Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients?

BACKGROUND: Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated. STUDY DESIGN: A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM. RESULTS: In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32). CONCLUSIONS: There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.     

Morphometry of isolated tumor cells in breast cancer sentinel lymph nodes: metastases or displacement?

Iatrogenic displacement and mechanical transport of epithelial cells to the sentinel node (SN) has been suggested to result in false-positive findings in breast cancer patients, but little biologic evidence has yet been presented for this hypothesis. As malignant nuclei are larger than benign ones, nuclear morphometry of SN isolated tumor cells (ITC) could provide relevant information with regard to the malignant origin-or-not of epithelial cells in the SN. In patients with primary invasive breast cancer and SN ITC with (N=16) or without (N=45) non-SN involvement, nuclear morphometry was performed on the primary tumor as well as on the ITC in the SN. Nuclear size in the primary tumor was compared with that in the corresponding ITC. Patients with SN micrometastases (N=30) and SN macrometastases (N=30) served as controls. Nuclear size of ITC was significantly smaller compared with nuclear size of the corresponding primary tumor (P<0.0001). In contrast, there were no differences in nuclear size between SN micrometastases and macrometastases on the one hand and their corresponding primary tumors on the other. In addition, a subgroup of cases (10/61, 16%) with benign morphometric features of SN ITC nuclei (small and isomorph) could be discerned that had no non-SN metastases. In conclusion, nuclei of SN ITC are significantly smaller compared with the corresponding primary tumor and are often not associated with non-SN involvement. This supports the hypothesis that some of these deposits could represent benign epithelium or degenerated malignant cells lacking outgrowth potential.     

The breast cancer patient with multiple sentinel nodes: when to stop?

BACKGROUND:

During sentinel lymph node (SLN) biopsy for breast cancer, most authors report identifying a mean of 1 to 3 SLNs, but a range of 1 to 8 (or more) SLNs per patient. A significant minority of patients have 4 or more SLNs. Here we seek to determine the significance for the breast cancer patient of finding multiple SLNs, and whether there is an optimal threshold number of SLNs that should be removed.

STUDY DESIGN:

1,561 patients who underwent successful SLN biopsy using blue dye and radioisotope in combination. Each SLN site was categorized prospectively by the operating surgeon as a dye success, an isotope success, or both. All SLNs containing counts at least four times greater than the postexcision axillary background were considered to be isotope successes.

RESULTS:

Fifteen percent of patients (241) had multiple (> 3) SLNs. Ninety-eight percent of node-positive patients (440 of 449) were identified within the first three SLN sites examined. In 2% of all SLN positive patients (9 of 449) or 4% of patients with multiple SLN (9 of 241), a positive SLN was detected at site four or more. In eight patients the first positive SLN was found at sites four or more. Blue dye and isotope were equally effective in identifying metastases in patients with multiple SLNs.

CONCLUSIONS:

Fifteen percent of patients having SLN biopsy for breast cancer have multiple SLNs. Although 98% of positive SLNs were identified within the first three sites sampled, a small number of patients had their first positive SLN at sites 4 to 8. These data suggest that there is no absolute upper threshold for the number of SLNs that should be removed. Sampling a few additional SLNs probably adds little morbidity to the procedure, yet may significantly alter the treatment of some individuals. SLN biopsy should be continued until all blue and hot nodes are removed.     

Oncogenes, granules and breast cancer: what has c-myc to do with apocrine changes?

This issue of The Breast includes an elegant study by Selim et al. on c-myc gene amplification and protein overexpression in apocrine metaplasia (APM) and apocrine adenosis (AA) of the breast using paraffin-embedded tissue. In their report, the authors observe that all cases of APM and AA harbored c-myc protein overexpression, but no definitive gene amplification was found. Most importantly, they observed that the percentage of cells expressing c-myc in APM and AA was significantly correlated with cell proliferation, as assessed by Ki-67 immunolabeling index. On the basis of their findings and of previously reported studies, the authors suggest that c-myc overexpression occurs in early stages of breast carcinogenesis, that c-myc gene amplification may be a late event, and that in APM and AA c-myc overexpression is related to cell proliferation. Selim et al. findings have brought to our attention two thorny but rather important issues regarding current concepts of apocrine changes and their association with breast carcinomas, and also the role of c-myc in breast carcinogenesis.     

Systemic treatment after sentinel lymph node biopsy in breast cancer: who, what, and why?

SLNB, although subject to numerous technical problems, has nonetheless shown great promise in predicting the status of the remaining axillary lymph nodes. The growing use of SLNB has presented the opportunity of using immunohistochemical and molecular markers to detect occult micrometastases. These micrometastases may be important for more accurate staging and prediction of patient outcomes. Current standards for the use of systemic therapy recommend multidrug chemotherapy for all but the most favorable disease (T1a/b, NO). The detection of micrometastases by SLNB in this low-risk group may change treatment recommendations to include systemic therapy. Because of the significant frequency of false-negative results in SLNB, which will depend upon the surgeon's experience, caution is urged in determining when ALND can be safely eliminated in patients with a negative SLNB.     

Selective lymphoscintigraphy: a necessary adjunct to dye-directed sentinel node biopsy for breast cancer?

BACKGROUND: Dye-directed sentinel node biopsy (SNB) for breast cancer provides accurate staging with low morbidity, but for tumors distant from the axilla, its use has been questioned. HYPOTHESIS: Can preoperative breast lymphoscintigraphy (BL) applied selectively to medial hemisphere tumors predict a subset of patients who may not require surgical staging of the axilla? DESIGN: Prospective cohort study. SETTING: Tertiary, multidisciplinary breast center. PATIENTS: Thirty-two women with breast tumors located in the medial hemisphere (30) or inframammary crease (2). INTERVENTION: Peritumoral injection of 500 microCi of technetium Tc 99m sulfur colloid and biplanar imaging. Nonpalpable lesions were localized with ultrasound or mammography. At the time of definitive breast surgery, isosulfan blue dye-directed SNB was performed. Axillary dissection was performed when the SN contained a tumor or could not be identified. MAIN OUTCOME MEASURES: Regional nodal basins identified by BL; success rate of SNB. RESULTS: Preoperative BL demonstrated axillary drainage in 28 patients (88%); 2 patients (6%) had isolated internal mammary radionuclide uptake, and 2 patients had no nodal uptake. Dye-directed axillary SNB succeeded in 27 (87%) of 31 patients, including both patients with failed BL. Breast lymphoscintigraphy had predicted isolated internal mammary drainage in 2 of 4 patients whose SNs could not be identified. Metastases were found in 5 patients (16%). CONCLUSIONS: Axillary radionuclide uptake predicts but does not augment dye-directed SN identification. In those few patients with isolated internal mammary drainage, BL may obviate the need for surgical staging of the axilla.     

Central mesenteric lymph node BER-Ep4+ cells in colorectal cancer: challenge to sentinel node concept?

BACKGROUND: The role of sentinel lymph nodes in colorectal cancer remains unclear. METHODS: Cryosections from central para-aortic mesenterial lymph nodes were stained using mAb BER-Ep4. Overall survival and distant recurrence were calculated using Kaplan-Meier plots. RESULTS: All patients (n = 48) were free of distant metastases and curatively resected (R0). 23 pN0, 13 pN1 and 12 pN2 stages were found. 21/48 patients (44%) showed BER-Ep4+ cells in their central lymph nodes (7/23 pN0, 8/13 pN1, 6/12 pN2). In 6/23 pN0 patients, BER-Ep4+ cells were also found in locoregional nodes (p = 0.03, Fisher's exact test). pN status predicted overall survival (p = 0.006, Kaplan-Meier curve, log-rank test). An impact was exerted by central mesenteric BER-Ep4+ cells on overall survival (p = 0.009 in pN0 patients, p = 0.07 for all pN) and distant recurrence-free survival (p = 0.001 in pN0 patients, p = 0.007 for all pN). Multivariate analysis showed an independent prognostic effect on overall survival in pN0 patients (p = 0.022). CONCLUSION: Central lymph nodes are sentinels of disease not amenable to extended lymphadenectomy and might identify patients at risk of distant organ recurrence.     

Is axillary lymph node dissection always necessary in breast cancer patients with a positive sentinel node?

Axillary lymph node dissection (ALND) is recommended for patients with breast cancer metastasis to a sentinel lymph node (SLN). However in 40-70% of cases, the SLN may be the only area of metastasis in the dissected axillary contents. In patients with a positive SLN, independently predictive factors for non-SLN metastasis include size of the primary tumor, the size of the SLN metastases, extracapsular extension, and the proportion of positive SLN's among all identified SLNs. Some authors have developed scores and nomograms to estimate a patient's risk for non-SLN metastases. These scores and nomograms should be applied prospectively to a large numper of SLN positive patients who thereafter undergo completion ALND. It is necessary to verify the predictive validity of these scores before we recommend the abandonment of ALND in patients with a very low likelihood of non-SLN metastasis. In this article we review the various predictive factors of non-SLN involvement and the scores or nomograms which have been developed to predict the likelihood of a positive ALND after a positive SLN biopsy.     

Can axillary lymph node dissection be omitted in patients with breast cancer and positive sentinel nodes?

Sentinel lymph node biopsy has evolved as the surgical procedure of choice for women with clinically negative axillae, as part of an effort to move toward the less invasive surgical management of breast cancer. Axillary lymph node dissection remains the standard of care for patients with a positive axillary node and was previously performed on all patients with breast cancer prior to the implementation of the sentinel lymph node biopsy. There is, however, controversy regarding whether or not all patients with a positive sentinel lymph node need to undergo completion axillary dissection for either prognostic or therapeutic purposes. This article reviews the literature related to this controversial and evolving topic.     

Does breast tumor location influence success of sentinel lymph node biopsy?

BACKGROUND: Controversy exists regarding the influence of sentinel lymph node (SLN) mapping technique or patient variables on the success rate of SLN mapping. We undertook a prospective study in a single institution series to evaluate multiple variables that could adversely affect SLN identification rates. STUDY DESIGN: Data were collected on 174 patients who underwent 177 SLN mapping procedures followed by axillary dissection from October 1996 through January 2000. Patient demographics, body mass index (BMI), biopsy method, tumor size, palpability, and location were recorded. SLNs were identified by blue dye only (n = 31), Tc-99m sulfur colloid only (n = 34), or combined techniques (n = 112). Data were analyzed by logistic regression analysis and expressed as the probability of failure to map the SLN. RESULTS: SLNs were identified successfully in 150 of 177 procedures (85%) with a false negative rate of 3.7%. Mapping success reached 93% using combination blue dye and isotope. Variables found to adversely affect SLN mapping success and the odds ratio of failure (OR) included lower inner quadrant (LIQ) location (OR 35.6), blue dye only (OR 42.4), BMI >30 and upper outer quadrant (UOQ) location (OR 14.6), and nonpalpable UIQ location (OR 25). LIQ location adversely affects mapping success independent of technique, tumor size, or obesity. Obesity and nonpalpability were adverse factors when tumors were located in the UOQ and UIQ, respectively. Age, biopsy technique, and tumor diameter did not affect SLN mapping success. CONCLUSIONS: SLN mapping success is influenced by technique and tumor location, with best results achieved using combined techniques and for lesions located in quadrants other than the LIQ. Obesity and tumor palpability influence success in the context of tumor location.     

Is there a requirement for axillary lymph node dissection following identification of micro-metastasis or isolated tumour cells at sentinel node biopsy for breast cancer?

IntroductionRecent decades have seen a significant shift towards conservative management of the axilla. Increasingly, immunohistochemical analysis of sentinel nodes leads to the detection of small tumour deposits, the significance of which remains uncertain. The aims of this study are to examine patients whose sentinel lymph nodes are positive for macro-metastasis, micro-metastasis or isolated tumour cells (ITCs) and to determine the rate of further nodal disease after axillary lymph node dissection (ALND).MethodsA retrospective analysis of all patients undergoing a sentinel lymph node biopsy (SLNB) between January 2007 and December 2010 in a tertiary referral breast unit was performed. Patients who underwent an axillary lymph node dissection for macro-metastasis, micro-metastasis or ITCs were identified. Demographics, histological data and the rate of further axillary disease were examined.ResultsIn total, 664 breast cancer patients attended the symptomatic breast unit during the study period, 360 of whom underwent a SLNB. Seventy patients had a SLNB positive for macro-metastasis. All of these patients underwent ALND. A positive SLNB with either micro-metastasis or ITCs was identified in 58 patients. Only 41 of the 58 patients went on to have an ALND, due primarily to variations in surgeons' preferences. Nineteen patients with micro-metastasis underwent an ALND. Four patients had further axillary disease (21%). Twenty-two patients had ITCs identified, of whom only one had further disease (4.5%). No statistically significant difference was found between the two groups in terms of tumour size, grade, lymphovascular invasion or oestrogen receptor status.ConclusionALND should be considered in patients with micro-metastasis at SLNB. It should rarely be employed in the setting of SLNB positive for ITCs.     

Lymphatic mapping and sentinel node biopsy: is the method applicable to patients with colorectal and gastric cancer?

The current status of lymphatic mapping and sentinel node biopsy in the treatment of patients with malignant melanoma and breast cancer is described. The possible use of a similar method in patients with colorectal and gastric cancer is outlined. Peroperative lymphatic mapping and identification of sentinel node(s) in patients with gastrointestinal cancer may lead to modified (tailored) resections and extended lymph node dissections only in those patients in whom the sentinel node(s) contains tumour cells. The method offers the possibility of improving staging by identification of patients with early disseminated disease who should be considered for adjuvant treatment or be included in trials of adjuvant treatment to speed up the breakthrough of more effective adjuvant regimens. Large studies are needed to find out if the sentinel node concept is as valid in gastrointestinal cancer as studies so far have shown that it is for malignant melanoma and breast cancer.