This is the largest published 3D cross sectional imaging dataset on the occurrence of healthy LN within the lymphatic drainage system of breast cancer patients. Our results indicate that LN are highly unlikely to be seen in CT imaging in LIII and thus this information should be taken into account during assessment of diagnostic imaging of breast cancer patients. Further we could show that different contouring recommendations are likely to result in different coverages of the healthy lymphatics and might have an impact on lymphedema risk.
With surgery and radiotherapy being the two pillars of local therapy in breast cancer, an inclusive definition of the same regions is imperative [11–13]. The most difficult question of lymphatics in breast cancer, is how to translate surgical information into cross sectional imaging information (such as CT, used in radiotherapy).
First of all, surgical studies are not always congruent with each other. As one of the first, Berg et al. investigated the localization and the positivity of axillary LN removed during radical mastectomies in 324 cases and related them to the primary tumor. He defined level I inferior and lateral, level II behind and level III medial and superior to the m. pectoralis minor muscle. Most LN were in level I (45%), then in level II (35%) and level III (20%) regardless of pathologic or healthy [14]. More recent studies with different surgical axillary approaches have shown a slightly different outcome. In 227 patients Clough et al. showed that the SLN localization in the axilla - using dye or nanocolloid tracer - was 214 (94.2%) in Berg’s level I and 13 (5.8%) in level II. While 51 patients have positive SLN, the remaining were negative (176 patients) [15]. In the study of Smith et al. 7370 LN were examined. The median was 18 per specimen. 1698 LN were positive and 5311 were negative. LN were classified according to a proximal (the part below the lower border of the m.pectoralis minor), a middle (between the upper and the lower border) and a distal level (above the upper border). 1177 negative LN were in the proximal level, 2477 in the middle level and 1657 in the distal level. The positive and negative LN combined were mostly located in the middle level (2968 LN of 7009, 42.3%) [16].
Secondly, the surgical information provided by all the SLN and ALND studies is very difficult to be translated into imaging. The definition of the limit of level I of Berg et al. is roughly comparable to the definition of level I by RTOG/ESTRO. Berg’s level II, the nodes behind the muscle, is approximately level II of RTOG/ESTRO. Level III by Berg et al. (superior and medial to the muscle) could be level III of the ESTRO/RTOG – but it is not apparent how far Berg’s level III extends cranially. Further, Berg’s postulated boundaries are quite vague to be translated into cross sectional imaging: modifying the arm position results in a different coverage of the LN levels in 3D imaging [17]. Similarly, Smith et al. describes only caudal and cranial limits of the levels without all other dimensions. In cross sectional imaging however, a three dimensional description is needed, with a definition also of the lateral, medial, anterior, posterior borders. These “lacking” surgical margins are intrinsically determined by the surgeon’s view on the surgical situs, but are elementary for cross sectional imaging [17].
Some educational reviews are available on CT diagnostic imaging and axillary levels. Lengelé et al. postulates the axilla to be limited ventral by the m.pectoralis minor and major, backwards by muscles like the m.latissimus dorsi, lateral there are the muscles of the arm and medial there is the m.serratus anterior [18]. The base is the lower boundary of the major muscle and m.latissimus dorsi, upwards and medially the clavicula and the first rib are the limits. The axilla is divided in level I-III using the inferolateral and superiomedial edges of the m.pectoralis minor and the inferior border of the m.pectoralis major as limitations. Again, drawbacks for the use of this information for treatment planning is that the position of the clavicula is highly dependent on the patient position and there is no clear anatomical correlation between the clavicular position and the location of the lymphatics.
Nonetheless, the atlas presented herein could help in closing the previously described knowledge gap in diagnostic imaging [10]. We could demonstrate, that healthy LN are highly unlikely to be found in level III in cross sectional imaging (only 1% of the 1939 contoured LN were found herein). This result can be taken into account in assessing breast cancer staging CTs with visible LN in level III.
Both, the ESTRO and the RTOG tried to provide a more specific definition of axillary levels for radiotherapy treatment planning in breast cancer taking vessels into account. However, the two definitions are significantly different. The ESTRO level I is limited medial by level II and the thoracic wall, cranial the axillary vein is still included and the humeral head is omitted, lateral there is a line between m.pectoralis major and m.deltoideus, the 4–5 rib is the caudal border, ventral the m.pectoralis minor and major and dorsal the limit is up to the thoraco-dorsal vessels and to a line between m.latissimus dorsi and the intercostal muscles [5]. RTOG’s level I is determined medial by the lateral border of the m.pectoralis minor, cranial the axillary vessels cross the lateral m.pectoralis minor, lateral the boundary is the medial site of the m.latissimus dorsi, the insertion into the ribs of the m.pectoralis major is the caudal border, ventral there is the anterior surface of the m.pectoralis major and m.latissimus dorsi and dorsal it is the anterior surface of the m.subscapularis [19].
Several studies are available on the coverage of pathological LN by these two atlases. None is available on the coverage of the healthy lymphatics. This is highly important as several large studies showed an important oncological effect of regional lymph node irradiation (RLNR) of lymphatics in breast cancer. For e.g. the AMAROS trial compared irradiation for regional control to ALND in cN0 patients with positive SLN. For regional control both options were acceptable. In ALND lymphedema occurs more frequently [2]. A more recent study, underlined these findings [20], with the 5-year cumulative incidence rates of lympedem being 30.1%, 24.9%, 10.7%, and 8.0% for ALND + RLNR, ALND alone, SLNB + RLNR, and SLNB alone, respectively. Nonetheless, in the AMAROS study the radiotherapy technique was mostly 2D [21] and in the screening study [20], LNs were contoured according to RTOG or RADCOMP atlases.
Modern radiotherapy is 3D based, with steep gradients to not irradiated tissues. Thus, a precise knowledge of the lymphatics (i.e. with LN used as surrogates for the region of the lymphatic drainage) and their coverage by different atlases is imperative.
We could demonstrate in our study, that treating lymphatics according to one of the two atlases – ESTRO or RTOG – translate in different coverage of the healthy lymph nodes. Hypothetically, treating patients with RLNR, but contouring according to ESTRO or to RTOG, might results in different lymph edema risk for these patients. If we consider our data, surgery of level I and level II (i.e. ALND) will remove 79.70% of the visible LN - i.e. a large part of the lymphatic drainage. RLNR irradiation of Level II, III, IV and IMA (as recommended after EORTC 22922/10925 and the MA.20 ) will spare a significant part of the healthy lymphatics (which will be outside/partly outside) the treatment field: 61.2% according to ESTRO CTV and 45.% according to RTOG CTV. This knowledge enables a better understanding of the lymphedema risk and can be used to generate a strategy to further reduce the rate of lymphedema.
A limitation of our study is the single institutional character of the database and the use of PET-CT data. Nonetheless, as all healthy LN were contoured contralateral to the PET-CT positive axilla, we tried to minimize the shortcoming of cross sectional imaging in healthy vs. pathological LN detection.