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- Materials and methods
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Relatively little is known about the functional anatomy of the lymphatic vessels draining the skin. To address this issue, we previously created a three-dimensional computer model of skin lymphatic drainage, using melanoma lymphoscintigraphy (LS) data from 5232 patients. In this study we sought to extend our model by performing a detailed statistical analysis of the mapped LS data to characterize the functional anatomy of the superficial lymphatics without any a-priori spatial bias. We investigated the commonly held assumption that lymphatic drainage is symmetric between the two sides of the body. Results indicated that, with the exception of the lower anterior torso, posterior leg and a small section of the posterior torso, most skin regions with sufficient data showed symmetric drainage. LS data from each symmetric skin region were then reflected to the opposite side of the body to provide an increased LS dataset for subsequent analysis. Cluster analysis was then applied to this reflected LS dataset to group regions of skin that drained in a similar manner. Results defined nine large clusters of skin, largely draining to the dominant axillary, groin, cervical level II and preauricular node fields. Each of the four axillary and groin node fields defined large clusters of skin on the torso, dividing it into regions similar to the historical ‘Sappey’s lines’, although a fifth region of highly ambiguous drainage was also shown in the anterior and posterior center of the torso. Collectively, these results provide important new insights into skin lymphatic drainage, both improving and quantifying our understanding of functional lymphatic anatomy.
- Top of page
- Materials and methods
- Author contributions
A relatively small number of detailed studies have been conducted to characterize the human lymphatic system and very few have been carried out to investigate the lymphatic vessels draining the skin. One of the most comprehensive and influential studies was that by Sappey (1874), who investigated lymphatic drainage by injecting mercury into the interstitial tissues and lymphatic vessels of cadavers. He published his results in an extensive lymphatic atlas that contained a number of highly detailed anatomical drawings.
For over 100 years, the atlas of Sappey (1874) and his conclusions about lymphatic drainage were accepted as correct by the scientific and medical community. He claimed that lymphatic drainage from the skin of the trunk was symmetric between the two sides of the body, never crossing the vertical midline of the body or a theoretical horizontal line drawn around the waist. These lines were termed ‘Sappey’s lines’ and defined four zones of skin on the trunk, from which Sappey (1874) claimed that lymphatic drainage would occur to the corresponding axillary or groin node field.
The concepts of Sappey (1874) about skin lymphatic drainage went largely unchallenged until the 1970s when new information became available. Most of this new information came from lymphatic mapping studies in patients with melanoma using lymphoscintigraphy (LS) imaging, which is used to locate the lymph nodes draining a primary melanoma site on the skin (Uren et al. 1999). Sugarbaker & McBride (1976) showed that lymphatic drainage was unpredictable from a strip of skin 2.5 cm wide on either side of Sappey’s lines. These authors still maintained, however, that drainage from skin outside these zones would follow the original predictions of Sappey (1874) and occur to the axillary or groin node fields. Additional investigation over subsequent decades demonstrated further variability of skin lymphatic drainage that often contradicted the guidelines of Sugarbaker & McBride (1976) (Fee et al. 1978; Meyer et al. 1979; Sullivan et al. 1981; Bergqvist et al. 1984; Eberbach & Wahl, 1989). Norman et al. (1991) expanded the area of ambiguous drainage to include the head and neck and a much larger area of skin on the trunk, up to 11 cm on either side of Sappey’s lines.
More recently, LS studies conducted at the Sydney Melanoma Unit (SMU) have also shown that lymphatic drainage is highly variable between patients and that the guidelines of Sappey (1874) would predict drainage to the wrong node field in 30% of patients (Thompson & Uren, 2005). LS studies conducted at other melanoma treatment centers around the world have similarly shown that skin lymphatic drainage is clinically unpredictable (Leong et al. 2000; O’Toole et al. 2000; Statius Muller et al. 2002). This observed variability and clinical unpredictability highlight the need for a detailed statistical analysis of available data and pre-empt the need for a reclassification of the key anatomical features of functional lymphatic drainage.
Our previous work has involved mapping the SMU’s extensive LS database of over 5232 patients onto a 3D computer model of the skin and lymph nodes (Reynolds et al. 2007a). In brief, the skin model was constructed of 1098 finite elements (Bradley et al. 1997) using anatomical images from the Visible Human dataset (Spitzer et al. 1996). The SMU defined 43 separate node fields that directly drained the skin as listed in Table 1 and each of these node fields has also been modeled relative to the skin model using Visible Human images. Each of the primary melanoma sites in the LS database was then mapped onto the skin model using techniques previously reported by Reynolds et al. (2007a), giving the mapped model in Fig. 1, which shows the melanoma sites scaled according to their frequency. Corresponding draining node fields for each patient were mapped onto one or more of the model’s 43 node fields (Reynolds et al. 2007a).
Table 1. Number of cases in the lymphoscintigraphy database that drained to each node field. Note that most node fields are located on both the left and right sides of the body.
|Node field||No. of cases|
|Head and neck node fields|
| Cervical level I||86||101|
| Cervical level II||274||295|
| Cervical level III||82||52|
| Cervical level IV||58||46|
| Cervical level V||209||201|
| Supraclavicular fossa||206||193|
|Torso and upper limb node fields|
| Triangular intermuscular space||95||97|
| Internal mammary||2||4|
| Costal margin||2||5|
| Paravertebral or para-aortic||36|
| Upper mediastinal||1|
|Lower limb node fields|
|Other node fields|
| Interval node||404|
Visualization of these mapped data showed that the most variable drainage patterns included skin on the head and neck (Reynolds et al. 2009), and skin on the torso close to Sappey’s lines (Reynolds et al. 2007b). This mapped model has provided the platform for the present study, where we have statistically analyzed patterns of skin lymphatic drainage. We investigated the last remaining assertions of Sappey (1874) that lymphatic drainage is symmetric between the two sides of the body. We then sought to functionally group regions of skin that drained in a similar manner, moving away from a-priori historical drainage assumptions towards a purely data-driven approach.
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- Materials and methods
- Author contributions
The statistical methods that were implemented have allowed for a detailed quantitative analysis of skin lymphatic drainage. The mapped anatomical model has enabled knowledge of the superficial lymphatics to move beyond anatomically based definitions of drainage based largely on variants of Sappey’s lines towards a purely data-driven approach.
The implied and arguably final remaining assumption from the work of Sappey (1874), that skin lymphatic drainage is symmetric, has been tested. The results indicated that most skin regions did in fact show symmetric lymphatic drainage about the coronal midline of the body. Skin regions that displayed asymmetry included the lower posterior neck, lower anterior torso, posterior legs and small regions of the anterior forehead and posterior torso. It was apparent, however, that the asymmetry in these regions was probably due to an asymmetric distribution of melanoma sites, which would have influenced the draining node fields. The lower anterior neck and lower coronal neck could not be analyzed because there were insufficient data. Hence, it is possible that both the asymmetric regions and those without sufficient data would have been symmetric if more LS data had been available.
This is a significant result, as other studies have indicated asymmetry in the lymphatic system. Investigations into the distribution of lymph nodes on either side of the body have shown that there are more lymph nodes on the right side than the left side (Sapin, 1980). In addition, analyses on patients with breast cancer with axillary node drainage have shown that, although there are more axillary lymph nodes in the left side of the body, they are smaller in size than those on the right side (Capello et al. 2001; Dane et al. 2008). Further to this asymmetry of the lymphatic anatomy, it has also been shown that there is a left-sided lateralization in patients who develop cutaneous melanoma (Brewster et al. 2007).
A number of reasons have been put forward in order to explain these inherent asymmetries, including the embryological development of the lymphatic system and various genetic factors but a full explanation remains unclear. It is known that the lymphatic system begins to develop at 5 weeks gestation, in parallel to the blood vasculature system (Oliver, 2004). The lymphatic capillaries develop in a manner similar to blood vessels and major lymph channels usually follow the course of the main veins (Uren et al. 1999). Hence, it is likely that if the veins are symmetric then the lymphatic vessels will also be symmetric. Although the major veins in the limbs and head and neck are symmetric in topology, in the torso they are not entirely symmetric due to the asymmetric position of the heart. This could provide a tendency for the lymphatic vessels in the torso to follow an asymmetric pattern. Given this knowledge it is noteworthy that a large area of the torso showed symmetrical lymphatic drainage.
Although this study shows that the entire body may have symmetric lymphatic drainage, it is important to remember that these results are based on accumulated data. It is possible that individual patients may still have asymmetric drainage and nuclear medicine physicians and clinicians should continue to treat specific individuals with this in mind.
There were a number of aspects of the symmetry testing that could have been carried out differently, which may have altered the results. Primarily, division of the skin into separate regions was not a clearly defined procedure. The torso was first divided according to its anatomy, into anterior and posterior regions both above and below the umbilicus. Further division of the upper anterior torso was based on the geometrical boundaries defined on the skin model, which were arbitrarily defined during skin mesh construction (Reynolds et al. 2007a). Meanwhile, the upper and lower limbs were divided according to the lymphatic anatomy in these regions, even though there were enough data in some areas to support a more spatially refined analysis. A number of alternative skin divisions for each of these regions could have been used, which may have given different results. However, as a significant proportion of regions showed symmetry using different skin division methods, these results are likely to be robust.
It is also important to note that the modified LS data that were required to implement the GLM method meant that the data were no longer independent. It was possible to correct for this non-independence using generalized estimator equations (GEEs) (Hardin & Hilbe, 2002); however, the current library of GEE functions in the R statistical package was unable to handle the quantity of LS data in the database. Utilizing GEEs would have given the same model parameter estimates as a GLM, although the SEs for these estimates would have been inflated. This means that skin regions that were considered asymmetric using the GLM approach may have been considered symmetric using GEEs. Therefore, some of the asymmetric skin regions could in fact be symmetric if the data had been corrected for non-independence. The GLM approach was still considered appropriate, however, as it provided a conservative assessment of symmetry.
Subsequent cluster analysis has provided additional insight into regions of skin that showed functionally similar patterns of lymphatic drainage, based solely on the LS data. The results showed a clear anatomic division of the skin into nine separate clusters, which primarily grouped regions of skin according to the dominant draining node fields. Interestingly, the clusters draining primarily to axillary and groin node fields divided the trunk into regions comparable to Sappey’s lines. Even though there was variability of lymphatic drainage on the torso between individuals, Sappey’s lines appeared to conform to the most likely drainage behavior of these data. Cluster 3, however, which formed in the center of the anterior and posterior torso (shown in Fig. 5), clearly demonstrated that there was still a significant region of skin with ambiguous drainage to axillary and groin node fields. Note that the sparsity of data available in the anterior groin region (shown in Fig. 1) accounts for considerable asymmetry in the upper boundaries of the groin clusters. These results can be directly compared with the heat maps that we presented in our previous work (Reynolds et al. 2007b), which visualized the likelihood that the skin drained to the axillary or groin node fields. Regions of skin displayed on the heat maps that showed approximately 100% likelihood of drainage to the axillas or groin node fields largely comprised the axillary and groin clusters.
As with symmetry testing, the cluster analysis also had limitations. The cluster algorithm grouped LS data according to elements on the skin model. The advantage of this approach was that it was computationally straightforward to implement; however, it also meant that the data were homogenized across elements that were arbitrarily chosen during skin mesh construction. Restriction of the boundaries of each cluster to the boundaries of the skin elements was another limitation. In an ideal situation, uniformly sized skin regions would have been used rather than skin elements that have large variations in size. In addition, there would be adequate LS data to provide probabilities that represent the entire population. A number of elements on the skin mesh did not have any data present and therefore could not be grouped in a cluster. To enable a comprehensive cluster analysis, more LS data would be required.
Although each of the statistical tests that were used had inherent limitations, they have provided important new insights into skin lymphatic drainage. Significantly, it has been demonstrated that lymphatic drainage of the skin is likely to be entirely symmetric. The cluster analysis has clearly defined areas of skin that nearly always showed drainage to the ipsilateral axilla, groin, cervical level II and preauricular node fields. In addition, the drainage statistics and associated confidence intervals that were calculated have provided quantitative information about the functional anatomy of the superficial lymphatics that was previously unknown.