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Pathways of Lymphatic Drainage From the Breast

From the Departments of Surgery (SDN, DLW, DG, JF), Radiology (KK), and Biostatistics (SH), Henry Ford Health System, Detroit, Michigan.

Correspondence: Address correspondence and reprint requests to: S. David Nathanson, MD, Henry Ford Health System, 2799 W. Grand Blvd., Detroit, MI 48202; Fax: 313-916-8193; E-mail: dnathan1{at}hfhs.org

	ABSTRACT

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Background: The current standard for obtaining accurate sentinel lymph node (SLN) mapping is intraparenchymal lymphophilic dye/radiocolloid injection close to the breast tumor. We hypothesized that common lymphatic trunks drain both a large volume of breast parenchyma and skin and that intradermal or intraparenchymal routes flow to the same axillary node.

Methods: ^99mTc-labeled filtered sulfur colloid was injected intradermally directly over the breast tumor in 119 patients. Blue dye was injected intraparenchymally in the same quadrant as the primary tumor (concordant quadrant) in 66 and in a discordant quadrant in 53 patients. During axillary exploration, both blue and gamma-emitting (hot) nodes were found. End points were SLNs that were hot and blue, either the same node or different nodes.

Results: In 62 (93.9%) of 66 of concordant quadrant and in 49 (92.5%) of 53 of discordant quadrant patients, the same SLN was both hot and blue (P = .99; Fisher’s exact test). In eight cases in which two distinct nodes were blue and not hot and hot but not blue, the lymph nodes were very close to each other.

Conclusions: The dermal and parenchymal lymphatics of the breast seemed to drain to the same axillary lymph nodes. Lymph from the entire breast seemed to drain through a small number of lymphatic trunks to one or two lymph nodes.

Key Words: Lymphatic • Breast quadrant • Drainage • Sentinel node

	INTRODUCTION

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Tumor metastasis to the regional lymph nodes is predicated on the Halstedian belief of an orderly mechanical progression through local lymphatic channels that lead directly through the afferent vessels to a series of regional lymph nodes.¹ The first of these is the sentinel lymph node (SLN).^2–7 Mouse hind footpad melanomas metastasize directly to the single popliteal lymph node.^8–10 In the mouse model, there is no alternative lymphatic route in the lower limb, and the popliteal lymph node is indeed the true SLN. In contrast, the cat has a number of lymph nodes in the groin, and injection of a lymphophilic dye into the dermis of the lower abdomen or upper thigh clearly shows distinct lymphatic trunks draining small areas of the skin to separate lymph nodes in the groin.¹¹

These observations led to intraoperative lymphatic mapping in human melanoma.⁴ The rich dermal lymphatic plexus¹² predicts multiple lymphatic trunks originating in distinct skin areas that have been mapped^4,13,14 and form the basis for the current recommendation that radiocolloid and blue dye be injected very close to the primary cutaneous melanoma.^4,13,14

Much larger volumes of blue dye, radiocolloid, or both are needed for lymphatic mapping of breast cancer^5,6 compared with cutaneous melanoma; this suggests that the diffusion distance of the injectate to major lymphatic trunks is greater in the breast than in the skin. Several techniques that use both blue dye and radiocolloid have been described for identifying breast SLNs,^7,15–20 including different routes of injection (subdermal, intradermal, and subareolar) and different dyes and radiocolloids. However, all these techniques are based on the belief that lymphatic drainage from one part of the breast goes to one SLN while another part of the breast drains to a different node. Therefore, precise injection near the tumor is thought by some to be the only correct way to map for the SLN.²¹

Combined use of blue dye and radiocolloid in breast lymphatic mapping produces the best results.^7,20 However, the exact site of intraparenchymal injection is debated. Most investigators advocate intraparenchymal injection immediately adjacent to the tumor or into the wall of the cavity of a surgically excised tumor, assuming that this route best represents the pathway of lymphatic metastasis. Axillary SLNs may be invisible on gamma camera images, when relatively large-volume intraparenchymal injections of radiocolloid may create a wide penumbra and obscure the axillary anatomy (S. D. Nathanson, 2001, unpublished results). By following the description by Borgstein et al.²² of intradermal blue dye and intraparenchymal radiocolloid injection and the description of Veronesi et al.¹⁶ of subdermal injection, we experimented with intradermal radiocolloid and intraparenchymal peritumoral blue dye and were immediately impressed with the high rate of accurate identification of hot and blue axillary SLNs, with a false-negative rate of <4% (S. D. Nathanson, 2001, unpublished results). The group at Memorial Sloan-Kettering Cancer Institute¹⁷ confirmed the accuracy of this technique of concordant quadrant (CQ) intraparenchymal dye and intradermal radiocolloid injection.

Studies of lymphatic drainage from the breast (summarized in Uren²³) showed that most lymph drained to the axilla irrespective of the site of injection. Some studies showed the major lymphatic trunks from the breast parenchyma connecting with lymphatics in the subareolar plexus.^24,25 Gray¹² did precise anatomical dissections of dermal and subcutaneous breast lymphatics and showed a rich anastomosis between the breast skin and the subcutaneous and parenchymal lymphatic trunks draining toward the axilla. None of these studies identified the number of lymphatic trunks draining to a specific axillary node, and none addressed the question of whether each breast quadrant had separate lymphatic trunks.

We set out to determine whether different quadrants of the female breast drained to different SLNs. We hypothesized that we could answer the question by injecting blue dye and radiocolloid into discordant quadrants (DQs) of the breast by using the hottest node in the axilla as the correct SLN.^5,7,17,19,20 We chose as our control the method that had been proven accurate in our patients, namely, intradermal radiocolloid directly superficial to the primary breast cancer and intraparenchymal blue dye directly between the breast tumor and the axilla.

	METHODS

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Patients
One hundred sixty consecutive breast cancer patients in whom an SLN was identified by lymphoscintigraphy were selected for study. The criteria for selection were T1 or T2 tumors diagnosed by needle core biopsy, no clinically suspicious axillary lymphadenopathy, preoperative lymphoscintigrams in every case, clearly demonstrable SLN on gamma camera image, no prior chemotherapy or radiation to the breast, successful identification of a hot node in the axilla by gamma probe, no prior mastectomy on the contralateral side, and an SLN found in the axilla by tracing a blue lymphatic to an obviously blue lymph node. All patients were properly informed and signed an institutional review board–approved consent form to participate in an SLN study

The following information was recorded with the Microsoft Excel Database (Microsoft Corporation, Seattle, WA) for each patient: age, site of tumor in the breast, size, quadrant (defined as upper outer [UOQ], lower outer [LOQ], upper inner [UIQ], lower inner [LIQ], or central), grade, hormone receptor status, pathology of the tumor, pathologic status of the SLNs, the quadrant of intraparenchymal injection of isosulfan blue dye (Lymphazurin, US Surgical Corporation, Norwalk, CT), whether the SLNs were hot and blue, hot but not blue, or blue but not hot, whether a complete axillary dissection was performed, and the number of nodes containing tumor.

Forty additional patients undergoing full axillary lymphadenectomy had discordant injections of blue dye but did not have radiocolloid injections. This was performed as a planned observational experiment to determine whether an SLN identified by blue dye would identify the same SLN as determined by tumor metastasis. These patients were not included in the analysis of the DQ and CQ patients but are reported because they strongly support the hypothesis that DQ lymphatic drainage goes to the same axillary lymph node as the lymphatics carrying tumor from the primary tumor site.

Lymphoscintigraphy
^99mTc-labeled sulfur colloid (CIS-US, Bedford, MA) was prepared to maximize smaller-sized colloid particles. After boiling 3.2 ml of technetium for 3 minutes, the solution was diluted v/v 1:1 with .9% sodium chloride and passed through a .22-µm filter (MILLEX-GV^TM, Millipore Corporation, Bedford, MA). A total of 18.5 MBq (500 µCi/.4 ml) was injected intradermally with a 26-gauge needle into the skin overlying the breast tumor 1 to 4 hours before the surgical procedure. The site of the injection was determined either by palpation of a lump or by prior placement of a Ghiatas^TM beaded breast localization wire (Inrad, Kentwood, MI) in the mammography department to identify nonpalpable lesions. Lymphoscintigraphic images were acquired with a gamma camera by use of planar imaging.

Intraoperative Lymphatic Mapping
All surgical procedures were performed under standard general anesthetic, with no local anesthetic injected into the breast or the axilla. Five milliliters of isosulfan blue was injected intraparenchymally, either in the same quadrant as the breast cancer (CQ) or into a quadrant distinct from the site of the breast tumor (DQ). The quadrant selected was entirely at the discretion of the surgeon and was not randomized. The injection needle was directed into the parenchyma, distributing the entire volume of dye into a widely dispersed area confined to one quadrant. For the CQ cases, dye was injected adjacent to a palpable tumor or adjacent to a breast localization wire. The site of the injection was massaged for 5 minutes. A transverse axillary incision was made just below the hairline and deepened until a blue lymphatic was identified and traced to a lymph node. Note was made of whether the node itself was blue. A sterile, ensheathed (Microtech Medical, Columbus, MS) gamma probe (Neoprobe, Dublin, OH) was used to determine the counts emitted from this node in vivo and ex vivo. The hottest node was regarded as the first SLN. After removal of the SLN, a check was made for additional nodes with significant gamma emission, which, if present, were removed. These additional nodes were carefully checked for blue dye. The exploration for SLNs was considered complete when the background count in vivo was <10% of the total ex vivo counts of the SLNs. If the first hot node was not blue, a search was made for a separate blue node. The patient was excluded from analysis if the SLN was found by gamma probe but no blue node was seen in the axilla, even if a blue lymphatic was identified going into the hot node. Any other blue nodes were also removed at this time. If the initial blue node was not hot, the gamma probe was used to find the hot node identified by lymphoscintigram. The axilla was also explored digitally to determine by palpation whether there were additional suspicious nodes.

After excision of the SLNs and adjacent suspicious nodes, either the rest of the level I and II axillary nodes were removed as part of the planned treatment protocol or the axilla was closed without removing any further lymph nodes. Attention was then directed to the primary tumor in the breast; this tumor was removed either by partial or complete mastectomy.

Pathology Review
All lymph nodes removed from the axilla were evaluated and assessed by the usual pathological procedures practiced in the pathology department. All tissue was fixed in buffered formalin and in paraffin wax. Lymph nodes were bivalved, and three to five sections were made and stained with hematoxylin and eosin. The lymph node was designated positive when tumor was identified in any part of the section. The lymph node was negative when no tumor was identified. We did not perform multiple-step sections. Immunohistochemical studies were performed only when the hematoxylin and eosin study showed an equivocal result.

The primary breast tumor specimen was painted with India ink, multiple sections were made, the size was measured with a ruler and calipers, and histological assessment of morphological type, grade, and margin status was recorded. Hormone receptor status was assessed by standard immunohistochemistry.

Statistics
Student’s t-tests were used to compare mean age and mean tumor size between the two groups. For the remaining variables, a ² or Fisher’s exact test was performed. Both tests are appropriate for categorical variables. However, when expected cell sizes were <5 cases, Fisher’s exact test was used instead of the ² test because the assumptions underlying the ² test may be violated in those cases.

	RESULTS

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Figure 1 shows the algorithm of patient distribution in this study. In 41 of 160 patients, a blue lymphatic was seen coursing to the anatomical site of the hottest node, but the node itself was not blue. On further evaluation of surrounding tissues, there were no blue nodes found in this group. Because we could not be sure that the hottest node in this cohort also drained the parenchyma into which blue dye had been injected, we excluded these patients from further analysis.

View larger version (25K): [in this window] [in a new window]   FIG. 1. The algorithm of the study patients.

During the operative procedure of lymphatic mapping, 119 patients had both blue and hot lymph nodes in the same axilla. Fifty-three (44.5%) of the patients had DQ injection of blue dye. In 49 (92.5%) of these, the blue node identified as the first SLN also had the highest gamma counts. In 4 (7.5%) of the 53 patients, the blue and the hot nodes were two different nodes, and there was only one radioactive and one blue node found in each case. In three of the four cases, the hot node that was not blue and the blue node that was not hot were immediately adjacent to each other (within a few millimeters), and they were both removed as part of the procedure. In one patient, the hot and blue nodes were 3 cm apart. One node only was removed in 14 (26%) of 53 patients; in these cases there was only one radioactive node, and it was blue; no other node was blue. More than one node was removed from 39 (74%) of 53 patients, yielding an average of 2.4 nodes per patient. In 37 (94.9%) of these cases, the additional nodes removed were slightly radioactive but not blue, whereas 2 of 39 were slightly radioactive and slightly blue.

Sixty-six of the patients in whom blue dye was injected into the CQ had both blue and hot lymph nodes in the same axilla. Of these, 62 (93.9%) had the highest gamma counts in the same blue node identified as the first SLN. In 4 (6.1%) of the 66 patients, the hot and blue nodes were not the same nodes, and in each case there was only one radioactive and one blue node. In three of the four patients, the hot node that was not blue and the blue node that was not hot were within a few millimeters of each other, whereas in one patient the hot and blue nodes were approximately 2 cm apart. In 26 (39%) of 66 patients, there was only one radioactive node, and it was also blue; no other node was blue. More than one node was removed from 40 (61%) of 66 patients: the 4 described previously and a further 36 in whom there were additional slightly radioactive nodes, yielding an average of 2.6 nodes per patient. Only 4 (11.1%) of these radioactive nodes showed faint blue staining, but not as clearly as the first SLN, whereas 32 of 36 showed no blue dye.

There was no statistically significant difference between the DQ and CQ groups in terms of the relative numbers of nodes that were both hot and blue (P = .99, Fisher’s exact test; confidence intervals, 81.7%–98.6% for DQ and 87.5%–98.6% for CQ).

Table 1 shows demographic, clinical, and pathologic data for the 119 patients described previously. The columns compare DQ with CQ. The tumor sizes in the DQ group were significantly larger (P = .018; t-test) than those in the CQ group. There was also a disproportionate number of lobular cancers in the DQ group (P = .06; Fisher’s exact test). There were no significant differences among the two groups for age (P = .79; t-test), nuclear grade (P = .95; ² test), hormone receptor expression (P = .31; Fisher’s exact test), SLN tumor status (P = .64; ² test), or the number of patients who underwent completion axillary lymph node dissections (P = .29; ² test).

Table 2 shows the tumor location in the breast for each of the patients. A Fisher’s exact test showed a slight statistical difference (P = .049) in distribution, with more DQ tumors in the LIQ and more CQ tumors in the UOQ.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
The study reported here confirms previous observations^{15–17,19,20} that the dermal and parenchymal lymphatics of the breast drain to the same axillary node. Injections of radiocolloid into the dermis overlying breast cancers drained to the same SLN as the lymphophilic dye, isosulfan blue, injected into the breast parenchyma adjacent to the breast tumor. However, our study is unique in that it showed that radiocolloid injected into the dermis immediately superficial to the tumor drained to the same SLN as blue dye injected into another quadrant of the same breast, in an area distinct from the site of the primary breast cancer. This uniform drainage pattern applied to every quadrant of the breast.

The first attempts to define the lymphatic drainage of the breast were published in the 18th century (summarized in Uren²³). One hundred years later, Sappey (quoted in Turner-Warrick²⁴) injected mercury into the parenchyma of lactating breasts and observed drainage to the subareolar plexus, followed by drainage to the axillary lymph nodes. Additional pathways of drainage from the breast were described that showed direct drainage from the breast to the axilla,²⁴ either directly or through the interpectoral space.

Anatomical studies¹² suggest that the skin of the breast and the underlying parenchyma, which originate embryologically in the ectoderm, share the same lymphatic drainage. Three interconnecting plexuses of lymphatics drain the skin of the breast.¹² Lymphatic capillaries lie in the superficial dermis surrounded by compact fibroareolar tissue, deep to the dermal arterioles and superficial to the venules. Deeper in the dermis, valved collecting lymphatic trunks pass into the subcutaneous tissues parallel to the lymphatics of the subcutaneous fatty tissue. These trunks occasionally anastomose in the subareolar plexus with lymphatic trunks from the breast parenchyma. Other lymphatic trunks tend to follow the blood supply from the axillary vessels²⁴ without going to the subareolar plexus. They run in the breast parenchyma or in the subcutaneous fat and are joined by tributaries draining the breast tissue before passing through the axillary fascia.

The accuracy of the intradermal route for lymphoscintigraphy and intraoperative gamma-probe-directed lymphatic mapping is debated. Some centers with extensive experience in intraparenchymal radiocolloid injection^21,23 have abandoned the intradermal route because they have not observed internal mammary node drainage from the breast skin, whereas intraparenchymal isotope is often seen in these nodes. Uren²³ reports radiocolloid drainage to the internal mammary nodes in 14 (78%) of 18 inner-quadrant lesions and in 17 (35%) of 49 of patients with outer-quadrant lesions. A comparison of lymphatic drainage to the axilla and internal mammary nodes from intramammary injections of radioactive colloidal gold injected preoperatively showed very little drainage to the internal mammary nodes. Ninety-seven percent of the radioactivity was found in the axillary nodes in postoperative radical mastectomy specimens, irrespective of the site of injection into the breast tissue.²⁵ Only 3% of the injectate was found in internal mammary nodes. We have seen 4 cases with internal mammary node drainage of 300 breast sentinel node procedures after intradermal breast radiocolloid injection (S. D. Nathanson, 2001, unpublished results).

A critical issue in determining whether intradermal radioisotope injection is accurate is whether this route identifies the correct sentinel node with a low incidence of falsely negative SLNs. A recent study¹⁹ that used intradermal radioisotope and intraparenchymal blue dye reported an accuracy of 100% for T1 tumors when patients with obvious macroscopic lymph node metastases were excluded. A larger study from the same institution²⁰ evaluated 12 variables associated with successful SLN localization and found intradermal isotope injection to be a highly significant predictor of accuracy. In our study, the intradermal route of radiocolloid injection correctly predicted the SLN in 95.5%, mirroring the experience of most other institutions that use the intraparenchymal route for lymphatic mapping.^5–7,21,23 The reasons for SLNs to be falsely negative are not known, although it is possible that both radioisotope and blue dye may be diverted from the true SLN if the lymph flow to that node is occluded by tumor replacement of the nodal tissue.¹⁹ It is apparent that blue dye and radioisotope traverse the same pathways to arrive at the same axillary node and that tumor cells often metastasize to that same node.

The intradermal route of radioisotope injection is easier than the intraparenchymal route because the radioisotope can be injected into a precisely confined area by relatively inexperienced personnel. The volume of injectate is small, and the radioactive tracer moves rapidly to the axilla, an efficient use of time in a busy operating room. The site of injection is easily covered by a small lead shield, preventing shine-through into the axilla with better gamma camera images than usually seen with the intraparenchymal route.

We occasionally found blue dye accumulating in the subareolar plexus. Grant et al.²⁶ observed pontamine Sky Blue in the subareolar space after injections around the periphery of the breast in several patients undergoing mastectomy. Although some would argue that observation of dye in the area of the nipple represents ductal dispersion of dye toward the nipple²⁴ and not interconnecting parenchymal and subareolar lymphatics, deliberate subareolar injection of blue dye was noted to accurately track to the SLN in breast cancer patients,^18,27 a finding fully in keeping with the concepts first enunciated by Sappey (quoted in Uren²³) and observed by others.²⁶

The eight patients in whom blue dye went to one axillary node and radioisotope to another introduce the intriguing possibility that there were at least two major lymphatic trunks draining the dermis and the parenchyma. This was not a common phenomenon, and it is important to note that the two separate nodes were immediately adjacent to each other and would probably have been removed during a standard SLN biopsy. This disturbing problem is exemplified by the two patients in whom the hot and blue nodes were approximately 2–3 cm apart from each other. This was not a problem unique to the DQ group. Because neither of these patients had a positive SLN or completion lymphadenectomies, we are unable to tell which of these nodes was the true SLN.

The findings in this study would be even more significant if we were to add the 41 cases in which a blue lymphatic led the surgeon directly to the hot SLN, but in whom the node was not blue. It is possible that the dye would have stained the node if more time had elapsed, although the actual reason why the node was not blue is unknown.

The 11 patients in whom micrometastases (<2 mm in diameter) were found in the SLN and in whom a DQ dye injection was performed are perhaps the most important corroborators of the hypothesis that drove this study. The expanding literature of SLN biopsy has already confirmed that dye and colloid accurately portray the actual metastatic pathway of tumor cells to lymph nodes. Breast cancer cells invade newly formed lymphatic capillaries at the tumor surface.²⁸ These capillaries enter larger lymphatic trunks and eventually reach the SLN. It is clear that blue dye injected some distance away from the primary breast tumor reached the same node, suggesting a convergence of the lymphatic pathways from the tumor and from distant breast parenchyma.

Many reports in the literature are from investigators who advise techniques for SLN mapping, and there are a number of differing methods that are effective. Our study does not advocate injection of blue dye at a distance from the primary tumor. Rather it shows that the breast parenchyma, and its overlying skin, probably drain through a relatively small number of lymphatic trunks to anatomically fairly constant SLNs. The practical implication of these observations is that it may not be essential to inject blue dye and radiocolloid very close to the primary breast tumor to obtain an accurate SLN biopsy. The study also confirms that intradermal injection of lymphophilic radiocolloid is a simple and accurate method for lymphatic mapping in breast cancer.

	Acknowledgments

 
Supported by the Stephen Bryant Surgical Oncology Fund and by the William and Happy Rands Chair in Breast Surgical Oncology.

	Footnotes

 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, from March 15–18, 2001.

Received for publication March 16, 2001. Accepted for publication August 20, 2001.

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