhD, FRCS1

1 Department of Surgery, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
2 Department of Radiology, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
3 Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
4 Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Maartje C. van Rijk, MD; E-mail: m.v.rijk{at}nki.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Some 30% to 40% of the breast cancer patients scheduled for sentinel node biopsy have axillary metastasis. Pilot studies suggest that ultrasonography is useful in the preoperative detection of such nodes. The aims of this study were to evaluate the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy could be avoided.

Methods: Between October 1999 and December 2003, 726 patients with clinically negative lymph nodes were eligible for sentinel node biopsy. A total of 732 axillae were examined. Preoperative ultrasonography with subsequent fine-needle aspiration cytology in case of suspicious lymph nodes was performed in all patients. The sentinel node procedure was omitted in patients with tumor-positive axillary lymph nodes in lieu of axillary lymph node dissection.

Results: Ultrasound and fine-needle aspiration cytology established axillary metastases in 58 (8%) of the 726 patients. These 58 were 21% of the total of 271 patients who were proven to have axillary metastasis in the end. Of the patients with ultrasonographically suspicious lymph nodes and negative cytology, 31% had tumor-positive sentinel nodes. Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes (P < .001) than patients with metastases established later on.

Conclusions: The sensitivity of ultrasonography and fine-needle aspiration cytology is 21%, and unnecessary sentinel node biopsy is avoided in 8% of the patients. This approach improves the selection of patients eligible for sentinel node biopsy.

Key Words: Ultrasonography • Mammary • Breast neoplasms • Lymphatic metastasis • Sentinel lymph node biopsy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients with breast cancer are usually scheduled for sentinel node biopsy if no axillary lymph nodes can be palpated. However, physical examination of these nodes is notoriously inaccurate; 15% to 60% of patients with nonpalpable nodes have, in fact, tumor-positive nodes.1–3 Several studies have suggested that ultrasonography might aid in the preoperative detection of involved lymph nodes.4–10

The aims of this study were to evaluate in a large series of patients the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy can be avoided. Another aim was to determine how the tumor load in the cytologically tumor-positive axillae differed from that in the tumor-positive axillae evaluated by means of sentinel node biopsy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between October 1999 and December 2003, 726 patients with clinical T1 to T3 unifocal breast cancer and clinically negative lymph nodes were eligible for sentinel node biopsy. Patients with T4 tumors due to involvement of the skin were also eligible for sentinel node biopsy. Six patients had bilateral breast cancer, so a total of 732 axillae were examined. Pathologic proof of breast cancer was obtained before surgery by either fine-needle aspiration cytology or core biopsy. Patient and tumor characteristics are listed in Table 1Go. Part of this group was the subject of an earlier article.4


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  		TABLE 1. Patient and tumor characteristics
 
Twenty-four of the patients received neoadjuvant chemotherapy. This was given after the ultrasonography and, in case of negative ultrasonographic results, after sentinel node biopsy. Before surgery, all patients underwent axillary ultrasonography, as well as fine-needle aspiration cytology if any suspicious nodes were identified. A 13-MHz transducer (Siemens Elegra, Erlangen, Germany) was used. Lymph nodes were classified as suspicious with the aid of the characteristics devised by Deurloo et al.,4 i.e., a round or ovoid shape, a hypoechoic core, a smallest diameter of the node exceeding 5 mm, an irregular cortex, or a cortex thickness of >2 mm. After this study of Deurloo et al., the criteria for a suspicious lymph node became solely a cortex thickness of >2.3 mm. Fine-needle aspiration of suspicious lymph nodes was performed with a 21-gauge (.8-mm) or 22-gauge (.7-mm) needle, and the cells were deposited on glass slides. The aspirated material was air-dried, methanol-fixated, and stained according to the May-Grünwald-Giemsa method. If fine-needle aspiration cytology did not show any lymphoid cells or normal lymphoid cells, patients were scheduled for sentinel node biopsy. Patients with tumor-positive fine-needle aspiration cytological results were scheduled for either wide local excision and axillary lymph node dissection or modified radical mastectomy.

A 2-day protocol was used for sentinel node biopsy. On the day before surgery, 99mTc-nanocolloid (Nanocoll; Amersham Cygne, Eindhoven, The Netherlands) was injected into the lesion in a mean volume of .2 mL and with a mean radioactivity dose of 116 MBq (3.1 mCi). In case of nonpalpable breast cancer, the intratumoral injection was guided by ultrasonography or stereotaxis. Static imaging was performed at 30 minutes, 2 hours, and 4 hours after injection. A dual-head gamma camera (Vertex; ADAC, Milpitas, CA) was used. Both anterior and prone lateral images were obtained. The location of the node was marked on the skin with indelible ink. In case of nonpalpable breast cancer, an intratumoral catheter was placed after lymphoscintigraphic imaging to enable intraoperative blue dye administration. During the operation, 1 mL of patent blue dye (Laboratoire Guerbet, Aulnay-Sous-Bois, France) and a gamma-ray detection probe (Neoprobe; Johnson & Johnson Medical, Hamburg, Germany) were used to identify the sentinel node.

All procedures were performed by one of four experienced surgeons or under their supervision by a resident or fellow. All sentinel nodes were formalin-fixated, bisected, paraffin-embedded, and cut at a minimum of six levels at 50- to 150-µm intervals. Pathologic evaluation included hematoxylin and eosin and immunohistochemical staining (CAM 5.2; Becton Dickinson, San Jose, CA). In principle, patients with a tumor-positive sentinel node underwent axillary lymph node dissection. Some received radiotherapy of the axilla as part of a randomized study.11

Statistical analysis was performed with the Kruskal-Wallis test to compare the total number of tumor-positive lymph nodes in patients with and without preoperatively established metastasis. Forty-eight patients received radiotherapy to the axilla because of an involved sentinel node. They were excluded from this calculation. The sensitivity and specificity of the fine-needle aspiration cytology results are based on the patients with suspicious ultrasonography results (Table 2Go).


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  		TABLE 2. Sensitivity and specificity of ultrasonography, fine-needle aspiration cytology, and the combined technique
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A suspicious lymph node was seen on the ultrasound images of 176 (24%) of the 732 axillae, thus prompting fine-needle aspiration (Fig. 1Go). Malignant cells were identified on the cytology slides in 59 axillae in 59 patients. These 59 patients were 8% of the total population eligible for sentinel node biopsy, and all except 1 of them had metastases >2 mm.


Figure 1
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  		FIG. 1. Flow-chart of axillary ultrasonography results, fine-needle aspiration cytology results, and final histological outcomes. FNAC, fine-needle aspiration cytology.

 
In the end, 271 axillae were tumor positive, which is 37% of the total of 732 axillae. The sensitivity and specificity of the ultrasonography, fine-needle aspiration cytology, and the combined technique are listed in Table 2Go. No complications occurred as a result of axillary fine-needle aspiration cytology. Of the axillae with an ultrasonographically suspicious lymph node and negative cytological results, 31% contained a tumor-positive sentinel node, of which 66% had macrometastatic disease (>2 mm).

Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes compared with patients with metastases that were established later on: 4.3 (median, 3; range, 1–18) versus 2.2 (median, 1.5; range, 1–21; P < .001). The total number of lymph nodes excised in the both groups was not significantly different: n =15 (P = .31).

One patient received an axillary lymph node dissection because of a false-positive cytological evaluation. Histological examination, including immunohistochemical staining, revealed no tumor in the axillary lymph node specimen. Repeated, more extensive examination of the axillary lymph nodes and of the cytological smear could not explain this discrepancy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that preoperative axillary staging of breast cancer patients can be improved with the aid of ultrasonography and fine-needle aspiration cytology. As a result, 8% of our patients could be spared lymphoscintigraphy and sentinel node biopsy because their metastases were already established. Such patients are then eligible for neoadjuvant chemotherapy as a result of the ultrasonography and fine-needle aspiration cytology without preceding axillary surgery.

Another advantage of preoperative ultrasonography and fine-needle aspiration cytology is that it may identify the very nodes that are likely to cause recurrences after sentinel node biopsy. Many surgeons have found themselves in the situation that a hot and blue node was found that was tumor free on frozen section, only to come across an unstained, nonradioactive rock-hard node during closure of the wound in the axilla.12 The most likely scenario is that lymph flow originally went to this latter node. When tumor invasion became so massive that the inflow was blocked, the lymph fluid was diverted to another lymph node—the one that was identified being hot and blue. This "neo"-sentinel node was still disease free at that time. Intraoperative evaluation of this rock-hard nonsentinel node, of course, results in axillary clearance, but the surgeon is left with the uneasy feeling that a false-negative sentinel node biopsy resulting in an axillary recurrence was just avoided. Ultrasonography with fine-needle aspiration cytology may well identify these nodes that are largely replaced by tumor.

Compared with patients with metastasis established through sentinel node biopsy, patients with a preoperatively established tumor-positive node had significantly more involved lymph nodes. Several investigators have shown that these patients also have a greater risk of lymphatic mapping failure. Lymphoscintigraphic visualization decreases with an increasing axillary tumor burden.13–16 Patients with more than four involved axillary nodes have a >50% chance of nonvisualization.17–19

One patient had a false-positive cytological result. In general, fine-needle aspiration cytology is a very reliable method for identifying potentially malignant cells both in the breast and in axillary lymph nodes. False-positive results are rare but not unknown. Potential reasons for a false-positive result could be interpretive error and inadequate sampling of the lymph node dissection.20 In this case, we hypothesize that the lesion was so small that the radiologist who performed the fine-needle aspiration was lucky and that the pathologist failed to find the remainder in the axillary dissection specimen despite making extra slides.

The relatively low 21% sensitivity of ultrasonography with cytology can be explained by the fact that only metastases between roughly 5 and 10 mm in size are identified. The larger and easier-to-spot metastases are often palpable, and these patients are scheduled for axillary clearance without sentinel node biopsy. The smaller ones are often not clearly visible with ultrasonography, and aspirating micrometastatic disease is a daunting task. These metastases are identified by subsequent sentinel node biopsy.

Table 3Go summarizes other studies of axillary ultrasonography and fine-needle aspiration cytology in patients with breast cancer. It is intriguing that the percentage of patients in whom sentinel node biopsy can be avoided varies between 1% and 26%. In part, this can be explained by the differences in study design. Sapino et al.6 obtained a high yield because they did not exclude patients with palpable lymph nodes. Bonnema et al.9 also have a high success rate (26%). In their study, a fine-needle aspiration sample was taken if a lymph node was visualized, regardless of the ultrasound pattern, with a maximum of four aspiration samples per axilla. Bedrosian et al.10 avoided sentinel node biopsy in just 1% of their patients, but they excluded all patients with obvious nodal metastases on ultrasonographic imaging. De Kanter et al.5 had a study design similar to this study’s design, but their yield was twice as high. One reason that could be entertained to explain this difference is their high (47%) involvement of the axilla. Another explanation might be that one of their radiologists had 5 years’ experience in axillary ultrasonography before the trial.


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  		TABLE 3. Summary of studies on axillary ultrasonography and fine-needle aspiration cytology
 
An earlier study from our own institution showed a higher percentage (14%) of involved nodes identified by ultrasonography compared with this study. This is in part due to a change in the study population. Since 2000, patients with nonpalpable breast cancer are also offered sentinel node biopsy, and these patients have a smaller chance of axillary metastasis. As a result, the percentage of involved axillae decreased from 45% to 37%. Also, lymph node–positive patients with small primary tumors have relatively more micrometastasis that are more difficult to detect with ultrasonography.21 Still, in our earlier study, 31% of the involved axillae were identified by ultrasonography, compared with a mere 22% in this work. An explanation may be that just a few radiologists—and not the residents—performed the ultrasonography in the earlier study. Also, the procedure was not yet a routine and was performed with special attention. In the subsequent years, other radiologists and radiologists in training have also performed these examinations. Their more limited experience may have affected the results.

In conclusion, the sensitivity of ultrasonography with fine-needle aspiration cytology is 21.0%, and the specificity is 99.8%. At our institution, patients with breast cancer are routinely examined with this approach. An additional 5 minutes to image and aspirate the axilla is a minor effort and spares 8% of the patients a more invasive, time-consuming, and costly sentinel node procedure.


   ACKNOWLEDGMENTS
 
The authors thank H. S. A. Oldenburg, MD, PhD, for her assistance in this study and Ninja Antonini for her feedback on the statistical analysis.

Received for publication February 1, 2005. Accepted for publication August 4, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  4. Deurloo EE, Tanis PJ, Gilhuijs KG, et al. Reduction in the number of sentinel lymph node procedures by preoperative ultrasonography of the axilla in breast cancer. Eur J Cancer 2003; 39:1068–73.[CrossRef][Medline]
  5. De Kanter AY, Van Eijck CHJ, Van Geel AN, et al. Multicentre study of ultrasonographically guided axillary node biopsy in patients with breast cancer. Br J Surg 1999; 86:1459–62.[CrossRef][Medline]
  6. Sapino A, Cassoni P, Zanon E, et al. Ultrasonographically-guided fine-needle aspiration of axillary lymph nodes: role in breast cancer management. Br J Cancer 2003; 88:702–6.[CrossRef][Medline]
  7. Motomura K, Inaji H, Komoike Y, et al. Gamma probe and ultrasonographically-guided fine-needle aspiration biopsy of sentinel lymph nodes in breast cancer patients. Eur J Surg Oncol 2001; 27:141–5.[CrossRef][Medline]
  8. Kuenen-Boumeester V, Menke-Pluymers M, De Kanter AY, Obdeijn IM, Urich D, van der Kwast TH. Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure. Eur J Cancer 2003; 39:170–4.[CrossRef][Medline]
  9. Bonnema J, Van Geel AN, van Ooijen B, et al. Ultrasound-guided aspiration biopsy for detection of nonpalpable axillary node metastases in breast cancer patients: new diagnostic method. World J Surg 1997; 21:270–4.[CrossRef][Medline]
  10. Bedrosian I, Bedi D, Kuerer HM, et al. Impact of clinico-pathological factors on sensitivity of axillary ultrasonography in the detection of axillary nodal metastases in patients with breast cancer. Ann Surg Oncol 2003; 10:1025–30.[Abstract/Free Full Text]
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  16. Tanis PJ, van Sandick JW, Nieweg OE, et al. The hidden sentinel node in breast cancer. Eur J Nucl Med Mol Imaging 2002; 29:305–11.[CrossRef][Medline]
  17. Brenot-Rossi I, Houvenaeghel G, Jacquemier J, et al. Nonvisualization of axillary sentinel node during lymphoscintigraphy: is there a pathologic significance in breast cancer?. J Nucl Med 2003; 44:1232–7.[Abstract/Free Full Text]
  18. Martin RC, Fey J, Yeung H, Borgen PI, Cody HS III. Highest isotope count does not predict sentinel node positivity in all breast cancer patients. Ann Surg Oncol 2001; 8:592–7.[Abstract/Free Full Text]
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