Clinical Cancer Research Molecular Diagnostics in Cancer Therapeutic Development: Fulfilling the Promise of Personalized Medicine Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsu, G.-C.
Right arrow Articles by Chao, T.-Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsu, G.-C.
Right arrow Articles by Chao, T.-Y.
Clinical Cancer Research Vol. 12, 3746-3753, June 15, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Application of Intraoperative Ultrasound to Nonsentinel Node Assessment in Primary Breast Cancer

Giu-Cheng Hsu1, Chih-Hung Ku5, Jyh-Cherng Yu2, Chung-Bo Hsieh2, Cheng-Pin Yu3 and Tsu-Yi Chao4

Authors' Affiliations: Departments of 1 Radiology; 2 General Surgery, Surgery; 3 Pathology; 4 Medicine, Tri-Service General Hospital; 5 School of Public Health, National Defense Medical Center, Taipei, Taiwan

Requests for reprints: Jyh-Cherng Yu, General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Cheng-Kung Road, Nei-Hu 114, Taipei, Taiwan. Phone: 886-287927191; Fax: 886-287927372; E-mail: doc20106{at}ndmctsgh.edu.tw.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To evaluate whether intraoperative ultrasonography can help surgeons to identify patients with breast cancer and metastases confined to the sentinel node.

Experimental Design: We used blue dye to identify sentinel node during 512 procedures done on 509 patients with breast cancers of <3 cm. After sentinel node biopsy, we used intraoperative ultrasonography to explore the whole axilla followed by at least level II axillary dissection. All sentinel nodes were evaluated histologically and immunohistochemically using anti-cytokeratin antibody. All nonsentinel nodes were examined by routine histology. Multiple logistic regression was used to assess the associations of interest and to adjust for potential confounders. Receiver operating characteristic curves were used to calculate the areas under the curves of interest and for comparisons.

Results: Sentinel nodes were identified in 506 of 512 (98.8%) procedures and sentinel node metastases were found in 161 of these (31.8%). Subsequent axillary dissection revealed tumor involvement in nonsentinel nodes in 93 of 161 (57.8%) procedures. Multivariate analysis showed that tumor size, number of positive sentinel nodes, and metastatic size in sentinel nodes were independent factors predicting the presence of tumor-positive nonsentinel nodes. The validity of using either node size or cortical thickness ascertained by intraoperative ultrasound to predict nonsentinel node metastases was highly significant (P < 0.0001). Intraoperative ultrasound not only detected metastatic nonsentinel nodes in 89 of 93 (95.7%) cases but also detected metastatic nonsentinel nodes in patients with false-negative sentinel node mapping.

Conclusion: Sentinel node biopsy combined with intraoperative ultrasonography can help breast surgeons decide whether to perform a subsequent nonsentinel node dissection after identification of a positive sentinel node.

Sentinel node biopsy is an accurate procedure with which to predict axillary lymph node involvement in breast cancer (1–4). Axillary dissection is a standard procedure for patients who exhibit sentinel node metastasis. However, according to reports from Europe and America, 60% to 70% of patients with sentinel node metastases received no benefit from axillary dissection when the disease was localized to the sentinel node only (5–9). Patients with small breast cancers who have micrometastatic disease in the sentinel node rarely have residual disease in nonsentinel nodes (8–10). However, collecting such data can be very time consuming. Selection of the appropriate procedure after a positive sentinel node is of major concern to breast surgeons, especially in patients with small breast cancers or with micrometastatic disease in only one sentinel node. Intraoperative ultrasound may be an alternative technique to assist breast surgeons in evaluating the axillary nonsentinel node status after a positive sentinel node (11, 12). This technique is noninvasive, effective in real time, and easy to use. The aim of this study was to explore the effectiveness of intraoperative ultrasonography in assessing nonsentinel nodes to determine whether axillary operations can be avoided in women with small breast cancers and a positive sentinel node.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient inclusion criteria. Intraoperative lymphatic mapping and sentinel node biopsy in patients with breast cancers in regions from T0 to T2 was initiated in October 1998 and also from July 2002 to December 2004. Patients were evaluated if their tumors were <3 cm. None had palpable axillary nodes identified by preoperative clinical assessment. Those who had had previous breast operations, axillary surgery, axillary radiation therapy, preoperative adjuvant chemotherapy, or rare types of breast cancer were excluded from the study. Patients with impaired liver or renal functions or an allergic reaction to patent blue V dye were also excluded. The clinical characteristics recorded were patient age, mode of tumor detection, and lymph node status. Other variables used to describe tumor characteristics were histologic type, nuclear grade, tumor size, presence of lymphovascular invasion, size of the metastasis in the sentinel node, estrogen receptor (ER) and progesterone receptor status, and HER-2/neu oncogene expression. The size of the primary tumor was determined by mammography and ultrasound and also by measuring the invasive component of the tumor using a histopathologic examination. All patients were enrolled in this study after their written informed consent had been obtained. The Institutional Review Board of the Tri-Service General Hospital approved this study.

Technique for sentinel node identification. With the patient under general anesthesia, 5 mL sterile patent blue V dye (Guerbet Laboratories, Roissy, France) was injected into the peritumor breast parenchyma with a 25-gauge needle. If the primary tumor had been excised previously, the dye was injected into the wall of the biopsy cavity and the surrounding breast parenchyma along the incision line under ultrasonographic guidance. The interval between dye injection and axillary incision was ~5 to 10 minutes. A transverse incision ~2 cm long was made just below the hair-bearing region of the axilla. Blunt dissection was used until a dye-filled lymphatic tract or blue-stained node was identified. The dye-filled tract was traced to the first blue node. We followed the dye-filled lymphatic tract proximally to the periphery of the breast to ensure that the blue-stained node was indeed the sentinel node. After the sentinel node had been identified, it was carefully excised. Intraoperative ultrasonography was then used by an experienced radiologist to explore the whole axilla. We then did either a modified radical mastectomy or quadrantectomy and axillary lymph node dissection. Lymph nodes were identified visually or with manual palpation. Axillary lymph node dissection included nodes at levels I and II, Rotter's node, and occasionally level III nodes. The pectoralis minor muscle was left intact. If the sentinel node was not identified, we did a complete axillary dissection. All operations were done by a single surgeon (J-C.Y.).

Touch imprint analysis. Before submitting each sentinel node to histopathologic examination, we prepared air-dried touch imprints for cytologic examination. Depending on its size, the node was cut longitudinally in halves or thirds immediately after excision. We gently touched each cut surface onto a microscope slide. Four slides were prepared, each with two impressions, and two were stained with DiffQuick. The remaining two were immunohistochemically stained for cytokeratin and epithelial membrane antigen (DAKO, Glostrup, Denmark) with horseradish peroxidase as the indicator label. Positive staining for cytokeratin or epithelial membrane antigen of morphologically atypical cells in the sentinel node was deemed to indicate metastasis. The results of these cytologic studies were made available within 1 hour after tissue procurement. The results of cytologic examinations were similar to those obtained with subsequent H&E-stained paraffin-embedded sections.

Intraoperative ultrasonography. Intraoperative sonography was done by a breast radiologist (G-C.H.) with 15 years of experience in breast sonography. The mammograms and sonograms of all patients in this study were reviewed before surgery. In the preoperative period, all patients were given a detailed verbal explanation by surgeons and radiologists of the complete surgical and sonographic procedures. We emphasized the benefits of intraoperative ultrasound that might help the surgeon to localize and excise suspicious lymph nodes with no delay to the operation, because it was done after the positive sentinel node had been removed and before the preliminary pathologic results were obtained.

After the sentinel node biopsies were done and before the preliminary results were available, all patients underwent axillary sonographic examination with a Logiq 500 unit (GE Medical Systems, Bothell, WA) equipped with a high-frequency transducer with a bandwidth of 5 to 12 MHz. The ipsilateral axilla was examined with overlapping scans in radial and antiradial planes at the sentinel node biopsy wound site to ensure a complete search of the levels I, II, and III and Rotter's lymph nodes. The procedure time was ~6 to 15 minutes (10 minutes on average).

The sonographic features of suspected malignant lymph nodes were defined in terms of size, morphology, and internal echogenicity (including the cortex and medulla of the visualized node) as well as by previously published sonographic criteria (11–14). Malignant lymphadenopathy was based on the presence of (a) eccentric or uneven cortical thickening and/or (b) a disproportionate enlargement of the lymph node, making it look round, with focal bulging or a lobulate shape rather than the usual oval or kidney-like shape.

Sonomorphologic features (the short-axis diameter and the thickness of peripheral cortex of the lymph node) were evaluated and compared with the pathologic findings. The short-axis diameter of the lymph node was measured and classified into one of three groups according to its degree of enlargement: group 1, a short-axis diameter of ≥10 mm; group 2, a short-axis diameter of ≥8 mm but <10 mm; group 3, a short-axis diameter of <8 mm. When we used a cutoff threshold >8 mm to indicate abnormal enlargement of the malignant lymph node, groups 1 and 2 were considered positive abnormal findings. Only group 3 would be a negative sonographic finding. When we used a higher cutoff threshold of >10 mm to indicate abnormal enlargement of the malignant lymph node, only group 1 was considered a positive abnormal finding. Groups 2 and 3 were defined as negative findings. Statistical analyses were done separately according to the different cutoff thresholds for the short-axis diameter.

The thickness of the peripheral cortex was also assessed and classified into three groups: group 1, eccentric cortical thickening of ≥3 mm; group 2, eccentric cortical thickening of ≥2 mm but <3 mm in width; group 3, a cortical width of <2 mm. When we used a smaller cortical thickness of 2 mm as the threshold to define a lymph node as a suspected malignant node, groups 1 and 2 constituted positive findings; only group 3 was considered a negative finding. If we used a thicker cortical thickness of 3 mm as the threshold to define a lymph node as a suspicious malignant lymph node, group 1 constituted a positive finding and groups 2 and 3 were considered negative findings. Statistical analyses were done separately according to the different cutoff thresholds for cortical thickness.

Pathology. Lymph nodes were classified as sentinel node and nonsentinel node. The sentinel nodes were cut longitudinally into halves or thirds depending on the size of the sentinel node. A touch imprint of each portion of the sentinel node was made immediately. The node was then processed and embedded in paraffin wax. Sections of each sentinel node were examined at five to eight additional levels after staining with H&E and immunohistochemical staining for cytokeratin. Every nonsentinel node >2 mm in diameter was grossly sectioned and all the nodal tissues were embedded in paraffin and subjected to routine histologic examination with H&E staining. Immunohistochemical staining for cytokeratin was done as indicated. An experienced histopathologist examined at least two sections of each nonsentinel node. In all the cases, the size of the metastasis in the sentinel node was measured with an ocular micrometer. A micrometastasis was defined as a tumor deposit of ≤2 mm. Metastases >2 mm in diameter were defined as macrometastases. If multiple tumor deposits were present in the sentinel node, the sum of the tumor deposits was used to classify them collectively as macrometastases or micrometastases. When more than one sentinel node was positive for tumor cells, the patient was classified according to the largest metastasis.

Statistical analysis. We used Student's t test for univariate continuous variables and the {chi}2 test for categorical variables and Fisher's exact test whenever the expected {chi}2 value for at least one cell was <5 (SAS version 9.13, Cary, NC). We also used receiver operating characteristic (ROC) curves to calculate the areas under the curves of interest and for comparisons (MedCalc version 8, Mariakerke, Belgium).


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient population. From July 2002 to December 2004, we did 512 procedures on 509 women, including 3 with bilateral synchronous breast cancers. The age of the patients ranged from 25 to 84 years with a mean of 45.7 years. These patients were followed up regularly at our outpatient department. The axillary region was checked by physical examination and ultrasound at 3-month intervals for at least 2 years. No patients experienced axillary recurrence.

Identification of sentinel nodes. Three patients developed an allergy to patent blue dye, but no serious adverse reactions or complications arose from the use of the dye. Blue-stained sentinel nodes were identified in 506 of 512 (98.8%) procedures. The size of the primary tumor did not correlate with the number of positive nodes detected. The success rate of sentinel node identification was >95% after the first 100 cases in our hospital (10). The number of sentinel nodes detected varied from 1 to 5 per patient. A total of 1,315 sentinel node (mean, 2.6 sentinel nodes per patient) were available for study and 336 nodes had been invaded by tumors. Almost all these sentinel nodes were located at level I; level II sentinel nodes were identified in 4 patients, 1 patient had sentinel nodes in Rotter's node, and another 15 patients had sentinel nodes at both levels I and II. No sentinel nodes were found at level III. One hundred sixty-one of 506 (31.8%) patients had nodal metastases; 68 of these 161 (42.2%) had metastases confined to the sentinel node. A total of 10,322 nonsentinel nodes (mean, 20.4 nodes per patient) were excised for study. Metastases in these nonsentinel nodes were found in 93 of 161 (57.8%) patients. A total of 98 cases exhibited nonsentinel node metastases. Five patients exhibited metastatic involvement at nonsentinel nodes but were tumor-free at the sentinel nodes. Of these 5 cases, one involved nonsentinel nodes at level I, another involved Rotter's node, and a third involved the lymph node at level II. Furthermore, 3 of the 5 patients with false-negative results had cancer cells in the sentinel node that were only identified by cytologic imprinting and immunohistochemical analysis and not by histologic analysis of paraffin-embedded sections. No correlation was observed between sentinel node metastasis and patient age, pathologic nuclear grading, hormone receptor status, or Erb-2/neu expression in the primary tumor. The overall accuracy in the detection of metastasis in sentinel nodes was 99% with a sensitivity of 97% and a specificity of 100%. The positive predictive value was 100% and the negative predictive value was 98.6%.

Relationship between clinicopathologic features and patients with positive nonsentinel nodes. Univariate comparisons indicated that the significant clinicopathologic features (Table 1 ) associated with nonsentinel node metastases included primary tumor size (P < 0.0001), sentinel node metastatic size (P < 0.0001), number of sentinel node metastases (P < 0.0001), negative status for the ER (P < 0.0001), and patient age (P = 0.0077). However, after adjustments were made for confounding variables, only the first three factors retained a significant association with positive nonsentinel nodes (Table 2 ). Accordingly, patients with primary tumors >20 mm or sentinel node metastases >2 mm had a 5.1- or 5.3-fold risk of being positive for nonsentinel node metastasis, respectively (adjusted odds ratio, 5.14; P = 0.0080; adjusted odds ratio, 5.27; P = 0.0009, respectively; Table 2). Moreover, an increase of one in the number of sentinel node metastases caused a 10-fold increase in the risk of positive nonsentinel node metastasis (adjusted odds ratio, 10.05; P < 0.0001; Table 2).


View this table:
[in this window]
[in a new window]
  		Table 1. Age and potential risk factors of nonsentinel node metastasis

 

View this table:
[in this window]
[in a new window]
  		Table 2. Significant risk factors for nonsentinel node metastasis

 
Relationship between intraoperative ultrasonography and nonsentinel node metastasis. With intraoperative ultrasonography, 129 of the 506 patients exhibited a node size of ≥8 mm at the nonsentinel node level, whereas other patients had nonsentinel nodes of <8 mm and 73 patients had nonsentinel node eccentric cortical thickness of ≥2 mm. Univariate analysis revealed that the nonsentinel node size on ultrasound was statistically significantly associated with several variables, which included the number of sentinel node metastases, nuclear grade, ER status, primary tumor size, metastatic size in the sentinel node, and eccentric cortical thickness of the nonsentinel node (Table 3 ).


View this table:
[in this window]
[in a new window]
  		Table 3. Age and clinical variable estimates of nonsentinel node metastasis between different ultrasound node sizes (≥8 versus <8 mm) in nonsentinel node level

 
The validity of using either node size of the nonsentinel node (≥8 versus <8 mm) or cortical thickness of the nonsentinel node (≥2 versus <2 mm) to predict nonsentinel node metastases was highly significant (P < 0.0001; Table 4 ). Moreover, as shown in Fig. 1 , the areas predicted by ROC curves for node size and cortical thickness were 0.971 [SE, 0.007; 95% confidence interval (95% CI), 0.952-0.984] and 0.841 (SE, 0.018; 95% CI, 0.806-0.872, respectively). The pairwise comparison of ROC curves (node size ≥8 mm versus cortical thickness ≥2 mm) was likewise highly significant. The difference between the areas was 0.130 (SE, 0.017; 95% CI, 0.097-0.163; P < 0.0001; Fig. 1).


View this table:
[in this window]
[in a new window]
  		Table 4. Validities of using node size or eccentric cortical thickness in nonsentinel node level to predict nonsentinel node metastases

 

Figure 1
View larger version (17K):
[in this window]
[in a new window]
  		Fig. 1. ROC curves of significant risk factors for nonsentinel node metastasis. ROC curve for ultrasound node size: area, 0.971; SE, 0.007; 95% CI, 0.952-0.984. ROC curve for eccentric cortical thickness: area, 0.841; SE, 0.018; 95% CI, 0.806-0.872. Pairwise comparison of ROC curves (nodal size ≥8 mm versus eccentric cortical thickness ≥2 mm). Difference between areas, 0.130; SE, 0.017; 95% CI, 0.097-0.163; P < 0.0001.

 
The association between the number of sentinel node metastases and the node size of the nonsentinel node (cutoff point, ≥8 mm) was highly significant (P < 0.0001; Fig. 2 ; Table 5 ). In this study, the proportion of nodes of ≥8 mm in groups defined by the number of sentinel node metastases (from 0 to 5) were 1.45% for no sentinel node (5 of 345), 21.74% for one sentinel node (15 of 69), 73.81% for two sentinel nodes (31 of 42), 100% for three sentinel nodes (22 of 22), 100% for four sentinel nodes (17 of 17), and 100% for five sentinel nodes (11 of 11; Fig. 2; Table 5, top). To check that this association was not caused by chance, we regrouped the patients with three, four, or five sentinel node metastases into one group (number of sentinel node, ≥3) and reanalyzed the data. The results were still significant (P < 0.0001; Table 5, bottom).


Figure 2
View larger version (7K):
[in this window]
[in a new window]
  		Fig. 2. Positive rate of node size ≥8 mm in different number of sentinel node (SN) metastases.

 

View this table:
[in this window]
[in a new window]
  		Table 5. Positive rate of node size ≥8 mm in nonsentinel node level in patients in different numbers of sentinel node metastases

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
Sentinel lymph node biopsy has changed the mode of axillary treatment for breast cancer patients (1–4). This procedure allows unnecessary axillary lymph node dissection to be avoided in patients with no axillary metastasis. The success of the procedure is dependent on the experience of surgeons, pathologists, and radiologists. The labeling methods, dyes, and radioisotopes used for the procedure have not yet been standardized (1–4, 15–18). However, the proposed blue dye method, which includes staining with methylene blue dye, has been shown to have the same predictive value as other types of lymphatic mapping (4, 10, 19).

The sentinel node biopsy is particularly important for patients with no axillary metastases as well as for those with metastases confined to the sentinel node. In the West, the majority of patients (60-70%) with sentinel node metastases are free from nonsentinel node involvement (5–9). The identification of this subgroup of patients with only sentinel node metastases presents a challenge for the breast surgeon. Until now, this problem has not been explored in Taiwan or Asia. There are significant differences between our experience in Taiwan and the experience reported in Western countries. The majority of patients in Taiwan with sentinel node metastases (57.8%) had nonsentinel node involvement. This suggests that breast cancer involving the axillary region is more extensive and aggressive in Taiwan than in the West (10, 20, 21). The clinicopathologic factors associated with nonsentinel node metastases in our study were not significantly different from those in the West (10). Our data are similar to those of Chu et al. (5) but show a higher incidence of nonsentinel node metastases, with more extensive nodal involvement.

In our study, 39 of 161 patients had metastatic lesions in the sentinel node <2 mm. Twenty of these 161 (12.4%) metastases were detected by immunohistochemical analysis but were not found with routine H&E staining of serial sections. Although the analysis of sentinel nodes by immunohistochemical staining of thin sections is costly and labor-intensive, it can detect more micrometastatic lesions than conventional staining (22–26). The rate of detection by immunohistochemistry alone may increase if thinner sections of specimens are cut. However, most of the lesions detected by immunohistochemistry alone were the only lesion in the sentinel node and they were rarely accompanied by other foci in sentinel nodes or even in nonsentinel nodes (10, 22, 23, 25, 26). Micrometastatic lesions in the sentinel node can allow the exacerbation of the disease, which may require changes to be made to subsequent systemic adjuvant therapy.

It has been shown that tumor size, metastasis size in the sentinel node, and number of sentinel nodes involved are very useful variables for surgeons deciding whether to perform a nonsentinel node dissection (10). Patients with small breast cancers and only micrometastatic disease in one sentinel node rarely have residual disease in nonsentinel node (5–10, 27, 28). Breast surgeons can perform sentinel node dissections for these patients. However, data collection is usually time consuming. A micrometastatic lesion in the sentinel node is difficult to detect in a short time by frozen section or imprint cytology analysis (29, 30), especially if immunohistochemical staining is necessary to identify occult lesions in a large sentinel node or sentinel nodes. It is reasonable to delay axillary surgery so that the pathologist can take the time to examine the sentinel nodes carefully. However, most patients with small breast tumors are free of nonsentinel node metastases (5–10, 27, 28). Intraoperative pathologic examination of sentinel nodes by frozen section or imprint cytology with rapid immunohistochemical staining has recently become more acceptable (31–33). Under these circumstances, intraoperative ultrasonography during pathologic analysis of the sentinel node is a reasonable technique with which surgeons can evaluate the status of all the remaining nonsentinel nodes before the presence/absence of sentinel node metastasis is known. This technique is noninvasive, effective in real time, and easy to perform but relies heavily on experience. As in our study, the success of using either node size or eccentric cortical thickness of the nonsentinel node to predict nonsentinel node metastases was highly significant (P < 0.0001; Table 4). However, node size had higher sensitivity, higher negative predictive rate, and higher false-positive rate but lower specificity, lower positive predictive rate, and lower false-negative rate (FNR) than those of cortical thickness (Table 6 ). The use of a lower cutoff threshold for node size of ≥8 mm and/or eccentric cortical thickness of ≥2 mm to predict nonsentinel node metastasis may have achieved greater sensitivity and a lower FNR. Defining a node as suspicious using a higher cutoff threshold for cortical thickness of ≥3 mm and/or for the short-axis diameter of ≥10 mm would increase the specificity of identifying patients with nonsentinel node metastasis but also increase the FNR (Table 6). In this situation, we prefer a lower FNR in identifying nonsentinel node metastases so that a lower incidence of local axillary recurrence will be achieved by ensuring fewer metastatic lesions are misdiagnosed in nonsentinel nodes. Because patients with small breast cancers may have a lower incidence of metastatic disease in sentinel nodes and even in nonsentinel nodes (5–10, 27, 28), we suggest that the removal of suspicious nonsentinel node with a cortical thickness of ≥2 mm and/or a short-axis diameter of ≥8 mm should not increase patient morbidity but should significantly reduce axillary failure. Therefore, this technique is recommended for now. Furthermore, patients with small breast cancers (<2 cm) and only micrometastatic disease in one sentinel node rarely have residual disease in nonsentinel nodes (10). If intraoperative ultrasonography also reveals no suspicious nodes in the rest of the axillary region, axillary dissection or sampling is unnecessary, because our study shows that none of these patients (0 of 24) had residual disease in nonsentinel nodes. Intraoperative ultrasound can be used by surgeons to confirm this.


View this table:
[in this window]
[in a new window]
  		Table 6. Comparison of the different cutoff thresholds for ultrasound node size and eccentric cortical thickness in predicting nonsentinel node metastases

 
The requirement for nonsentinel node dissection is still controversial for patients with small breast cancers (<2 cm) but who exhibit macrometastatic lesions in only one sentinel node or those with T2 breast cancer who exhibit only micrometastatic disease in one sentinel node (5–10, 27, 28). For these patients, the use of intraoperative ultrasound to explore the entire axilla is a reliable technique that should assist the surgeon in his decision to perform a subsequent nonsentinel node dissection. In our study, intraoperative ultrasound accurately estimated the axillary status in 17 of 18 cases. Breast surgeons can use this technique to clearly identify patients free from nonsentinel node metastasis to avoid unnecessary nonsentinel node dissection.

The FNR for sentinel node mapping of invasive breast cancer is ~1% to 9% (1–10). The prevention of false-negative results is a great challenge for breast surgeons. These cases are potentially susceptible to local relapse and systemic exacerbation. However, in our experience, all these cases (5 of 5) were identified by careful intraoperative exploratory ultrasound as having suspicious nodes at the nonsentinel node level. For patients with no sentinel node metastasis, the removal of suspicious nonsentinel nodes with cortical thickness of ≥2 mm and/or short-axis diameters of ≥8 mm, identified by intraoperative ultrasound, may slightly increase axillary morbidity but can reduce the FNR of sentinel node mapping. The routine removal of suspicious nodes at the nonsentinel node level, identified by intraoperative ultrasound, in patients lacking sentinel node metastasis requires further study.

The significance of micrometastatic lesions in immunohistochemistry-detected nonsentinel nodes requires further study. However, they may not be detected by intraoperative ultrasound or by H&E staining. According to our data, four cases exhibited micrometastatic disease (<2 mm) in nonsentinel nodes that could not be detected by intraoperative ultrasound. An adjuvant therapy, such as chemotherapy and/or radiotherapy, is required for patients who already exhibit a tumor-positive sentinel node. In this situation, it may be reasonable to omit subsequent nonsentinel node dissection. In our study, when sentinel node biopsy combined with intraoperative ultrasound was used to remove suspicious nodes at the nonsentinel node level (those with a short-axis diameter of ≥8 mm and/or an eccentric cortical thickness of ≥2 mm), the residual disease in the remaining nonsentinel nodes was only 1.06%, and these were all only micrometastatic lesions. Thus, intraoperative ultrasound allows surgeons to achieve adequate disease control at the nonsentinel node level.

In conclusion, patients with small breast cancers and only micrometastatic disease in one sentinel node rarely have residual disease in nonsentinel nodes. In this situation, routine nonsentinel node dissection is not recommended for these patients after diagnosis of a positive sentinel node. However, data collection with the pathologic analysis of a sentinel node is time consuming. Intraoperative ultrasonography is a useful technique with which to explore the entire nonsentinel node level during a sentinel node histopathologic examination. It can accurately predict the nonsentinel node status. Intraoperative ultrasound is a noninvasive, real-time, convenient technique. However, it is also highly experience dependent. If a patient displays a positive sentinel node, breast surgeons can use the pathologic features of the sentinel node and intraoperative ultrasound to determine whether the patient requires subsequent axillary surgery, especially in patients with T1 breast cancer and only one sentinel node macrometastasis or a T2 lesion with only micrometastatic disease in the sentinel node. Breast surgeons can use intraoperative ultrasound as a guide to the removal of suspicious nodes at the nonsentinel node level based on a short-axis diameter of ≥8 mm and/or an eccentric cortical thickness of ≥2 mm. This technique should result in adequate disease control in the axillary region without increasing morbidity. With this technique, the possibility of residual disease at the nonsentinel node level is only 1.06%, and the residual disease only involves micrometastatic foci. For patients with no sentinel node metastasis, breast surgeons can also use this technique to remove suspicious nodes at the nonsentinel node level to decrease the possibility of false-negative sentinel node mapping. This should allow breast surgeons to achieve adequate disease control in the axillary region.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/20/06; accepted 4/24/06.


   References
Top
 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

  1. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391–401.[Medline]
  2. Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oncol 1997;15:2345–50.[Abstract/Free Full Text]
  3. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864–7.[CrossRef][Medline]
  4. Yu JC, Hsu GC, Liu YC, Sheu LF, Li SH, Chao TY. Sentinel node biopsy in early breast cancer in Taiwan. World J Surg 2002;26:1365–9.[CrossRef][Medline]
  5. Chu KU, Turner RR, Hansen NM, Brennan MB, Bilchik A, Giuliano AE. Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 1999;229:536–41.[CrossRef][Medline]
  6. Rahusen FD, Torrenga H, Diest PJ, et al. Predictive factors for metastatic involvement of nonsentinel nodes in patients with breast cancer. Arch Surg 2001;136:1059–63.[Abstract/Free Full Text]
  7. Reynolds C, Mick R, Donohue JH, et al. Sentinel lymph node biopsy with metastasis: can axillary dissection be avoided in some patients with breast cancer. J Clin Oncol 1999;17:1720–6.[Abstract/Free Full Text]
  8. Bakker MA, Weeszenberg A, Kanter AY, et al. Nonsentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance. J Clin Pathol 2002;55:932–5.[Abstract/Free Full Text]
  9. Guenther JM, Hansen NM, DiFronzon LA, et al. Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes. Arch Surg 2003;138:52–6.[Abstract/Free Full Text]
  10. Yu JC, Hsu GC, Hsieh CB, Sheu LF, Chao TY. Prediction of metastasis to non-sentinel nodes by sentinel node status and primary tumor characteristics in primary breast cancer in Taiwan. World J Surg 2005;29:813–9.[CrossRef][Medline]
  11. Vasallo P, Wernecke K, Roos N, Peters PE. Differentiation of benign from malignant superficial lymphadenopathy: the role of high resolution US. Radiology 1992;183:215–20.[Abstract/Free Full Text]
  12. Shin JH, Choi HY, Moon BI, Sung SH. In vitro sonographic evaluation of sentinel lymph nodes for detecting metastasis in breast cancer: comparison with histopathologic results. J Ultrasound Med 2004;23:923–8.[Abstract/Free Full Text]
  13. Thomas Stavros A. Evaluation of regional lymph nodes in breast cancer patients. In: Breast ultrasound. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 855–65.
  14. Tateishi T, Machi J, Feleppa EJ, et al. In vitro B-mode ultrasonographic criteria for diagnosing axillary lymph node metastasis of breast cancer. J Ultrasound Med 1999;18:349–56.[Abstract]
  15. Borgstein PJ, Meijer S, Pijpers R. Intradermal blue dye to identify sentinel lymph node in breast cancer. Lancet 1997;349:1668–9.[Medline]
  16. 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]
  17. 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]
  18. 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]
  19. Simmons RM, Thevarajah S, Brennan MB, Christos P, Osborne M. Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization. Ann Surg Oncol 2003;10:242–7.[Abstract/Free Full Text]
  20. Lo YL, Yu JC, Huang CS, et al. Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int J Cancer 1998;79:580–7.[CrossRef][Medline]
  21. Cheng SH, Tsou MH, Liu MC, et al. Unique features of breast cancer in Taiwan. Breast Cancer Res Treat 2000;63:213–23.[CrossRef][Medline]
  22. Schreiber RH, Pendas S, Ku NN, et al. Microstaging of breast cancer patients using cytokeratin staging of the sentinel lymph node. Ann Surg Oncol 1999;6:95–101.[Abstract]
  23. Pargaonkar AS, Beissner RS, Snyder S, Speights VO, Jr. Evaluation of immunohistochemistry and multiple-level sectioning in sentinel lymph nodes from patients with breast cancer. Arch Pathol Lab Med 2003;127:701–5.[Medline]
  24. Clare SE, Sener SF, Wilkens W, Goldschmidt R, Merkel D, Winchester DJ. Prognostic significance of occult lymph node metastasis in node-negative breast cancer. Ann Surg Oncol 1997;4:447–51.[Abstract]
  25. Cox CE. Clinical relevance of serial sectioning of sentinel nodes and the detection of micrometastatic nodal disease in breast cancer. Ann Surg Oncol 1998;5:297–8.[CrossRef][Medline]
  26. Motomura K, Komoike Y, Inaji H, et al. Multiple sectioning and immunohistochemical staining of sentinel nodes in patients with breast cancer. Br J Surg 2002;89:1032–4.[CrossRef][Medline]
  27. Barranger E, Coutant C, Flahault A, Delpech Y, Darai E, Uzan S. An axilla scoring system to predict non-sentinel lymph node status in breast cancer patients with sentinel lymph node involvement. Breast Cancer Res Treat 2005;91:113–9.[CrossRef][Medline]
  28. Martelli G, Boracchi P, De Palo M, et al. A randomized trial comparing axillary dissection to no axillary dissection in older patients with T1N0 breast cancer: results after 5 years of follow-up. Ann Surg 2005;242:1–6; discussion 7–9.[CrossRef][Medline]
  29. Aubard Y, Mollard J, Ducloux T, et al. Detection of the sentinel lymph node under local anaesthesia in early-stage breast cancer: feasibility study in a series of 78 unselected patients. Eur J Gynaecol Oncol 2004;25:178–82.[Medline]
  30. Aubard Y, Mollard J, Fermeaux V. How to avoid the uncertainties of intraoperative examination of the sentinel lymph node in breast cancer? Gynecol Obstet Fertil 2004;32:981–4.[Medline]
  31. Leikola JP, Toivonen TS, Krogerus LA, von Smitten KA, Leidenius MH. Rapid immunohistochemistry enhances the intraoperative diagnosis of sentinel lymph node metastases in invasive lobular breast carcinoma. Cancer 2005;104:14–9.[Medline]
  32. Perez N, Vidal-Sicart S, Zanon G, et al. A practical approach to intraoperative evaluation of sentinel lymph node biopsy in breast carcinoma and review of the current methods. Ann Surg Oncol 2005;12:313–21.[Abstract/Free Full Text]
  33. Brogi E, Torres-Matundan E, Tan LK, Cody HS III. The results of frozen section, touch preparation, and cytological smear are comparable for intraoperative examination of sentinel lymph nodes: a study in 133 breast cancer patients. Ann Surg Oncol 2005;12:173–80.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsu, G.-C.
Right arrow Articles by Chao, T.-Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsu, G.-C.
Right arrow Articles by Chao, T.-Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online