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. 2020 Feb 27;236(6):1146–1153. doi: 10.1111/joa.13167

Anatomy of the lymphovenous valve of the thoracic duct in humans

Lomani Archibald O’Hagan 1,2, John Albert Windsor 2, Anthony Ronald John Phillips 3, Maxim Itkin 4, Peter Spencer Russell 2,3, Seyed Ali Mirjalili 1,✉
PMCID: PMC7219621  PMID: 32103496

Abstract

The majority of lymph generated in the body is returned to the blood circulation via the lymphovenous junction (LVJ) of the thoracic duct (TD). A lymphovenous valve (LVV) is thought to guard this junction by regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system. Despite these important functions, the morphology and mechanism of this valve remains unclear. The aim of this study was to investigate the anatomy of the LVV of the TD. To do this, the TD and the great veins of the left side of the neck were harvested from 16 human cadavers. The LVJs from 12 cadavers were successfully identified and examined macroscopically, microscopically, and using microcomputed tomography. In many specimens, the TD branched before entering the veins. Thus, from 12 cadavers, 21 LVJs were examined. Valves were present at 71% of LVJs (15/21) and were absent in the remainder. The LVV, when present, was typically a bicuspid semilunar valve, although the relative size and position of its cusps were variable. Microscopically, the valve cusps comprised luminal extensions of endothelium with a thin core of collagenous extracellular matrix. This study clearly demonstrated the morphology of the human LVV. This valve may prevent blood from entering the lymphatic system, but its variability and frequent absence calls into question its utility. Further structural and functional studies are required to better define the role of the LVV in health and disease.

Keywords: lymphatic system, lymphovenous junction, lymphovenous valve, thoracic duct

The lymphovenous valve of the thoracic duct (TD), seen from the venous side, and using microcomputed tomography. Our study demonstrated the morphology of this valve in humans, which historically has received little attention. Interest in the TD and the lymphovenous junction (LVJ) is growing as the lymphatic system is understood to play a key role in the promotion of systemic inflammation and organ dysfunction during acute and critical illness. This has implicated the terminal TD and LVJ as locations for potential minimally invasive intervention, highlighting the importance of understanding the anatomy of this area.

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1. INTRODUCTION

Lymph is returned to the blood circulation via bilateral lymphovenous junctions (LVJs), typically found at the confluence of the jugular and subclavian veins (the venous angles). Lymphovenous valves (LVVs) are thought to guard these connections, regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system (Breslin et al., 2019). The vast majority of the body's lymph, including chyle from the gut, is carried by the thoracic duct (TD), which terminates via the left LVJ (for simplicity, ‘LVJ’ is used hereafter to refer to the LVJ associated with the TD). This connection is important for fluid balance, nutrition and immune function. In disease, the LVJ is a portal to the bloodstream for metastatic cancer cells (Karaman and Detmar, 2014), as well as for toxic and inflammatory factors that promote organ dysfunction in critical illness (Deitch, 2001, 2010, 2012; Fanous et al., 2007; Windsor et al., 2017; Shanbhag et al., 2018).

Clinically, the LVJ can be used in interventional radiology to access the lymphatic system [e.g. TD embolisation for treatment of chylothorax (Toliyat et al., 2017; Kariya et al., 2018)]. Furthermore, the terminal TD has been identified as a frontier for a range of minimally invasive diagnostic and therapeutic opportunities, including TD drainage for critical illness (Wang et al., 2016; Windsor et al., 2017; Itkin and Nadolski, 2018). A precise knowledge of the anatomy of the terminal TD and the LVV is essential for the development of novel medical devices in this area.

Despite the physiological and clinical significance of the LVJ, its structure and function remains unclear in humans. Although the LVV is thought to play a key role in separating the lymphatic and venous systems at the mammalian LVJ (Srinivasan and Oliver, 2011; Hess et al., 2014), cadaveric studies show that a valve is not consistently present at this location in humans (Van Pernis, 1949; Jacobsson, 1972; Miyakoshi et al., 1984), and in vivo ultrasonography has only visualised valves at the LVJ in 40% of individuals (Seeger et al., 2009).

There is a paucity of clear and direct visual evidence of the LVV in the human anatomical literature. Descriptions of the valve are often conflicting, with current understanding based on written descriptions (Langford, 2002), cartoon diagrams (Pflug and Calnan, 1968; Jacobsson, 1972), and two‐dimensional ultrasound images (Seeger et al., 2009; Kunze and Staritz, 2017). Studies have investigated the histology of the human LVV (El Zawahry et al., 1983; Shimada and Sato, 1997; Chiba et al., 2017), but these do not convey the structure's overall form. The aim of the present study was to investigate the morphology of the LVV in humans.

2. METHODS

The TD and the great veins of the left side of the neck (internal jugular, subclavian and brachiocephalic) were harvested from 16 formalin‐embalmed human cadavers. The cadavers were embalmed using Dodge anatomical mix (Dodge Chemical Co. Inc.). All cadaveric tissue was obtained under the New Zealand Human Tissue Act 2008, from cadavers bequeathed to the University of Auckland for research and teaching purposes. Cadavers with a clinical history of congestive cardiac failure and/or liver cirrhosis were excluded from this study.

The thoracic part of the TD was identified in the posterior mediastinum, dissected superiorly and removed en bloc with the veins. Venotomy was performed and the internal venous lumina examined. A guidewire (0.9 mm; Cook Medical) and antegrade flushing of the TD with distilled water were used to identify the LVJ (or LVJs, if multiple) associated with the TD.

In four cadavers, the LVJ could not be confidently identified. In total, the LVJs from 12 cadavers were successfully identified and examined (six males, six females; age range 59–93 years, mean age 81 years). Low‐magnification photographs were taken with a surgical microscope (Leica MZ16) mounted with a digital camera system (Nikon DS‐5Mc‐U1 running NIS Elements software).

Microcomputed tomography (microCT; Bruker SkyScan 1172) was performed on 12 LVJs (from seven different cadavers, selected randomly). No chemical processing or stains were used on the tissue. MicroCT data were examined and analysed using three‐dimensional visualisation software (CTVOX, version 3.3; Bruker).

For microscopic analysis, eight LVJs (from six different cadavers, selected randomly) were dehydrated with ethyl alcohol and embedded with paraffin wax. Sections 10 µm in thickness were cut with a rotary microtome (Leica HistoCore MULTICUT). Sections were stained with Masson's trichome to highlight smooth muscle (red) and collagen fibres (blue; Suvarna et al., 2019).

3. RESULTS

3.1. Gross anatomy

The terminal TD commonly branched and had multiple openings into the veins. Thus from 12 cadavers, 21 LVJs associated with the TD were identified and examined in total. Valves were present at 15 of these 21 LVJs (71%). Valves were absent at six LVJs (29%). See Table 1 for summary.

Table 1.

Summary of human cadaveric dissections.

Subject identifier Number of LVJ(s) Valve status of LVJ(s) Valve morphology
1 1 Present Bicuspid semilunar
2 2 Absent in 2/2 –
3 1 Absent –
4 2 Present in 2/2 2× bicuspid semilunar
5 3 Present in 3/3

2× bicuspid semilunar

1× mixed semilunar‐ostial
6 4 Present in 4/4

3× bicuspid semilunar

1× mixed semilunar‐ostial
7 1 Absent –
8 1 Absent –
9 1 Present Bicuspid semilunar
10 1 Present Bicuspid semilunar
11 1 Present Bicuspid semilunar
12 3 Present in 2/3 2× bicuspid semilunar
Total subjects = 12 Total LVJs = 21 Total LVVs = 15

Total morphologies:

13× bicuspid semilunar

2× mixed semilunar‐ostial
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Abbreviations: LVJ, lymphovenous junction; LVV, lymphovenous valve.

When present, the LVV was bicuspid and the valve cusps were typically semilunar, originating from the internal lymphatic wall immediately proximal to the LVJ. Each cusp projected downstream (towards the vein) and into the lumen, terminating as a free edge at the LVJ. In this way, a sinus was formed to the downstream and leeward side of each cusp. The free edge of each cusp was suspended across the LVJ. Its lateral‐most points were tethered to the margin of the orifice, either separately, or by forming a buttress with the opposite cusp (Figures 1 and 2).

Figure 1.

Figure 1

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Example of a lymphovenous valve (from subject 6). Scale bar ≈ 2 mm. (A) The lymphovenous junction (LVJ), viewed from the venous side. An asymmetrical bicuspid semilunar valve was present at the orifice. The valve sinuses were filled with water and scissors (metallic object) were placed in the larger sinus. The free edges of the cusps formed a buttress on one side (arrow) but anchored separately on the opposite side (arrowheads). (B) The valve splayed open using the scissors. (C) Microcomputed tomography of the valve, longitudinal cross‐section. The semilunar cusps (arrows) originated proximal to the LVJ. Grey dots aid visualisation of the larger cusp, which was faintly resolved in this plane. V, venous lumen; TD, thoracic duct lumen

Figure 2.

Figure 2

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Example of a lymphovenous valve (subject 11). Scale bar = 2 mm. Another example of an asymmetrical bicuspid semilunar valve. In this specimen, the free margins of the valve cusps merged on both sides, forming two buttresses (arrowheads) that tethered the valve to the lymphovenous junction. This tissue specimen was excised and held between forceps (metallic objects).

The LVV cusps were translucent. The surface of the cusps formed many ridges that ran parallel to the free edge, which was thickened (Figure 3A). The origin of each cusp described a semi‐elliptical curve on the internal TD wall. This could be felt externally as a slight thickening in the vessel wall and was demonstrated as an opaque line when the tissue was backlit (Figure 3B).

Figure 3.

Figure 3

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Detail of a lymphovenous valve (specimen from Fig. 1, excised and trimmed). Scale bars = 2 mm. (A) Ridges were present on the downstream/venous surface of the cusps and the free borders were thickened (arrowheads). Forceps (metallic object) were used to reflect the tissue. (B) The semi‐elliptical line of origin of the valve cusp (arrows) could be seen when the tissue was backlit

The size and position of the valve cusps relative to one another were variable. One cusp was typically wider or deeper than its pair (Figures 1 and 2), or the cusps were not aligned directly opposite one another (Figure 6). In two cases, the LVV morphology was ‘mixed’: one cusp was semilunar, but the other cusp was ostial (i.e. originated from the margin of the orifice itself, projecting flush with the inner surface of the vein wall; Figure 4).

Figure 4.

Figure 4

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Examples of mixed morphology lymphovenous valves (from subjects 6 and 5). Scale bars ≈ 2 mm. (A) In this case (subject 6), the lymphatic lumen joined the venous lumen tangentially. One valve cusp was semilunar (arrow) and formed a sinus, while the other cusp was ostial (asterisk), projecting in line with the vein wall. (B) The mixed morphology valve from subject 5: semilunar cusp (arrow), ostial cusp (asterisk)

Six of the 21 LVJs lacked valves (29%). In these cases, the LVJs were simple ovoid orifices in the vein wall (Figure 5).

Figure 5.

Figure 5

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Examples of valveless lymphovenous junctions (LVJs; A/B from subject 3, C/D from subject 2). Scale bars ≈ 2 mm. (A) The LVJ in this case was a simple ovoid opening in the vein wall (arrow). It was located partially under a cusp of the internal jugular vein valve (asterisk). (B) The LVJ (from A) was cut (scissor‐lines) and the tissue reflected to reveal a terminal lymph chamber. The thoracic duct (TD) and other lymphatic trunks opened into the back of this chamber. Valve‐like structures were present at the openings of these trunks into the back of the chamber. (C) In this case, the terminal thoracic duct bifurcated and entered the vein obliquely, forming two adjacent LVJs (arrows), both were valveless and located under the cover of a venous valve cusp (cut and reflected). (D) View looking directly up the thoracic duct lumina (from C). Pre‐terminal valves (arrowheads) were seen further upstream in the lymphatic lumina. The valve on the left was open, the valve on the right was closed

In four cadavers, the TD emptied into a terminal lymphatic chamber, or sac, and this sac formed the LVJ proper (Figure 5).

The large venous valves of the internal jugular and subclavian veins were consistently present. In five cadavers, a cusp of these valves (which were bicuspid or tricuspid) either partially or fully overlaid the LVJ (Figure 5).

MicroCT allowed non‐destructive examination of the cross‐sectional anatomy of the LVJ and LVV (Figures 1 and 6). Computer‐generated volume renderings that demonstrated morphology in three dimensions were also produced (Figure 6). These reconstructions compared favourably with low‐magnification photographs taken with the surgical microscope (Figure 7).

Figure 6.

Figure 6

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Microcomputed tomography of valved and valveless lymphovenous junctions (LVJs; both from subject 12). Scale bars = 1 mm. (A) Example of a bicuspid semilunar valve; note the valve cusps (arrows) were not aligned directly opposite one another. (B) Cutaway volume rendering of (A). (C) Valveless LVJ. In this case, two terminal branches of the thoracic duct reanastomosed and a poorly formed valve‐like structure was located at this confluence, but a valve was absent at the actual LVJ (arrow). (D) Cutaway volume rendering of (C). V, venous lumen; TD, thoracic duct lumen

Figure 7.

Figure 7

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Computer‐generated reconstruction of a lymphovenous junction (LVJ) using microcomputed tomography data, compared to a photograph (bottom right) of the same specimen seen in situ during cadaveric dissection. Scale bar ≈ 2 mm. This specimen was from subject 12 and is seen in cross‐section in Fig. 6c. TD, thoracic duct; LVJ, lymphovenous junction; V, internal venous wall (in this case, the brachiocephalic vein)

3.2. Microscopic anatomy

Eight LVJs (from six different cadavers) were examined using light microscopy. Each LVV cusp comprised an endothelium that enveloped a thin core of connective tissue matrix (Figure 8). The subendothelial layer stained strongly for collagen. Flecks of smooth muscle were sparsely distributed amongst the collagen fibres. Erythrocytes were present in the venous and lymphatic lumina.

Figure 8.

Figure 8

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Low‐magnification photomicrograph of the lymphovenous junction (LVJ) using Masson's trichrome stain (from subject 1). The thoracic duct merges with the vein tangentially. A valve was present at the LVJ (arrows). Collagen is stained blue, smooth muscle (and erythrocytes) are stained red. V, venous lumen; TD, thoracic duct lumen

4. DISCUSSION

To the best of our knowledge, this was the first study to clearly demonstrate the morphology of the LVJ and LVV of the TD in humans.

In the present study of 12 human cadavers, 21 LVJs associated with the TD were identified. Valves were present at the LVJ in 71% of cases (15/21) and were absent in the remainder. When present, the LVV was typically a bicuspid semilunar valve. The relative size and position of the valve cusps varied (Figure 9). Each semilunar cusp originated proximal to the LVJ, describing a semi‐elliptical arch on the internal lymphatic wall. The cusps projected into the terminal TD lumen, such that a sinus was formed to the downstream and leeward side of each cusp. At the LVJ, the free margins of the cusps were tethered to the orifice, either separately, or by fusing with the opposite cusp to form a buttress. All 15 valves in the present study conformed to this description (i.e. bicuspid semilunar), except for two ‘mixed’ morphology valves. In these cases, a single cusp of the LVV formed in an ostial fashion (i.e. originated from, and projected across the LVJ), while the other cusp was semilunar and formed a sinus. No fully ostial valves were observed in the present study.

Figure 9.

Figure 9

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Schematic diagram summarising the variable morphology of the lymphovenous valve observed in the present study. The two cusps comprising the valve may vary in size (left), or they may not be aligned directly opposite one another (right). In some cases, one cusp may be semilunar and form a sinus, but the other cusp may arise directly at the lymphovenous junction, projecting in line with vein wall (mixed morphology) (centre). Green = thoracic duct wall; blue = vein wall; black = lymphovenous valve cusps

The bicuspid semilunar morphology demonstrated in the present study is consistent with many previous descriptions and diagrams of the LVV in the human anatomical literature (Bartholin, 1653; Cruickshank, 1790; Jacobsson, 1972; Miyakoshi et al., 1984), but is in contrast with the conventional understanding of the ‘ostial valve’, described by some authors (Pflug and Calnan, 1968; El Zawahry et al., 1983; Langford, 2002). It is noteworthy that none of the studies reporting ostial valves at the human LVJ have furnished clear visual evidence of the ostial morphology, instead relying on written descriptions and cartoon diagrams based on human and canine cadaveric inspection (Pflug and Calnan, 1968; El Zawahry et al., 1983; Langford, 2002). Single flap‐like structures (Bresadola et al., 1973; Shimada and Sato, 1997), and a complex multi‐leaflet morphology (Chiba et al., 2017) have also been described at the human LVJ, but these were not observed in the present study.

The LVV is thought to guard the confluence of the lymphatic and venous systems in mammals (Srinivasan and Oliver, 2011; Breslin et al., 2019). Interestingly, this study demonstrated that no valves were present at over a quarter of LVJs (six of 21 LVJs). Other cadaveric studies also suggest that the human LVJ may commonly be without a valve (Parsons and Sargent, 1909; Van Pernis, 1949; Jacobsson, 1972; Teixeira, 1972; Cui, 1984; Miyakoshi et al., 1984; Zavgorodnii et al., 2002), and the terminal‐most valve (of the TD) may be located anywhere within the last 10–30 mm of the TD (Van Pernis, 1949; Jacobsson, 1972; Miyakoshi et al., 1984). Using high‐definition ultrasonography, Seeger et al. (2009) visualised the terminal TD in vivo in 96% of human subjects (n = 585), but valves were seen at the LVJ in only 40% of individuals. The apparent absence of the LVV is interesting. Especially considering the recently proposed physiological clotting mechanism, lymphovenous haemostasis, which posits that LVVs, as well as platelet plugs, are required at the LVJs to maintain normal separation of the blood and lymphatic systems throughout life (Hess et al., 2014; Welsh et al., 2016).

The absence of valve leaflets at the LVJ does not necessarily preclude the junction itself from acting as a physiological valve. Multiple authors have observed the TD obliquely traversing the vein wall before forming the actual LVJ, likening the arrangement to the oblique course of the ureter across the bladder wall (i.e. the ureterovesical junction; Buy and Argaud, 1906; Kampmeier, 1928; Rouvière, 1932), or the ampulla of Vater within the duodenal wall (Parsons and Sargent, 1909). It has been hypothesised that the intramural portion of the TD would be subject to the distension of the vein at times of increased venous pressure, which would obliterate the lymphatic lumen and render blood reflux impossible (Buy and Argaud, 1906; Rouvière, 1932). Moreover, Zavgorodnii et al. (2002) studied the number and orientation of the smooth muscle myocytes surrounding the intramural portion of the terminal TD, and found that they formed a distinct cuff muscle, which was thought to function as a terminal sphincter in life. Modern medical imaging studies have not yet corroborated or repudiated these inferences. TDs that joined the veins tangentially and travelled within the vein wall were observed in the present study, although no comment can be made on the functional significance of this based on morphological analysis alone. Further in vivo imaging studies are required to clarify the functional anatomy of this area. High‐definition ultrasonography or optical coherence tomography seem to be suitable imaging methods as they are minimally invasive and allow real‐time visualisation of intra‐luminal structures. Visualising the LVV in vivo, across a range of morphologies (including when absent), and under various physiological conditions (e.g. high central venous pressure) are important next steps in understanding the significance of this structure.

In one‐third of the cadavers dissected in the present study, the TD did not directly anastomose with the veins. Instead, it joined a discrete chamber, or lymph sac, and it was this chamber that formed the LVJ proper. Other studies have described similar lymph sacs in the adult (Cui, 1984; Chiba et al., 2017). The embryology of this area would suggest that these structures represent a persistent portion of the left jugular lymph sac, the embryonic precursor of the terminal TD (Kampmeier, 1928; van der Putte, 1975).

Also observed in this study was the close proximity of the LVJ to the large venous valves belonging to the internal jugular and subclavian veins. This has been reported by numerous other studies (Cruickshank, 1790; Buy and Argaud, 1906; Parsons and Sargent, 1909; Kampmeier, 1928; Pflug and Calnan, 1968; El Zawahry et al., 1983; Zavgorodnii et al., 2002). Ultrasound has visualised these proximate venous valves (Seeger et al., 2009), but how they affect lymphatic outflow when they overlie the LVJ is not known. The functional significance of these venous valves, in relation to the LVJ, remains uncertain.

The sample size of the present study limits our ability to confirm other morphological variations described in the literature, these include flap‐like (Shimada and Sato, 1997) and ostial (Pflug and Calnan, 1968) variants. However, neither of these other morphologies have been directly demonstrated, with authors instead relying on histological sections, cartoon diagrams, or written descriptions.

In conclusion, the present study confirmed that a valve is inconsistently present at the termination of the TD into the venous system in humans. When the valve is present, it is typically bicuspid and semilunar in morphology. The relative size and position of its cusps are variable. Further structural and functional studies are needed to understand how this part of the human body works in health and disease.

CONFLICTS OF INTEREST

None declared.

ACKNOWLEDGEMENTS

The authors wish to acknowledge those individuals who bequeathed their bodies to the University of Auckland School of Medicine for research. This study could not have taken place without their generous donation. The authors also wish to thank Dr B. Ratnayake, for his assistance in the collection of cadaveric tissue, and Dr S. Amirapu and Mr D. Gernecke for their expertise in histology and microtomography respectively.

O’Hagan LA, Windsor JA, Phillips ARJ, Itkin M, Russell PS, Mirjalili SA. Anatomy of the lymphovenous valve of the thoracic duct in humans. J. Anat. 2020;236:1146–1153. 10.1111/joa.13167

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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