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Annals of Surgical Oncology 8:432-437 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Factors Correlating With Lymph Node Metastases in Patients With T1 Breast Cancer

David R. Brenin, MD, Donna-Marie Manasseh, MD, Mahmoud El-Tamer, MD, Andrea Troxel, ScD, Freya Schnabel, MD, Beth Ann Ditkoff, MD and David Kinne, MD

From the Department of Surgery (DRB, D-MM, ME-T, FS, BAD, DK), Columbia-Presbyterian Medical Center; and Division of Bio-statistics (AT), Mailman School of Public Health; Columbia University, New York, New York.

Correspondence: Address correspondence and reprint requests to: David R. Brenin, MD, Columbia-Presbyterian Medical Center, 161 Fort Washington Avenue, New York, NY 10032; Fax: 212-305-0727; E-mail: db403{at}columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Identification of reliable predictors of axillary metastases (ALNM) may be useful in selecting appropriate management for patients with T1-size breast cancer. This study was undertaken to determine the degree of correlation between ALNM and several variables, including age, race, menopausal status, palpability, tumor size, positive margin on initial excision, histology, grade, lymphatic invasion (LI), estrogen receptor status (ER), progesterone receptor status, S-phase, and ploidy.

Methods: Data from 1416 patients with T1 breast cancers treated at Columbia-Presbyterian Medical Center between 1989 and 1998 was reviewed. Patients with multifocal tumors were excluded.

Results: Mean patient age was 57.5 years (SD = 12.0); 65% of the patients were postmenopausal. One hundred thirty-one patients with T1a (<=0.5 cm), 435 with T1b (0.6–1.0 cm), and 850 patients with T1c (1.1–2.0 cm) lesions were studied. The overall rate of ALNM was 23%. AM was identified in 11% of T1a, 15% of T1b, and 29% of T1c patients. Statistically significant factors from univariate analysis were age, palpability, skin changes, tumor size, LI, histology, grade, ER status, and positive margin on initial excision.

Conclusions: Axillary staging by either sentinel lymph node biopsy or level I/II axillary dissection is indicated for most T1 breast cancer patients. Omission of axillary staging can be considered for highly selected patients with T1a cancers.

Key Words: TI-breast size cancer • Predictors of anxillary metastases • Axillary staging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Axillary dissection is the primary source of surgical morbidity for breast cancer patients treated with breast preservation. As the practical clinical morbidity attributable to local therapy has decreased, much attention has been focused on the sequelae of axillary dissection (ALND).1 The recent increase in the detection rate of small, nonpalpable lesions by screening mammography, coupled with a heightened awareness of morbidity related to axillary dissection, has resulted in the suggestion that axillary lymphadenectomy may be safely eliminated for selected patients with small breast cancers.2–5 This suggestion is based on the low reported incidence of lymph node metastases in patients with small tumors. Unfortunately, there has been significant variability in the rate of axillary metastases (ALNM) observed among studies of patients with American Joint Committee on Cancer (AJCC) T1 cancers. Overall, the rate of ALNM in patients with T1 (<=2.0 cm) breast cancers has been reported to be from 18% to 31%.3,6,7 Axillary metastasis rates for T1a (<=0.5 cm) tumors have varied even more widely, from 0% to 28%. 5,6,8–10 This wide variation makes tumor size a problematic variable for the determination of appropriate management for the axilla. Identification of other predictive factors associated with ALNM would have value in selecting patients who may be safely spared ALND and who may be offered alternative strategies including observation, axillary irradiation, and sentinel node biopsy. This study was undertaken in order to identify patient and pathologic features associated with the presence or absence of ALNM in patients with T1 breast cancer.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Data from 1416 patients with T1-infiltrating breast cancer treated at Columbia-Presbyterian Medical Center between 1989 and 1998 were reviewed retrospectively. All patients underwent axillary dissection (ALND) with a minimum of eight lymph nodes removed. Patient characteristics evaluated were age at diagnosis, race, height, weight, menopausal status, and palpability. Primary tumor characteristics evaluated were tumor size, histologic type, histologic grade, the presence of lymphatic/vascular invasion (LI), estrogen receptor status (ER), progesterone receptor status (PR), S-phase, DNA ploidy, and true positive margin on initial excision. A true positive margin was defined as additional tumor identified at the time of re-excision for a positive margin (re-excision lumpectomy or mastectomy). Patients with no tumor present at re-excision for an initial positive margin were placed in the negative margin group. Depending on its size, one or two levels were obtained from each lymph node dissected for microscopic examination using routine hematoxylin and eosin (H&E) preparations. Immunohistochemical techniques were used only if there was a question of metastasis seen on routine H&E staining. No patient in this study underwent sentinel lymph node biopsy alone. The AJCC protocol was followed to determine tumor size (T-size). Tumor size was measured as the largest dimension of the invasive component of the lesion present in the initial excision. Histologic grade was scored according to the Elston-Scharff-Bloom-Richardson system.11,12 Lymphatic/vascular channel invasion was determined from routine hematoxylin and eosin preparations. Tumor histologic types were divided into four groups: invasive ductal, invasive lobular, invasive tubular, and other invasive breast cancers. Patients with multifocal tumors were excluded from the study.

Data was analyzed utilizing SAS statistical software (SAS Institute, Cary, NC).13 Statistical techniques included the {chi}2 test with Yates correction for 2x2 tables14 and without Yates correction for all other tables. Statistical analysis also included logistic regression. The logistic models were built using a backward selection process where insignificant variables were eliminated from the models. In addition, the appropriateness of the models was evaluated using goodness-of-fit statistics.15 All P-values reported are two-tailed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
A total of 1416 patient records were reviewed. Mean patient age was 57.5 years (range, 23–88; SD = 12.1). Three hundred seventy-seven women were premenopausal (27%), 926 women (65%) were postmenopausal, and menopausal status was unknown for 113 patients (8%). Five hundred two patients (36%) presented with palpable tumors. The mean pathologic tumor size was 1.26 cm (range, 0.1–2.0 cm; SD = 0.5 cm). One hundred thirty-one patients had T1a (<=0.5 cm) tumors, 435 had T1b (0.6–1.0 cm) tumors, and 850 patients had T1c (1.1–2.0 cm) lesions. A mean of 16 lymph nodes were excised from each patient (SD = 6.4). Infiltrating ductal carcinoma (75%) was the most common histologic tumor type. A total of 326 patients (23%) were found to have ALNM. Fourteen patients with T1a size tumors (10.7%) were found to have ALNM, 67 patients with T1b tumors had ALNM (15.4%), and 245 T1c patients (28.8%) were found to have positive axillary lymph nodes (Table 1). The mean age of patients with ALNM was 56.1 vs. 57.9 years for those without metastases (SD, 12.5 vs. 11.9; P = .02).


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  		TABLE 1. Number of axillary lymph nodes containing metastatic breast cancer versus T-size
 
Univariate analysis factors found to be significantly associated with ALNM were palpability (palpable > nonpalpable), T size (T1c > T1b > T1a), LI (yes > no), histology (infiltrating ductal > lobular > other > tubular), grade (III > II > I), ER status (negative > positive), and true positive margin on initial excision (positive > negative) (P < .05), see Table 2.


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  		TABLE 2. Patient demographics and univariate analysis of factors associated with lymph node metastasis
 
When data variables (found to be significant during univariate analysis) were subjected to analysis using a multivariate logistic regression model with backward elimination of insignificant variables, the following were found to be independently associated with ALNM: larger tumor size (T1c >T1b >T1a) (OR = 2.9; 95% CI, 1.9–4.3; P = .0001), the presence of LI (OR = 2.6; 95% CI, 1.80–3.64; P = .0001), high tumor grade (III > II > I) (OR = 1.6; 95% CI, 1.2–2.1; P = .0004), and the presence of a true positive margin on initial biopsy (OR = 23.8; 95% CI, 5.6–101.2; P = .0001) (Table 3). An interaction variable, labeled TST (OR = 0.34; 95% CI, 0.2–0.6; P = .0001), was required to account for the negative interaction between true positive margins and T-stage. That is, subjects with true positive margins had risks largely unaffected by T-stage, while increasing T-stage conferred a considerable increase in risk for subjects with negative margins. This can be seen in Table 4 by comparing the probabilities in row 4 for patients with T1a, b, and c size tumors with the probabilities in row 3 for patients with T1a, b, and c size tumors. Palpability, histology, ER status, and age at diagnosis were not significant on multivariate analysis.


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  		TABLE 3. Multivariate analysis of factors associated with lymph node metastasis{dagger}
 

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  		TABLE 4. Predicted probabilities of nodal metastasis by T-size, tumor grade, lymphatic invasion, and margin status
 
The results of the above multivariate analysis were used to develop a risk table based on the variables of tumor size, grade, lymphatic invasion, and the true margin status of the initial excision (Table 4). Predicted risk of ALNM varied from 2% to 54% based on these variables.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Axillary lymph node status and tumor size have long been considered to be the most significant prognostic factors for breast cancer patients.16,17 The importance of determining pathologic axillary lymph node status makes axillary dissection a significant component in the treatment of many patients with breast cancer. Unfortunately, the morbidity associated with axillary lymph node dissection is not insignificant. Long-term morbidity related to axillary lymphadenectomy includes loss of sensation in the upper inner aspect of the arm, shoulder dysfunction, chronic upper extremity pain, and lymphedema of the arm and breast.1

Complete axillary dissection was considered a mandatory part of the surgical cure for breast cancer until the 1970s. Currently, the role of axillary dissection in the treatment of breast cancer is less clear. Several investigators have attempted to evaluate the indications for axillary lymphadenectomy and have called for a more selective approach in its application. 2–5 However, over the past decade, axillary dissection has remained in routine use. In 1994, a National Cancer Data Base survey18 of 17,151 patients with early-stage breast cancer treated throughout the United States found that 93.2% of the patients underwent axillary dissection. As the risk of ALNM declines with decreasing tumor size, the potential benefits derived from axillary dissection must be weighed against the risk of morbidity. The risk of ALNM has been reported to be low in patients with T1-size breast cancers.3,6,7 Silverstein and coworkers5 reported an ALNM rate of 3% in 96 patients with T1a-size breast cancers. However, others have reported higher rates, ranging from 0% to 28%.6–10 The variability observed in reported rates of ALNM for patients with small breast cancers makes tumor size an inexact variable for the preoperative prediction of axillary disease. Our study attempts to identify other independent predictors of ALNM which may be useful for preoperative risk assessment of breast cancer patients.

The incidence of ALNM in the 1416 women studied was 23% and is similar to other, smaller studies.3,19 It is generally accepted that the incidence of ALNM increases with tumor size.6,19,20 Our study of women with T1 breast cancers indicates that the presence of ALNM is strongly associated with larger tumor size, the presence of LI, high tumor grade, and the presence of a true positive margin. Women with T1a-size tumors were found to have ALNM in 11% of the cases compared with 29% in women with T1c-size tumors (P = .001). Patients with LI were found to have ALNM in 43% of the cases compared with 18% for women without LI (P = .001). Women with grade III tumors were found to have ALNM in 32% of the cases compared with 11% for women with grade I tumors (P = .001). Patients found to have a true positive margin on initial excision had ALNM in 26% of the cases compared with 21% for women with negative margins on initial excision.

Multivariate analysis of our data shows that T-size, LI,umor grade, and the presence or absence of a true positive margin are significantly associated with an increase in the odds of ALNM (Table 3). Tumor size has long been accepted as a significant predictor of ALNM.6 However, our data indicate that, as tumor size decreases, the presence of a true positive margin becomes more significant than tumor size. The interaction between true positive margins and T-stage is negative, so that the two effects tend to cancel each other out. The TST interaction variable accounts for the negative interaction in the model. This effect is best demonstrated by examination of the change in odds of nodal metastases conferred by a true positive margin for each of the three T-stages. For patients with T1a tumors, the difference in the odds of ALNM between patients with true positive margins and patients with negative margins is 7.24. For T1b patients, the difference drops to 2.68, and for T1c subjects, the difference between patients with true positive margins and negative margins is only 0.9. The presence of a true positive margin confers considerable additional risk in patients with T1a-size tumors, moderate risk in subjects with T1b-sized tumors, and is essentially negligible in subjects with T1c-size tumors.

The significance of a true positive margin for patients with small tumors can be seen clearly in Table 4. When the variables of LI and histologic grade and are accounted for, patients with a true positive margin at the time of initial excision had similar rates of ALNM, regardless of T-size. A patient having a histologic grade I, no LI, T1a tumor with a true positive margin had the same predicted probability of ALNM as a patient with a T1c tumor and the same histologic variables.

The presence of additional tumor identified at the time of re-excision for a positive margin has been previously demonstrated to be associated with an increased likelihood of ALNM.21 The increased incidence of ALNM observed in patients with true positive margins is likely due to the bias toward understaging built into the American Joint Committee on Cancer (AJCC)22 staging guidelines. The current AJCC protocol bases tumor size exclusively on the specimen obtained at the time of the initial excisional biopsy or lumpectomy. Additional microscopic tumor found at re-excision is not taken into account for size determination. Therefore, patients whose tumor is completely excised at the initial surgical procedure have a smaller volume of tumor at risk for metastasis to the axilla when compared with patients in the same tumor stage group (T-stage) who have microscopic residual disease detected at the time of re-excision. This difference would become more important as the total volume of tumor at risk for metastasis becomes smaller. The 4 mm of residual cancer identified at re-excision of a patient whose tumor was staged as T1a would be much more significant then the 4 mm of residual cancer identified in a patient whose initial excision was that of a T2 tumor.

The results of the model developed from the patients in our study indicate that those with T1a cancers, lacking lymphatic invasion and removed with negative margins, can be predicted to have an axillary metastasis rate of less than 5%. Our results are similar to those that Silverstein and coworkers5 who reported an ALNM rate of 3% in 96 patients with T1a-size breast cancers. Given the possible morbidity associated with level I/II axillary lymph node dissection, the omission of pathologic axillary staging for this group of patients should be considered if sentinel lymph node biopsy is not available.

Sentinel lymph node biopsy has been shown to be a safe and accurate technique for staging the axilla in patients with breast cancer. Recently, several investigators have questioned the need for completion lymphadenectomy in selected patients found to have sentinel lymph node metastasis. In a study of 157 women who underwent completion lymphadenectomy after the identification of a tumor involved sentinel lymph node, Chu and coworkers23 found that 33.5% of the patients had additional axillary lymph nodes with metastatic disease. After analysis of their data, they concluded that some patients with T1a lesions found to have a positive sentinel node may not require completion axillary node dissection. This conclusion was based on a low likelihood of finding a second positive axillary lymph node. Our data does not support their conclusion. Fourteen patients with T1a size breast cancers in our study were found to have ALNM. Seven of the 14 (50%) had two or more nodes involved (Table 1). The omission of completion lymphadenectomy when caring for patients with T1a breast cancer who also have a positive sentinel node may put them at high risk for axillary failure. The risk of axillary recurrence for patients with positive sentinel nodes who do not undergo completion lymphadenectomy is currently being addressed in the American College of Surgeons Oncology Group protocol Z0011.24 Until data from that study becomes available, completion axillary dissection for patients with T1 breast cancers and positive sentinel nodes would be prudent.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Appropriate identification of patients at extremely low risk of ALNM would allow the practitioner to select patients who may be safely spared axillary staging. Patients with T1a size tumors, no LI, and negative margins have a <5% rate of ALNM. Their low incidence of ALNM may make them good candidates for treatment without axillary staging. However, these patients are rare, accounting for only 4% of the 1416 T1-size breast cancer patients studied. Thus, even in a large group of women with small breast cancers, we were unable to identify a significant number of patients who could have been preoperatively selected for treatment without axillary staging.

Axillary staging is important for patients with small breast cancers. The presence of ALNM in patients with T1-sized tumors will probably affect the adjuvant treatment offered to them. Therefore, surgical axillary staging by either sentinel lymph node biopsy or level I/II ALND is still indicated for most breast cancer patients with T1-size tumors.


   Footnotes
 
Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7,1999.

Received for publication October 24, 2000. Accepted for publication February 1, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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