Owen H Wangensteen, Jerome A Urban, and the pursuit of extraaxillary lymph node metastases from breast cancer

HISTORY

Owen H Wangensteen, Jerome A Urban, and the Pursuit of Extraaxillary Lymph Node Metastases from Breast Cancer Todd M Tuttle, MD, FACS In 1894, William Stewart Halsted1 and Willy Meyer2 described the radical mastectomy as a single en bloc operation to remove the breast, pectoralis muscles, and axillary lymph nodes. Radical mastectomy became the primary treatment for breast cancer for three-quarters of a century. But, after World War II, many clinicians became disappointed with the results of radical mastectomy because women continued to die from breast cancer. At that time, surgeons were already performing more radical operations for other malignancies, including pancreatic, hepatic, and gastric cancer.3 In 1950, at the annual meeting of the American Surgical Association, Owen H Wangensteen4 suggested that similar approaches should be used for the treatment of breast cancer: “Today, it should be said, I believe, the Halsted operation for cancer of the breast is outmoded: it is not radical enough.” Wangensteen, at the University of Minnesota, and Jerome A Urban, at Memorial Hospital in New York, argued that conventional radical mastectomy was an incomplete operation because extraaxillary lymph node metastases were not removed. They recognized that some breast cancer patients developed recurrent tumor in the supraclavicular and internal mammary lymph node basins after radical mastectomy. So Wangensteen performed “super-radical” mastectomies and Urban performed “extended-radical” mastectomies to treat extraaxillary lymph node metastases. Clinical trials later found that those operations did not improve breast cancer survival, so they were eventually abandoned. But the practice today of sentinel lymph node (SLN) biopsy has renewed interest in detecting extraaxillary lymph node metastases in breast cancer. Recent changes in the breast cancer staging system reflect the pioneering work of

Wangensteen and Urban. These two men made important contributions that are still significant to the modern treatment of breast cancer. Before Wangensteen and Urban

The rationale for removing extraaxillary lymph nodes was established decades before Wangensteen and Urban. In 1898 Halsted5 was the first surgeon to suggest removing internal mammary lymph nodes: “We shall, in the near future, remove the mediastinal contents at some of our primary operations.” In the same article, Halsted described a series of 53 patients treated with radical mastectomy combined with supraclavicular lymph node dissection; 23% of them had metastases in supraclavicular lymph nodes. Halsted wrote, “Our rule should be, operate on the neck in every case.” In 1927, WS Handley,6 of the Middlesex Hospital, reported that internal mammary lymph nodes often contain breast cancer metastases; he advocated placement of radium tubes in the intercostal spaces. Twentytwo years later, in 1949, his son, Richard Handley, and AC Thackray described 50 consecutive patients who underwent mastectomy plus removal of ipsilateral internal mammary lymph nodes through the second intercostal space; 38% of them had internal mammary lymph node metastases.7 Beginning in 1948, Mario Margottini,8 of Rome, routinely removed internal mammary lymph nodes. Andreassen and Dahl-Iversen,9 from Copenhagen, reported that dissection of supraclavicular lymph nodes yielded metastases in 17% of breast cancer patients. In that same year, Robert McWhirter,10 of Edinburgh, advocated simple mastectomy, followed by radiation therapy to the internal mammary lymph nodes. In the early 1950s, radiation therapy was not widely used in the United States, and effective chemotherapy was not yet available. The most useful cancer-fighting tool was the scalpel. Although Wangensteen’s and Urban’s approaches were slightly different, each believed that extraaxillary lymph node metastases should be surgically removed. Wangensteen’s operation was more ex-

Received March 11, 2004; Revised April 2, 2004; Accepted April 6, 2004. From the Division of Surgical Oncology, University of Minnesota, Minneapolis, MN. Correspondence address: Todd M Tuttle, MD, FACS, Division of Surgical Oncology, University of Minnesota, Mayo Mail Code 195, Minneapolis, MN 55455.

© 2004 by the American College of Surgeons Published by Elsevier Inc.

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I have felt on occasion, and I suspect many of you have felt similarly in attacking cancerous lymph nodes extending up along the axillary vessels to the point where the vessels pass over the first rib, much like a hunting dog must feel when he is chasing a pheasant and the pheasant flies over a fence. The surgeon has the alternative, of course, of taking the fence down.11

Figure 1. Owen H Wangensteen (Courtesy University of Minnesota Archives).

tensive and treated the supraclavicular, internal mammary, and mediastinal lymph nodes. Urban performed a more “Halsted-like” en bloc resection of the internal mammary lymph nodes in continuity with conventional radical mastectomy; he omitted supraclavicular lymph node dissection. Owen H Wangensteen

Born and raised on a farm in northwestern Minnesota, Wangensteen spent his entire professional life at the University of Minnesota (Fig. 1). His clinical and research interests included intestinal obstruction, appendicitis, peptic ulcer disease, and “second-look” operations for cancer. He was also interested in breast cancer and believed that the current treatment was inadequate. At the American Surgical Association meeting in 1949, he publicly described his disappointment with conventional radical mastectomy in terms of his background in rural Minnesota:

Wangensteen believed that the internal mammary and supraclavicular lymph nodes were important sites of metastases that could not be ignored. He hypothesized that some patients had extraaxillary lymph node metastases without systemic metastases. He reasoned that selected breast cancer patients might benefit from removal of supraclavicular and internal mammary lymph nodes combined with conventional radical mastectomy. For Wangensteen, the clavicle and sternum represented anatomic barriers to a more complete operation; superradical mastectomy was his method of “taking the fence down.” His first such operation was in November 1948. He described the findings of his first five patients at the meeting of the American Surgical Association in April 1949.11 Wangensteen initially advocated a two-stage operation (Fig. 2). In stage 1, the conventional radical mastectomy was performed through the usual elliptical incision.12 If the axillary lymph nodes were involved, then super-radical mastectomy was performed. A segment of the first rib was routinely resected. The wound was then closed with either primary sutures or a split-thickness skin graft, depending on the extent of the local skin excision. In stage 2, performed 4 to 6 weeks later, Wangensteen created a separate incision that extended from the level of the thyroid cartilage down to the sternum, ending at the fourth intercostal space. The sternocleidomastoid muscle was detached at its lower insertion to facilitate the supraclavicular dissection. The strap muscles were divided at their lower attachments. The carotid sheath was dissected and the omohyoid muscle divided. The supraclavicular lymph node dissection started at the level of the upper border of the thyroid cartilage and extended to the mediastinum. The sternum was cut longitudinally from the jugular notch to the fourth intercostal space and then cut transversely at the fourth intercostal space. The clavicle and half of the manubrium were then retracted laterally to expose the subclavicular

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Figure 2. Super-radical mastectomy: stage 1 (left), stage 2 (right). (From: Wangensteen, Lewis, Arhelger. The extended or super-radical mastectomy for carcinoma of the breast. Surg Clin North Am 1956;36:1051–1063, with permission.)

area. The brachial plexus and the subclavian vessels were dissected and all lymphatic tissue was removed. Next, the divided sternum was retracted, exposing the tissues of the anterior mediastinum (Fig. 3). The internal mammary vessels and associated lymph node chains were removed from the origin of the vessels in the neck down to the fifth intercostal space. The adjacent pleura

Figure 3. Super-radical mastectomy. AA, ascending aorta; LCCA, left common carotid artery; LIV, left innominate vein; SVC, superior vena cava (Courtesy University of Minnesota Archives).

and fat were widely excised, along with the internal mammary lymph nodes. The areolar and lymphatic tissues were dissected from the great vessels of the superior and anterior mediastinum. Finally, removal of the thymus gland completed the dissection. The sternum was closed with interrupted stainless-steel wire, and the skin was closed with interrupted silk sutures. The operation was performed as four dissections yielding four lymph node specimens: breast and axillary lymph nodes; internal mammary lymph nodes; upper mediastinal lymph nodes, including the thymus and lymph nodes adjacent to innominate veins; and supraclavicular lymph nodes, including all lymphatic tissue inferior to the omohyoid muscle, plus lymph nodes adjacent to the internal jugular vein and the confluence of the jugular, subclavian, and innominate veins. Wangensteen did not recommend super-radical mastectomy for all breast cancer patients. With few exceptions, the operation was performed only for patients with medial tumors or with known axillary lymph node metastases. In a series of 64 patients with advanced breast cancer, Wangensteen and colleagues12 reported that 36 (58%) patients had extraaxillary lymph node metastases. In that series, the location of the tumor

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Table 1. Incidence of Extraaxillary Lymph Node Metastases12 Extraaxillary lymph node basin

Internal mammary* only Internal mammary* plus supraclavicular† Supraclavicular only Overall

Metastases (%)

25 27 6 58

*“Internal mammary” includes both internal mammary and deeper mediastinal lymph nodes. † “Supraclavicular” includes both supraclavicular and cervical lymph nodes.

within the breast influenced the prevalence of extraaxillary lymph node metastasis. Of 11 tumors in the medial part of the breast, 7 (64%) had internal mammary lymph node metastasis; of 36 tumors in the lateral part of the breast, only 14 (39%) had internal mammary lymph node metastasis. Regardless of tumor location, internal mammary lymph node metastases were more common than supraclavicular metastases (Table 1). Unfortunately, super-radical mastectomy resulted in significant morbidity and a higher mortality rate than conventional radical mastectomy did. In Wangensteen’s first 64 patients, 8 died, resulting in an operative mortality rate of 12.5%. (Later, he recommended a one-stage procedure.13) In that first series of 64 patients, the actual 5-year survival rate was only 17%; only 3 patients were alive with no evidence of disease 5 years after surgery. Of course, patients undergoing super-radical mastectomy were a select group with advanced breast cancer and a poor prognosis. In 1956, only 6 years after his bold declaration at the American Surgical Association, Wangensteen described his experience with super-radical mastectomy as “disappointing.” Wangensteen hypothesized that the recurrence rates after super-radical mastectomy may be high because the lymph node dissections were not performed en bloc. He also predicted that if radiation therapy proved effective, then super-radical mastectomy would not be necessary. He later expressed his frustration with adjuvant therapies and emphasized the importance of complete surgical resection: “Until the promised help from other sources is near enough that evidences of such assistance can be seen or felt, I would say: let us plod on.”13

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I breast cancer died of metastatic disease, often when the primary tumor was in the medial half of the breast. In a series of 350 patients treated at Memorial Hospital from 1940 through 1944, he reported that tumor location within the medial breast was associated with a worse survival rate.14 He believed that metastases were present in the internal mammary lymph nodes that conventional surgery could not treat. One year before his first description of extended-radical mastectomy, Urban15 reported that more than 70% of all chest wall recurrences after radical mastectomy were in the parasternal region. He hypothesized that these recurrences arose from untreated metastases in the internal mammary lymph nodes. Urban designed an original operation for removing the internal mammary lymph nodes en bloc with radical mastectomy. He called the extended-radical mastectomy an “effective surgical attack upon the primary breast cancer together with both of its primary depots of lymphatic drainage.”14 He first described it at the James Ewing Society on March 7, 1952. With extended-radical mastectomy, Urban made an

Jerome A Urban

Urban had a long and productive career as a breast surgeon at Memorial Hospital in New York (Fig. 4). Like Wangensteen, he observed that some patients with stage

Figure 4. Jerome A Urban (Courtesy of Neil Selkirk Photography).

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with the knife going through the sternum about 1 cm from its ipsilateral border (Urban later modified this step of the operation and excised half the width of the sternum). This portion of the chest wall was separated by cutting through the ribs and intercostal muscles just lateral to the costal-chondral junctions of the second, third, fourth, and fifth ribs. The free portion of the chest wall with the internal mammary chain was then reflected laterally, remaining in continuity with the overlying muscle and breast. Before the dissection was complete, the chest wall defect was closed with a fascia lata graft (Fig. 6). The pleural cavity was routinely drained with an underwater drainage tube for 2 days. After closure of the chest, the operation was continued as in the classic radical mastectomy. In the final step of the operation, the opposite breast was dissected free from the pectoralis fascia and rotated toward the operative side to reinforce the chest wall repair (this step was later abandoned). Surprisingly, Urban reported no postoperative mortality and “actually very little increase in postoperative

Figure 5. Extended-radical mastectomy. The sternum-splitting incision allows en bloc resection of the chest wall and internal mammary lymph nodes. (From: Urban, JA. Radical mastectomy with en bloc resection of internal mammary lymph node chain. Surg Clin North Am 1956;36:1065–1082, with permission.)

elliptical skin incision in the manner of a conventional radical mastectomy. Skin flaps were developed medially to the opposite side of the sternum and then laterally to the outer aspect of the latissimus dorsi muscle. The pectoral muscles were dissected and the anterior surface of the sternum was cleared. The pectoralis major muscle was divided between the sternal and clavicular heads, exposing the first rib. From below, the anterior rectus muscle was divided, exposing the sixth rib. The first and fifth intercostal spaces were dissected while leaving the perforating vessels intact. Next, an incision was made through the intercostal muscles and pleura in the first intercostal space. The internal mammary vessels were transected and ligated behind the lower edge of the first rib. In a similar manner, the fifth intercostal space was entered, and the internal mammary vessels were again transected and ligated at the upper border of the sixth rib (Fig. 5). A “trap door” was fashioned in the chest wall by joining both intercostal incisions using a sternal-splitting incision,

Figure 6. Extended-radical mastectomy. The chest defect shown in Figure 5 was closed with a fascia lata graft; a chest tube was used for pleural drainage. (From: Surgery: The best hope of all. Time Magazine May 3, 1963:44 – 60, with permission.)

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Table 2. Survival after Extended-Radical Mastectomy16,17 Variable

Axillary and internal mammary lymph nodes negative Only axillary lymph nodes positive Only internal mammary lymph nodes positive Axillary and internal mammary lymph nodes positive All patients

At 5 years (n ⴝ 500), %

At 10 years (n ⴝ 315), %

87

75

68

53

64

52

54 73.4

21 55.5

morbidity” in his first 40 patients. The operation was completed in about 4 or 5 hours. The average patient required 3 pints of blood and was discharged from the hospital 8 days after surgery. Extended-radical mastectomy was performed for patients with stage I or II breast tumors located in the central or medial portion of the breast. In his series of 725 patients, Urban and Marjani16 reported that 47% had axillary nodal metastases, 33% had internal mammary nodal metastases, and 8% had isolated internal mammary nodal metastases. Tumors that were closer to the sternal margin had a greater risk of internal mammary metastases. The most common locations of internal mammary metastases (in decreasing order) were the second, third, and first intercostal spaces. Outcomes after extended-radical mastectomy are shown in Table 2.16,17 The survival of patients with isolated internal mammary metastases was similar to the survival of patients with isolated axillary nodal metastases. The prognosis was much worse if metastases were present in both internal mammary and axillary lymph nodes. The 10-year local recurrence rate was only 6%. Urban performed extended-radical mastectomy for several decades, treating about 1,000 patients. He was convinced that en bloc dissection of internal mammary lymph nodes improved patient survival. In 1976, he reported that the 10-year survival of breast cancer patients was significantly improved after extended-radical mastectomy as compared with historical controls treated with conventional radical mastectomy at Memorial Hospital (54% versus 33%).18 Urban’s extended-radical mastectomy was featured in a Time Magazine cover story highlighting seven innovative operations.19 The title of the article was “Surgery: the best hope of all.” Beginning in the 1960s, results were reported from the first of several clinical trials comparing extended-

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radical mastectomy to either conventional radical mastectomy or simple mastectomy plus radiation.20-23 Those results demonstrated that extended-radical mastectomy offered no survival benefit over conventional surgery. Undeterred, in 1977, Urban17 declared: “Extendedradical mastectomy has proven to be an effective primary treatment for patients with operable breast cancer.” Extraaxillary lymph node metastases today

After randomized clinical trials demonstrated that extended-radical mastectomy did not improve overall survival, extraaxillary lymph nodes in breast cancer patients were often ignored. But the success today of SLN biopsy has renewed interest in identifying extraaxillary lymph node metastases. SLN biopsy accurately identifies axillary lymph node metastases. At most major breast cancer treatment centers, it has now replaced routine axillary dissection. Recently, several reports demonstrated that internal mammary SLN biopsy is feasible.24-26 Galimberti and associates26 described a series of 182 patients who underwent internal mammary SLN biopsy. Internal mammary SLN biopsy was performed if lymphoscintigraphy demonstrated uptake to those nodes or if the tumor was in the medial portion of the breast. Of those 182 patients, an internal mammary SLN was identified in 160 patients; 14 (8.8%) of those 160 patients had metastases. In 4 of those 14 patients with metastases in the internal mammary SLN, the axillary nodes were negative for metastases. In the Galimberti series, the most common location of internal mammary SLN metastases was the second intercostal space, a finding that Urban reported more than 50 years ago. Lymphoscintigraphy can identify extraaxillary lymph nodes in about 10% to 15% of patients after peritumoral injection of technetium-99.27-29 But many surgeons have now replaced conventional peritumoral injections with either dermal or subareolar injections. Those alternative injection methods are accurate and easy to learn, and they result in high SLN identification rates.30-35 But technetium-99 injected into the skin or beneath the areola rarely travels to the extraaxillary lymph nodes. So surgeons who decide to identify and remove extraaxillary SLNs must use peritumoral injection. Internal mammary SLNs are identified by splitting the fibers of the pectoralis major muscle and dividing the intercostal muscles. The hand-held gamma probe then localizes the SLN. Because internal mammary SLNs can

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be removed with minimal access surgery, many surgeons now advocate that procedure. But internal mammary SLN biopsies are not risk-free; potential complications include pneumothorax, bleeding, scarring, and additional operating time. Wangensteen and Urban removed extraaxillary lymph nodes as part of an overall surgical strategy to treat local and regional disease. In contrast, internal mammary lymph SLN biopsy has been proposed as a staging tool to guide decisions regarding adjuvant therapy. Today, adjuvant systemic therapy (chemotherapy, hormonal therapy, or both) is usually recommended for patients with axillary lymph node metastases or with tumors that are at least 1 cm in diameter. So, the finding of internal mammary SLN metastases may alter the systemic treatment for patients with a negative axillary SLN and with tumors that are less than 1 cm in diameter. But the risk of isolated internal mammary lymph node metastases, in the absence of axillary node metastases, is less than 5%, so relatively few patients will benefit from the procedure. Radiation therapy to the internal mammary chain has been recommended for patients with internal mammary SLN metastases. Nevertheless, the efficacy of chest wall radiation for those patients has never been demonstrated. Currently, the exact role of extraaxillary SLN biopsy is not clear. Wangensteen and Urban recognized that survival of patients with extraaxillary lymph node metastases was poor. The new breast cancer staging system approved by the American Joint Committee on Cancer (AJCC) incorporates information on extraaxillary lymph nodes.36 The new system was officially adopted for use in tumor registries in January 2003. In the revised sixth edition of the AJCC Cancer Staging Manual, internal mammary metastases identified by SLN dissection, but not by imaging studies, are classified as pN1b in the absence of positive axillary lymph nodes; pN1c in the presence of one to three positive axillary lymph nodes; and pN3b in the presence of four or more positive axillary lymph nodes. Positive internal mammary nodes detected by physical examination or imaging studies (including CT or ultrasonography) are classified as N2b/pN2b in the absence of positive axillary nodes, and as N3b/pN3b in the presence of positive axillary lymph nodes. In the previous (fifth) edition of the AJCC Cancer Staging Manual, supraclavicular nodal metastases were classified as distant metastasis (M1) or stage IV.37 As a result, patients were considered incurable and were usu-

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ally given palliative therapy. A recent study by Brito and colleagues38 challenged that approach. They treated 70 patients with supraclavicular metastases with preoperative chemotherapy, surgery, postoperative chemotherapy, and radiation. Overall survival rate at 5 years was 41%, at 10 years, 31%. The prognosis was similar for stage IIIB cancer without distant metastases and significantly better than for stage IV. At last, the effective adjuvant therapies that Wangensteen desired are now available. The revised system now classifies metastases to the supraclavicular lymph nodes as N3c/pN3c (stage IIIC). In conclusion, modern critics unfairly dismiss the work of Wangensteen and Urban as radical assaults on women with breast cancer. Indeed, their operations caused morbidity and deformity, and did not improve overall survival. But Wangensteen and Urban recognized that many breast cancer patients had metastases in extraaxillary lymph nodes that were not treated by conventional therapy. They were the first surgeons in the United States to propose a strategy to treat these metastases. Their work should not be judged by current standards because modern therapies (sentinel lymph node biopsy, chemotherapy, radiation therapy) were not widely available in the 1950s. Although their efforts were ultimately unsuccessful, their work greatly contributed to our current understanding and management of breast cancer. Acknowledgment: I thank Mary Knatterud, PhD, for her editorial assistance. I also acknowledge editorial input from Patrick I Borgen, MD, John S Najarian, MD, and John P Delaney, MD, PhD.

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6. Handley WS. Parasternal invasion of the thorax in breast cancer and its suppression by the use of radium tubes as an operative precaution. Surg Gynec and Obstet 1927;45:721–728. 7. Handley RS, Thackray AC. The internal mammary lymph chain in carcinoma of the breast: study of 50 cases. Lancet 1949; 2:276–278. 8. Margottini M. Arguments in favor of super radical operations for cancer of the breast. Acta Unio Internat Contra Cancrum 1958;15:1037. 9. Andreassen M, Dahl-Iversen E. Recherches sur les metastases microscopiques des Ganglions lymphatiques sus-claviculaires dans le cancer du sein. J Internati Chir 1949;9:27–40. 10. McWhirter R. Treatment of cancer of breast by simple mastectomy and roentgenotherapy. Arch Surg 1949;59:830–842. 11. Wangensteen OH. Remarks on extension of the Halsted operation for cancer of the breast. Ann Surg 1949;130:315–316. 12. Wangensteen OH, Lewis FJ, Arhelger SW. The extended or super-radical mastectomy for carcinoma of the breast. Surg Clin North Am 1956;36:1051–1063. 13. Wangensteen OH. Another look at the super-radical operation for breast cancer. Surgery 1957;41:857–861. 14. Urban JA, Baker HW. Radical mastectomy in continuity with en bloc resection of the internal mammary lymph-node chain. Cancer 1952;5:992–1008. 15. Urban JA. Radical excision of the chest wall for mammary cancer. Cancer 1951;4:1263–1285. 16. Urban JA, Marjani MA. Significance of internal mammary lymph node metastases in breast cancer. Am J Roentgen 1971; 1:130–136. 17. Urban JA. Is there a rationale for an extended radical procedure? Int J Radiat Oncol Biol Phys 1977;2:985–988. 18. Urban JA. Changing patterns of breast cancer. Cancer 1976;37: 111–117. 19. Time Magazine. Surgery: The best hope of all. May 3, 1963: 44–60. 20. Kaae S, Johansen H. Five year results: two random series of simple mastectomy with postoperative irradiation versus extended radical mastectomy. Am J Roentgen 1962;87:82–88. 21. Lacour J, Le M, Caceres E, et al. Radical mastectomy versus radical mastectomy plus internal mammary dissection: ten year results of an international cooperative trial in breast cancer. Cancer 1983;51:1941–1943. 22. Veronesi U, Valagussa P. Inefficacy of internal mammary nodes dissection in breast cancer surgery. Cancer 1981;47:170–175. 23. Morimoto T, Monden Y, Takashima S, et al. Five-year results of a randomized clinical trial comparing modified radical mastectomy and extended radical mastectomy for stage II breast cancer. Surg Today 1994;24:210–214.

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24. Tanis PJ, Nieweg OE, Valdes Olmos RA, et al. Impact of nonaxillary sentinel node biopsy on staging and treatment of breast cancer patients. Br J Cancer 2002;87:705–710. 25. Dupont E, Cox CE, Nguyen K, et al. Utility of internal mammary lymph node removal when noted by intraoperative gamma probe detection. Ann Surg Oncol 2001;8:833–836. 26. Galimberti V, Veronesi P, Arnone P, et al. Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients. Ann Surg Oncol 2002;9:924–928. 27. Dupont EL, Kamath VJ, Ramnath EM, et al. The role of lymphoscintigraphy in the management of the patient with breast cancer. Ann Surg Oncol 2001;8:354–360. 28. McMasters KM, Wong SL, Tuttle TM, et al. Preoperative lymphoscintigraphy for breast cancer does not improve the ability to identify sentinel lymph nodes. Ann Surg 2000;231:724–731. 29. Carcoforo P, Basaglia E, Soliani G, et al. Sentinel node biopsy in the evaluation of the internal mammary node chain in patients with breast cancer. Tumori 2002;88:S5–7. 30. Borgstein PJ, Meijer S, Pjipers RJ. Intradermal blue dye to identify sentinel lymph node in breast cancer. Lancet 1997;349: 1668–1669. 31. McMasters KM, Wong SL, Martin RCG II, et al. Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 2001;233:676–687. 32. Klimberg V, Rubio I, Henry R, et al. Subareolar versus peritumoral injection for location of the sentinel lymph node. Ann Surg 1999;229:860–865. 33. Kern KA. Breast lymphatic mapping using subareolar injections of blue dye and radiocolloid: Illustrated technique. J Am Coll Surg 2001;192:545–550. 34. Tuttle TM, Colbert M, Christensen R, et al. Subareolar injection of technetium-99 facilitates sentinel lymph node identification. Ann Surg Oncol 2002;9:77–81. 35. Smith LF, Cross MJ, Klimberg VS. Subareolar injection is a better technique for sentinel lymph node biopsy. Am J Surg 2000;180:434–437. 36. Green FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2002. 37. Fleming ID, Cooper JS, Henson DE, et al. AJCC Cancer Staging Manual. 5th ed. Philadelphia: Lippincott-Raven; 1997. 38. Brito RA, Valero VV, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas MD Anderson Cancer Center Experience. J Clin Oncol 2001;19:628–633.