The deltopectoral lymph node: a potential protective biomarker for breast cancer-related lymphedema

Abstract

Background

The lateral upper arm lymphatic pathway is theorized as a route of superficial lymphatic drainage protective against breast cancer-related lymphedema (BCRL) after axillary lymph node dissection (ALND). This study describes lymph nodes draining the lateral upper arm pathway.

Methods

Healthy female volunteers underwent bilateral ICG lymphography and nuclear lymphoscintigraphy. Nuclear tracer was injected over the cephalic vein in the upper arm. Lymph nodes with tracer uptake were recorded as deltopectoral, Station 1 (Axillary Levels I or II and Interpectoral), or Station 2 (Axillary Level III, Infraclavicular, Supraclavicular Levels IV or Vb, and Cervical Level Va).

Results

72 arms of 36 volunteers were included. Functional drainage to deltopectoral lymph nodes was observed in 38% (27/72) of arms. Drainage to Station 1, Station 2, and neither station was observed in 96% (69/72), 36% (26/72), and 3% (2/72) of arms, respectively. No differences were observed between arms with or without deltopectoral lymph nodes draining to Station 1 lymph nodes (93% vs 98%, p = 0.286) or neither station (4% vs 2%, p = 0.711), respectively. A significant difference was observed between arms with or without deltopectoral lymph nodes draining to Station 2 lymph nodes (52% vs 27%, p = 0.031).

Conclusions

Deltopectoral lymph node drainage is significantly correlated with Station 2 lymph node drainage. As Station 2 lymph nodes are preserved in an ALND, the presence of deltopectoral lymph node drainage represents an important potential protective biomarker for BCRL development.

Introduction

Breast-cancer-related lymphedema (BCRL) of the upper extremity is most commonly caused by treatment of breast cancer with axillary lymph node dissection (ALND). While there are clear population-level risk factors for BCRL, individual variations in upper extremity lymphatic anatomy and functional drainage remain underrecognized risk factors [1, 2]. The presence of collateral drainage routes has been theorized as an explanation for why most patients do not develop BCRL after an ALND. The lateral upper arm pathway, or Mascagni-Sappey pathway, is one drainage route of the arm that courses along the cephalic vein in the upper arm and drains to the deltopectoral groove, distinct from the arm’s main collecting vessels that terminate in the axilla. Anatomic variations of the lateral upper arm pathway have been previously described in cadaveric dissections and imaging studies using ICG lymphography [3-8]. However, targeted functional lymph node drainage of the lateral upper arm pathway in healthy volunteers has never seen studied in-vivo. Given that the lateral upper arm pathway is theorized to be protective against BCRL after ALND, individuals with drainage of the pathway exclusively to lymph nodes in the axilla may be predisposed to BCRL after ALND.

Contemporary knowledge of lymphatic anatomy is built upon the works of Paolo Mascagni and later by Marie Philibert Constant Sappey, both of whom developed comprehensive anatomic atlases of the human lymphatic system published in the late eighteenth and early nineteenth centuries, respectively [3, 4]. With the advent of surgical treatment for cancer and the growing incidence of breast-cancer-related lymphedema among breast cancer survivors, basic anatomic descriptions of the arm’s lymphatic system were seen in a new light. More recently, Kubik et al. described two variations of the lateral upper arm pathway’s vascular anatomy and terminal lymph nodes based on cadaveric dissections of patients who previously underwent ALND [5]. Specifically, they described a short lateral pathway that began in the upper arm (short bundle), and a lateral upper arm pathway directly connected to forearm lymphatic channels (long bundle). Kubik et al. also described variations of the lateral upper arm pathway’s draining lymph nodes, which they termed “stations.” Specifically, the lateral upper arm pathway drains to the deltopectoral lymph node, after which vessels in the pathway may terminate in the axillary station (axillary lymph nodes) and/or higher-level station comprising the apical axillary, clavicular, and cervical lymph nodes. They hypothesized that following ALND, drainage through the lateral upper arm pathway becomes more likely if this pathway connects to lymph nodes outside the axilla which are spared during ALND [5]. Later, Leduc et al. also specified three variations of the lateral upper arm pathway’s draining lymph nodes based on cadaveric dissections: only axillary lymph nodes, only cervical lymph nodes, or both axillary and supraclavicular lymph nodes [6]. The authors reported that variations of the lateral upper arm pathway that drain to the cervical and supraclavicular lymph nodes may be especially important for preventing BCRL after ALND [6]. As ALND most commonly includes removal of only Levels I and II axillary lymph nodes, axillary level III and non-axillary lymph node groups would be spared and may represent drainage patterns protective against BCRL. Sarri et al. previously performed lymphatic mapping with SPECT/CT lymphoscintigraphy in the affected arms of 39 female breast cancer patients within 60 days of treatment with sentinel lymph node biopsy (SLNB) or ALND [9]. They observed drainage to the deltopectoral lymph nodes in three patients treated with ALND but no patients treated with SLNB, suggesting activation or increased flow through the lateral upper arm pathway caused by substantial outflow obstruction following ALND [9]. Lee et al. also performed lymphatic mapping of the affected upper extremities with SPECT/CT lymphoscintigraphy in 29 female breast cancer patients with BCRL after ALND [10]. They observed less severe lymphedema in the 52% of patients with “bypass circulation,” which they defined as functional drainage from the deltopectoral lymph nodes to the infraclavicular, supraclavicular, and cervical lymph nodes [10]. Their findings provided early support for the deltopectoral lymph node as a biomarker of superficial collateral drainage and lymphedema severity.

In this study, we performed functional mapping of the lateral upper arm pathway to define its draining lymph nodes in healthy female volunteers without prior axillary or head and neck surgery. We utilized a radiocolloid tracer injection over the cephalic vein in the lateral upper arm to target the lateral upper arm pathway and performed imaging with SPECT/CT lymphoscintigraphy 2 h after injection to allow for detailed description of functional lymphatic drainage. This study enables us to provide further clarity to variations of the lateral upper arm pathway that may be protective against the development of BCRL.

Methods

Study population

Healthy female volunteers were recruited at the Boston Lymphatic Center of Beth Israel Deaconess Medical Center (Table 1). Institutional review board approval was previously obtained (IRB Protocol #2021P-000209) prior to initiating study activities. Volunteers were eligible if they were at least 18 years of age, assigned female sex at birth, and identified as female. Exclusion criteria were history of lymphedema, breast cancer, chronic inflammatory conditions, filarial infections, upper extremity deep vein thrombosis, venous thoracic outlet syndrome, or congestive heart failure. Volunteers with previous chemotherapy, surgical procedures to the upper extremity and axilla, or radiotherapy to the axilla, upper extremity, or head and neck were also excluded. Additionally, volunteers who were breastfeeding, pregnant, or had a known iodine allergy were excluded from the study. Prior to undergoing lymphoscintigraphy, baseline limb measurements were obtained by a certified lymphedema physical therapist to (1) rule out lymphedema (defined as a volume measurement difference > 10% between upper extremities and/or bioimpedance spectroscopy L-Dex score outside of −10 to 10 units) and (2) to obtain objective confirmation of subject-reported hand-dominance. These measurements included hand grip strength using a Jamar dynamometer and a nine-hole peg test.

Table 1.

Study eligibility criteria

Inclusion criteria

Exclusion criteria

Female At least 18 years of age Ability to understand the protocol and willingness to participate

Prior history of: Breast cancer Radiotherapy to the axilla, upper extremity, head, or neck Chemotherapy Surgical procedures to upper extremity including the axilla Chronic inflammatory conditions (e.g. rheumatoid arthritis) Filarial infections Lymphedema Upper extremity deep vein thrombosis Congestive heart failure Venous thoracic outlet syndrome Iodine allergy Currently pregnant Currently breastfeeding

Lymphoscintigraphy

A single intradermal injection was placed over the cephalic veins in the lateral upper arm, identified by ultrasound, of both upper extremities 4 cm proximal to the antecubital crease [7, 8, 11-13]. Each intradermal injection consisted of 0.1 mCi Tc-99 m filtered sulfur colloid (0.22 micron Millipore filter) in 0.1 ml saline. Following injection of the tracer, protocoled exercises were performed consisting of arm motion and squeezing a rubber ball. This exercise routine was repeated every 15 min prior to the 2-h imaging session. Whole-body planar images were obtained with the arms down at 30 min and repeated at two hours. At two hours, SPECT/CT was obtained which included visualization of the neck, chest, upper abdomen, and upper extremities proximal to the antecubital crease. The presence or absence of tracer uptake in anatomically defined lymph node groups was documented (see Table, Supplementary Digital Content 1). Two nuclear medicine physicians (K.D. and A.P.) independently interpreted SPECT/CT lymphoscintigraphy and resolved any discrepancies using a standardized consensus form. Persistent disagreements were resolved by an independent evaluation of the lymphoscintigraphic imaging (D.S.). Data were entered into a prospectively maintained REDCap database.

Lymph node groups with tracer uptake visualized on SPECT/CT in volunteer arms were further classified based on Kubik et al.’s description of lymph node drainage patterns from the lateral upper arm pathway [5]. Axillary lymph node groups (Level I and Level II) and Interpectoral lymph nodes were classified as Station 1 lymph nodes [5]. Lymph nodes groups commonly spared during axillary lymph node dissection (Axillary Level III, Infraclavicular, Supraclavicular, and Cervical) were classified as Station 2 lymph nodes (Fig. 1) [5].

Fig. 1.

Anatomic visualization of station 1 and station 2 draining lymph nodes from the lateral upper arm pathway (bolded green portrays a long bundle of the lateral upper arm pathway). Created with Biorender.com

Data analysis

Participant demographics and lymphatic anatomical data were extracted. Participant age, BMI, race, and ethnicity were characterized descriptively. We present continuous variables as median, quartile 1, and quartile 3, and categorical variables as count and percentage. Draining lymph nodes were recorded in each volunteer arm. Drainage to Station 1 and Station 2 lymph nodes was recorded in each volunteer arm. Volunteer arms were further categorized by the presence or absence of drainage to the deltopectoral lymph nodes. Volunteers were randomized to one arm (left or right, n = 36) to test associations between deltopectoral lymph node drainage with volunteer BMI and age using Mann–Whitney U tests (SPSS Statistics software).

Proportions of arms with drainage to Station 1 lymph nodes, Station 2 lymph nodes, or neither station were compared between all (n = 72) volunteer arms with or without deltopectoral lymph node drainage using chi-squared tests (SPSS Statistics software).

Results

Both arms of 36 healthy female volunteers (n = 72) met inclusion criteria. The median age and BMI of volunteers was 29 and 24.6, respectively. A full demographic summary of volunteers is included in Table 2. Volunteers were randomized to one arm, resulting in 53% (19/36) right arms and 36% (13/36) with deltopectoral lymph node drainage. Volunteer age was not significantly different between volunteers with (median 32.1 years) or without (median 25.4 years) deltopectoral lymph node drainage (U = 105; p = 0.149). Volunteer BMI was not significantly different between volunteers with (median BMI 24.7) or without (median BMI 24.2) deltopectoral lymph node drainage (U = 121; p = 0.361).

Table 2.

Volunteer characteristics and demographics

Characteristic
Total volunteers, n	36
Age: Median (Q1–Q3)	29 (24.3–39.9)
BMI: Median (Q1–Q3)	24.6 (21.1–27.6)
Race, n (%)
White	22 (61)
Black or African American	2 (6)
Asian	5 (14)
Biracial	2 (6)
Others	5 (14)
Ethnicity, n (%)
Not Hispanic or Latino	28 (69)
Hispanic	8 (31)

Drainage to Station 1, Station 2, and neither station was observed in 96% (69/72), 36% (26/72), and 3% (2/72) of arms, respectively (Fig. 2). Overall, functional drainage to deltopectoral lymph nodes was observed in 38% (27/72) of arms. The proportions of arms draining to Station 1 lymph nodes did not differ between volunteer arms with (93%, 25/27) or without (98%, 44/45) deltopectoral lymph node drainage (X² = 1.136 (1), p = 0.286). The proportions of arms draining to Station 2 lymph nodes differed between volunteer arms with (52%, 14/27) or without (27%, 12/45) deltopectoral lymph node drainage (X² = 4.639 (1), p = 0.031). The proportions of arms draining neither Station 1 or Station 2 lymph nodes did not differ between volunteer arms with (4%, 1/27) or without (2%, 1/45) deltopectoral lymph node drainage (X² = 0.137 (1), p = 0.711) (Fig. 3).

Fig. 2.

Lymph node station drainage patterns of the lateral upper arm pathway in all 72 upper extremities of 36 healthy female volunteers. Created with Biorender.com

Fig. 3.

Lymph node station drainage patterns of the lateral upper arm pathway compared between upper extremities with (top row, n = 27) or without (bottom row, n = 45) deltopectoral lymph node drainage. Created with Biorender.com

Discussion

We describe major variations of lymph node drainage from the lateral upper arm pathway in 72 upper extremities of 36 healthy female volunteers. We found that 36% (26/72) of arms demonstrated drainage to protective Station 2 lymph nodes, specifically Level III axillary, infraclavicular, supraclavicular, and cervical lymph node groups. Additionally, 38% (27/72) of arms demonstrated drainage to the deltopectoral lymph nodes. Importantly, we identified that the proportion of arms draining to Station 2 lymph nodes was significantly greater in volunteer arms with deltopectoral lymph node drainage (52%) than without deltopectoral lymph node drainage (26%).

This study is the first to provide functional in-vivo evidence in healthy female volunteers that the lateral upper arm pathway may be a protective route of drainage to lymph node groups spared during ALND. We found that 36% (26/72) of arms demonstrated drainage to Station 2 lymph nodes from the lateral upper arm pathway. Individual variations in lymphatic pathways draining the upper extremity represent under-recognized risk factors for BCRL. Both Kubik and Leduc, based on cadaveric dissections, proposed that protective collateralization of lymphatic drainage through the lateral upper arm pathway is dependent on its draining lymph nodes. They hypothesized that lateral upper arm pathway protection against BCRL may require drainage to non-axillary lymph node groups spared during ALND, specifically the cervical and clavicular lymph nodes [5, 6]. Our finding that 36% (26/72) of arms drain to Station 2 lymph nodes provides further support to existing functional evidence that the lateral upper arm pathway may be protective in some women with upper extremity lymphatic drainage to apical axillary, cervical, and clavicular lymph node groups [14-16]. Importantly, this study expands upon our understanding of variations in lymphatic vascular anatomy of the lateral upper arm pathway. Granoff et al. recently described that approximately 60% of women demonstrate the long bundle and 40% demonstrate the short bundle on ICG lymphography [8]. As the long bundle variant represents a connection from forearm lymphatic channels to the lateral upper arm pathway, it may be more protective against BCRL than the short bundle variant by enabling the entire upper extremity to access this pathway [6, 8]. In light of our new findings, variations of lymph node drainage to Station 2 lymph nodes from the pathway may be an additional protective factor against BCRL. In arms without drainage to Station 2 lymph nodes, the lateral upper arm pathway may be obstructed by removal or damage of lymph nodes during ALND [5, 6].

We also found that 38% (27/72) of arms demonstrated drainage to the deltopectoral lymph nodes. The deltopectoral lymph nodes were first described by Mascagni and Sappey’s anatomic atlases of the human lymphatic system in the late eighteenth and early nineteenth centuries, respectively. They associated the deltopectoral lymph nodes with the lateral upper arm pathway lymphatic drainage to clavicular and cervical lymph nodes [3, 4]. Outside of cadaveric dissections, knowledge of the deltopectoral lymph nodes is limited and its population incidence is unknown. However, the variable presence of the deltopectoral lymph node has previously been suggested [10]. Our finding that approximately one third of volunteer arms demonstrated drainage to the deltopectoral lymph nodes improves our understanding of population-level variations in baseline lymphatic anatomy of the upper extremity.

Most importantly, we determined that drainage to Station 2 lymph nodes was significantly higher in volunteer arms with deltopectoral lymph node drainage (52%) than arms without (26%). Our findings suggest that deltopectoral lymph node drainage may serve as an important biomarker for more robust or protective drainage through the lateral upper arm pathway and may translate to reduced BCRL risk and severity after ALND. As our findings were in healthy female volunteers, our study does not answer how the upper extremity lymphatic system may collateralize after outflow obstruction caused by ALND. Specifically, while 48% of arms with deltopectoral lymph node drainage did not demonstrate Station 2 drainage, it is possible that Station 2 drainage may be activated following ALND. Future prospective studies using preoperative and postoperative lymphatic mapping in patients undergoing ALND may improve our understanding of the lateral upper arm pathway’s response to ALND and improve our ability to predict BCRL development with baseline anatomy.

This study is not without limitations. Notably, our cohort’s younger age and lower BMI is not reflective of the breast cancer patient population and may limit this study’s generalizability. As our cohort was healthy female volunteers, we cannot definitively determine whether variations of lymphatic drainage from the lateral upper arm pathway represent anatomic risk factors for BCRL after breast cancer treatment with ALND and regional lymph node radiation. However, prospective mapping of variations in the lateral upper arm pathway is a necessary step to confirm that these variations represent BCRL risk factors. Additionally, we may continue to discover additional variations of the pathway’s drainage with continued enrollment of study volunteers. We also acknowledge that lymphatic drainage patterns may not be adequately mapped by visualization of lymph nodes alone. Specifically, lymphatic drainage pathways may bypass lymph nodes altogether and lymphatic channels alone are difficult to visualize with filtered sulfur colloid.

Conclusion

In approximately half of volunteer arms with deltopectoral lymph node drainage, the lateral upper arm pathway drains to Station 2 lymph nodes. In contrast, only 26% of volunteer arms demonstrated Station 2 lymph node drainage without deltopectoral lymph node drainage. As Station 2 lymph nodes are spared during ALND, this anatomic variation of the pathway’s drainage may be protective against BCRL. Our findings associating deltopectoral lymph node drainage with Station 2 lymph node drainage suggest the deltopectoral lymph node may represent an important biomarker for upper extremity lymphatic drainage that bypasses levels I and II in the axilla. This study provides functional in-vivo evidence of the lateral upper arm pathway as a collateral route of superficial lymphatic drainage that may prevent or alleviate BCRL after ALND.

Supplementary Material

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s10549-025-07748-w.

Data availability

Available upon reasonable request from the corresponding author.