Breast Cancer With Positive Sentinel Lymph Node: Now What?
Article Outline
- The Problem
- Surgical Oncologists' Expert Opinion
- Medical Oncologists' Expert Opinion
- Summary and Assessment
- References
- Copyright
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.
Gloria J. Morris, MD, PhD
Current Clinical Practice Feature Editor
The locoregional treatment of breast cancer, once the sole domain of surgeons, now involves radiation oncologists and medical oncologists. Our understanding that treatment failure after breast cancer surgery is usually due to the systemic dissemination of cancer cells beforehand has led to a major departure from the Halsteadian principles of en bloc excision. Surgery at the primary site is now more conservative.
The wisdom of excising clinically positive regional lymph nodes has never been challenged. Our appreciation that lymph nodes are not tumor sieves but markers of dissemination has led to a more conservative approach to clinically negative regional lymph nodes. Lymph node mapping with sentinel lymph node dissection is the latest chapter in this retreat. This minimally invasive procedure allows identification of truly microscopic (and not just clinically negative) lymph node involvement with almost no morbidity. Indeed, the procedure is widely practiced. What is not so clear is how the information impacts clinical practice. The following case report is illustrative.
The Problem
A 41-year-old woman with a suspicious mammographic finding on the left side had on repeat study 6 months later a concerning lesion at the 2 o'clock position 0.9 cm in diameter and 4.1 cm from the nipple. The presence of the lesion was confirmed by ultrasound. An image-guided core needle biopsy showed invasive ductal carcinoma of at least 0.8 cm in size with foci suspicious for vascular invasion, a nuclear grade of 2/3, tubule formation 3/3, and mitotic activity of 2/3 (Figure 1A and B). Immunohistology revealed that estrogen receptors (ERs) were positive on 85% of cells, while progesterone receptors were present on less than 5% of cells. The tumor was 1+ positive for HER-2/neu. A magnetic resonance image of the breasts showed a left axillary node measuring 0.9 cm suspicious for tumor involvement, while the right breast showed diffuse stippled enhancement with a benign pattern. A needle-localized lumpectomy revealed a 2.7-mm focus of residual, grade III ductal carcinoma of nuclear grade II (stage T1b in toto). The frozen section of the left sentinel lymph node biopsy was negative. However, the permanent hematoxylin and eosin (H&E) sections showed very rare identifiable groups of metastatic carcinoma cells (Figure 2). Immunoperoxidase stains (Figure 3A and B) showed a minute focus of metastatic carcinoma consisting of rare single cells and rare groups with the largest focus measuring 0.2 mm on deep-stained sections. The patient was referred for evaluation and recommendations regarding further axillary node dissection.
Figure 1.
(A) H&E stain of primary breast biopsy showing invasive ductal carcinoma (10x original magnification). (B) H&E stain of primary breast biopsy showing invasive ductal carcinoma (40x original magnification).
Figure 2.
H&E stain of sentinel lymph node with micrometastases of ductal carcinoma of the breast (40x original magnification).
Figure 3.
(A) Immunohistochemical stain of sentinel lymph node showing small foci of metastatic ductal carcinoma (10x original magnification). (B) Immunohistochemical stain of sentinel lymph node showing small foci of metastatic ductal carcinoma (40x original magnification).
This case was referred to surgical and medical oncologists for review and advice. Their responses follow.
Surgical Oncologists' Expert Opinion
This patient is young and presumably premenopausal with an ER+, T1b (∼1.1cm) invasive ductal carcinoma of the upper outer quadrant of the left breast. Interestingly, if you put all of her clinical information in the Memorial Sloan-Kettering Cancer Center (MSKCC) predictive nomogram,1 she would be calculated to have a 51% chance of having spread to her sentinel lymph node. When she underwent sentinel lymph node biopsy, it was negative by frozen section but positive on permanent section when serial sections and immunohistochemistry (IHC) and H&E staining were performed (a not uncommon scenario). The likelihood of additional regional lymph node metastases can be predicted again using a MSKCC nomogram, which has been validated in numerous studies. Using this nomogram, we can predict the likelihood of this patient having additional spread to axillary lymph nodes to be 37%. This is primarily driven by the fact that there is vascular invasion and a higher nuclear grade, and that there were no additional negative sentinel nodes.
With a much higher likelihood of this patient having additional non-sentinel lymph nodes positive, we would advocate that she undergo completion axillary dissection. If she does have additional positive axillary lymph nodes, this will impact her pathologic stage and thus treatment paradigm. Several recent studies have shown a relationship between nodal micrometastases and overall survival. Cox et al2 showed in their study that patients with micrometastatic nodal (N1mic) disease had significantly worse overall and disease-specific survival than those patients with N0 disease. Breast cancer–specific survival also was shown to be poorer for those with Nmic disease, but less so than macroscopic nodal metastasis (Nmac), in a review of the Surveillance Epidemiology and End Results (SEER) database.3 Thus, the presence of the micrometastases alone gives valuable prognostic information that can be used in treatment decisions regarding chemotherapy and radiation.
It is possible that with a completion axillary lymph node dissection (CALND), she will be upstaged to a stage 2b or 3 cancer, which is very important prognostic information to have. The number of positive lymph nodes in the axilla versus the number of uninvolved lymph nodes also has significant prognostic value in this patient. The SEER database review performed by Truong et al3 also established that mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR (the ratio of axillary lymph nodes positive for micrometastases or macrometastases versus those that were negative for tumor). Despite the fact that most studies have shown no effect of Nmic disease on local control, the LNR has been shown to have a significant effect on locoregional recurrence, especially in premenopausal patients.2, 4 Some studies also have shown a survival advantage in patients with Nmic disease who underwent CALND.2
There are currently no data that would support axillary radiation solely on the basis of a single micrometastatic focus of disease in the axilla. However, it is clear that a CALND is warranted in this case. If additional disease were found in the axilla, especially if a higher number of positive axillary nodes (generally >4) were found, axillary and supraclavicular radiation would be recommended. Some even argue that a younger patient (premenopausal or age <60) with one to three positive nodes may benefit from axillary radiation just as much as a similar patient with four or more positive nodes.4 Thus, the results of a CALND would certainly be beneficial in determining the utility of axillary radiation in this patient.
A premenopausal patient with a hormone-responsive T1b tumor would most likely receive chemotherapy regardless of axillary status. However, a recent report by Regan et al5 documents the findings in this exact population of two trials by the International Breast Cancer Study Group. They found that adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node-positive treated v 46% of node-negative). Nagashima et al demonstrated that 73% of their patient population with Nmic disease received chemotherapy (v 16% of those with similar tumor size who were node-negative).6 None of the patients with Nmic disease suffered a distant recurrence in 48 months of follow-up (v 0.3% distant recurrence in the node-negative patients). These findings suggest that this young patient, with a small, ER+ tumor, would benefit from chemotherapy (in addition to hormonal therapy), even more so due to the presence of Nmic disease.
In review, we would recommend CALND in this young (presumably premenopausal) patient with a small, hormone-receptive tumor. The likelihood of additional disease is high and the prognostic significance of the ratio of positive versus negative nodes in the axilla can be used to guide further treatment (chemotherapy and radiation therapy) in this case. Even in the absence of further axillary staging, the patient may derive benefit from chemotherapy in addition to hormonal therapy. However, without further demonstration of disease in the axilla, axillary radiation would not be warranted for Nmic disease only, and many medical oncologists may be uncomfortable treating this patient without knowledge of the full extent of axillary metastasis. There still remains no clear consensus on the significance of axillary micrometastasis, but in this patient the benefit of treating this as a true metastasis seems clear.
Kandace McGuire, MD
Surgical Oncology/Breast Fellow
H. Lee Moffitt Cancer Center
Tampa Bay, FL
Adam C. Berger, MD, FACS
Assistant Professor
Department of Surgery
Thomas Jefferson University
Philadelphia, PA
Medical Oncologists' Expert Opinion
Decisions toward treatment with further adjuvant therapy are currently based on axillary lymph node information, as well as primary tumor characteristics. From a medical oncology standpoint, completion axillary lymph node dissection would indeed provide further prognostic information, and likely confirm the exclusion of the need for chemotherapy in this patient's risk reduction planning, with chemotherapy being included only if further lymph nodes were found to be frankly positive for metastases. One helpful tool in determining further chemotherapy for borderline situations (ie, tumors near 1 cm, with ER positivity) would be the use of the Oncotype DX assay (Genomic Health, Inc, Redwood, CA). Recently presented prognostic and predictive information derived retrospectively from patients enrolled in previous chemotherapy trials for lymph node–positive breast cancer found that the Oncotype DX assay further stratified patients into those who had a correlative benefit from adjuvant chemotherapy. This tool can be applied to the situation of micrometastatic disease to gain further insight into the biologic risk of recurrence of otherwise lymph node–negative breast cancers. Oncotype DX is advocated by us in this situation to guide the further need for chemotherapy based on a high-risk result and the further confirmation of low risk with axillary lymph node dissection.
In summary, from a medically oncologic perspective, this 41-year old patient with a nearly 1-cm breast cancer with sentinel lymph node micrometastases would benefit from a completion axillary lymph node dissection in order to gain further prognostic information as to the patient's risk for recurrence. This tool, in addition to the consideration of biologic prognostic information from the use of the Oncotype DX assay, may further predict the patient's benefit for adjuvant chemotherapy, as a high-risk result, even in the absence of further axillary dissection, would impact on decisions to offer the patient adjuvant chemotherapy to reduce her risk of recurrence.
Richard G. Emanuelson, MD
W. Edward Jordan, III, MD
Lisa C. Thomas, MD
Attending Physicians
Hematology and Oncology Associates of Northeast PA, PC
Dunmore, PA
Summary and Assessment
The need for further axillary lymph node dissection is clearly established for frank positive involvement of the sentinel lymph node on biopsy. Further axillary dissection is less clearly established and is usually recommended based on the likelihood of involvement of additional lymph nodes, the type of specimen assayed, and the overall projected prognosis of the patient. New additions to lymph node staging system for breast cancer list categories that hinge on the definition of Ni+ as 2-mm micrometastases by IHC: pN0 contains no regional lymph node metastases histologically, and no additional isolated tumor cells; pN0(I+) contains positive cells by IHC but no cluster greater than 0.2 mm. These can be confirmed molecularly in some laboratories by reverse transcription polymerase chain reaction and are further delineated as mol− or mol+. PN1Mi+, however, is the classification containing micrometastases greater than 0.2 mm but no larger than 2 mm.
CALND is usually recommended in case of sentinel node micrometastases (pN1mic >0.2 mm) and discussed for sub-micrometastases (pN0i+ <0.2 mm). The predictions yielded from nomograms have been found to be more dependent on invasive tumor size, tumor grade, and level of lymphovascular invasion, rather than on the size of the micrometastases, which can be subjective. Other studies have found a low rate of axillary nodal positivity in patients with isolated tumor cells or micrometastases less than 2 mm.7
In regards to prognostic information, however, which can drive therapeutic decisions in these situations, prospective studies have shown that patients with pN0(I+) or pN1mic have a disease-free interval and overall survival similar to that of patients with negative sentinel lymph nodes.8 Additional symposia have suggested that, in general, sub-micrometastasis (<0.2 mm) or isolated tumor cells can be ignored, and if micrometastasis (0.2–2.0 mm) are found, further axillary lymph node dissection is warranted, especially if the need for adjuvant systemic treatments is uncertain.9 If other nodes are negative or only micrometastatic, adjuvant treatment should be based only on primary tumor characteristics.
Isolated tumor cells themselves do not usually show evidence of malignant activity, eg, proliferation or stromal reaction. However, prediction of the likelihood of further involvement by additional axillary lymph nodes has been attempted by the use of statistical nomograms. One such nomogram has indeed been validated for sentinel lymph nodes; this nomogram takes into account the size of the original breast tumor, as well as the technique by which the sentinel lymph is preserved.10 Regardless, current studies have shown that adjuvant systemic therapy indeed improves disease-free survival in patients with isolated tumor cells or micrometastases to the sentinel lymph node despite relatively small primary tumor size.11
A consensus is given toward consideration of aggressive therapy to the axilla in this young patient to theoretically enhance the level of risk reduction. The oncologists solicited would favor completion axillary lymph node dissection in order to provide full prognostic information on this patient and to rule out further lymph node involvement. The medical and surgical oncologists solicited would favor a taxane-containing chemotherapy regimen based on further prognostic information by either surgery or by Oncotype DX to delineate biologic behavior, since Oncotype DX also has served to prognosticate lymph node–positive breast tumors.12 As prognostic information from isolated tumor cells has been borne out to be controversial, and inconsistent, it is my opinion that further treatment recommendations should be made based on the pursuit of further prognostic information that can rule out high-risk disease and further characterize this breast cancer as high-risk lymph node–negative or lymph node–positive disease.
In closing, it is becoming more and more widely recognized that the detection of micrometastatic disease in the sentinel lymph node of a breast cancer patient warrants further, more aggressive staging for prognostic purposes, and a more aggressive treatment course with the potential to further reduce recurrence risk over purely lymph node–negative disease. While ongoing trials (such as International Breast Cancer Study Group [IBCSG] 2301) seek to finally answer whether breast cancer patients with micrometastatic sentinel lymph nodes truly benefit from CALND versus surveillance,13 we have sought to highlight the current clinical opinion of practicing oncologists as described here. We welcome further comments to the address below to be published in this venue.
References
- A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol. 2003;10:1140–1151
- Significance of sentinel lymph node micrometastasis in human breast cancer. J Am Coll Surg. 2008;206:261–268
- The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer. Eur J Cancer. 2008;44:1670–1677
- The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer. J Clin Oncol. 2007;25:2019–2026
- Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?. Ann Oncol. 2008;19:1231–1241
- Sentinel node micrometastasis and distant failure in breast cancer patients. Breast Cancer. 2006;13:186–191
- Incidence of axillary nodal positivity in patients presenting with isolated tumor cell clusters or micrometastases in sentinel lymph nodes. [abstract 2001]. Proceedings of the San Antonio Breast Cancer Symposium 2006;San Antonio, TX
- The impact of micrometastases in the sentinel nodes of patients with invasive breast cancer [abstract 52]. Proceedings of the San Antonio Breast Cancer Symposium 2007;San Antonio, TX
- . Micrometastases in the sentinel node: take it or leave it? [abstract P-3]. Proceedings of the San Antonio Breast Cancer Symposium 2006;San Antonio, TX
- . Validation and limitations of use of a breast cancer nomogram predicting the likelihood of non-sentinel node involvement after positive sentinel node biopsy [abstract 2002]. Proceedings of the San Antonio Breast Cancer Symposium 2006;San Antonio, TX
- Micrometastases and isolated tumor cells: relevant and robust or rubbish?. (MIRROR): preliminary results of the MIRROR study from the Dutch Breast Cancer Trialists' Group (BOOG) [abstract 23]. Proceedings of the San Antonio Breast Cancer Symposium 2008;San Antonio, TX
- Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814, INT0100) [abstract 10]. Proceedings of the San Antonio Breast Cancer Symposium 2007;San Antonio, TX
- . Risk factors for non-sentinel lymph node metastases in patients with breast cancer (The outcome of a multi-institutional study). Ann Surg Oncol. 2007;14:181–189
PII: S0093-7754(09)00002-5
doi:10.1053/j.seminoncol.2009.01.001
© 2009 Elsevier Inc. All rights reserved.
