Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
To Do or Not to Do: Axillary Nodal Evaluation after ACOSOG Z0011 Trial1 Kathryn L. Humphrey, MD Mansi A. Saksena, MD Phoebe E. Freer, MD Barbara L. Smith, MD, PhD Elizabeth A. Rafferty, MD
After completing this journal-based SACME activity, participants will be able to: ■■Identify abnormal axillary lymph nodes in patients with invasive breast cancer.
Methods of axillary evaluation in invasive breast cancer continue to evolve. The recent American College of Surgeons Oncology Group Z0011 Trial is a prospective, randomized, multicenter trial that compared the survival and locoregional recurrence rates after complete axillary lymph node dissection (ALND) versus sentinel node biopsy (SNB) alone in women with a positive sentinel node in an effort to avoid the complications associated with ALND. As the results of this trial are implemented clinically, affecting surgical management of axillary metastatic disease, radiologists may need to redefine their role in the preoperative assessment of the axilla. Before the Z0011 trial, breast imagers worked to identify axillary metastases preoperatively, allowing appropriate patients to proceed directly to ALND and avoiding the need for SNB. However, the Z0011 trial concluded that ALND may not be necessary in women with metastatic axillary disease who meet the trial criteria. In the Z0011 trial, after 6 years of median follow-up there was no difference in either locoregional recurrence or survival among the women who underwent SNB alone compared with those who underwent ALND, suggesting that ALND is unnecessary in a subset of women with a positive node at SNB. These results raise questions about how aggressively radiologists should pursue percutaneous sampling of axillary nodes, as some practitioners conclude that, in an otherwise eligible woman, positive results from imaging-guided percutaneous biopsy preclude a Z0011 trial–directed pathway. Debate about the best way to implement the results of the Z0011 trial into daily clinical practice exists. It is important for breast imagers to work closely with breast surgeons to provide the most appropriate treatment course for each patient.
■■Describe
©
Abbreviations: ACOSOG = American College of Surgeons Oncology Group, ALND = axillary lymph node dissection RadioGraphics 2014; 34:1807–1816 Published online 10.1148/rg.347130141 Content Code: From the Division of Breast Imaging, Department of Radiology (K.L.H., M.A.S., P.E.F., E.A.R.), and Department of Surgical Oncology (B.L.S.), Massachusetts General Hospital, 55 Fruit St, Wang ACC 2, Boston, MA 02114. Recipient of a Cum Laude award for an education exhibit at the 2012 RSNA Annual Meeting. Received May 21, 2013; revision requested August 9 and received March 30, 2014; final version accepted June 11. For this journal-based SA-CME activity, the author E.A.R. has provided a disclosure (see page 1815); all other authors, the editor, and the reviewers have disclosed no relevant relationships. Address correspondence to M.A.S. (e-mail: [email protected]). 1
SA-CME LEARNING OBJECTIVES
various techniques for axillary lymph node sampling. the impact of the ACOSOG Z0011 trial on the management of metastatic axillary disease in patients with invasive breast cancer.
RSNA, 2014 • radiographics.rsna.org
■■Discuss
See www.rsna.org/education/search/RG.
Introduction
Evaluation of the axillary lymph nodes remains an integral part of breast cancer management, influencing the stage, treatment plan, and overall prognosis (1). However, the various methods for assessing and treating the axilla have evolved over the years. As early as the 1500s, breast cancer was treated with radical mastectomy, including removal of the breast parenchyma, pectoralis musculature, and axillary lymph nodes (2). Over the past 3–4 decades, modified radical mastectomies and breast conservation procedures have become standard. However, dissection of the axillary lymph nodes, with its associated morbidity, remained a key component of breast cancer surgery until the 1990s (3). With the goal of providing more customized therapy and achieving lower morbidity, sentinel node biopsy was introduced into the
BREAST IMAGING
1807
1808 November-December 2014
radiographics.rsna.org
Figure 1. US features of metastatic axillary nodes. (a) US image shows a metastatic axillary node with a thickened cortex (arrow). Calipers measure 10 mm. (b) US image shows a metastatic axillary node with an abnormal round shape (calipers) and loss of the fatty hilum. (c) US image shows an abnormal focal bulge in the cortex (arrow) of a metastatic axillary node. (d) US image shows a loss of fatty hilum (arrow) in a metastatic axillary node. (e) US image shows a normal axillary node (arrow) with a thin cortex (1.5 mm [calipers]) and a prominent fatty hilum.
treatment algorithm. In their large-scale study, Veronesi and colleagues (4) showed that patients with negative findings from sentinel lymph node biopsy who did not undergo complete axillary dissection had an improved quality of life, with no ill effects on eventual disease outcome compared with those who underwent complete dissection. In 2005, an expert panel from the American Society of Clinical Oncology published guidelines recommending sentinel node biopsy as an initial alternative to axillary lymph node dissection (ALND) in patients with early-stage breast cancer and advocating that only women with positive findings in the sentinel nodes undergo complete dissection (5). However, the recently published American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that complete ALND offers no additional benefit in select women with stage T1 or T2 primary tumors with only one or two positive lymph nodes at the time of sentinel node biopsy, further changing the clinical paradigms for breast cancer treatment (6). As radiologists have played a crucial role in the preoperative evaluation of the axilla, it is imperative that breast imagers understand how this role may evolve as the Z0011 trial algorithm is adopted. In this article, we highlight the current approaches for preoperative imaging of the axilla, summarize the results of the Z0011 trial, and discuss how these results can be best integrated into daily practice.
Role of Radiologist before Z0011 Trial
As sentinel node biopsy became accepted as the standard of care for axillary evaluation in the setting of invasive breast cancer with a clinically negative axilla, preoperative imaging assessment of the ipsilateral axilla became more common (7). Preoperative identification of metastatic disease in a nonpalpable axillary lymph node with ultrasonography (US) and imaging-guided sampling eliminated the need for sentinel node biopsy and allowed patients to directly proceed to axillary node dissection (7). In addition, it helped reduce the rate of false-negative results from sentinel lymph node biopsy (8). The average false-negative rate for sentinel node biopsy is approximately 8.4%. Nodes that are completely replaced by tumor and unable to take up the sulfur colloid account for some of these false-negative results (5). Preoperative evalu-
RG • Volume 34 Number 7
Humphrey et al 1809
Figure 2. Metastatic disease in a 52-year-old woman who presented with a palpable lump in the upper outer quadrant of the right breast. (a) Mediolateral mammogram shows a focal asymmetry in the superior right breast (bottom arrow) and a prominent axillary lymph node in the right axilla (top arrow). (b) Craniocaudal mammogram of the right breast shows a focal asymmetry (arrow) in the outer breast. (c) US image of the upper outer right breast shows a 3.0-cm irregular hypoechoic mass (arrow), which was found to be invasive ductal carcinoma at biopsy. (d) US image of the right axilla shows a suspicious lymph node (arrow) with cortical thickening and loss of the fatty hilum. Core biopsy results of the lymph node confirmed the presence of metastatic disease. ALND was performed at the time of mastectomy.
ation could potentially help identify a deep nonpalpable—yet significant—axillary tumor burden that may lead to false-negative sentinel node biopsy results (9). Finally, early identification of metastatic disease in the axilla allowed earlier, more candid discussions between clinicians and patients regarding treatment options and prognosis.
Imaging Evaluation of the Axilla
US is the most studied and reliable imaging modality for evaluating the axilla in women with newly diagnosed breast cancer. However, it remains difficult to confidently distinguish between a benign, reactive lymph node and one
that is involved with metastatic disease. One systematic review of the literature found the sensitivity of US to be 49%–87% for depicting nonpalpable metastatic lymph nodes when based on size and 26%–76% when based on morphologic criteria (10). Specificity was 55%–97% when based on size and 88%–98% when based on morphologic characteristics (10). Imaging characteristics that have been used to predict metastatic disease with varying degrees of success include a cortical thickness greater than 2.5–3.0 mm, focal cortical lobulation, loss of the fatty hilum, a round shape, and abnormal peripheral blood flow (Figs 1–3) (9,11,12).
1810 November-December 2014
radiographics.rsna.org
Figure 3. Metastatic disease in a 52-year-old woman who presented with a palpable lump in the upper outer quadrant of the right breast. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms of the right breast show an irregular mass with spiculated margins (arrow) at the 10-o’clock position. (c) US image of the upper outer region of the right breast shows a 2.5-cm irregular hypoechoic mass (arrow), which was proved to be invasive ductal carcinoma. (d) US image of the right axilla shows a lymph node with subtle cortical thickening and a focal cortical bulge (arrow). Results from core biopsy of the lymph node confirmed the presence of metastatic disease, and neoadjuvant chemotherapy was begun.
Figure 4. US images show the subtle in (a) and out (b) motion of a 25-gauge needle (arrow) during fine-needle aspiration of a positive axillary node.
RG • Volume 34 Number 7
Humphrey et al 1811
Figure 5. Use of a no-throw device during imaging-guided biopsy of the abnormal lymph node seen in Figure 3d. (a) US image shows an area of increased cortical thickness, which measured approximately 5 mm. (b) US image shows the open bowl (arrow) traversing the lymph node before deployment. (c) US image shows the closed bowl (arrow) after deployment of the device.
Figure 6. Use of an automatic throw device during imaging-guided lymph node core biopsy. (a) US image shows the prefire position (arrow) just within the cortex of the lymph node. (b) US image shows the postfire position (arrow) through the length of the cortex.
Percutaneous Sampling Techniques
When US of the axilla depicts an axillary lymph node that is suspicious for metastatic disease, it may be sampled with US-guided fine-needle aspiration or core-needle biopsy (13). To perform fine-needle aspiration, a 21- or 25-gauge needle is quickly and repeatedly moved in and out of the cortex of the most suspicious-appearing lymph node with or without gentle suction and with US guidance (Fig 4). At our institution, the sample is then prepared on a slide by the cytopathologist, who assesses its adequacy with a microscope, allowing for further sampling if necessary, a process that often allows immediate diagnosis. Fine-needle aspiration sampling is quick, well-tolerated, and associated with minimal morbidity (14). It has sensitivity and specificity of approximately 75% and 100%, respectively (13). In contrast, core biopsy of axillary nodes provides a larger sample, has higher sensitivity, and
does not require the use of a specialized cytopathologist (13,14). Core biopsy can be performed with either a semiautomatic “no-throw” device or an automatic “throw” device. With a no-throw device and US guidance, an open bowl is advanced through the lymph node, and a cutting cannula is then released over the open bowl (Fig 5). While it is being deployed, the tip of the device does not advance past its initial, visualized location, allowing more precise control of the needle track and decreasing the chance of vascular or neurologic injury (14,15). With a throw device, the bowl and cutting cannula of the biopsy needle are fired in rapid succession (Fig 6). This sampling method produces core samples of excellent quality but requires careful assessment of the needle trajectory during sampling. Ideally, use of a throw device should be reserved for lymph nodes that are located low in the axilla and far from dominant vascular or neurologic structures.
1812 November-December 2014
Z0011 Trial
Currently, treatment of limited metastatic disease in the axilla is changing as the results of the Z0011 trial are being adopted into clinical practice. Radiologists must understand these changes and how they influence their role in the preoperative evaluation of the axilla. The Z0011 trial was designed and initiated by the ACOSOG in the late 1990s as a prospective, randomized, multicenter trial to compare the survival and locoregional recurrence rates in women with positive results from sentinel node biopsy who underwent complete ALND with those who underwent sentinel node biopsy without complete dissection (6,16). The study included a total of 856 women undergoing lumpectomy for clinical stage T1 or T2, N0, M0 breast cancer who were found to have one or two positive sentinel nodes at the time of lumpectomy. Pertinent exclusion criteria included those who were undergoing mastectomy, those who were undergoing neoadjuvant systemic therapy, those with positive lumpectomy margins, those with clinically positive axillary disease, those with three or more positive sentinel lymph nodes, those with gross extranodal extension, and those with matted lymph nodes. The 856 women were then randomized to one of two groups: complete ALND or no further axillary surgery. ALND consisted of level I and II dissection and removal of at least 10 lymph nodes. Almost 95% of patients (equal numbers in both treatment arms) underwent adjuvant chemotherapy, and all participants underwent whole-breast radiation therapy, with none undergoing a specific third field of axillary radiation therapy. However, it is recognized that most level I nodes and some level II nodes receive tangential field radiation during whole-breast radiation therapy. The median follow-up time was 6.3 years (6,16). Of the 856 participating women, 420 were randomized to the sentinel node biopsy plus complete ALND group, with 388 undergoing ALND, and 436 were randomized to the sentinel node biopsy–only group, with 425 undergoing only sentinel node biopsy (6,16). Twentyseven percent of the patients who underwent complete ALND had additional positive lymph nodes at the time of completion dissection, and it can be assumed that a similar number of patients in the sentinel node biopsy–only group had residual axillary disease. The overall rate of locoregional recurrence was 3.4%. Within the group treated with complete ALND, fifteen (3.6%) had an in-breast recurrence, and two (0.5%) had a recurrence in the ipsilateral axilla. Of those who were treated with sentinel node biopsy alone, eight (1.8%) had a local recurrence,
radiographics.rsna.org
and four (0.9%) had a regional recurrence in the ipsilateral axilla (6,16). No significant difference was found in locoregional control between the two treatment groups and overall survival, and recurrence-free survival was equivalent between the groups (6,16). Given the assumption that an equal number of patients in the sentinel node biopsy–only group had residual axillary disease, it can be postulated that not all residual metastatic disease in the axilla becomes clinically significant or that current approaches to adjuvant systemic and radiation therapy provide adequate locoregional control. The ability to achieve comparable levels of locoregional control while avoiding the additional morbidity associated with axillary dissection makes sentinel lymph node biopsy alone an attractive option for identifying limited metastatic disease within the axilla and should spur adoption of the algorithm in appropriate candidates.
Clinical Implications
The results of the Z0011 trial are increasingly being incorporated into clinical practice, and in August 2011 the American Society of Breast Surgeons published a position statement regarding the management of axillary disease in women with invasive breast cancer. The statement proposes that ALND may no longer be routinely required for patients with a stage T1 or T2 tumor and one or two positive sentinel lymph nodes with no extracapsular extension. Patients must also accept and complete wholebreast radiation therapy without extended fields of therapy and accept and complete adjuvant chemotherapy (hormonal, cytotoxic, or both). As these results are applied to clinical practice, it is important to emphasize that not all patients meet the eligibility criteria for the Z0011 approach; ineligible women include those with stage T3 tumors, clinically positive lymph nodes, three or more positive sentinel lymph nodes, or gross extranodal tumor extension and those who are undergoing mastectomy, neoadjuvant chemotherapy, or partial-breast radiation therapy (17). In a survey of the American Society of Breast Surgeons that was conducted out of the University of Texas MD Anderson Cancer Center, 56.9% of respondents reported that they would “infrequently or never” perform complete axillary dissection on a woman with a positive sentinel node who meets all of the inclusion criteria for the Z0011 trial (18). When looking at the evolving practice patterns at MD Anderson Cancer Center before and after the Z0011 trial, investigators found that among women with positive sentinel nodes who met the inclusion criteria for the trial, 85% underwent complete
RG • Volume 34 Number 7
axillary dissection before the trial was published compared with only 24% after publication (19). As surgeons integrate the results of the Z0011 trial into their clinical practice, breast imagers must follow suit. Imagers should continue to evaluate the axilla in most patients with a suspicious breast lesion at the time of the diagnostic workup. The additional information gleaned from evaluation of the axilla may provide surgeons with knowledge of a clinically occult, grossly abnormal lymph node, an entity that has clinical relevance, may influence treatment, and allows accurate preoperative discussions with patients (20). In addition, at the time of the diagnostic workup, it is not always clear which women will remain candidates for the Z0011 trial–directed pathway, even if they initially appear to meet criteria based on tumor size and clinical manifestation. Patients who choose to undergo mastectomy or partial-breast radiation therapy no longer meet inclusion criteria and will benefit from preoperative percutaneous sampling of a US-detected abnormal lymph node. Once such treatment decisions have been made, if the surgeon is aware of the status of the axilla at US, imaging-guided sampling may prevent unnecessary sentinel node biopsy. Furthermore, for women who undergo neoadjuvant chemotherapy, pretreatment US of the axilla may depict a lymph node that could be percutaneously sampled before beginning chemotherapy, thereby avoiding the need for pretreatment sentinel node biopsy. Pretreatment sampling results in the most accurate evaluation of nodal status and allows clinicians to monitor the treatment response of potential metastases (21). Finally, continuing to image the axilla with advanced techniques and technology may eventually lead to improved sensitivity and specificity of imaging, eliminating the need for surgical evaluation of the axilla altogether. Whether to proceed with US-guided percutaneous biopsy of an abnormal lymph node that was detected at US in a woman who otherwise meets the inclusion criteria for the Z0011 trial is less well-defined. Investigators from Memorial Sloan-Kettering Cancer Center detailed their new practice standards in light of the recent Z0011 trial data (22). In regard to preoperative axillary US with US-guided core biopsy, they thought that biopsy should be reserved for patients with more than two abnormal lymph nodes at imaging and that all remaining patients should undergo sentinel node biopsy in hopes of meeting Z0011 trial eligibility criteria (22). With these guidelines, a patient with a single abnormal lymph node found at US should forego percutaneous sampling and await the results of sentinel node biopsy (Fig 7). There are differences of opinion as to whether positive preoperative percutaneous lymph node biopsy
Humphrey et al 1813
results preclude a potential Z0011 trial–directed treatment course in an otherwise eligible woman. In a recent review published in the Journal of the American Medical Association (JAMA), the authors stated that complete ALND is indicated in patients who present with palpable or needle biopsy–proved axillary metastases (23), and a review from the Mayo Clinic advised that patients with preoperative biopsy-proved axillary disease undergo complete ALND (24). Even within the authors’ clinical practice, there are various interpretations of the Z0011 trial data. Some surgeons believe that preoperative identification of a single nonpalpable positive axillary lymph node precludes a potential Z0011 trial–directed treatment course and commits patients to complete axillary node dissection. Thus, these surgeons prefer that preoperative axillary sampling be reserved for women who do not meet Z0011 trial eligibility criteria (based on tumor size or treatment plan) or who have a significant axillary tumor burden at US. According to this philosophy, sampling of a single axillary lymph node with minimal abnormality should be avoided in favor of sentinel node biopsy to preserve Z0011 trial eligibility. Conversely, other surgeons elect to proceed with sentinel node biopsy to establish Z0011 trial eligibility even in the setting of positive preoperative lymph node biopsy results and prefer to have as much preoperative information as possible (Fig 8). Although some ambiguity in the implementation of Z0011 trial guidelines remains, it is crucial that radiologists work collaboratively with breast surgeons and maintain ongoing open communication to allow the most appropriate treatment course for each patient. The results of the Z0011 trial are provocative and practice-changing, and they shed new light on the significance of residual axillary disease in women with early-stage breast cancer. Future efforts should be focused on improving the sensitivity and specificity of imaging in hopes of gathering accurate information about the status of the axilla and potentially reducing the need for sentinel lymph node biopsy. In their series of 988 women undergoing definitive breast surgery and surgical axillary evaluation, Hieken et al (20) found that two-thirds of the women with a stage T1 or T2 tumor and positive percutaneous lymph node biopsy results, in addition to multiple suspicious lymph nodes at the time of axillary US, were found to have more than two positive lymph nodes at the time of sentinel node biopsy, a finding that excluded them from a potential Z0011 trial–directed treatment course. The authors suggested that while these patients may fit the remaining criteria for the Z0011 trial, the preoperative US findings should eliminate their inclusion
1814 November-December 2014
radiographics.rsna.org
Figure 7. Invasive ductal carcinoma in a 50-year-old woman with a focal asymmetry in the right breast who was called back after undergoing screening imaging. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms of the right breast show a focal asymmetry (arrow) in the right breast. (c) US image shows an irregular hypoechoic mass (arrow) at the 2-o’clock position that was proved to be invasive ductal carcinoma at core biopsy. (d) US image of the right axilla shows a lymph node (arrow) with a borderline enlarged hypoechoic cortex measuring 2.7 mm (calipers). No preoperative sampling was performed; however, at the time of surgery, one sentinel lymph node was found to contain metastatic disease. The patient did not undergo complete ALND because she met all of the inclusion criteria for the Z0011 trial. She is expected to have the same outcome as if she had undergone complete ALND.
and direct them straight to complete dissection (20). Continued innovative research will ensure that breast imagers continue to play an integral role in the clinical evaluation of patients with newly diagnosed breast cancer.
Conclusions
In the setting of invasive breast cancer, US of the axilla helps determine whether metastatic disease is present with moderate accuracy that is improved with the use of imaging-guided percutaneous sampling. However, as the results of the Z0011
trial are implemented and change the surgical approach to the axilla, breast imagers should simultaneously evaluate their current imaging practices. Arguably, US assessment of the axilla is reasonable in all patients with highly suspicious lesions. However, the decision to preoperatively biopsy the axilla has become less straightforward. Women with suspicious nodes who are not eligible for Z0011 trial–directed treatment or those with obvious, bulky axillary nodal disease burden should undergo sampling before surgery to streamline their surgical management, allowing them to pro-
RG • Volume 34 Number 7
Humphrey et al 1815
Figure 8. Metastatic carcinoma in a 43-year-old woman with a focal asymmetry in the left breast who was called back after undergoing screening imaging. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms show an irregular mass (arrow) in the upper outer area of the left breast. (c) US image shows an irregular hypoechoic mass (arrow) at the 2-o’clock position, which was proved to be invasive ductal carcinoma at biopsy. (d) US image of the axilla shows a clinically occult lymph node with focal cortical thickening and lobulation (arrow). This patient presented before publication of the Z0011 trial data and underwent core biopsy of the lymph node, which ultimately revealed metastatic carcinoma. She then directly underwent complete ALND at the time of surgery, given the positive axillary biopsy finding. However, in the post-Z0011 trial era, this patient may have proved eligible for Z0011 trial–directed treatment at the time of sentinel node biopsy if the preoperative biopsy had been avoided, thereby eliminating axillary dissection. Alternatively, other surgeons may now go forward with sentinel node biopsy, even in light of positive preoperative biopsy findings, in an attempt to prove Z0011 trial eligibility.
ceed directly to axillary dissection. On the other hand, the presence of a single, mildly abnormalappearing lymph node at biopsy in a woman who is otherwise eligible for the Z0011 trial treatment algorithm may have significant treatment implications and should be a multidisciplinary decision.
Disclosures of Conflicts of Interest.—E.A.R.: Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: research grant to Massachusetts General Hospital for the investigation of breast tomosynthesis. Other activities: disclosed no relevant relationships.
1816 November-December 2014
References 1. Fisher B, Bauer M, Wickerham DL, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer: an NSABP update. Cancer 1983;52(9):1551–1557. 2. Sakorafas GH. The origins of radical mastectomy. AORN J 2008;88(4):605–608. 3. Sakorafas GH, Safioleas M. Breast cancer surgery: an historical narrative—Part III—from the sunset of the 19th to the dawn of the 21st century. Eur J Cancer Care (Engl) 2010;19(2):145–166. 4. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349(6):546–553. 5. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005;23(30): 7703–7720. 6. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010;252(3):426–432; discussion 432–433. 7. Rattay T, Muttalib M, Khalifa E, Duncan A, Parker SJ. Clinical utility of routine pre-operative axillary ultrasound and fine needle aspiration cytology in patient selection for sentinel lymph node biopsy. Breast 2012;21(2):210–214. 8. Sato K, Tamaki K, Tsuda H, et al. Utility of axillary ultrasound examination to select breast cancer patients suited for optimal sentinel node biopsy. Am J Surg 2004;187(6):679–683. 9. Cho N, Moon WK, Han W, Park IA, Cho J, Noh DY. Preoperative sonographic classification of axillary lymph nodes in patients with breast cancer: node-to-node correlation with surgical histology and sentinel node biopsy results. AJR Am J Roentgenol 2009;193(6):1731–1737. 10. Alvarez S, Añorbe E, Alcorta P, López F, Alonso I, Cortés J. Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review. AJR Am J Roentgenol 2006;186 (5):1342–1348. 11. Bedi DG, Krishnamurthy R, Krishnamurthy S, et al. Cortical morphologic features of axillary lymph nodes as a predictor of metastasis in breast cancer: in vitro sonographic study. AJR Am J Roentgenol 2008;191(3):646–652. 12. Yang WT, Chang J, Metreweli C. Patients with breast cancer: differences in color Doppler flow and grayscale US features of benign and malignant axillary lymph nodes. Radiology 2000;215(2): 568–573.
radiographics.rsna.org 13. Rao R, Lilley L, Andrews V, Radford L, Ulissey M. Axillary staging by percutaneous biopsy: sensitivity of fine-needle aspiration versus core needle biopsy. Ann Surg Oncol 2009;16(5):1170–1175. 14. Abe H, Schmidt RA, Kulkarni K, Sennett CA, Mueller JS, Newstead GM. Axillary lymph nodes suspicious for breast cancer metastasis: sampling with US-guided 14-gauge core-needle biopsy—clinical experience in 100 patients. Radiology 2009;250 (1):41–49. 15. Abe H, Schmidt RASC, Sennett CA, Shimauchi A, Newstead GM. US-guided core needle biopsy of axillary lymph nodes in patients with breast cancer: why and how to do it. RadioGraphics 2007;27 (suppl 1):S91–S99. 16. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305(6): 569–575. 17. The American Society of Breast Surgeons. Position statement on management of the axilla in patients with invasive breast cancer. https://www.breastsur geons.org/statements/PDF_Statements/Axillary _Management.pdf. Published 2011. Accessed February 20, 2013. 18. Gainer SM, Hunt KK, Beitsch P, Caudle AS, Mittendorf EA, Lucci A. Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: a survey of the American Society of Breast Surgeons. Ann Surg Oncol 2012;19(10):3152–3158. 19. Caudle AS, Hunt KK, Tucker SL, et al. American College of Surgeons Oncology Group (ACOSOG) Z0011: impact on surgeon practice patterns. Ann Surg Oncol 2012;19(10):3144–3151. 20. Hieken TJ, Trull BC, Boughey JC, et al. Preoperative axillary imaging with percutaneous lymph node biopsy is valuable in the contemporary management of patients with breast cancer. Surgery 2013; 154(4):831–838; discussion 838–840. 21. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinellymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 2013;14(7):609–618. 22. Cody HS 3rd, Houssami N. Axillary management in breast cancer: what’s new for 2012? Breast 2012; 21(3):411–415. 23. Rao R, Euhus D, Mayo HG, Balch C. Axillary node interventions in breast cancer: a systematic review. JAMA 2013;310(13):1385–1394. 24. Shah-Khan M, Boughey JC. Evolution of axillary nodal staging in breast cancer: clinical implications of the ACOSOG Z0011 trial. Cancer Contr 2012; 19(4):267–276.
TM
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See www.rsna.org/education/search/RG.
Teaching Points
November-December Issue 2014
To Do or Not to Do: Axillary Nodal Evaluation after ACOSOG Z0011 Trial Kathryn L. Humphrey, MD • Mansi A. Saksena, MD • Phoebe E. Freer, MD • Barbara L. Smith, MD, PhD • Elizabeth A. Rafferty, MD RadioGraphics 2014; 34:1807–1816 • Published online 10.1148/rg.347130141 • Content Code:
Page 1808 In their large-scale study, Veronesi and colleagues (4) showed that patients with negative findings from sentinel lymph node biopsy who did not undergo complete axillary dissection had an improved quality of life, with no ill effects on eventual disease outcome compared with those who underwent complete dissection. Page 1808 However, the recently published American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that complete ALND offers no additional benefit in select women with stage T1 or T2 primary tumors with only one or two positive lymph nodes at the time of sentinel node biopsy, further changing the clinical paradigms for breast cancer treatment (6). Page 1809 Imaging characteristics that have been used to predict metastatic disease with varying degrees of success include a cortical thickness greater than 2.5–3.0 mm, focal cortical lobulation, loss of the fatty hilum, a round shape, and abnormal peripheral blood flow (Figs 1–3) (9,11,12). Page 1811 In contrast, core biopsy of axillary nodes provides a larger sample, has higher sensitivity, and does not require the use of a specialized cytopathologist (13,14). Page 1812 The statement proposes that ALND may no longer be routinely required for patients with a stage T1 or T2 tumor and one or two positive sentinel lymph nodes with no extracapsular extension. Patients must also accept and complete whole-breast radiation therapy without extended fields of therapy and accept and complete adjuvant chemotherapy (hormonal, cytotoxic, or both).
To Do or Not to Do: Axillary Nodal Evaluation after ACOSOG Z0011 Trial1 Kathryn L. Humphrey, MD Mansi A. Saksena, MD Phoebe E. Freer, MD Barbara L. Smith, MD, PhD Elizabeth A. Rafferty, MD
After completing this journal-based SACME activity, participants will be able to: ■■Identify abnormal axillary lymph nodes in patients with invasive breast cancer.
Methods of axillary evaluation in invasive breast cancer continue to evolve. The recent American College of Surgeons Oncology Group Z0011 Trial is a prospective, randomized, multicenter trial that compared the survival and locoregional recurrence rates after complete axillary lymph node dissection (ALND) versus sentinel node biopsy (SNB) alone in women with a positive sentinel node in an effort to avoid the complications associated with ALND. As the results of this trial are implemented clinically, affecting surgical management of axillary metastatic disease, radiologists may need to redefine their role in the preoperative assessment of the axilla. Before the Z0011 trial, breast imagers worked to identify axillary metastases preoperatively, allowing appropriate patients to proceed directly to ALND and avoiding the need for SNB. However, the Z0011 trial concluded that ALND may not be necessary in women with metastatic axillary disease who meet the trial criteria. In the Z0011 trial, after 6 years of median follow-up there was no difference in either locoregional recurrence or survival among the women who underwent SNB alone compared with those who underwent ALND, suggesting that ALND is unnecessary in a subset of women with a positive node at SNB. These results raise questions about how aggressively radiologists should pursue percutaneous sampling of axillary nodes, as some practitioners conclude that, in an otherwise eligible woman, positive results from imaging-guided percutaneous biopsy preclude a Z0011 trial–directed pathway. Debate about the best way to implement the results of the Z0011 trial into daily clinical practice exists. It is important for breast imagers to work closely with breast surgeons to provide the most appropriate treatment course for each patient.
■■Describe
©
Abbreviations: ACOSOG = American College of Surgeons Oncology Group, ALND = axillary lymph node dissection RadioGraphics 2014; 34:1807–1816 Published online 10.1148/rg.347130141 Content Code: From the Division of Breast Imaging, Department of Radiology (K.L.H., M.A.S., P.E.F., E.A.R.), and Department of Surgical Oncology (B.L.S.), Massachusetts General Hospital, 55 Fruit St, Wang ACC 2, Boston, MA 02114. Recipient of a Cum Laude award for an education exhibit at the 2012 RSNA Annual Meeting. Received May 21, 2013; revision requested August 9 and received March 30, 2014; final version accepted June 11. For this journal-based SA-CME activity, the author E.A.R. has provided a disclosure (see page 1815); all other authors, the editor, and the reviewers have disclosed no relevant relationships. Address correspondence to M.A.S. (e-mail: [email protected]). 1
SA-CME LEARNING OBJECTIVES
various techniques for axillary lymph node sampling. the impact of the ACOSOG Z0011 trial on the management of metastatic axillary disease in patients with invasive breast cancer.
RSNA, 2014 • radiographics.rsna.org
■■Discuss
See www.rsna.org/education/search/RG.
Introduction
Evaluation of the axillary lymph nodes remains an integral part of breast cancer management, influencing the stage, treatment plan, and overall prognosis (1). However, the various methods for assessing and treating the axilla have evolved over the years. As early as the 1500s, breast cancer was treated with radical mastectomy, including removal of the breast parenchyma, pectoralis musculature, and axillary lymph nodes (2). Over the past 3–4 decades, modified radical mastectomies and breast conservation procedures have become standard. However, dissection of the axillary lymph nodes, with its associated morbidity, remained a key component of breast cancer surgery until the 1990s (3). With the goal of providing more customized therapy and achieving lower morbidity, sentinel node biopsy was introduced into the
BREAST IMAGING
1807
1808 November-December 2014
radiographics.rsna.org
Figure 1. US features of metastatic axillary nodes. (a) US image shows a metastatic axillary node with a thickened cortex (arrow). Calipers measure 10 mm. (b) US image shows a metastatic axillary node with an abnormal round shape (calipers) and loss of the fatty hilum. (c) US image shows an abnormal focal bulge in the cortex (arrow) of a metastatic axillary node. (d) US image shows a loss of fatty hilum (arrow) in a metastatic axillary node. (e) US image shows a normal axillary node (arrow) with a thin cortex (1.5 mm [calipers]) and a prominent fatty hilum.
treatment algorithm. In their large-scale study, Veronesi and colleagues (4) showed that patients with negative findings from sentinel lymph node biopsy who did not undergo complete axillary dissection had an improved quality of life, with no ill effects on eventual disease outcome compared with those who underwent complete dissection. In 2005, an expert panel from the American Society of Clinical Oncology published guidelines recommending sentinel node biopsy as an initial alternative to axillary lymph node dissection (ALND) in patients with early-stage breast cancer and advocating that only women with positive findings in the sentinel nodes undergo complete dissection (5). However, the recently published American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that complete ALND offers no additional benefit in select women with stage T1 or T2 primary tumors with only one or two positive lymph nodes at the time of sentinel node biopsy, further changing the clinical paradigms for breast cancer treatment (6). As radiologists have played a crucial role in the preoperative evaluation of the axilla, it is imperative that breast imagers understand how this role may evolve as the Z0011 trial algorithm is adopted. In this article, we highlight the current approaches for preoperative imaging of the axilla, summarize the results of the Z0011 trial, and discuss how these results can be best integrated into daily practice.
Role of Radiologist before Z0011 Trial
As sentinel node biopsy became accepted as the standard of care for axillary evaluation in the setting of invasive breast cancer with a clinically negative axilla, preoperative imaging assessment of the ipsilateral axilla became more common (7). Preoperative identification of metastatic disease in a nonpalpable axillary lymph node with ultrasonography (US) and imaging-guided sampling eliminated the need for sentinel node biopsy and allowed patients to directly proceed to axillary node dissection (7). In addition, it helped reduce the rate of false-negative results from sentinel lymph node biopsy (8). The average false-negative rate for sentinel node biopsy is approximately 8.4%. Nodes that are completely replaced by tumor and unable to take up the sulfur colloid account for some of these false-negative results (5). Preoperative evalu-
RG • Volume 34 Number 7
Humphrey et al 1809
Figure 2. Metastatic disease in a 52-year-old woman who presented with a palpable lump in the upper outer quadrant of the right breast. (a) Mediolateral mammogram shows a focal asymmetry in the superior right breast (bottom arrow) and a prominent axillary lymph node in the right axilla (top arrow). (b) Craniocaudal mammogram of the right breast shows a focal asymmetry (arrow) in the outer breast. (c) US image of the upper outer right breast shows a 3.0-cm irregular hypoechoic mass (arrow), which was found to be invasive ductal carcinoma at biopsy. (d) US image of the right axilla shows a suspicious lymph node (arrow) with cortical thickening and loss of the fatty hilum. Core biopsy results of the lymph node confirmed the presence of metastatic disease. ALND was performed at the time of mastectomy.
ation could potentially help identify a deep nonpalpable—yet significant—axillary tumor burden that may lead to false-negative sentinel node biopsy results (9). Finally, early identification of metastatic disease in the axilla allowed earlier, more candid discussions between clinicians and patients regarding treatment options and prognosis.
Imaging Evaluation of the Axilla
US is the most studied and reliable imaging modality for evaluating the axilla in women with newly diagnosed breast cancer. However, it remains difficult to confidently distinguish between a benign, reactive lymph node and one
that is involved with metastatic disease. One systematic review of the literature found the sensitivity of US to be 49%–87% for depicting nonpalpable metastatic lymph nodes when based on size and 26%–76% when based on morphologic criteria (10). Specificity was 55%–97% when based on size and 88%–98% when based on morphologic characteristics (10). Imaging characteristics that have been used to predict metastatic disease with varying degrees of success include a cortical thickness greater than 2.5–3.0 mm, focal cortical lobulation, loss of the fatty hilum, a round shape, and abnormal peripheral blood flow (Figs 1–3) (9,11,12).
1810 November-December 2014
radiographics.rsna.org
Figure 3. Metastatic disease in a 52-year-old woman who presented with a palpable lump in the upper outer quadrant of the right breast. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms of the right breast show an irregular mass with spiculated margins (arrow) at the 10-o’clock position. (c) US image of the upper outer region of the right breast shows a 2.5-cm irregular hypoechoic mass (arrow), which was proved to be invasive ductal carcinoma. (d) US image of the right axilla shows a lymph node with subtle cortical thickening and a focal cortical bulge (arrow). Results from core biopsy of the lymph node confirmed the presence of metastatic disease, and neoadjuvant chemotherapy was begun.
Figure 4. US images show the subtle in (a) and out (b) motion of a 25-gauge needle (arrow) during fine-needle aspiration of a positive axillary node.
RG • Volume 34 Number 7
Humphrey et al 1811
Figure 5. Use of a no-throw device during imaging-guided biopsy of the abnormal lymph node seen in Figure 3d. (a) US image shows an area of increased cortical thickness, which measured approximately 5 mm. (b) US image shows the open bowl (arrow) traversing the lymph node before deployment. (c) US image shows the closed bowl (arrow) after deployment of the device.
Figure 6. Use of an automatic throw device during imaging-guided lymph node core biopsy. (a) US image shows the prefire position (arrow) just within the cortex of the lymph node. (b) US image shows the postfire position (arrow) through the length of the cortex.
Percutaneous Sampling Techniques
When US of the axilla depicts an axillary lymph node that is suspicious for metastatic disease, it may be sampled with US-guided fine-needle aspiration or core-needle biopsy (13). To perform fine-needle aspiration, a 21- or 25-gauge needle is quickly and repeatedly moved in and out of the cortex of the most suspicious-appearing lymph node with or without gentle suction and with US guidance (Fig 4). At our institution, the sample is then prepared on a slide by the cytopathologist, who assesses its adequacy with a microscope, allowing for further sampling if necessary, a process that often allows immediate diagnosis. Fine-needle aspiration sampling is quick, well-tolerated, and associated with minimal morbidity (14). It has sensitivity and specificity of approximately 75% and 100%, respectively (13). In contrast, core biopsy of axillary nodes provides a larger sample, has higher sensitivity, and
does not require the use of a specialized cytopathologist (13,14). Core biopsy can be performed with either a semiautomatic “no-throw” device or an automatic “throw” device. With a no-throw device and US guidance, an open bowl is advanced through the lymph node, and a cutting cannula is then released over the open bowl (Fig 5). While it is being deployed, the tip of the device does not advance past its initial, visualized location, allowing more precise control of the needle track and decreasing the chance of vascular or neurologic injury (14,15). With a throw device, the bowl and cutting cannula of the biopsy needle are fired in rapid succession (Fig 6). This sampling method produces core samples of excellent quality but requires careful assessment of the needle trajectory during sampling. Ideally, use of a throw device should be reserved for lymph nodes that are located low in the axilla and far from dominant vascular or neurologic structures.
1812 November-December 2014
Z0011 Trial
Currently, treatment of limited metastatic disease in the axilla is changing as the results of the Z0011 trial are being adopted into clinical practice. Radiologists must understand these changes and how they influence their role in the preoperative evaluation of the axilla. The Z0011 trial was designed and initiated by the ACOSOG in the late 1990s as a prospective, randomized, multicenter trial to compare the survival and locoregional recurrence rates in women with positive results from sentinel node biopsy who underwent complete ALND with those who underwent sentinel node biopsy without complete dissection (6,16). The study included a total of 856 women undergoing lumpectomy for clinical stage T1 or T2, N0, M0 breast cancer who were found to have one or two positive sentinel nodes at the time of lumpectomy. Pertinent exclusion criteria included those who were undergoing mastectomy, those who were undergoing neoadjuvant systemic therapy, those with positive lumpectomy margins, those with clinically positive axillary disease, those with three or more positive sentinel lymph nodes, those with gross extranodal extension, and those with matted lymph nodes. The 856 women were then randomized to one of two groups: complete ALND or no further axillary surgery. ALND consisted of level I and II dissection and removal of at least 10 lymph nodes. Almost 95% of patients (equal numbers in both treatment arms) underwent adjuvant chemotherapy, and all participants underwent whole-breast radiation therapy, with none undergoing a specific third field of axillary radiation therapy. However, it is recognized that most level I nodes and some level II nodes receive tangential field radiation during whole-breast radiation therapy. The median follow-up time was 6.3 years (6,16). Of the 856 participating women, 420 were randomized to the sentinel node biopsy plus complete ALND group, with 388 undergoing ALND, and 436 were randomized to the sentinel node biopsy–only group, with 425 undergoing only sentinel node biopsy (6,16). Twentyseven percent of the patients who underwent complete ALND had additional positive lymph nodes at the time of completion dissection, and it can be assumed that a similar number of patients in the sentinel node biopsy–only group had residual axillary disease. The overall rate of locoregional recurrence was 3.4%. Within the group treated with complete ALND, fifteen (3.6%) had an in-breast recurrence, and two (0.5%) had a recurrence in the ipsilateral axilla. Of those who were treated with sentinel node biopsy alone, eight (1.8%) had a local recurrence,
radiographics.rsna.org
and four (0.9%) had a regional recurrence in the ipsilateral axilla (6,16). No significant difference was found in locoregional control between the two treatment groups and overall survival, and recurrence-free survival was equivalent between the groups (6,16). Given the assumption that an equal number of patients in the sentinel node biopsy–only group had residual axillary disease, it can be postulated that not all residual metastatic disease in the axilla becomes clinically significant or that current approaches to adjuvant systemic and radiation therapy provide adequate locoregional control. The ability to achieve comparable levels of locoregional control while avoiding the additional morbidity associated with axillary dissection makes sentinel lymph node biopsy alone an attractive option for identifying limited metastatic disease within the axilla and should spur adoption of the algorithm in appropriate candidates.
Clinical Implications
The results of the Z0011 trial are increasingly being incorporated into clinical practice, and in August 2011 the American Society of Breast Surgeons published a position statement regarding the management of axillary disease in women with invasive breast cancer. The statement proposes that ALND may no longer be routinely required for patients with a stage T1 or T2 tumor and one or two positive sentinel lymph nodes with no extracapsular extension. Patients must also accept and complete wholebreast radiation therapy without extended fields of therapy and accept and complete adjuvant chemotherapy (hormonal, cytotoxic, or both). As these results are applied to clinical practice, it is important to emphasize that not all patients meet the eligibility criteria for the Z0011 approach; ineligible women include those with stage T3 tumors, clinically positive lymph nodes, three or more positive sentinel lymph nodes, or gross extranodal tumor extension and those who are undergoing mastectomy, neoadjuvant chemotherapy, or partial-breast radiation therapy (17). In a survey of the American Society of Breast Surgeons that was conducted out of the University of Texas MD Anderson Cancer Center, 56.9% of respondents reported that they would “infrequently or never” perform complete axillary dissection on a woman with a positive sentinel node who meets all of the inclusion criteria for the Z0011 trial (18). When looking at the evolving practice patterns at MD Anderson Cancer Center before and after the Z0011 trial, investigators found that among women with positive sentinel nodes who met the inclusion criteria for the trial, 85% underwent complete
RG • Volume 34 Number 7
axillary dissection before the trial was published compared with only 24% after publication (19). As surgeons integrate the results of the Z0011 trial into their clinical practice, breast imagers must follow suit. Imagers should continue to evaluate the axilla in most patients with a suspicious breast lesion at the time of the diagnostic workup. The additional information gleaned from evaluation of the axilla may provide surgeons with knowledge of a clinically occult, grossly abnormal lymph node, an entity that has clinical relevance, may influence treatment, and allows accurate preoperative discussions with patients (20). In addition, at the time of the diagnostic workup, it is not always clear which women will remain candidates for the Z0011 trial–directed pathway, even if they initially appear to meet criteria based on tumor size and clinical manifestation. Patients who choose to undergo mastectomy or partial-breast radiation therapy no longer meet inclusion criteria and will benefit from preoperative percutaneous sampling of a US-detected abnormal lymph node. Once such treatment decisions have been made, if the surgeon is aware of the status of the axilla at US, imaging-guided sampling may prevent unnecessary sentinel node biopsy. Furthermore, for women who undergo neoadjuvant chemotherapy, pretreatment US of the axilla may depict a lymph node that could be percutaneously sampled before beginning chemotherapy, thereby avoiding the need for pretreatment sentinel node biopsy. Pretreatment sampling results in the most accurate evaluation of nodal status and allows clinicians to monitor the treatment response of potential metastases (21). Finally, continuing to image the axilla with advanced techniques and technology may eventually lead to improved sensitivity and specificity of imaging, eliminating the need for surgical evaluation of the axilla altogether. Whether to proceed with US-guided percutaneous biopsy of an abnormal lymph node that was detected at US in a woman who otherwise meets the inclusion criteria for the Z0011 trial is less well-defined. Investigators from Memorial Sloan-Kettering Cancer Center detailed their new practice standards in light of the recent Z0011 trial data (22). In regard to preoperative axillary US with US-guided core biopsy, they thought that biopsy should be reserved for patients with more than two abnormal lymph nodes at imaging and that all remaining patients should undergo sentinel node biopsy in hopes of meeting Z0011 trial eligibility criteria (22). With these guidelines, a patient with a single abnormal lymph node found at US should forego percutaneous sampling and await the results of sentinel node biopsy (Fig 7). There are differences of opinion as to whether positive preoperative percutaneous lymph node biopsy
Humphrey et al 1813
results preclude a potential Z0011 trial–directed treatment course in an otherwise eligible woman. In a recent review published in the Journal of the American Medical Association (JAMA), the authors stated that complete ALND is indicated in patients who present with palpable or needle biopsy–proved axillary metastases (23), and a review from the Mayo Clinic advised that patients with preoperative biopsy-proved axillary disease undergo complete ALND (24). Even within the authors’ clinical practice, there are various interpretations of the Z0011 trial data. Some surgeons believe that preoperative identification of a single nonpalpable positive axillary lymph node precludes a potential Z0011 trial–directed treatment course and commits patients to complete axillary node dissection. Thus, these surgeons prefer that preoperative axillary sampling be reserved for women who do not meet Z0011 trial eligibility criteria (based on tumor size or treatment plan) or who have a significant axillary tumor burden at US. According to this philosophy, sampling of a single axillary lymph node with minimal abnormality should be avoided in favor of sentinel node biopsy to preserve Z0011 trial eligibility. Conversely, other surgeons elect to proceed with sentinel node biopsy to establish Z0011 trial eligibility even in the setting of positive preoperative lymph node biopsy results and prefer to have as much preoperative information as possible (Fig 8). Although some ambiguity in the implementation of Z0011 trial guidelines remains, it is crucial that radiologists work collaboratively with breast surgeons and maintain ongoing open communication to allow the most appropriate treatment course for each patient. The results of the Z0011 trial are provocative and practice-changing, and they shed new light on the significance of residual axillary disease in women with early-stage breast cancer. Future efforts should be focused on improving the sensitivity and specificity of imaging in hopes of gathering accurate information about the status of the axilla and potentially reducing the need for sentinel lymph node biopsy. In their series of 988 women undergoing definitive breast surgery and surgical axillary evaluation, Hieken et al (20) found that two-thirds of the women with a stage T1 or T2 tumor and positive percutaneous lymph node biopsy results, in addition to multiple suspicious lymph nodes at the time of axillary US, were found to have more than two positive lymph nodes at the time of sentinel node biopsy, a finding that excluded them from a potential Z0011 trial–directed treatment course. The authors suggested that while these patients may fit the remaining criteria for the Z0011 trial, the preoperative US findings should eliminate their inclusion
1814 November-December 2014
radiographics.rsna.org
Figure 7. Invasive ductal carcinoma in a 50-year-old woman with a focal asymmetry in the right breast who was called back after undergoing screening imaging. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms of the right breast show a focal asymmetry (arrow) in the right breast. (c) US image shows an irregular hypoechoic mass (arrow) at the 2-o’clock position that was proved to be invasive ductal carcinoma at core biopsy. (d) US image of the right axilla shows a lymph node (arrow) with a borderline enlarged hypoechoic cortex measuring 2.7 mm (calipers). No preoperative sampling was performed; however, at the time of surgery, one sentinel lymph node was found to contain metastatic disease. The patient did not undergo complete ALND because she met all of the inclusion criteria for the Z0011 trial. She is expected to have the same outcome as if she had undergone complete ALND.
and direct them straight to complete dissection (20). Continued innovative research will ensure that breast imagers continue to play an integral role in the clinical evaluation of patients with newly diagnosed breast cancer.
Conclusions
In the setting of invasive breast cancer, US of the axilla helps determine whether metastatic disease is present with moderate accuracy that is improved with the use of imaging-guided percutaneous sampling. However, as the results of the Z0011
trial are implemented and change the surgical approach to the axilla, breast imagers should simultaneously evaluate their current imaging practices. Arguably, US assessment of the axilla is reasonable in all patients with highly suspicious lesions. However, the decision to preoperatively biopsy the axilla has become less straightforward. Women with suspicious nodes who are not eligible for Z0011 trial–directed treatment or those with obvious, bulky axillary nodal disease burden should undergo sampling before surgery to streamline their surgical management, allowing them to pro-
RG • Volume 34 Number 7
Humphrey et al 1815
Figure 8. Metastatic carcinoma in a 43-year-old woman with a focal asymmetry in the left breast who was called back after undergoing screening imaging. (a, b) Mediolateral oblique (a) and craniocaudal (b) mammograms show an irregular mass (arrow) in the upper outer area of the left breast. (c) US image shows an irregular hypoechoic mass (arrow) at the 2-o’clock position, which was proved to be invasive ductal carcinoma at biopsy. (d) US image of the axilla shows a clinically occult lymph node with focal cortical thickening and lobulation (arrow). This patient presented before publication of the Z0011 trial data and underwent core biopsy of the lymph node, which ultimately revealed metastatic carcinoma. She then directly underwent complete ALND at the time of surgery, given the positive axillary biopsy finding. However, in the post-Z0011 trial era, this patient may have proved eligible for Z0011 trial–directed treatment at the time of sentinel node biopsy if the preoperative biopsy had been avoided, thereby eliminating axillary dissection. Alternatively, other surgeons may now go forward with sentinel node biopsy, even in light of positive preoperative biopsy findings, in an attempt to prove Z0011 trial eligibility.
ceed directly to axillary dissection. On the other hand, the presence of a single, mildly abnormalappearing lymph node at biopsy in a woman who is otherwise eligible for the Z0011 trial treatment algorithm may have significant treatment implications and should be a multidisciplinary decision.
Disclosures of Conflicts of Interest.—E.A.R.: Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: research grant to Massachusetts General Hospital for the investigation of breast tomosynthesis. Other activities: disclosed no relevant relationships.
1816 November-December 2014
References 1. Fisher B, Bauer M, Wickerham DL, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer: an NSABP update. Cancer 1983;52(9):1551–1557. 2. Sakorafas GH. The origins of radical mastectomy. AORN J 2008;88(4):605–608. 3. Sakorafas GH, Safioleas M. Breast cancer surgery: an historical narrative—Part III—from the sunset of the 19th to the dawn of the 21st century. Eur J Cancer Care (Engl) 2010;19(2):145–166. 4. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349(6):546–553. 5. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005;23(30): 7703–7720. 6. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010;252(3):426–432; discussion 432–433. 7. Rattay T, Muttalib M, Khalifa E, Duncan A, Parker SJ. Clinical utility of routine pre-operative axillary ultrasound and fine needle aspiration cytology in patient selection for sentinel lymph node biopsy. Breast 2012;21(2):210–214. 8. Sato K, Tamaki K, Tsuda H, et al. Utility of axillary ultrasound examination to select breast cancer patients suited for optimal sentinel node biopsy. Am J Surg 2004;187(6):679–683. 9. Cho N, Moon WK, Han W, Park IA, Cho J, Noh DY. Preoperative sonographic classification of axillary lymph nodes in patients with breast cancer: node-to-node correlation with surgical histology and sentinel node biopsy results. AJR Am J Roentgenol 2009;193(6):1731–1737. 10. Alvarez S, Añorbe E, Alcorta P, López F, Alonso I, Cortés J. Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review. AJR Am J Roentgenol 2006;186 (5):1342–1348. 11. Bedi DG, Krishnamurthy R, Krishnamurthy S, et al. Cortical morphologic features of axillary lymph nodes as a predictor of metastasis in breast cancer: in vitro sonographic study. AJR Am J Roentgenol 2008;191(3):646–652. 12. Yang WT, Chang J, Metreweli C. Patients with breast cancer: differences in color Doppler flow and grayscale US features of benign and malignant axillary lymph nodes. Radiology 2000;215(2): 568–573.
radiographics.rsna.org 13. Rao R, Lilley L, Andrews V, Radford L, Ulissey M. Axillary staging by percutaneous biopsy: sensitivity of fine-needle aspiration versus core needle biopsy. Ann Surg Oncol 2009;16(5):1170–1175. 14. Abe H, Schmidt RA, Kulkarni K, Sennett CA, Mueller JS, Newstead GM. Axillary lymph nodes suspicious for breast cancer metastasis: sampling with US-guided 14-gauge core-needle biopsy—clinical experience in 100 patients. Radiology 2009;250 (1):41–49. 15. Abe H, Schmidt RASC, Sennett CA, Shimauchi A, Newstead GM. US-guided core needle biopsy of axillary lymph nodes in patients with breast cancer: why and how to do it. RadioGraphics 2007;27 (suppl 1):S91–S99. 16. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305(6): 569–575. 17. The American Society of Breast Surgeons. Position statement on management of the axilla in patients with invasive breast cancer. https://www.breastsur geons.org/statements/PDF_Statements/Axillary _Management.pdf. Published 2011. Accessed February 20, 2013. 18. Gainer SM, Hunt KK, Beitsch P, Caudle AS, Mittendorf EA, Lucci A. Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: a survey of the American Society of Breast Surgeons. Ann Surg Oncol 2012;19(10):3152–3158. 19. Caudle AS, Hunt KK, Tucker SL, et al. American College of Surgeons Oncology Group (ACOSOG) Z0011: impact on surgeon practice patterns. Ann Surg Oncol 2012;19(10):3144–3151. 20. Hieken TJ, Trull BC, Boughey JC, et al. Preoperative axillary imaging with percutaneous lymph node biopsy is valuable in the contemporary management of patients with breast cancer. Surgery 2013; 154(4):831–838; discussion 838–840. 21. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinellymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 2013;14(7):609–618. 22. Cody HS 3rd, Houssami N. Axillary management in breast cancer: what’s new for 2012? Breast 2012; 21(3):411–415. 23. Rao R, Euhus D, Mayo HG, Balch C. Axillary node interventions in breast cancer: a systematic review. JAMA 2013;310(13):1385–1394. 24. Shah-Khan M, Boughey JC. Evolution of axillary nodal staging in breast cancer: clinical implications of the ACOSOG Z0011 trial. Cancer Contr 2012; 19(4):267–276.
TM
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See www.rsna.org/education/search/RG.
Teaching Points
November-December Issue 2014
To Do or Not to Do: Axillary Nodal Evaluation after ACOSOG Z0011 Trial Kathryn L. Humphrey, MD • Mansi A. Saksena, MD • Phoebe E. Freer, MD • Barbara L. Smith, MD, PhD • Elizabeth A. Rafferty, MD RadioGraphics 2014; 34:1807–1816 • Published online 10.1148/rg.347130141 • Content Code:
Page 1808 In their large-scale study, Veronesi and colleagues (4) showed that patients with negative findings from sentinel lymph node biopsy who did not undergo complete axillary dissection had an improved quality of life, with no ill effects on eventual disease outcome compared with those who underwent complete dissection. Page 1808 However, the recently published American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that complete ALND offers no additional benefit in select women with stage T1 or T2 primary tumors with only one or two positive lymph nodes at the time of sentinel node biopsy, further changing the clinical paradigms for breast cancer treatment (6). Page 1809 Imaging characteristics that have been used to predict metastatic disease with varying degrees of success include a cortical thickness greater than 2.5–3.0 mm, focal cortical lobulation, loss of the fatty hilum, a round shape, and abnormal peripheral blood flow (Figs 1–3) (9,11,12). Page 1811 In contrast, core biopsy of axillary nodes provides a larger sample, has higher sensitivity, and does not require the use of a specialized cytopathologist (13,14). Page 1812 The statement proposes that ALND may no longer be routinely required for patients with a stage T1 or T2 tumor and one or two positive sentinel lymph nodes with no extracapsular extension. Patients must also accept and complete whole-breast radiation therapy without extended fields of therapy and accept and complete adjuvant chemotherapy (hormonal, cytotoxic, or both).
