1 2 4 5 7 8 9 In this study we evaluated the frequency of lymphatic drainage to the IM chain, the rate of metastases in the IM SLN and the clinical implications of IM LN metastases. PATIENTS AND METHODS Between June 1999 and April 2005, 523 consecutive patients underwent surgical treatment including SLN biopsy as a staging procedure for clinically stage T1-2N0 breast cancer. Data regarding all procedures were collected prospectively in a database of the nuclear medicine department. A diagnosis of invasive breast cancer was established preoperatively by fine-needle aspiration or image-guided large core needle biopsy. Sixteen patients who underwent SLN biopsy as a secondary operative procedure following previous excisional biopsy of the primary tumor and one patient who eventually turned out to have multicentric breast cancer were excluded from the study. The study cohort consisted of 506 patients. At the time of the introduction of the sentinel node procedure the ethical committee of the hospital approved the routine use of the SLN biopsy as a staging procedure. All patients received written information regarding the SLN procedure and the possibility of SLNs in the IM chain. The unknown clinical implications of surgically removing IM LNs were discussed with the patients. 99m 99m 1 To assess the additional operative time of IM SLN biopsy we compared the time between incision and skin closure needed for lumpectomy and mastectomy with and without IM SLN biopsy. We selected four groups of ten patients: those who underwent lumpectomy with or without IM SLN biopsy and those who had had mastectomy with or without IM SLN biopsy. In all patients the operative procedure had started with axillary SLN biopsy. We only evaluated patients who did not have axillary dissection to avoid the potential bias of extra time awaiting the result of frozen section analysis. For each category we selected the last ten patients to avoid the learning curve effect. 1 TABLE 1. Indications for adjuvant chemo- and hormonal systemic therapy according to the Dutch national guidelines 2005 Axillary lymph node metastases Primary tumor characteristics  Tumor >3 cm  Tumor >2 cm and BR grade II  Tumor >1 cm and BR grade III Other conditions Age  <35 years: always systemic therapy 60-69 years: chemotherapy when ER- or ≥4 axillary lymph node metastases ≥70 years: no chemotherapy ER status Hormonal therapy for the aforementioned indications at all ages if the tumor is ER receptor positive. BR, Bloom-Richardson; ER, estrogen receptor. Chi-square analysis was performed to evaluate differences in IM SLN visualization rates between groups of patients with various clinicopathological variables and to explore the relation between IM and axillary LN metastases. The ANOVA test was used to explore the relation between age and the visualization of IM SLNs, as well as for the analysis of operative time differences. RESULTS 2 TABLE 2. Comparison of characteristics of patients who had visualized internal mammary sentinel lymph nodes (IM SLNs) versus those who had not visualized IM SLNs on preoperative lymphoscintigraphy  All patients IM SLN visualized IM SLN not visualized P n  n  n  Median age (years)  60 (range 24–92)   57 (range 30–91)  61 (range 24–92)  0.016* Gender       0.36   Male  3 (0.6) 0 (0) 3 (0.8)    Female  503 (99.4) 109 (100) 394 (99.2)  T-stage       0.47   T1 316 (62.5) 73 (67.0) 243 (61.2)    T2 184 (36.4) 36 (33.0)  148 (37.3)    T3 4 (0.8) 0 (0) 4 (1.0)    Tx 2 (0.4) 0 (0) 2 (0.5)  Tumor localization        <0.001   Cranial 47 (9.3) 11 (10.1) 36 (9.1)    Craniolateral 230 (45.5) 30 (27.5) 200 (50.4)    Lateral 25 (4.9) 2 (1.8) 23 (5.8)    Caudolateral 40 (7.9) 10 (9.2) 30 (7.6)    Caudal 18 (3.6) 1 (3.6) 17 (4.3)    Caudomedial 30 (5.9) 13 (11.9) 17 (4.3)    Medial 11 (2.2) 4 (3.7) 7 (1.8)    Craniomedial 80 (15.8) 34 (31.2) 46 (11.6)    Central 25 (4.9) 4 (3.7) 21 (5.3)  Malignancy grade       0.63   BRI 206 (40.7) 48 (44.0) 158 (39.8)    BRII 196 (38.7) 38 (34.9) 158 (39.8)    BRIII 104 (20.6) 23 (21.1) 81 (20.4)  Estrogen receptor status        0.24   Positive 427 (84.4) 88 (80.7) 339 (85.4)    Negative 79 (15.6) 21 (19.3) 58 (14.6)  Axillary lymph node involvement       0.58   No axillary metastases 296 (58.5) 68 (62.4) 228 (57.4)    1–3 lymph node metastases 174 (34.4) 35 (32.1) 139 (35.0)    *4 lymph node metastases  36 (7.1) 6 (5.5) 30 (7.6)  Values in parentheses are percentages. BR, Bloom-Richardson grade. * Age difference between the groups was compared by ANOVA. 1 P 2 FIG. 1. Summary of search for internal mammary sentinel lymph nodes (IM SLNs).  P 3 4 TABLE 3. Operative time of surgical exploration for internal mammary sentinel lymph nodes (IM SLNs) (n = 40) Mean operative time in minutes (range)   P Axillary SLN biopsy/lumpectomy/IM SLN biopsy 60 (27–76) 0.02 Axillary SLN biopsy/lumpectomy/no IM SLN biopsy 44 (32–83)  Axillary SLN biopsy/mastectomy/IM SLN biopsy 72 (42–104) 0.8 Axillary SLN biopsy/mastecomy/no IM SLN biopsy 69 (30–100)  TABLE 4. Complications of surgical exploration for internal mammary sentinel lymph nodes (IM SLNs) (n = 109)  n  Intraoperative complications Pleural breeching 4 (4) Internal mammary vessel damage 6 (6) Postoperative complications Pneumothorax −  Bleeding necessitating reoperation −  Values in parentheses are percentages. IM LN Metastases P 5 TABLE 5. Clinical postsurgical implications of internal mammary lymph nodes IM LN metastases (n = 20) No. Tumor characteristics Axillary metastases Postsurgical treatment Treatment changed due to IM metastases IM SLN not considered IM SLN considered Size (cm) Grade (BR) ER n CT HT RT CT HT RT  Axilla N4+/age<70 1) 63, BCT 1.5 I + 7 + + LR + + LR No 2) 45, BCT 1.6 III + 4 + + LR + + LR No 3) 47, mastectomy 1.8 I + 4 + + LR + + LR No Axilla N1-3+/age<70 4) 39, mastectomy 2.5 II + 3 + + BCT + + BCT+PS RT 5) 46, BCT 3.5 III − 3 + − BCT + − BCT+PS RT 6) 58, BCT 1.8 II + 2 + + BCT + + BCT+PS RT 7) 45, BCT 2.4 I + 2 + + BCT + + BCT+PS RT Axilla N1-N1a or unfavorable primary tumor characteristics/age<70 8) 43, BCT 1.8 I + 1mi − − BCT + + BCT+PS CT/HT/RT 9) 54, BCT 2.2 II + 1mi + + BCT + + BCT+PS RT 10) 66, BCT 2.5 II + 1mi − + BCT − + BCT+PS RT 11) 50, BCT 2.5 III + 1mi + + BCT + + BCT+PS RT 12) 42, mastectomy 3.0 I + 1 + + No + + PS RT Axilla N0/favorable tumor characteristics/age<70 12) 54, BCT 2.1 I + 0 − − BCT + + BCT+PS CT/HT/RT 14) 60, BCT 2.5 I + 0 − − BCT + + BCT+PS  CT/HT/RT 15) 67, mastectomy 0.8 I + 0 − − No − + PS HT/RT 16) 61, BCT 1.1 I − 0 − − BCT + − BCT+PS CT/RT Age>70            17) 82, mastectomy 2.8 II + 2 − + No − + PS? RT? 18) 71, BCT 2.1 II + 1 − + BCT − + BCT+PS RT 19) 72, BCT 2.1 II + 1mi − + BCT − + BCT+PS RT 20) 85, mastectomy 0.9 I + 1mi − − No − + PS? HT/RT? BCT, breast-conserving therapy; BR, Bloom-Richardson grade; ER, estrogen receptor status; Nax+, number of positive axillary lymph nodes; IM SLN, internal mammary sentinel lymph node; ST, systemic therapy; CT, chemotherapy; HT, hormonal therapy; RT, radiotherapy; PS, parasternal radiotherapy; 1mi, micrometastases. In 3 of the 20 patients axillary tumor load (≥4 tumor-positive lymph nodes) was a reason for locoregional radiotherapy including the IM lymphatic chain, leaving 17 patients in whom the radiotherapy field was adjusted because of metastases in the IM SLN. These 17 patients in whom the radiotherapeutic strategy was changed made up 20% of the patients in whom IM sentinel nodes were visualized. Conversely, there were three patients with ≥4 axillary metastases and IM SLNs without metastases, and in these patients parasternal irradiation was omitted. In addition, parasternal irradiation could also be omitted in 30 patients with ≥4 axillary metastases who had no IM lymphatic drainage on preoperative lymphoscintigraphy. DISCUSSION In the present study, SLNs in the IM chain were visualized in approximately one-fifth of the patients who underwent surgery for primary breast cancer. Retrieving these nodes by parasternal intercostal exploration was feasible in the majority of patients. One-fifth of the retrieved IM LNs contained metastases and radiation treatment was adjusted in most of these patients. 5 6 8 10 11 6 99m 5 7 12 13 8 14 15 TABLE 6. Visualization and surgical extirpation rate of internal mammary sentinel lymph nodes (IM SLNs) in breast cancer patients Author Year  n Method of tracer injection Visualized IM SLNs (%) Surgically removed IM SLNs (%)* Madsen et al. 2006 506 PT and SC 22 78 10 2005 984 IT 14 88 6 2005 383 SC, later IT/PT  0–17 73 5 2004 225 SC, later IT/PT  11–17 69 8 2003 681 IT 22 87 11 2002 256 PT 25 63 * Proportion of the visualized IM SLNs. SC, subcutaneous; PT, peritumoral; IT, intratumoral. 6 5 6 8 10 11 8 9 11 16 17 8 11 18 19 8 10 19 20 3 10 In conclusion, lymphatic drainage of breast cancer to IM LNs is a common feature and retrieving these nodes is relatively easy. The clinical impact of metastases in IM lymph nodes is substantial and justifies surgical exploration for these nodes. We advocate routine parasternal intercostal exploration for IM SLNs whenever preoperative lymphoscintigraphy visualizes IM SLNs. For that purpose we also advocate the (additional) intraparenchymatous tracer injection to optimize the visualization of IM SLNs.