Quantification of level I neck lymph nodes for lymph node transfer in lymphedema treatment: an anatomical study and review of literature

Introduction

Lymphedema is a chronic, debilitating condition caused by the obstruction or impairment of lymphatic fluid transport (1). It is caused by multiple oncological treatments, especially in breast cancer, melanoma, gynecological cancer, and genitourinary cancers (1-3). As lymphedema progresses, resulting tissue fibrosis, chronic interstitial inflammation, and poor proteolytic and phagocytic function of the macrophages leads to irreversible changes (4). Despite an understanding of the pathogenesis and having a gold standard of care (multi-phase congestive physiotherapy), lymphedema remains incurable.

Advancements in our understanding of lymphatic system anatomy and physiology have facilitated the evolution of surgical techniques to ameliorate the symptoms and disability associated with lymphedema. The refinement of microsurgical techniques has led to development of two common surgical treatments options; lymphovenous anastomosis and vascularized lymph node transfer (VLNT) (5,6). VLNT employs microsurgical techniques to reconstructs the lymphatic circulation to bypass the obstruction or reconnect the efferent and afferent lymphatic flow leading to a decongestive effect (7-9). Lymph node transfer has been developed with several variations including vascularized versus non-vascularized transfer, and lymph node-lymphatic anastomosis versus no anastomosis at the recipient site (5,6,10).

Knowledge about the distribution of donor site lymph nodes, its vascular pedicle and adjacent critical structures are vital for VLNT and success for lymphedema treatment. Features of a donor site should have a degree of redundancy or represent a “watershed” area of lymphatic drainage such that the harvest of lymph nodes does not cause lymphedema in the donor site. Furthermore, a well-defined, consistent, and reliable vascular pedicle is required to allow for vascularized nodal transfer (11). The groin region lymph nodes have shown reliability and success worldwide but in cases of lower extremity lymphedema alternative VLNT flaps are needed to avoid possibility of inducing iatrogenic lower extremity lymphedema (12-15). As a result, submental, submandibular, axillary lymph nodes have been described as alternative and potential reliable source for VLNTs (10).

There are an estimated 3–5 lymph nodes contained within level I of the neck, however very few studies have contributed to this knowledge and their anatomy needs to be better identified for surgery optimization and safety (10,16-19). The current study aims to validate the current literature by quantifying the lymph nodes of level I of the neck. We also aim to describe the regional anatomy within level I so that donor sites for VLNT are better understood and can aid planning for future surgeries wishing to harvest these lymph nodes. Additionally, this study will also provide a review of relevant literature.

Methods

This study was approved by the Victorian Health Research Ethics Committee, as a low and negligible risk study (No. PHLNR2021). Informed written consent was obtained from included participants. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Data were collected from patients undergoing consecutive neck dissections between 2002 and 2012, collected by chart review at Peninsula Health, Victoria, Australia. Quantification of lymph nodes identified by level from pathology specimens of 73 patients who underwent radical, modified, and selective neck dissection was performed. Patient demographic data including age, gender, neck dissection type, and prior chemo/radiotherapy was collected and anonymized. Body mass index (BMI) and ethnicity were not included. A comparison was made for these factors, and an arbitrary assessment of <60 and ≥60 years of age was used for age comparison.

The indications for surgery were all for head and neck malignancy, comprising squamous cell carcinoma in 71 cases and melanoma in 2 cases. Surgery was performed by plastic surgeons and ear, nose and throat surgeons. All patient data were assessed retrospectively via electronic medical records, and thus there was no prospective standardization of surgical technique.

The types of neck dissection performed were divided into categories corresponding to the American Head and Neck Society 2001 classification, shown in Table 1 (20). All dissections which included the entirety of level I regional nodes were included. A selection of dissections further subdivided level I nodes into submental (sublevel IA) and submandibular (sublevel IB), as shown in Figures 1,2, although this was not the primary endpoint of the study, as described above. Level IA was defined as lymph nodes within the triangular boundary of the anterior belly of the digastric muscles and the hyoid bone. Level IB included lymph nodes within the boundaries of the anterior belly of the digastric muscle, the stylohyoid muscle, and the body of the mandible (20). It included the preglandular and postglandular nodes and the prevascular and postvascular nodes.

Figure 1 Schematic drawing of selection of dissections further subdivided level I nodes into submental (sublevel IA) and submandibular (sublevel IB). Yellow represents lymph nodes and red represents artery. SA, submental artery; FA, facial artery; STA, superior thyroid artery.

Figure 2 Computed tomography image of level I neck lymph nodes. The arrows point out the location of lymph nodes.

All specimens were submitted for microscopic examination by a single pathology department, with 3 pathologists involved in the reporting of specimens. These were all processed in formalin, and the number of lymph nodes in each level was then determined under microscopic examination. Using microtome, 4–5 micrometer thin sections of lymph node tissue were cut, stained with hematoxylin and eosin. The basic structure and components of the lymph nodes include the capsule, subcapsular sinus, cortex, paracortex, and medulla were examined.

Search strategy and study selection

PubMed, Google Scholar, Science Direct, Cochrane CENTRAL, and trial registries (http://clinicialtrials.gov/) were searched for relevant studies published from infinity to September 2021. The search terms included: (“vascularized lymph nodes transfer” OR “VLNT”) AND (“lymphedema” OR “lymphoedema”) AND (“quantification”). The inclusion criteria included research published in peer-reviewed journals, studies with target population including lymphedema treatment, studies reporting outcomes with VLNT. The exclusion criteria included studies not published in English language, pre-prints, conference proceeding, conference abstracts, and studies did not have relevant outcomes to the aim of this study.

Statistical analysis

Mean, range, and standard deviation were used to quantify the number of level I lymph nodes. The lymph nodes were greater than 1cm in diameter. A comparison of different age and gender groups was performed using the Student’s t-test. A P value of less than 0.05 represented a statistically significant difference.

Results

A total of 73 patients who underwent level I neck dissections were included in this study. The cohort’s mean age was 65.5±13.7 years and comprised of 51 males and 22 females. All patients had no documented prior neck surgery or previous chemo/radiotherapy. A total of 20 patients underwent radical neck dissection or a modified neck dissection and 53 patients underwent selective neck dissection.

The count of level I nodes yielded a range of 2 to 16 lymph nodes, with a mean quantity of 5.2±2.9, Table 2. A total of 6 patients were further subcategorized into level IA and level IB. The quantity of lymph nodes identified in level IA ranged from 1 to 5 nodes, with an average quantity of 3.7±1.6. The average quantity for level IB was 4.7±3.0 with a range of 2 to 8. As most of the treating surgeons did not require subcategorization of level I from an oncologic perspective, the majority of specimens were not separated into level IA or level IB. There was no difference in the quantity of lymph nodes between gender or age (<60 versus ≥60 years old) as shown in Table 3.

Discussion

The present anatomical study included 73 patients who underwent level I neck dissections, with a mean of 5.2±2.9 mean lymph nodes identified per level I zone. The results were further subcategorized into submental (level IA) and submandibular (level IB) lymph nodes. The quantity of lymph nodes identified in level IA and IB were 3.7±1.6 and 4.7±3.0, respectively, and no differences between age or gender were identified. To our knowledge, this is the largest study to quantify the number of lymph nodes of level I of the neck region and findings from this study provides anatomical knowledge for VLNT as potential treatment of lymphedema.

Knowledge of quantity lymph nodes and regional anatomy of donor site is essential for surgery optimization and this study’s result reflect the findings of previous literature. Cheng et al. reported a mean of 3.3±1.5 lymph nodes on submental artery VLNT to the ankles of six patients with lower limb lymphedema (21). Another study by Tan et al. transferred a mean of 3.2 lymph nodes in the submandibular vascularized lymph node (VLN) to the upper arm in one patient with upper limb lymphedema (22). Patel et al. reviewed prospective databases for patients who had undergone preoperative planning for submental VLNT (a mean of 3.3 lymph nodes) with duplex ultrasonography (23). Findings from this study contributes to growing body of evidence of level I neck lymph nodes and may aid in transferring a lymphatic flap with intact microcirculation for lymphedema treatment.

Of note, the arterial territory of the anterior neck has been well described. There are three vessels which supply the region: the submental artery, facial artery, superior thyroid artery, and inferior thyroid artery. In a detailed lymphatic dissection study, it was observed that submental island flaps based on the submental artery can involve the mental lymphatic branches that drain to level IA and level IB of the neck (24). Atamaz Pinar et al. described the use of a submental flap based on facial artery branches including the submental artery which supplied level IA and IB of the neck (25). They studied 50 submental arteries from 25 cadavers and found the external diameter of the submental artery varied between 0.82 and 2.80 mm with a mean of 1.8 mm (25). If pedicle length is required, the vessels can be traced back to the facial artery, which can be safely dissected. Perforators of the superior thyroid artery have been extensively studied by Majoufre-Lefebvre et al. who demonstrated their cutaneous distribution (26). Wilson et al. evaluated 90 superior thyroid artery perforators with 45 consecutive computer tomographic angiograms of the neck (27). They found the presence of perforators originating from the superior thyroid artery in all subjects with the mean diameter of 0.9 mm and the range of 0.5–1.3 mm. The arterial territory is demonstrated in Figures 1,2. The venous blood of the submental/mandibular region drains entirely into the anterior facial vein, which accompanies the facial artery. These studies validate the use of lymph node chains of level I of the neck as a free vascularized lymphoid tissue transfer (28,29).

VLNT has been considered the main surgical treatment for lymphedema in many centers (1,30). The mechanism of action of VLN flaps is thought to be based on intrinsic lymphovenous connections and lymphangiogenesis (31-34). Thus, VLNT helps clear the static lymphatic fluid from an area devoid of functioning lymphatics. Lymphatic venous anastomosis, first reported in 1962 (35), bypasses the obstructive lymphedema without replacing the lymphoid tissue (5,36-39). This procedure represents an alternative to direct lymphatic venous shunts and can be achieved due to the abundance of nearby large-caliber venous tributaries (39). Studies have found the efficacy of these techniques is proportional to the number of lymphatics that can be identified and anastomosed, and multiple anastomoses (greater than two anastomoses) of the same limb showed long term lymphedema volume improvement and improvement in patient-reported quality of life (14,39,40). The authors’ previous work utilizing submental and submandibular free VLNT demonstrated significant improvement in genital lymphedema with no donor site morbidity (Figure 3) (41). Gratzon et al. investigated VLNT for its effectiveness and found a significant reduction in upper limb circumferential volume, reduction in pain and heaviness, and improved quality of life at 12 months postoperatively (14). Despite this, lymphedema still recurred over time. It is hypothesized that repeated episodes of inflammation and fat deposition eventually destroyed the collecting lymphatic channels resulting in occlusion (14). Furthermore, VLNT has significantly reduced the incidence of severe cellulitis postoperatively, reducing the need for prophylactic antibiotics, which may improve patient morbidity, health care cost, and lowers the risk for antibiotic-resistance bacteria (39,42). Additionally, a recent meta-analysis demonstrates harvesting of level I lymph nodes is associated with low donor site morbidity, with main patient concern reported of beard hair growth (43). Treating lymphedema with simultaneous VLNT is a promising emerging technique however larger longitudinal studies with longer follow up (>24 months postoperative) studies are required to validate its true utility.

Figure 3 Submandibular and submental nodes with their draining facial artery and vein artery anastomosed to the deep inferior epigastric artery and vein. Reproduced with permission from Phan R, Seifman MA, Dhillon R, et al. Use of submental and submandibular free vascularized lymph node transfer for treatment of scrotal lymphedema: Report of two cases. Microsurgery 2020;40:808-13. https://doi.org/10.1002/micr.30651.

Several clinical and animal studies have demonstrated that redistribution of lymphatics can be achieved spontaneously after a transpositional flap including lymphatic bundles to replace missing or damaged lymphatic chains (44-51). Slavin et al. studied the use of rectus abdominis myocutaneous flap in the treatment of tail lymphedema in a rat model (45). The myocutaneous flap was raised and inset over lymphatic obstruction created in the tail. Using lymphoscintigraphy and fluorescence micro-lymphangiography, the authors restored lymphatic continuity and function. Alongside the success of and potential for lymphatic regeneration has come the development of free flaps containing lymphoid tissue (45). The replication of animal model studies to stimulate and treat human lymphedema has been challenging due to the remarkable regenerative capacity of lymphatics and formation of collateral pathways around congested lymphatics in animal models compared with humans. Furthermore, animal models use significant surgical manipulation and may remove extensive amounts of tissue mass to dissect lymphatic vessels and nodes to achieve lymphangiogenesis which is not feasible in humans.

Lin et al. demonstrated a novel technique of groin VLNT for reconstruction of post-mastectomy upper extremity lymphedema (31). The hypothesis is that vascularized lymphoid tissue has internal pumping and suction driven by the pressure difference between the arterial and venous systems. The subcutaneous hydrostatic tissue pressure reduces and an expanded ‘catchment’ area for lymph drainage from surrounding tissue is recruited. Over time the lymphedema resolves with sufficient opening of old lymphatic channels and formation of new lymphatics by way of lymphogenesis (31). The study transferred a groin flap using superficial inguinal lymph nodes which were inset into the lymphedematous wrist. At a mean of 56.31 months follow up, reductions in arm circumference were found in 12 of 13 patients with a mean reduction rate of 50.55%. They found one wound infection with no donor site complications, and no lymphedema in the abdomen or lower limbs (31). Viitanen et al. reviewed 13 patients who underwent groin lymph node transfer to the axilla for treatment of lymphedema (52). Of 13 patients, four developed seroma, two developed donor site wound infection and three had delayed wound healing. In two cases, they dissected the cutaneous femoral nerve skin area before a lymphoscintigram was performed post groin lymphatic transfer. In six of 10 patients, the lymphatic transport index lowered in comparison with the contralateral side. Two of the 10 patients developed abnormal lymphatic function of the donor site limb (52). Therefore, VLNT to the upper limbs is a good treatment with few complications, however more studies of greater cohort size and follow up time is needed to validate these findings.

An overlying skin island can also be taken for flap monitoring if desired. Donor site morbidity is limited, with reduced risk of regional lymphedema in the head and neck compared to the limbs. Scar visibility and contour deformity remain an issue however it is uncommon for patients to complain of after neck dissection for malignancy (53).

While age and gender were evaluated in this study, the study was not powered to look at finer effects of aging, especially with the use of an arbitrary divisor of 60 years of age. Similarly, BMI and ethnicity were not assessed. A potential bias also exists with the pathology and pathologic assessment, whereby processes can cause clumping/matting of nodes, reducing the number of counted nodes. Similarly, reactive nodes are bigger and may overestimate the number of nodes.

Conclusions

A mean of 5.2±2.9 lymph nodes was identified in level I of neck contributing to the growing body of evidence. This study’s findings validate the level I of the neck offers a consistent quantity of lymph nodes and is suitable for VLNT as potential lymphedema treatment. The current literature states VLNT is an effective technique for lymphedema treatment, however, surgeons performing these procedures must have detailed knowledge of anatomy of these regions to avoid straying into drainage pathways of extremities and causing potential donor-site morbidity.

Acknowledgments

Funding: None.

Footnote

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-23/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-23/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-23/coif). WMR serves as an unpaid editorial board member of Gland Surgery from March 2023 to February 2028. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Victorian Health Research Ethics Committee, as a low and negligible risk study (No. PHLNR2021). Informed written consent was obtained from included participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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