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Right arrow Sentinel lymph node
Annals of Surgical Oncology 8:675-681 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Occult Metastases in Sentinel Nodes of 200 Patients With Operable Breast Cancer

Kambiz Dowlatshahi, MD, Ming Fan, MD, Joseph M. Anderson, MD and Kenneth J. Bloom, MD

From the Departments of General Surgery (KD, MF) and Pathology (JMA, KJB), Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois.

Correspondence: Address correspondence and reprints to: Kambiz Dowlatshahi, MD, 1725 W. Harrison Street, Suite 848, Chicago, IL 60612; Fax: 312-563-2091; E-mail: kdowlat{at}rush.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Up to 30% of patients with operable breast cancer and negative regional lymph nodes experience disease recurrence within 10 years. Serial sectioning and immunohistochemical staining of these nodes have revealed 9% to 30% occult metastases.

Methods: Sentinel nodes from 200 patients with T1 and T2 invasive breast carcinoma were step-sectioned at 2- to 3-mm intervals, fixed in 10% formalin, and embedded in paraffin. Sections were taken from the face of the blocks and stained with hematoxylin and eosin (H&E). The blocks were then cut completely, and sections at .25-mm intervals were stained with cytokeratin and examined.

Results: Tumor metastases were found in 34 patients when the sentinel nodes were examined at 2- to 3-mm intervals and in an additional 51 patients when the nodes were sectioned in their entirety at .25-mm intervals and stained with cytokeratin, bringing the total number of patients with metastases to 85. Of the 51 patients whose metastases were detected by 2- to 3-mm sectioning and cytokeratin staining, 27 had isolated tumor cells and 24 had clusters of innumerable malignant cells, all of which were visualized and confirmed by H&E staining of the adjacent sections.

Conclusions: Histologic examination of sentinel nodes of patients with invasive breast cancer sectioned at 2- to 3-mm intervals and stained with H&E significantly underestimates nodal metastases. Sectioning of the entire sentinel nodes at .25-mm intervals and staining with cytokeratin detects metastases as either isolated cells or as clusters.

Key Words: Breast carcinoma • Sentinel nodes • Occult metastases • Serial sectioning • Cytokeratin staining


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel node biopsy (SNB) is being increasingly practiced as a less invasive method of staging patients with breast cancer, and its accuracy has been shown to be close to that of axillary node dissection.1–5 Many published reports indicate that single sectioning of lymph nodes underestimates the true metastatic status of breast cancer.6–10 This is not surprising when one considers that the 5-µm section represents .1% of a 5-mm lymph node. Additionally, occult metastases, defined as any cluster smaller or equal to 2 mm, may be overlooked because of both staining and size resemblance between malignant cells, especially lobular carcinoma and normal cellular components of the lymph node. Several retrospective studies, as well as more recent prospective reports, indicate that additional sectioning of the nodes stained with cytokeratin (CK) reveal occult metastases that were undetected by the routine bivalving and hematoxylin and eosin (H&E) staining of the nodes.11–15 However, the clinical significance of SNB as a substitute for axillary node dissection with regard to local recurrence and overall survival has not yet been established.

Our group has previously published a preliminary report on the detection of occult metastases in the sentinel nodes of patients with early breast carcinoma, demonstrating that the examination of the entire node at .25-mm intervals stained with immunohistochemical techniques (IHC) reveals occult metastases at a higher rate.16 This article describes our experience with 200 patients with operable breast cancer whose sentinel nodes were prospectively evaluated with serial sections at .25-mm intervals through the entire nodes and stained with the CK technique.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Demographics
A prospective examination of 217 patients with invasive breast carcinoma who underwent partial mastectomy and axillary SNB between December 1997 and March 2000 is described. Seventeen patients were excluded from further analysis because no sentinel node was detected in 13 patients, and in 4 patients the slides were unavailable for analysis. The diagnosis of invasive carcinoma was made either by needle core or by excisional biopsy in 136 (68%) palpable and 64 (32%) nonpalpable, mammographically detected tumors. None of the patients had axillary nodes that were clinically or radiographically suspicious for metastases.

Technique of Sentinel Node Mapping and Processing
Details of the procedure have been previously described.4 Briefly, each patient’s breast was initially examined by a 7.5-MHz ultrasound linear transducer (ATL, Bothel, Washington) to visualize the tumor in 131 patients (65%) or to visualize the biopsy cavity, if the tumor had been removed, in 69 patients (35%). The boundaries of the tumor or the biopsy site were marked on the skin. Four milliliters of unfiltered sulfur colloid solution labeled with 1 mCi of 99mTc was injected before surgery around the tumor or the biopsy site into the parenchyma, guided by ultrasound and avoiding the scar tissue and seroma cavity. The injected site was massaged for 5 minutes to enhance the tracer migration. The location of the sentinel node was identified as a hot spot with a hand-held gamma probe (C-Trak, Carewise, Morgan Hill, CA) before surgery. A hot spot was defined as a focus of radionuclide concentration with a signal count of 25 per 10 seconds. If no radioactive hot spot was found before surgery, 5 ml of isosulfan blue was injected in a similar manner 15 minutes before making the axillary incision, and the blue stained lymph node was searched for.

Tissue Preparation
Each sentinel node was serially sectioned at 2- to 3-mm intervals perpendicular to its long axis for ease of handling and placement in the minimum number of tissue cassettes that would accommodate all of the sections. The tissue samples were fixed in 10% formalin for approximately 8 hours. The temperature of the paraffin (SurgiPath, Richmond, IL) during embedding did not exceed 50°C. A single 5-µm-thick paraffin section was stained with H&E and examined for routine reporting. The remainder of the block was then completely cut, and only ribbons containing tissue sections at .25-mm intervals were examined for occult metastases (Fig. 1). The intervening ribbons were archived. The sections were subjected to protease (.1% trypsin; Sigma, St. Louis, MO) treatment before exposure to the primary monoclonal CK antibody, CK 8/18 (Novocastra/Vector, Burlingame, CA). Single-label immunostaining was performed by the avidin-biotin-peroxidase technique by using commercial reagents (Ventana, Tucson, AZ). Binding sites were visualized with 3,30-diaminobenzidine (Ventana), and sections were briefly counterstained with hematoxylin. All slides were examined by the project pathologists (K.J.B. and J.M.A.), and the results of the single H&E sections were compared with the CK-stained serial sections.



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  		FIG. 1. Diagrammatic representation of the histologic processing of a sentinel lymph node. (A) A typical 1-cm sentinel lymph node cut at 2-mm intervals. (B) The pieces are placed into a cassette. (C) The paraffin block is step-sectioned at 5-µm-thick intervals. The first ribbon is stained with hematoxylin and eosin. Ribbons at 250 µm are stained with CK 8/18.

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic features of 200 patients with detected sentinel nodes are listed in Table 1. The mean age of the patients was 55 years, and the mean tumor size was 1.4 cm; 81% of patients in this series were in the T1 category, and 32% had mammographically detected tumors. This is consistent with most reported series of operable breast cancers.17 The average number of sentinel lymph nodes was 1.9. Table 2 correlates the tumor size to nodal metastases, as noted by histological examination of the sections taken from 2- to 3-mm tissue blocks of the sentinel nodes stained with H&E. The additional 51 occult metastases (24 clusters and 27 isolated cells) detected only on examination of sections at .25-mm intervals stained with CK is smaller than previously reported preliminary results. In 24 patients, the sentinel nodes contained a large number of malignant cells (cluster) noted in several consecutive sections (Fig. 2). The presence of these occult metastases was confirmed by reexamining the H&E-stained adjacent sections in all 24 cases; this indicates that additional sections of the sentinel nodes would have detected such metastases. Measurement of the largest metastases in 34 patients detected on H&E-stained sections at 2- to 3-mm intervals versus in 24 cases detected by IHC at .25-mm steps revealed the mean size (range) to be 3.1 (.8–12) mm and .75 (.1–2.7) mm, respectively. The greatest diameter of each metastatic cluster was measured either from its x- and y-dimensions on a nodal section or its thickness (z-axis) through several adjacent sections. These numbers for the case shown in Fig. 2 are 2.5 and 1.75 mm, respectively. This observation is further evidence that lymph node metastases have irregular shape and that their detection rate is not similar to that of spherical nodal metastases hypothesized by Gusterson and Ott.18


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  		TABLE 1. Demographic features of 200 patients with invasive breast carcinoma undergoing sentinel lymph node biopsy
 

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  		TABLE 2. Distribution of tumor stage and sentinel lymph node metastases in 200 patients with invasive breast carcinoma. Sections were examined at 2-2 mm intervals, stained with H&E and at 0.25 mm intervals stained with CK 8/18.
 


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  		FIG. 2. Consecutive sections of a lymph node showing innumerable malignant cells spanning at least seven steps of 0.25-mm thick intervals of the sentinel node. Magnification x20.

 
The ratio of occult metastases observed as isolated cells to those seen as clusters (Fig. 3) is reversed from T1a to T2 tumors; this supports the hypothesis that small tumors have small metastases that may grow in time to become clinically significant. Others may not survive. In this series, the subset number of occult metastases (cells, clusters) per tumor size are too small to draw a definite conclusion, but a linear trend is observed as noted on Figure 3.



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  		FIG. 3. Correlation between the tumor size and sentinel lymph node metastases. Metastases were noted on hematoxylin and eosin–stained sections at 2- to 3-mm intervals. Clusters and isolated malignant cells were found on cytokeratin (CK)-stained sections at 0.25-mm intervals.

 
Table 2 shows that by using the cutting and staining protocol described previously, no metastases were identified in 115 patients. There was a total absence of malignant cells in 115 of 200 patients (57.5%) whose sentinel nodes were examined at .25-mm intervals and stained with CK 8/18. This suggests that more than half of the tumors in this series did not metastasize to the sentinel nodes. Of equal significance is the absence of malignant cells in the nodes of 57 (28.5%) patients with tumors larger than 1 cm (T1c, 43; T2, 14).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Tumor size and nodal status are the two most important factors that determine prognosis and the need for systemic therapy of patients with breast cancer. Generally, patients with tumors larger than 1 cm or with the presence of metastases in the regional nodes, regardless of the tumor size, are recommended to receive a course of chemotherapy. The American Joint Commission on Cancer defines nodal metastases as any cluster of malignant cells >=2 mm found in the regional lymph nodes by H&E stain.19 During the past decade, widespread screening mammography and increasing practice of SNB in lieu of level I and II axillary node dissection have resulted in detection of smaller tumors. Smaller tumors seem to have smaller metastases. Furthermore, the pathologist has time to examine an average of two sentinel nodes more extensively than 15 to 20 axillary nodes.

Consequently, many investigators have reported detecting metastases smaller than 2 mm when the nodes were subjected to multiple sections and stained with CK.11–14 Review of many retrospective studies also confirms underestimation of nodal metastases, with an adverse effect on patient survival.20

With that background in mind, our group began to examine, in a prospective fashion, the sentinel nodes of patients with operable breast cancers. We decided to first step-section the sentinel node at 2- to 3-mm intervals, staining one section from each slice with H&E, and then to cut the entire block at 5-µm intervals. Initially we reported our findings on sections examined at .5-mm intervals stained with CK 8/18, and 23% additional occult metastases were detected.15 We then examined nodal sections at .25-mm intervals. The preliminary reports on 52 patients indicated 58% occult metastases.16 In this article we report our experience with 200 patients whose sentinel lymph nodes were examined at 250-µm intervals and stained with CK 8/18.

Serial Sectioning of Lymph Nodes
Close review of the reports by investigators searching for occult metastases in the "negative" lymph nodes of patients with breast cancer reveals that most of them took additional and not serial sections at arbitrary intervals from archival tissue. The intervals between sections varied from 5 µm to 2 or 3 mm, and the number of sections examined varied from four to six.6–8,10–12 Most of these studies were retrospective and were performed on available paraffin blocks of one half of each lymph node.

This technique results in incomplete examination of the lymph nodes. Cote et al.,12 in a recent report of 720 node-negative patients previously reported by the Ludwig Group, noted 7% occult metastases when an additional six levels of the remaining paraffin blocks stained with H&E were examined, compared with 20% when the same sections were examined with IHC stains. The intervals between six sections were 30 µm; therefore, approximately .2 mm of each node was examined. Schreiber et al.13 reported detecting occult metastases in an additional 17 of 210 patients whose sentinel nodes were stained with IHC but did not specify the intervals and the number of sections examined. Weaver et al.14 reported on deeper sections taken from two levels at 100 and 200 µm from the sentinel and nonsentinel negative nodes of patients with operable breast cancers. They detected additional 10% metastases smaller than 1 mm. Hsueh et al.21 reported on additional sections taken from the negative sentinel node of patients with breast cancer stained with IHC. The incidence of metastases was 42% in the sentinel node group and 29% in the axillary node. Thus, there is a transitional phase in the processing and examination of the sentinel nodes in patients with operable breast cancer. Currently there is no generally accepted guideline for the processing of sentinel nodes. Most pathologists section the sentinel node in its longitudinal axis, examining faces of the block initially with H&E and using CK stain selectively. A recent national survey of the practice pattern among Fellows of the American College of Surgeons indicated that 80% of the respondents routinely perform IHC on sentinel nodes.22

At our institution on a routine basis, the submitted nodes are step-sectioned at 2- to 3-mm intervals, stained with H&E, and examined. CK stain is used if suspicious cells are noted. However, in cases of invasive lobular carcinoma, the sections are routinely stained with CK 18 as described.

The presence and effect of occult metastases on disease recurrence and patient survival are under investigation in two prospective national trials in the United States. In National Surgical Adjuvant Breast and Bowel Project protocol B32, sentinel nodes are cut at 2- to 3-mm slices and placed in paraffin blocks, and sections are stained with H&E for routine examination. The blocks of the negative lymph nodes are then sent to a central laboratory, and additional 6-µm-thick sections are taken from 20 to 30 µm and 90 to 100 µm deep from the surface of the block and stained with anti-CK technique for detection of metastases. The investigators expect to examine 18% to 25% of the sentinel nodes to detect .3- to .5-mm metastases. In the American College of Surgeons Oncology Group protocol Z0010, unspecified additional sections are examined for occult metastases with the IHC technique. In our study, we have examined an average of 1.9 sentinel nodes at .25-mm intervals of the entire nodes. Thus, the average number of sections examined per patient with a mean of 1.9 sentinel nodes, each measuring an average of 10 mm in long axis, was 10 with H&E (Fig. 1B) and 80 with IHC (Fig. 1C). Every time occult metastases were detected as clusters by the CK staining, an adjacent section was stained with H&E to confirm its presence. Single malignant cells are difficult to visualize on H&E staining, but groups of 5 to 10 cells, especially in the subcapsular spaces, can be detected with relative ease. We strongly believe that stem to stern examination of the sentinel node is essential for more accurate detection of occult metastases and that partial sampling leads to their underestimation.

In five patients in this study, a single large cluster of malignant cells was the only metastasis found in one part of a sentinel node. The technique described here is more labor intensive for routine laboratory application. Immunostaining is more expensive than the H&E staining technique. Thus, case for case, the overall pathology charges to the health payers may be twice as much for sentinel lymph nodes compared with current routine axillary node processing. It is anticipated that with automated scanning of slides in the near future, the pathologist will be able to review selected images for evaluation.23

Passive Transportation Versus Active Migration of Malignant Cells
The presence of metastases smaller than 2 to 3 mm in the regional lymph nodes of patients with breast cancer has been attributed to manipulation of the tumor during surgery or needle biopsy24–25 as well as to massaging of the breast after injection of the radionuclide or the blue dye at the time of sentinel node mapping.26 Carter et al.27 consider the presence of malignant as well as benign cells in the subcapsular sinus of the lymph nodes a passive transportation phenomenon without clinical significance. The number and the size of these metastases varied from isolated tumor cells to small clusters of cells in lymphatic spaces or in subcapsular sinuses.

Active migration of malignant cells initially through the basement membrane and subsequently into the lymphatic and vascular capillaries is the subject of intense research. One of the earliest steps of this process may be surmised in patients with ductal carcinoma in situ and microinvasive tumors. Klauber-DeMore et al.28 noted metastases in 9 of 76 (12%) high-risk ductal carcinoma in situ patients. In two patients the metastases measured >2 mm. They also noted metastases in 3 of 31 (10%) patients with microinvasive breast cancer, and one of these metastases was >2 mm. Lympho-vascular invasion was seen in two patients in each group. Pendas et al.29 reported 5 of 87 (6%) patients with ductal carcinoma in situ (one with microinvasion) to have sentinel node metastases. The malignant cells were initially detected by CK staining and subsequently confirmed by H&E stain. Many of these tumors were found to have a focus of comedo carcinoma.

In our study we found 51 occult metastases in the sentinel nodes of 200 patients with invasive breast cancer; 27 were isolated tumor cells, and 24 were clusters of hundreds and thousands of cells. It is conceivable that single or small groups of cells were passively pushed into the terminal lymphatic vessels and on to the sentinel nodes. However, it is very unlikely that a large number of cells can be passively pushed through the narrow endothelial spaces of terminal lymphatic channels and onto the sentinel nodes occupying a space of up to 2.5 x 1.8 x 1.75 mm in diameter (Fig. 2). Furthermore, if passive transportation of malignant cells were true, one should expect to find metastases in the sentinel nodes of all patients. The preoperative preparation, diagnostic biopsy techniques, sentinel node mapping, and massaging of the breast, as well as the surgical handling of the tumor and the sentinel nodes, were identical in all patients in this series. Yet in 115 of 200 patients (57%; Table 2), not a single cell was found in the sentinel nodes examined at .25-mm steps. This is compelling evidence against passive transportation of malignant cells to the sentinel or regional lymph nodes. Therefore, one has to consider the active migration of malignant cells into the lymphatic channels and blood vessels as a starting point for dissemination. Considering the tumor sizes and their respective metastases as shown on Table 2 and Fig. 3, as well as the 17-year survival of breast cancer patients reported by Tabar et al.,30 one can surmise that not all of the occult metastases will result in disease recurrence. We hypothesize that the occult nodal metastases of significance are the cell clusters that are presumably multiplying and thriving and not the isolated cells that may perish. Under that assumption, the disease recurrence for T1a tumors is 7% and not 30%. Similarly the recurrence rates for T1b, T1c, and T2 tumors are 20%, 28%, and 54%, respectively. In today’s clinical practice, patients with tumors larger than 1 cm and those with regional node metastases are treated with adjuvant chemo-hormonal therapy; resulting in a further 30% reduction in disease recurrence. Thus the final outcome of such patients will be closer to clinically observed disease-free survival rate. Patients who may not receive adjuvant therapy are those with tumors smaller than 1 cm (T1a and T1b) and node negative by routine (2- to 3-mm cut) processing. These patients may benefit from .25-mm sectioning and CK staining of the sentinel nodes. An equally important observation is the total absence of occult metastases in the sentinel nodes of some larger tumors. Fifty-seven of 200 patients (28.5%) in this series (T1c, 43; T2, 14) had no malignant cells in their sentinel nodes. On the basis of the tumor size, these patients were recommended to receive chemotherapy. Should the tumor size be an overriding factor in the decision-making process for adjuvant therapy?

In conclusion, the metastases from 10% to 30% of patients with invasive breast cancer escape detection with the current pathologic examination system. These metastases may be detected by complete examination of the sentinel lymph nodes, as described in this study.


   Acknowledgments
 
The authors thank Thomas R. Witt, MD, Barbara Loris, MD, Darius Francescatti, MD, and Constantine V. Godellas, MD, for inclusion of their patients in this study. Supported by grants from Chicago Bears Research Foundation and Mary Kay Ash Charitable Foundation. We acknowledge the technical assistance of Donna Suta, RT, and the administrative support of Eulonda Lacy.

Received for publication . Accepted for publication June 4, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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