The patient is a 39-year-old premenopausal woman who presents with a new diagnosis of breast cancer to our multidisciplinary second opinion clinic.
The patient originally noticed a lump at the 3 o'clock position in her left breast approximately 1 ½ years ago. A mammogram and ultrasound were negative at that time, and no further studies were pursued. Several months before the woman presented to us, however, the lump began to change. Another mammogram was obtained and followed by an ultrasound-guided core biopsy demonstrating adenocarcinoma of the breast. She did not have any symptoms or laboratories findings suggestive of metastatic disease.
The patient underwent lumpectomy and sentinel node biopsy 1 month later. Histology revealed a 0.8-cm grade 2 invasive ductal adenocarcinoma with negative margins. The lesion was strongly positive for estrogen and progesterone receptors (ER/PR) and negative for HER2. One of two sentinel lymph nodes was positive for microscopic involvement measuring 1.1 mm, signifying a diagnosis of T1b, pN1mi, M0 stage IIA breast cancer. The Oncotype DX recurrence score—obtained prior to knowledge about the nodal micrometastasis—was 21. With this information, the patient presented 1 month after her lumpectomy to the University of Colorado Breast Center for further management.
The patient has no other significant medical history. Her status is G2P2 with menarche at age 11, and she has ongoing, regular menses. She bore her first child at age 33 years and does not smoke or drink alcohol. Her maternal grandmother developed breast cancer at age 53.
Dr. Daniel Bowles: This case brings up the role of micrometastatic nodal involvement and Oncotype DX in the prognosis and treatment of breast cancer, two areas of significant controversy. Let's start by discussing microscopic nodal involvement.
Micrometastatic Lymph Node Disease
Dr. Bowles: What is the exact definition of micrometastatic lymph node disease in breast cancer?
Dr. Meenakshi Singh: According to the 6th edition of the American Joint Committee on Cancer (AJCC) staging manual, micrometastases are defined as tumor deposits within the lymph node greater than 0.2 mm but not larger than 2.0 mm. There must also be a stromal reaction or other evidence of metastatic activity to identify a micrometastatic lymph node to avoid confusion with ectopic glands or artifact from biopsies.
Dr. Anthony Elias: The reason we care about micrometastatic lymph node disease is because its presence changes disease stage, prognosis, and treatment choices, including further surgery. For this woman, is an axillary node dissection necessary?
Dr. Christina Finlayson: Currently, American Society of Clinical Oncology (ASCO) guidelines recommend an axillary dissection when the sentinel lymph node contains micro- or macrometastatic disease. This recommendation is based on the 20% to 35% incidence of additional nodal disease found when an axillary dissection is performed for the finding of micrometastatic disease. Although axillary dissection improves the quality of staging, there is little or no evidence regarding the impact on local recurrence or disease survival.
Predictive models are being developed to further identify patients at highest risk for additional nodal disease. The Van Zee nomogram has been widely discussed as a possible mechanism for further defining the risk of nonsentinel lymph node metastases and balancing that risk against the risks of surgery. Using the Van Zee nomogram, this patient has a 10% risk of further lymph node involvement.
Dr. Bowles: The Van Zee nomogram may not address microscopic nodal disease specifically. A recent abstract found that compared to an area under the receiver-operator curve (ROC) for macrometastatic lymph node disease of 0.724, the area under the ROC was 0.538 for microscopic nodal disease. This suggests that the nomogram is less predictive of microscopic nodal disease. However, several other studies suggest that microscopic nodal disease increases the likelihood of disease within other axillary lymph nodes.
Two studies found that 13% to 18% of women with micrometastatic lymph node disease had additional positive lymph nodes on axillary dissection, compared to 51% with macrometastatic lymph node disease. The size of the primary tumor, the size of the micrometastasis, and the presence of lymphovascular invasion increased the risk.[5,6] These studies contrast with an earlier study suggesting that only 6% of patients have positive nonsentinel lymph nodes.
While these data are somewhat disparate, a recent meta-analysis of women with micrometastatic sentinel lymph nodes found a pooled proportion of positive nonsentinel lymph nodes of 10% to 15%, depending on the detection method. It's unclear to me whether axillary lymph node dissection is necessary if several studies suggest roughly a 10% to 20% chance of having additional positive nodes.
H&E Staining vs IHC
Dr. Finlayson: It is also important to know whether the disease deposit within the sentinel node was identified on hematoxylin and eosin (H&E) stain or by cytokeratin immunohistochemistry (IHC). Deposits identified by IHC only are staged as N0(i+). The most recent ASCO guidelines do not provide specific recommendations for or against axillary dissection in this situation. However, there has been some debate about whether to screen sentinel lymph nodes with IHC instead of H&E in order to increase sensitivity. It is unclear whether increased sensitivity will change prognosis and treatment in a meaningful way.
Dr. Bowles: That is an area where the data are somewhat mixed. One recent investigation evaluated sentinel lymph nodes using H&E staining and immunostaining for cytokeratin. They found that 26% of patients have lymph node disease by H&E staining, whereas IHC identified another 4% of patients, half of which had micrometastatic disease that was retrospectively seen on H&E staining, as well. Other studies have corroborated that IHC increases the sentinel node involvement rate over H&E staining alone.[10,11]
The real issue is whether micrometastatic disease detected only by IHC portends a worse prognosis than node-negative disease or disease identified on H&E. Several small studies suggest that micrometastases detected only by IHC, and staged as pN0(i+) disease, are of little clinical significance, particularly in the context of adjuvant therapies.[12-14] These results were corroborated by a larger study of almost 700 women, which found that occult metastases identified by IHC were not associated with a worse prognosis. On the contrary, the authors of another 700-patient study concluded that the risk of positive nonsentinel nodes was increased when sentinel node micometastases were detected only by IHC, and that this justifies completion axillary node dissection. Clearly this is still an area of significant debate, although the majority of data seems to suggest that disease identified on H&E confers a worse prognosis than disease identified solely by IHC.
What is the University of Colorado Hospital Breast Center's protocol for identifying cancer within the lymph nodes?
Dr. Singh: Nodes that appear benign after touch/imprint cytology undergo permanent fixation and are stained with H&E. For ductal carcinomas, we do not perform IHC if the permanent section of the lymph node is negative by H&E. It is more difficult to distinguish between lobular carcinoma and the native lymphocytes in the sentinel lymph nodes. Therefore, lobular cancers with negative sentinel nodes by H&E will undergo cytokeratin immunostaining. If the sentinel lymph node is grossly abnormal, we perform an H&E stain on fresh frozen samples taken during surgery and submit the remainder of the node for permanent fixation. We feel this maximizes our ability to diagnose clinically important disease in the axilla and is in line with current guidelines.
Axillary Dissection and Radiotherapy
Dr. Rachel Rabinovitch: I agree that standard therapy would be to perform a completion axillary dissection in order to (1) achieve tumor control in the axilla and (2) improve our understanding of the patient's axillary disease burden, staging, and risk of occult systemic disease. Knowing which patients have significant axillary disease and may benefit from an axillary dissection is important because completion axillary node dissection can result in the most chronic and life-affecting toxicities of breast cancer therapy. Another option for this patient would be axillary irradiation. If identification of further axillary disease would not affect systemic therapy recommendations, it's difficult to argue against offering axillary radiotherapy as an option.
In general, no axillary radiotherapy would be needed after a level I/II axillary dissection. We have reasonably good evidence that radiation to the level I and II nodes in a clinically negative axilla is an effective modality to prevent progression in the axillary tissue, even with a positive pathologic sentinel node.[17,18] Two studies have demonstrated equivalent survival in patients randomized to axillary dissection vs axillary radiotherapy, with only a 3% axillary failure rate at 15 years in the radiotherapy group. Unfortunately, there are no data addressing our specific patient's scenario—the efficacy of axillary radiotherapy when a micrometastatic sentinel node has been identified. I would postulate that the likelihood of residual disease is the same or even smaller in our patient than in a patient whose sentinel node status is unknown, and would therefore feel that radiotherapy is certainly a reasonable treatment option.
Prognosis and Additional Treatment Options
Dr. Alexander Urquhart: I think microscopic nodal disease does provide some important prognostic information. It tells me that there is a population of cells within the tumor that has the ability to metastasize locally and spread distantly. The degree of risk for distant metastasis is still being determined and was a driving force to include N1mi and N0(i+) in the staging criteria. Retrospective analyses suggest that prognosis is a continuum, with microscopic nodal disease leading to a risk of distant recurrence somewhere in between node-negative and macroscopic nodal involvement.[19,20]
Dr. Virginia Borges: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial attempted to definitively answer the role of microscopic nodal disease and completion axillary dissection after sentinel node biopsy confirmation. Unfortunately, it closed without meeting its target accrual. Further axillary dissection would not likely alter my treatment recommendations, as I lean toward treating a situation like this with a regimen typical for node-positive breast cancer, especially given her young age and excellent health.
Dr. Elias: When counseling patients on the importance of further axillary surgery, an important consideration is whether it would make a difference in other therapies such as radiation therapy or the choice of chemotherapy.
For example, radiation therapy might be changed if she had chosen a mastectomy. There is controversy about postmastectomy radiation when one to three axillary lymph nodes are positive. Two randomized control trials support its use, although neither is from the United States.[21,22] These studies have been discounted by some investigators, in part because of the limited amount of surgery performed. On the other hand, less axillary surgery is performed now and those studies are closer to real life. However, I do not believe that there is consensus to irradiate the chest wall postmastectomy for N1mi disease. If the patient received a mastectomy and had a 2.5-cm tumor with lymphovascular invasion, would the presence of N1mi push you to recommend postmastectomy radiation therapy?
Dr. Rabinovitch: This is a controversial area with not enough available data. Randomized controlled trials of limited nodal disease suggest that even one positive lymph node increases the risk of locoregional recurrence—and that the risk of locoregional failure increases with increasing nodal disease. Prevention of locoregional recurrence translates into improvement in survival. Unfortunately, there's no breakdown in the published trials about the subgroup of patients with only one positive lymph node, let alone micrometastatic involvment in a single lymph node.
I would definitely consider offering postmastectomy radiation therapy to a premenopausal woman with lymphovascular invasion and a solitary micrometastatic lymph node, being frank that the benefit is likely to be small and the evidence supporting this approach is not available. We need to remember that the survival of women with chest wall recurrence is ultimately dismal.
What about the 0.8-cm tumor?
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