Axillary dissection: When and how radical?

Seminars in Surgical Oncology 12:321-327 (1996)

Axillary Dissection: When and How Radical?

MONICA MORROW, MD

From the Clinical Breast Programs, Northwestern University Medical School, Chicago, Illinois

Since the 1970s, axillary dissection has been regarded primarily as a staging procedure, with a secondary purpose of maintaining local control in the axilla. The widespread administration of adjuvant systemic therapy to women with breast cancer, as well as the increasingly frequent detection of very small breast cancers by mammography, has prompted an examination of the need for axillary dissection in all women with invasive breast cancer. This article reviews the rationale for eliminating axillary dissection, the incidence of nodal metastases in small and apparently favorable breast cancers, and discusses how often the findings of axillary dissection actually alter therapy in patients with clinically node-negative breast cancers. The extent of axillary dissection necessary to provide accurate staging and maintain local control is examined, and patients who will benefit from axillary dissection are identified. @ 1996 WiIey-Liss, Inc.

KEY WORDS: lymph node excision, axilla, lymph nodes, breast neoplasms, axillary sampling

INTRODUCTION Axillary dissection was initially considered a critical component of the surgical cure of breast cancer, and the enbloc resection of the axillary nodes was standard surgical practice. However, by the 1970s it was recog- nized that radical surgery failed to cure most women with node-positive breast cancer. This, coupled with the awareness that axillary node status was the primary predictor of prognosis after surgery, caused axillary dissection to be regarded as a staging, rather than a therapeutic procedure. Accurate axillary staging to direct postoperative therapy was mandated by clinical trials demonstrating a prolongation of survival for women with node-positive breast cancer treated with adjuvant chemotherapy or hormonal therapy. In the absence of reliable, noninvasive techniques for deter- mining axillary nodal status, axillary dissection has remained an important element in the management of breast carcinoma. Recently, the need for routine axillary dissection has been questioned. This re-evaluation has been prompted by the increased frequency of detection of very small breast cancers by mammography screening, the increasing use of breast-conserving treatment, the widespread use of adjuvant systemic chemotherapy and hormonal therapy for women with

node-negative breast cancer, and a greater awareness of the morbidity of axillary dissection.

RATIONALE FOR ELIMINATING AXILLARY DISSECTION

Major complications of axillary dissection are infre- quent, and include injury or thrombosis of the axillary vein and injury to the motor nerves of the axilla. Minor complications are more common, including edema of the arm and breast, loss of sensation in the distribution of the intercostobrachial nerve, shoulder dysfunction, and seroma formation. Seroma formation is the most frequent complication, and closed suction drainage is employed by most surgeons in an effort to prevent this problem.

The incidence of many other complications of axillary dissection is probably underestimated, since they are not life threatening and do not require hospitaliza- tion. Ivens et al. evaluated 106 patients at least 6 months after axillary dissection, using the patients’ untreated arm as a control [l]. Seventy percent com- plained of numbness, 300/0 had pain, and 25% noted weakness. Approximately 15% of respondents felt that

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322 Morrow

their symptoms were severe enough to interfere with daily living. Lin et al. observed similar findings in 122 patients evaluated at least 1 year after surgery [2]. Numbness in the intercostobrachial nerve distribution was present in 78%, 22% had numbness and pain, and 9% had 15' or more of restriction of shoulder motion. Hladiuk et al. prospectively assessed subjective feelings of pain and stiffness, as well as objective measures of strength and mobility, in 63 patients using pre- operative arm function as a control [3]. Overall, 42% of patients had subjective or objective impairment of arm function 1 year after surgery. Pain and reduced grip strength were the most common problems.

Lymphedema of the arm is the most commonly rec- ognized long-term sequelae of axillary dissection. The reported incidence of lymphedema varies widely, de- pending on the definition of lymphedema used, the extent of the axillary surgery, and the length of the follow-up. In Ivens' study [ 11, 38% of women reported subjective feelings of arm swelling between 2 and 4 years after surgery, and 14% had a difference in volume between the treated and untreated arm of 200 ml. In Lins' retrospective study, 16%) of patients had a 2 cm increase in arm circumference of the operated side [2]. Hladiuk et al. observed that the incidence of lymphedema increased over the 2-year follow-up period of their study, while other arm complaints stabilized or decreased over time [3]. Werner et al. reported that 19.5% of 282 patients undergoing breast conserving surgery, which included axillary dissection, developed arm edema [4]. In 21 patients (7.4%) the edema was transient, although sometimes severe. The median time to the development of edema was 14 months, but ranged from 2 to 92 months. The incidence of lymphedema in modern surgical series is not insignificant: it ranges from 10-20%, and patients remain at risk for the remainder of their lives. In addition, for the women without lymphedema, a lifetime of lymphedema precautions may impair her ability to per- form job-related functions or enjoy vigorous recrea- tional activities.

This data indicate that long-term sequelae of axillary dissection are fairly common, even in contempo- rary surgical series when conservative surgical techniques are employed. Individualizing breast cancer therapy so that axillary disscction is limited to women who are most likely to benefit from the procedure is a worthwhile goal. Two general approaches to eliminating axillary dissection have been taken: first, to identify patients whose tumors have such a low risk of nodal metastases that axillary dissection is not war- ranted; and second, to identify patients whose therapy would not be altered by axillary dissection. This article will examine each of these approaches in an attempt to

determine when axillary dissection is necessary and when it can be safely omitted. It is important to em- phasize that any discussion of eliminating axillary dissection applies only to patients without palpable ade- nopathy. In the presence of palpable axillary nodes, axillary dissection is mandatory to prevent the local complications of uncontrolled tumor growth.

IDENTIFICATION OF PATIENTS WITH A LOW RISK OF NODAL INVOLVEMENT

The incidence of axillary node metastases is related to tumor size. However, nodal metastases are present in 15-25% [5-81 of patients with tumors measuring 1 cm or less in size. Even with tumors 0.5 cm or smaller, axillary metastases are reported in 3 to 28% [5-81 of women (Table I). Silverstein et al. have suggested that the risk of axillary metastases is related to the method of tumor detection [9]. They observed a 5% incidence of axillary metastases in 80 women with mammographically detected cancers between 0.6 and 1 .O cm in size, compared to a 27% incidence of metastases for tumors in the same size range detected clinically (P = 0.002). Similar differences in the incidence of nodal metastases were seen for larger T1 as well as T2 lesions. Tumor less than 5 mm in size had a uniformly low incidence of nodal metastases which did not vary with the method of tumor detection. Walls et al. observed that only 3% of 3 I mammographically detected tumors less than 1 cm had nodal metastases [ 101. Other authors have failed to observe a relationship between the method of tumor detection and the incidence of nodal metastases. A review of patients treated at the University of Chicago found no difference in the incidence of nodal metastases by method of tumor detection, with 19% of clinically detected T1 lesions and 18% of mammographically detected T1 lesions having positive nodes [ll]. Wilhelm et al. also noted no de- crease in the incidence of axillary metastases in mammographically detected breast cancers [ 121. There are a number of possible explanations for these differing results. In Silverstein et al.'s report, significant size differences were present between the mammographically detected and the clinically detected tumors for all groups except those with tumors less than 5 mm in size [9]. In addition, the definition of tumor size across studies may not have been uniform. Size may be a measurement of only the invasive component of a tumor, or may include the intraductal component as well. In addition, patient age may differ between women undergoing screening and those whose tumors are detected clinically. Before drawing a firm conclu- sion regarding the effect of method of detection on tumor size, these issues must be addressed.

An alternative approach to identifying women at

Indications for Axillary Dissection 323

TABLE I. Axillary Node Metastases in Small Breast Cancers*

Tumors 5 1 cm Tumors 5 0.5 cm

nodal metastases are seen in fewer than 5% of patients with microinvasive tumors. However, Schuh et al. [26] and Kinne et al. 1271 reported nodal metastases in 20 and 10% of cases, respectively. The lack of a standard definition for microinvasion is probably responsible for Study Number YO Metastases Number YO Metastases

ACS [5] 1,134 25 149 28 this variation in the incidence of nodal involvement. SEER [6] 996 21 339 21 The final subset ofpatients withanextremelylow risk of

l o axillary metastases are those with pure tubular car- Van Nuys 156 17 96 3 cinomas less than 1 cm in size [28,29] NCDB [7] 26 8,037

Breast Center 181 *ACS = American College of Surgeons; SEER = Surveillance, Epidemiology and End Results Program; NCDB = National Can- cer Data Base.

low risk for nodal metastases has been to use a combination of tumor size and other pathologic characteris- tics of the primary tumor to define a low-risk group. Chadha et al. analyzed 263 clinically node negative patients with T1 carcinomas to assess the value of tumor size, histologic type, nuclear grade, lymphatic or vascular invasion (LVI), and host reaction to the tumor in predicting nodal status [13]. Multivariate analysis identified tumor size and LVI as significant variables. Of 77 patients with tumors smaller than 1 cm and without LVT, only 9% had nodal metastases. In comparison, tumors between 1 and 2 cm with LVI had a 68% incidence of nodal disease. In a similar study, Ravdin et al. analyzed data from 11,964 patients to determine if tumor size, age, S-phase fraction, receptor status, and ploidy could accurately predict nodal involvement [14]. No subset of patients with a less than 10% or greater than 75% risk of involvement was identified. The addition of epidermal growth factor receptor, HER2 neu expression, and cathepsin D to the model in 324 patients did not improve its predic- tive value. This data suggests that tumor size, whether alone or in combination with other prognostic factors, cannot reliably identify a group of breast cancers with a less than 5% risk of axillary nodal metastases.

Only three groups of breast cancer patients with an extremely low risk of axillary metastases have been identified. They are patients with ductal carcinoma in situ (DCIS), patients with microinvasive carcinoma, and patients with pure tubular carcinoma. In older studies of palpable or gross DCIS, the incidence of axillary metastases ranged from 0.9 to 3.8% [15-171. More recent reports of mammographically detected DCIS indicate nodal metastases in less than 1% ofcases (Table 11) [18-211. A review of published reports of 845 patients with DCIS identified only 1 I (1.3%) patients with axillary nodal disease. This low incidence of axillary metastases does not justify the routine use of axillary dissection. Similar data are available for microinvasive carcinoma. In the majority of reports [22-251,

IDENTIFICATION OF PATIENTS WHOSE THERAPY WILL NOT BE ALTERED BY

IDENTIFICATION OF NODAL METASTASES Women with tubular carcinoma and microinvasive

carcinomas represent a small percentage of the popu- lation with invasive breast cancer. At present, a reliable means of identifying patients outside of these groups with a very low risk of axillary metastases is not available. An alternative approach is to identify patients whose therapy would not be altered by the findings of axillary dissection (i.e., patients who would receive chemotherapy or hormonal therapy regardless of their nodal status). Based on the findings of the overview analysis [30], adjuvant systemic therapy is routinely recommended for patients with tumors measuring l cm or larger [30-321. Lin et al. retrospectively reviewed the records of 240 clinically node negative patients to determine the impact of axillary dissection on the use of adjuvant therapy [2]. Sixty-three percent of patients were considered to require adjuvant therapy on the basis of primary tumor size, receptor status, ploidy, or S-phase. Of the remaining 88 patients, 1 1 ( 1 3%) were found to have nodal metastases. Over- all, the findings at axillary dissection were the deciding factor in the recommendation for systemic therapy for only 5% of the clinically node negative patients. In addition, the likelihood of clinically node-negative women having four or more positive nodes was examined, since these high-risk patients were felt to be can- didates for chest wall radiotherapy or experimental

TABLE 11. Axillary Node Metastases in Intraductal Cancer*

Author

Ashikari et al. [I51 Westbrook and Galleger

ACS [I71 BCDDP [21] Von Reuden and Wilson

Silverstein et al. [I91 Solin et al. [20] Total

1161

[181

Year Number YO Metastases

1971 113 0.9 1975 64 I .5

1978 202 3.8 1979 212 I .o 1984 32 0

1990 136 0 1991 86 0

845 1.3Y0

*ACS = American College of Surgeons; BCDDP = Breast Cancer Detection Demonstration Project.

324 Morrow

high-dose chemotherapy. Seventeen of the 240 patients (7%) had 4 or more positive nodes, but only eight (3%) and five (2%) actually received radiotherapy or high-dose chemotherapy. This study suggests that the findings of axillary dissection are not the indication for adjuvant therapy in the majority of patients nor do they determine the type of chemotherapy which is given.

Another group of patients in whom the findings of axillary dissection are unlikely to influence therapy are elderly, postmenopausal women whose tumors are hormone receptor positive. In this patient group, tamoxifen is the treatment of choice, regardless of nodal status [30-31, 331. Even for the elderly receptor negative patient, tamoxifen has been shown to be of benefit [30], and avoidance of axillary dissection can be considered.

LOCAL CONTROL IN THE AXILLA Although axillary dissection may not be necessary

to direct the use of adjuvant therapy, it is a valuable technique for maintaining local control in the axilla. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B04 [34] demonstrated a 17.8% axillary recurrence rate if the axillary was left untreated in clinically node negative women, despite the fact 40% of women randomized to the axillary dissection arm of this trial had nodal metastases. This figure may be an underestimate, since 35% of the patients in this trial had some degree of nodal sampling. However, other studies have demonstrated isolated axillary failure rates of approximately 20-30% when the axilla is observed [35, 361.

Axillary dissection provides excellent local control for both the positive and negative axilla. In NSABP protocol B04, isolated axillary recurrence was seen in only 1.4% of node negative patients and 1% of node positive patients [34]. Haagensen noted only 2 axillary recurrences (0.25%) among 794 Columbia Stage A and B patients treated with complete axillary dissection [37]. Among patients treated with a level 1-2 dissection as part of breast-conserving treatment, axillary recurrence rates of less than 3% have been reported [38.39].

An alternative technique for maintaining local control in the clinically node negative axilla is axillary irradiation. Recht et al. observed only 3 axillary failures (0.8%) in 355 patients who did not have an axillary dissection but were irradiated with an axillary field [38]. Haffty et al. observed no differences in the rate of axillary node failures in 432 patients undergoing irradiation or dissection in a non-randomized study [40]. The actuarial rate of nodal control was 96% at 10 years for both groups. Axillary control rates of

98 to 99% at 5 years have been reported by a number of groups for patients undergoing breast conserving surgery without axillary dissection using modern radiation techniques [4 1,421. A randomized trial examin- ing the value of axillary dissection in patients undergoing breast conserving surgery has been reported [43]. Six hundred fifty-eight patients with tumors less than 3 cm in diameter and clinically negative nodes were treated by lumpectomy, axillary dissection, and breast irradiation. Patients randomized to axillary dissection received adjuvant chemotherapy if positive nodes were identified. No significant difference in the incidence of axillary failures was observed between groups. However, the 5-year survival was better in the axillary dissection group (97 vs. 93%, P = 0.01). Al- though the authors conclude that these findings justify routine axillary dissection, the selective use of adjuvant chemotherapy in the axillary dissection group makes it difficult to draw any firm conclusions.

Finally, it should be emphasized that although axillary irradiation is as effective as surgery in maintaining local control in the clinically node negative axillary, surgery is the preferred technique in the presence of gross nodal disease. In NSABP protocol B04 [34], a 12% incidence of nodal recurrence was observed after irradiation of women with clinically positive nodes, and 29% of women with positive nodes treated with irradiation in the Royal Marsden Study [42] relapsed locally.

TECHNIQUE OF AXILLARY DISSECTION It is clear that the role of axillary dissection is in

evolution. While axillary dissection can be eliminated for patients with DCIS or with DCIS and small areas of microinvasion, as well as for those with pure tubular carcinomas less than 1 cm in size, many patients continue to benefit from axillary dissection (Table 111). In women undergoing mastectomy it makes no sense to add a time-consuming and expensive course of irradiation to the treatment plan simply to avoid axillary dissection. Many patients desire the prognostic information which can only be obtained with knowledge of nodal status, and this is a valid reason for performing the procedure. To date, axillary dissection is an eligi- bility requirement for participation in clinical trials. Thus, even if axillary dissection is abandoned for a subset of women undergoing breast conserving therapy, many more women will continue to undergo the operation.

A variety of surgical procedures have been described for the removal of axillary nodes ranging from an anatomic dissection of all visible axillary fat to attempts to identify and remove individual lymph nodes. The axillary contents are divided into three


TABLE 111. Indications for Routine Axillary Dissection

Mastectomy as operative procedure Patient desire for prognostic information Therapy changed by identification of positive nodes

Tumor < 1 cm in size Tumor 1-2 cm, favorable prognostic features

Therapy changed by identification of number of positive nodes Different adjuvant therapy for node-positive and node-negative

Participation in clinical trials requiring knowledge of nodal tumors

status

levels: Level I, the nodal tissue inferior and lateral to the pectoralis minor; Level 11, the tissue posterior to the pectoralis minor and inferior the axillary vein; and Level 111, the nodes medial to the pectoralis minor against the chest wall. The Halstedian concept of axillary dissection emphasized the removal of all three levels of nodal tissue. As axillary dissection came to be regarded as a staging procedure, a number of studies were undertaken to determine the extent of axillary surgery needed to determine whether nodes were positive or negative.

One approach to this problem was to examine the incidence of “skip metastases,” that is, involvement of nodes in the upper axilla in the absence of involvement of the Level I nodes. Rosen et al. reviewed 1,228 specimens of complete axillary dissection, 429 of which contained positive nodes [44]. Isolated metastases to Level 111 were found in only 0.2% of cases. Veronesi et al., evaluating 539 specimens, found a 0.4% incidence of skip metastases to Level 111 [45]. The low incidence of isolated disease in Level 111 is not surprising since Veronesi et al. identified a mean of only 2.2 nodes per patient in Level 111. In contrast to the uniformly low incidence of skip metastases to Level 111, there is con- siderable variability in the risk of isolated nodal disease in Level 11. Danforth et al. [46] and Pigott et al. [47] reported that more than 20% of patients with axillary metastases had skip disease to Level 11, compared to less than 2% in the reports of Rosen et al. [44] and Veronesi et al. [45]. Much of this variability may be due to differences in the definition of which nodal tissue constitutes Level I and 11, and has led some authors [45] to conclude that a Level I dissection provides accurate staging information, while others be- lieve that the removal of both Levels I and I1 is re- quired [46].

The procedures described above are based on the removal of an anatomically defined volume of axillary tissue. A number of lesser, imprecisely defined sampling procedures have also been studied. Axillary “sampling” refers to the removal of some of the lower axillary contents, often without reference to anatomic structures. Kissin et al. observed a 24% error rate in

staging when sampling performed to the level of the intercostobrachial nerve was followed by a Level I and I1 dissection [48]. A mean of 4 lymph nodes was removed by sampling compared to 14 for the anatomic dissection. In contrast, Steele et al. randomized 401 patients to axillary dissection or sampling and found no significant difference in the incidence of positive nodes between the two groups [49]. In a subset of 67 patients who underwent sampling followed by dissection, the mean number of nodes recovered increased from 4.1 to 19.7, but no patient’s stage was changed. The most likely explanation for the conflict- ing results in these studies is the difference in the amount of axillary tissue removed. Large sampling procedures are very similar to Level I dissection and will accurately stage the majority of patients.

When patients undergo axillary sampling procedures, the likelihood of axillary recurrence is related to the number of nodes removed. The Danish Breast Cancer Group analyzed the relationship between the number of lymph nodes removed and the risk of axillary recurrence in 3,128 clinically node negative patients [50]. The 5-year probability of an axillary recurrence was 19Y0 in patients with no nodes examined, 10% when 1 to 2 negative nodes were removed, 5% when 3 to 4 negative nodes were removed, and 3% when more than 5 negative nodes were seen. Similar findings were noted in the mastectomy-alone arm of NSABP B04 [34] in which a 12% axillary recurrence rate was seen in patients with fewer than 5 nodes removed as compared to a 0% recurrence rate after the removal of 5 or more nodes. Thus, very limited nodal sampling runs the risk of failure to accurately stage the patient and failure to maintain local control in the axilla. As larger numbers of nodes are excised, the distinction between sampling and dissection becomes blurred. However, formal identification of the axillary vein, and the thoracodorsal and long thoracic nerves allows these structures to be protected during the surgical procedure. A Level I and I1 dissection accurately stages the patient and provides excellent local control. When grossly positive nodes are identified intraopera- tively, a Level 111 dissection is usually carried out to maximize local control. Recently, Giuliano et al. has suggested that it may be possible to identify node positive patients by the biopsy of a sentinel node, as is done in patients with melanoma [5 11. This technique accurately staged 95% of patients in his report, but a learning curve for the technique was clearly present since the sentinel node was identified in only 96 of the initial 152 cases (63%) in the series. This technique has the potential to allow axillary dissection to be limited to patients with nodal involvement who require the dissection for local control and quantification of the

326 Morrow

number of involved nodes, while sparing node-negative women the morbidity of axillary dissection. Fur- ther studies are needed to confirm these results before sentinel node biopsy replaces axillary dissection.

FUTURE DIRECTIONS The potential for eliminating axillary dissection in

some women is based on our current inability to reliably predict the biologic behavior of an individual breast carcinoma and our inability to tailor treatment strategies to the individual patient. There are several possible future scenarios. If aggressive therapies such as dose intensification or high dose chemotherapy with stem cell rescue are shown to be of benefit to women with positive axillary nodes, then routine dissection will again become necessary. Alternatively, if we become more selective in our use of adjuvant therapy for relatively low-risk node-negative women, accurate surgical staging will again be important for all women. On the other hand, if advances in molecular biology allow us to more accurately predict the biologic behavior of breast cancer, axillary node status may no longer be the major prognostic factor used to determine the need for adjuvant therapy. This state of uncertainty makes the wholesale abandonment of axillary dissection premature. However, close scrutiny of the value of axillary dissection to the individual patient is important, as are attempts to minimize the morbidity of axillary dissection.

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Axillary dissection: When and how radical?