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Should decisions on internal mammary lymph node irradiation be based on current lymphoscintigraphy techniques for sentinel lymph node identification?
Article first published online: 12 DEC 2003
Copyright © 2003 American Cancer Society
Volume 100, Issue 3, pages 518–523, 1 February 2004
How to Cite
Benda, R. K., Cendan, J. C., Copeland, E. M., Feezor, R. J., Lind, D. S., Morris, C. G. and Mendenhall, N. P. (2004), Should decisions on internal mammary lymph node irradiation be based on current lymphoscintigraphy techniques for sentinel lymph node identification?. Cancer, 100: 518–523. doi: 10.1002/cncr.11918
- Issue published online: 20 JAN 2004
- Article first published online: 12 DEC 2003
- Manuscript Accepted: 28 OCT 2003
- Manuscript Received: 17 SEP 2003
- lymph nodes;
- breast neoplasms;
Treatment of internal mammary lymph node (IMN) metastases remains controversial because of the difficulty in predicting involvement, potential treatment-related morbidity, and questionable efficacy. Lymphoscintigraphy with sentinel lymph node biopsy offers a means to identify occult involvement of IMN, allowing appropriate patient selection for IMN treatment.
The authors retrospectively reviewed 262 lymphoscintigraphies (LS) of 248 patients treated at the University of Florida (Gainesville, FL) between 1998 and 2002. Tumor characteristics were assessed for their value in predicting IMN drainage and their association with IMN radiation.
Lymph flow to the IMN was documented with LS in 23 of 262 tumor specimens (9%). Flow to the IMN was not correlated with any of the five factors: tumor location, tumor size, lymphovascular invasion, pathologic lymph node status, and laterality of the involved breast (right vs. left breast). Identification of IMN flow increased from 5.7% to 10.1% with the use of a deep injection technique. IMN radiotherapy was used more frequently in patients with larger tumors (15 of 188 in Tis/T1 vs. 31 of 70 in T2–T4; P < 0.0001) and positive lymph nodes (17 of 91 in lymph node–negative patients vs. 28 of 66 in lymph node–positive patients; P < 0.0001). In patients with T2N0 tumors (n = 32), IMN radiotherapy was used more frequently with medial tumors (5 of 11 [45%]) than with lateral tumors (4 of 21 [19%]).
The incidence of flow to the IMN documented with the current LS technique was low compared with other LS and extended radical mastectomy series. Histopathologic information was obtained for the sentinel IMN when IMN flow was identified on the LS. In the absence of histopathologic information, treatment decisions should continue to be based on clinical factors known to be correlated with occult IMN involvement. Cancer 2004. © 2003 American Cancer Society.
The first published documentation of internal mammary lymph node (IMN) evaluation dates back to 1918. Sampson Handley proposed the removal of IMN in patients with breast carcinoma, especially when disease was present in the inner quadrant of the breast. This led to the evaluation of the number and location of IMN by Philip Stibbe.1 The IMN chain is one of the primary lymphatic drainage pathways of the breast. Anatomic studies2 based on an extended radical mastectomy (ERM) series demonstrated that approximately 75% of breast lymphatic drainage is directed to the axilla and 25% to the IMN. Lymphoscintigraphy (LS) studies3 revealed IMN drainage in 28–44% of all patients with breast carcinomas with an incidence as high as 65% among patients with medial/central lesions.4
Zucali et al.5 reported a poor prognosis in patients with medial breast carcinomas. In that study, 2396 patients (1619 patients with lateral lesions and 777 patients with medial/central lesions) were treated for early-stage breast carcinoma without any surgery or radiotherapy (RT) of the IMN. A 30% increase in distant metastases (DM) accompanied by a 20% increase in the mortality rate was observed among patients with medial/central breast carcinomas. Some ERM studies showed that removal of the IMN led to a higher incidence of pathologically positive IMN in patients with medial/central tumors.2, 6–11 Patients with medial/central tumors have increased DM and decreased survival, suggesting that untreated microscopic disease in the IMN may serve as a nidus for DM.5
Several studies have failed to conclusively demonstrate a survival benefit associated with either RT12, 13 or surgery7 for treatment of IMN. A study at the University of Chicago14 (Chicago, IL) randomized patients with clinical Stage I/II disease to either radical mastectomy (RM) or ERM. Although a 14% difference in survival was observed between patients undergoing RM and those undergoing ERM (60% vs. 74%), it was not statistically significant (P = 0.13). In a subgroup analysis, the survival benefit in patients with medial/central tumors was statistically significant (60% with RM and 86% with ERM; P = 0.025). No benefit was observed in patients with lateral tumors (58% vs. 56%; P = 0.62). A large retrospective French series15 reported a significant decrease in risk of DM and death associated with treatment of IMN in patients with medial tumors. This benefit was observed regardless of whether the IMN were treated with surgery or RT.15 RT to the IMN provided the same survival advantage as an ERM with a greater local control benefit. Treatment of IMN added no benefit in patients with lateral tumors and negative axillary lymph nodes, who might be expected to have a lower risk of occult IMN involvement. Other studies showing a lack of benefit from treatment of IMN have also included patients at low risk for IMN involvement, which may have diluted potential treatment benefits.7, 12
The survival benefits achieved with postmastectomy RT in recent trials were associated with treatment of all first echelon lymph nodes, including undissected axillary lymph nodes and IMN, as well as the second echelon supraclavicular lymph nodes. Although there is some consensus among radiation oncologists that decisions regarding treatment of axillary and supraclavicular lymph nodes should be based on histopathologic information of the axillary lymph nodes identified on sentinel lymph node biopsy or axillary lymph node dissection (ALND), there is a lack of consensus on treatment for the IMN, in part because of concern about cardiovascular toxicity.16 As a result, some radiation oncologists never treat the IMN and others always do, resulting in undertreatment of patients who may benefit from treatment and overtreatment of patients who have no drainage to this lymph node basin. As we use sentinel lymph node dissection in the axilla to govern axillary management, it is reasonable to ask whether LS with sentinel lymph node biopsy can also guide the treatment of IMN.
MATERIALS AND METHODS
We retrospectively reviewed 262 LS of 248 patients who underwent treatment for breast carcinoma at the University of Florida (Gainesville, FL) between 1998 and 2002. LS was performed on the day before surgery. Initially, LS was performed using an intradermal injection of 2 millicuries (mCi) of technetium sulfur colloid. In February 2000, a two-step injection technique was initiated to improve IMN visualization. This technique called for 4 mCi of 99m-technetium sulfur colloid to be injected intradermally adjacent to the patient's biopsy scar. Sequential imaging was performed from the anterior projection with the patient in the supine position. IMN were visualized after a second deep injection of 2 mL at the site of abnormality in the breast tissue and after a 2-hour delay (Fig. 1). Twenty-three patients had IMN drainage on LS. IMN were not surgically dissected. All patients with a histologically positive axillary sentinel lymph node underwent an ALND. Five tumor characteristics were evaluated for their value in predicting IMN drainage and their association with physician decisions to treat IMN: tumor location, size, lymphovascular invasion, pathologic lymph node status, and laterality of the involved breast (right vs. left breast). Tumor location was separated into central/medial, lateral, and multicentric. Tumor size was reported as Tis, T1, T2, or T3/T4. These factors also were evaluated using the Fisher exact test, with documented lymphatic flow and irradiation of the IMN chain as endpoints. The policy was to base clinical decisions regarding regional lymph node irradiation on tumor size, grade, location, and axillary lymph node status. IMN RT was recommended for patients with positive axillary lymph nodes and/or T2 medial lesions. Patients with medial T1N0 tumors with high grade and/or lymphovascular invasion also were considered for IMN RT.
LS was performed in 262 cases for 248 consecutive patients with primary breast carcinoma. The median age of the patients was 59 years (range, 29–89 years). In 111 cases (42%), the tumor was located in the medial/central quadrant; in 131 cases (50%), the tumor was located laterally; there were 13 cases (5%) of multicentric disease; and the location of tumor was unknown in 7 cases (3%). T classification was as follows: Tis, 37 cases (14%); T1, 151 cases (58%); T2, 65 cases (25%); T3/T4, 5 cases (2%); and unknown, 4 cases (1%). Thirty-five patients (13%) had tumors with lymphovascular invasion. One hundred ninety-one tumors (73%) were N0, and 66 tumors (25%) were N1. Nodal status was unknown in 5 cases (2%). One hundred twenty-five patients (50%) had left-sided breast primaries, while 107 patients (43%) had right-sided primaries. Sixteen patients (7%) had bilateral primaries; 14 of these patients had a bilateral lymphoscintigraphy performed at the same setting.
IMN drainage was observed in 23 of 262 LS: 12 cases of lateral tumors, 9 cases of medial tumors, and 2 cases of multicentric disease (Table 1). None of the five factors (T classification, lymph node status, location of tumor, laterality of tumor, or lymphovascular invasion) were significantly associated with IMN drainage on LS (Table 2). The three factors that were associated with inclusion of the IMN in the radiation fields were tumor size (P < 0.0001), lymph node status (P < 0.0001), and lymphovascular invasion (P = 0.0011) (Table 2), reflecting the treatment policy in place during this time interval. The location of the tumor alone did not predict irradiation of the IMN fields, as all patients with lymph node–positive disease received IMN RT. Patients with lymph node–negative medial tumors received IMN RT only if the primary was T2 or T1 with other high-risk features such as high grade and/or lymphovascular invasion. Tumor location was predictive of IMN radiation in a subset of patients with T2N0 tumors, reflecting the treatment policy in place. Laterality of tumor (left vs. right breast) did not impact the decision to treat IMN with RT. In cases of medial/central lesions, IMN uptake was observed in 3 of 52 LS (6%) performed with a superficial injection alone and in 6 of 59 LS (10%) performed with the addition of a deep injection. None of seven cases of multicentric disease had IMN uptake with the superficial injection alone, compared with two of six cases with a deep injection (Table 3).
|Characteristic||IMN drainage||No IMN drainage||Total|
|Characteristic||IMN flow documented||IMN flow P value||IMN RT||IMN RT P value|
|Characteristic||No. of cases||No. with IMN uptake|
|Superficial injection only||60||5|
|Superficial injection only||52||3|
|Superficial injection only||7||0|
Our goal in treating regional lymphatics is to improve survival as achieved in the Danish and Canadian postmastectomy RT trials.17, 18 To improve survival with locoregional treatment, a patient population at moderate to high risk for DM should be selected, either because overall disease stage is early or chemotherapy is effective. Patients with minimal lymph node disease are more likely to gain a survival advantage from postmastectomy RT. To improve survival with locoregional treatment, survival should not be compromised by introducing excessive morbidity. The increased cardiac mortality reported in patients receiving postmastectomy RT16 was observed mostly in trials using older techniques of RT. We believe that this risk has been minimized, if not eliminated, with modern RT techniques. Knowledge of who would potentially benefit from IMN irradiation should have a positive impact both on assessing treatment for those who need it and minimizing RT risks for those who do not need it.
Cody and Urban19 suggested that all T1N0 patients with medial and central tumors should be considered for chemotherapy. The Danish and Canadian data17, 18 revealed a survival benefit resulting from postmastectomy RT for all patients with positive lymph nodes. A greater benefit was observed for patients with minimal disease (one to three lymph nodes). It is reasonable to assume similar benefits for patients with isolated IMN metastases. Patients with negative axillary lymph nodes and micrometastatic disease in the IMN chain may benefit most from the evaluation of the IMN. These patients would otherwise be understaged and, possibly, not offered either locoregional or systemic adjuvant therapy.
Identifying IMN metastases in patients with small primary tumors and a negative axilla may be most crucial, but should be beneficial in all patients with metastases in the IMN chain. The morbidity of ERM is substantial. Therefore, a minimally invasive procedure to evaluate the IMN is needed. Currently, LS-guided harvesting of IMN is only successful in 75–80% of patients, compared with > 90% of the axillary lymph nodes.20 Continued efforts at improving this technique are needed. In addition, a thoracoscopic approach at IMN dissection as described by Ogawa et al.21 may significantly improve our ability to stage patients and therefore ensure proper treatment. Other authors also report IMN removal as simple and safe.4, 22
Historical data on ERM and other contemporary experiences suggest a much higher IMN flow rate than the 9% detected with our technique. In the current series, the IMN identification rate was 6.7% before the addition of the deep injection and 11% in the 136 recent cases using the new injection protocol. Paganelli et al.4 reported a 65.6% identification rate in patients with medial tumors after a deep injection, compared with a rate of 2.1% after a superficial injection. Although the identification rate for medial/central tumors increased from 5.7% to 10.1% with a deep injection in our series, it remains low when compared with both LS and ERM data.4, 20, 23, 24 One factor that may affect IMN flow identification is the 2-hour interval between injection and scanning used in the current study. Carcoforo et al.23 recommended a peritumoral injection of Tc (10 megabecquerels), with scintigraphy being performed 17 hours after tracer administration. Using this method, IMN uptake was observed in 19% of patients. In 20 of 27 patients (74%), Carcoforo et al. were successful in harvesting the IMN-sentinel lymph nodes. Four of the 20 harvested IMN-sentinel lymph nodes had micrometastatic disease. None of the four patients had disease in their axillary sentinel lymph nodes. Other investigators have reported similar results.20, 22, 25 It is possible that series with a higher incidence of IMN uptake used a longer interval between injection and scanning.20, 23 In one study, knowledge of the status of IMN resulted in a change of treatment in 17% of patients.20 In this study, the nonaxillary sentinel lymph node detection rate was 27%, with IMN uptake observed in 18% and an intraoperative identification rate of IMN of 80%.
There is a wide range in the incidence of IMN uptake among studies. The dose of radioactive isotope, method of injection, interval between injection and scanning, the positions of imaging, and the number of patients with medial/central tumors vary among studies. Perhaps as this technology moves out of its infancy, we will observe similar rates of IMN flow. Because of the substantial discrepancy in IMN flow rates identified with various LS techniques, we do not believe that the absence of detected flow can be considered a reliable indicator of the absence of IMN metastases. Therefore, when IMN flow is not identified, we recommend management of the IMN based on traditional factors such as axillary lymph node status and tumor size. When IMN flow is identified at LS, a process similar to that in place with the axilla should be developed to guide the therapy. First, a minimally invasive technique should be employed to remove the sentinel lymph node for histopathologic evaluation. Second, validation of the accuracy of this technique in identifying the IMN should be established. This requires surgical removal of nonsentinel IMN for histopathologic evaluation. Only after substantial experience is acquired globally within an institution and by an individual surgeon should LS-guided IMN-sentinel lymph node biopsy be considered a reliable means for identifying patients who do need IMN irradiation.
In conclusion, LS has proven to be extremely helpful in identifying axillary sentinel lymph nodes. Sentinel lymph node biopsy is likely to revolutionize the care of patients with breast carcinoma. The breast parenchyma has dual drainage to the axilla and the IMN. Both IMN and axillary metastases are equally important prognostic factors.24 Historically, IMN recurrence rates have probably been underestimated. Many are identified incidentally when a chest tomographic scan is performed for other reasons. Others are recorded as a chest wall recurrence (parasternal) or as isolated bone metastases (sternal). With axillary lymph node staging alone, treatment failures are ultimately observed in 15–30% of lymph node-negative patients with long-term follow-up. There may be several factors associated with the high failure rates, but one possible source has been a lack of attention to a known lymph node drainage site for breast carcinoma. In the past, due to the high morbidity and absence of apparent benefit of ERM, evaluation of these lymph nodes was abandoned. Today, however, LS and sentinel lymph node biopsy may offer a means to identify patients most likely to benefit from IMN treatment.
IMN drainage was observed in only 9% of LS performed in the current series. For treatment decisions to be based on IMN LS, LS techniques must yield IMN flow rates similar to those found in historical data. Many factors may affect the accuracy of LS in identifying IMN flow (e.g., site and depth of injection and interval between injection and scanning). Until these factors are better understood and IMN flow rates are similar to historical controls, we recommend basing IMN treatment on clinical factors. Our current criteria include all patients with lymph node–positive disease, patients with T2–T3N0 medial/central tumors, and patients with medial T1N0 tumors with high-grade histology and/or lymphovascular invasion. When LS does identify IMN flow, surgical evaluation of the IMN–sentinel lymph nodes with a minimally invasive procedure is needed to identify subsets of patients who may benefit from or should avoid radiation of the IMN. We recommend validation of IMN–sentinel lymph node status with procedures similar to those followed in the axilla, with histopathologic evaluation.
- 11An evaluation of radical mastectomy and extended radical mastectomy for cancer of the breast. Surg Gynecol Obstet. 1967; 125: 337–341..