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Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: Clinical implications
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Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: clinical implications Usama Abdelfattah MD , Patricia M. Jaimez Msc , Juan A. Clavero MD , Vittoria Bellantonio MD , Gemma Pons MD, PhD , Jaume Masia MD PhD PII: DOI: Reference:
S1748-6815(19)30564-9 https://doi.org/10.1016/j.bjps.2019.11.053 PRAS 6359
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
2 October 2019 23 November 2019
Please cite this article as: Usama Abdelfattah MD , Patricia M. Jaimez Msc , Juan A. Clavero MD , Vittoria Bellantonio MD , Gemma Pons MD, PhD , Jaume Masia MD PhD , Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancerrelated lymphedema: clinical implications, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.11.053
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: clinical implications
Authors:
Usama Abdelfattah, MD1,2 Patricia M. Jaimez, Msc3,4 Juan A. Clavero MD5 Vittoria Bellantonio, MD3,6 Gemma Pons, MD, PhD1,3 Jaume Masia, MD PhD1,3
Author Affiliations: 1
Department of Plastic and Reconstructive Surgery, Hospital de la Santa Creu I Sant
Pau, School of Medicine at Universitat Autònoma, Barcelona, Spain 2
Plastic and Reconstructive Surgery department, Al-Azhar University Hospitals, Cairo,
Egypt 3
Lymphedema and Breast Reconstructive Unit, Clinica Planas Hospital, Barcelona,
Spain 4
Nursing Department, Faculty of Medicine and Health Science, Universitat Internacional
de Catalunya, Barcelona, Spain 5
Department of Radiology, Clínica Creu Blanca, Barcelona, Spain
6
Universita degli studi di Messina, Messina, Italy
Corresponding Author:
Jaume Masià, MD PhD
1
Chief, Plastic Surgery Department, Hospital de la Santa Creu i Sant Pau; Professor of Plastic and Reconstructive Surgery, School of Medicine at Universitat Autònoma de Barcelona; Director, Microsurgery and Breast Reconstructive Unit, Clinica Planas, Barcelona, Spain Sant Quintí, 89 08041 Barcelona T: +34618779199 Fax: 5607 E-mail: [email protected]
Keywords: Lymphedema, Upper limb lymphedema, superficial lymphatics, deep lymphatics, lymphatic perforator
2
Abstract
Background: Magnetic resonance lymphangiography (MRL) has increased our knowledge of lymphatic anatomy and lymphedema pathophysiology and improved the efficacy of microsurgical procedures to manage peripheral lymphedema. The aim of this study was to investigate the ability of MRL to detect communications between superficial and deep lymphatic systems in breast cancer-related lymphedema (BRCL) and to investigate whether these communications could preserve lymphatic drainage of the hand.
Methods: Between 2008 and 2017 we used MRL imaging in 59 women with BCRL. Lymphedema of the arm and hand was detected in 30 patients while the hand was spared in 29. Using axial and coronal MRL reconstruction images we investigated the existence of any communication between the superficial and deep lymphatic systems.
Results: Among the 29 patients with spared hand, MRL revealed that 24 had at least one communicating lymphatic perforator at the wrist region (p <0.001). Lymphatic flow at the axilla was clearly visualized in 16 of the 29 patients (55.2%), no perforating lymphatic vessels were detected in the group with lymphedema in the hand (30 patients). Conclusions: Communications between the deep and superficial lymphatic systems at the wrist region in BCRL patients without hand lymphedema should be considered when planning microsurgical lymphatic procedures at the wrist and in postoperative compression therapy.
3
Introduction Lymphedema is a chronic and progressive condition in which high-protein fluid accumulating
in the interstitium induces cellular proliferation and inflammation that
results in thickening and fibrosis of lymphatic vessels and surrounding tissue. (1) The resulting swelling may have a pivotal impact on quality of life. Upper limb lymphedema is mainly the consequence of lymph node dissection for cancer treatment with or without radiotherapy. The incidence of lymphedema after breast cancer surgery ranges from 24% to 49% after mastectomy and from 4% to 28% after lumpectomy.(2) In patients requiring more aggressive surgery or radiotherapy, the risk of developing breast cancer-related lymphedema (BCRL) is greater. According to the International Society of Lymphedema, the diagnosis of lymphedema is mainly based on patient history, anamnestic data, clinical evaluation and volume differences between limbs.(3) The regional distribution of swelling along the arm is not usually uniform; it may be predominantly localized in the proximal forearm or in the distal arm, and it may or may not involve the hand.(4) BCRL is most commonly assessed using one of two diagnostic imaging techniques: indocyanine green (ICG) lymphography and lymphoscintigraphy. Both methods provide a functional assessment of the lymphatic circulation in the limb. They can show functional imaging of the lymphatic transport capacity but the anatomic definition is poor.(5) Stanton et al stated that lymph drainage in BCRL can be evaluated using quantitative lymphoscintigraphy (QL) to measure the drainage rate constant (k) for a radiotracer bound to a plasma protein injected into the subcutis (epifascial compartment) or muscle (subfascial compartment.(6) Using this approach, they found that by injecting radiotracer
4
in the second web space of the ipsilateral side spared hand, k was no lower than in the normal contralateral hand. They concluded that a collateral route of drainage from the spared hand along the subcutis possibly accounted for the preserved hand drainage.(7) The pattern of lymph channels was first described in the 19th century when Sappey injected mercury into human cadavers and dissected the lymphatic systems.(8)More recently, Chuan-Xiang et al. described the deep lymphatic system of the hand using hydrogen peroxide. They described five groups of deep lymph vessels of the hand. Each group first drained in different directions and then they all turned and ran towards the wrist in different layers.(9) Later anatomical and lymphoscintigraphic studies have suggested that connections between the superficial and deep system facilitate lymph drainage. However, as these connections were not observed in patients with a normal lymphatic system of the upper limb it was hypothesized that these connections may be found only when the lymph flow has been altered.(10) In recent years, magnetic resonance lymphangiography (MRL) has emerged as a novel non-invasive technique that can provide high-resolution three-dimensional data-set images of an entire limb with sufficient resolution to detect individual lymphatic channels and areas of dermal backflow.(11) The aim of this study was to investigate the capacity of MRL to identify communications between superficial and deep lymphatic systems at the level of the wrist in BRCL patients and to determine whether these communications could preserve the lymphatic drainage of the hand.
5
Materials and methods Patients This study included 59 women who were recruited from the Lymphedema Unit at Clinica Planas hospital (Barcelona) between 2008 and 2017 and referred for MR lymphangiography. All patients had undergone surgery for breast cancer and had been diagnosed of lymphedema of the ipsilateral upper limb in accordance with the criteria proposed by the International Society of Lymphology.(3) Thirty of the 59 patients were diagnosed with lymphedema of the ipsilateral hand, while the hand was spared from swelling in 29 patients. At examination, the volume of the lymphedematous limb was measured using the upper limb lymphedema index, calculated on the basis of a four-point circumference analysis of the limb (the olecranon, 5 cm above and 5cm below the olecranon, and the wrist) and body mass index for quantitative assessment of lymphedema severity. Imaging: Magnetic resonance lymphangiography protocol All patients were subjected to MRL using a 3T Magnetic Resonance system (MAGNETOM Verio, Siemens, Enlargen Germany). Coronal T1-3DGRE sequences with fat suppression (TR/TE 8/4; matrix of 320 x 380; flip angle 80°; FOV of 30 x 30 cm; repetition time of 5.7 ms, echo time of 2.5 ms acquisition time 120 seconds) were taken after contrast injection of “an 0.8 ml solution containing gadobenate dimeglumine (MultiHance ®, Bracco, Italy) and 0.2 ml of SCANDINIBSA (Braun Medical, SA) in the interdigital spaces of the hand. Images were processed and interpreted using MIP 6
(maximum intensity projection), a modality that shows the course of lymph vessels. Multiple projection reconstruction (MPR) is also useful to understand the anatomy, and volume rendering (VR) reconstructions provide global imaging of the limb and its lymphatics. To map the lymphatic channels, we placed hyperintense markers (vitamin A pills) on the skin surface to give a high signal intensity in the lymphography sequences. The markers were placed at fixed, predefined points along a reference line traced from the medial epicondyle of humerus to the base of the thumb (x-axis), while y-axis is defined by the central point of cubital fossa. Starting from the central point of the cubital fossa (point 0), the markers were placed every 10 cm along that X-axis (Figure.1). MRL analysis All studies were examined retrospectively. The course of the lymph vessels was studied from the dorsum of the hand to the elbow to identify at least one perforator lymphatic vessel that connected the superficial (epifascial) system with the deep (subfascial) system. The axial views and coronal reconstructions were of great help to assess and locagte the perforator lymph vessels. Results The examinations were well tolerated by all patients and no complications were reported. The lymphatic vessels visualized were considered functional because MRL enhancement of the lymphatic channels is the result of these lymphatics absorbing and transporting the intradermally-injected contrast agent. Patients with lymphedema of the hand
7
Lymphatic flow to the axilla was not visualized in any of the patients with lymphedema of the hand. About 30% of these patients had dermal backflow at the forearm level, and 63.3% had backflow at the wrist level. No lymphatic vessel perforators were at the wrist or anywhere in the arm (Table 1). Patients without lymphedema of the hand Lymph flow to the axilla was visualized in 55.2% of these patients. Unlike patients with lymphedema of the hand, a high percentage (38.4%) showed backflow at the arm level (Table 1). MRL images for all 29 patients studied showed a statistically significant correlation between the absence of hand swelling and the existence of a communicating lymphatic perforator at the wrist (Chi-square, p < 0.001). In 24 (82.75%) patients, we located at least one adequate communicating lymphatic perforator vessel at the wrist. Nineteen of the 24 patients (65.5%) had only one communicating lymphatic perforator between the deep and superficial system (confusing) (Figure 2), In 3 patients (10.3%) we identified two perforator communicating lymphatic vessels (Figure 3) and in 2 other patients we identified a perforator lymphatic vessel, but we were unable to identify the superficial lymphatic vessel. In the remaining 5 patients we were unable to identify any perforator lymphatics with dermal backflow at the wrist (Figure 4). In the 11 patients with lymphedema of the left arm, the dominant perforating vessel was located at an average of 22.4 cm in the y-axis (centre of the elbow) and 0.67 cm in the x-axis (In other words for easy understanding, 22.4 cm from central point of elbow(ycoordinate) and 0.67cm posterior/dorsal to the x-axis) (Figure 1 & 5). In the 8 patients with lymphedema of the right arm, the dominant perforating vessel was 8
located at an average area of 19.7 cm in the y-axis and 0,89 cm in the x-axis. Discussion An individualized approach to the management of breast cancer-related lymphedema (BCRL) is crucial as the clinical presentation and the pattern of swelling of the upper extremity varies among individuals. Patients with spared hand should undergo a thorough evaluation because according to our findings, communications between the superficial and deep lymphatics may exist in the distal portion of the forearm in a significant number of these patients (p value< 0.001). These communications could be responsible for maintaining the lymphatic drainage of the hand. Many reports investigated the characteristics of arm and hand swelling following BCRL report a higher incidence of swelling in the upper arm than in the lower arm and hand.(13, 14) These findings have been supported by quantitative lymphoscintigraphic studies suggesting lympho-venous connections (LVC) between the superficial and deep system facilitate distal lymph drainage. It has been suggested that these LVCs act as choke vessels, possibly protecting patients from developing lymphedema of the hand. However, direct visualization of these LVC has been challenging.(15,16) Using lymphangiography, Aboul-Enein et al demonstrated the existence of a lymphaticovenous shunt in a patient with a non-edematous post-mastectomy arm.(15) According to Stanton et al, muscular lymph drainage always exceeds subcutis drainage in BCRLaffected arms and muscular lymph drainage in the ipsilateral arm is unimpaired relative to the contralateral arm. This could explain the lymphatic flow that is seen through the axilla in a significant number of our patients who had communications between the deep and superficial lymphatic system.(7) Using the Stanton technique of quantitative lymphoscintigraphy (QL), Pain et al performed QL using a scintillation detector and a 9
dual-isotope technique in women with BCRL but spared hands. They found that lymph drainage in the ipsilateral hand did not differ significantly from that in the contralateral hand.(16) New imaging techniques developed in lymphatic dissection in cadavers have helped to improve our understanding of the anatomy of the lymphatic system in extremities. Using hydrogen peroxide and a lead oxide mixture for lymphangiography Suami et al found no connections between the superficial and deep lymphatics in the hand and forearm of a normal upper limb; they found only one connection, located at the elbow along the basilic veinin one cadaver .(17) They also found several types of variations in the lymphatic pathway in the affected arm, and identified a circuitous pathway that bypassed the fibrotic obstructed lymphatics in the arm to reach the deep system. (18) In another recent cadaveric study, Chuan-Xiang et al used hydrogen peroxide and barium sulfate lymphography and found a communicating perforator at the wrist and sometimes at the elbow, but the direction of lymphatic flow was uncertain.(19) These studies, however, were performed on normal upper extremity specimens and the cadaveric lymphography techniques used cannot be applied in lymphedema patients. Furthermore, the lymphatic channels in a lymphedema arm arm cannot be clearly demonstrated either with common lymphoscintigraphy methods because of their insufficient resolution or with ICG lymphography because of its limited penetration. High-resolution magnetic resonance lymphangiography (MRL) has recently proved useful in the diagnosis of peripheral lymphatic system disorders. It is a particularly useful technique to study structural changes of peripheral lymphatic channels in both primary and secondary lymphedema.(20, 21) Using MRL in patients with BCRL, Liu and Wang found that damage to the lymphatic circulation induces alterations such as lymph
10
stagnation, ectasis, stretching, and disruption. These alterations lead to fibrosis and sclerosis of the wall, with narrowing and eventual obstruction of the lumen. It is interesting to note, however, that the lymphatic collectors had not declined in number with the development of the disease but showed a trend towards increasing numbers and an extensive opening of numerous communicating branches. They also found that swelling was located only within the subcutis (the superficial lymphatics) and not in the muscle (the deep lymphatics) of the affected arm of patients, but they were unable to visualize any connections between the two systems on MRL imaging. (22) Our study demonstrates a communication branch between deep and superficial lymphatic system at the wrist in patients with BCRL with spared hand and shows that this connection can be clearly visualized with MR lymphangiography. Lymphaticovenous anastomosis (LVA) is a common supermicrosurgery procedure in the management of BCRL, usually routinely performed through 2-3 skin incisions at the wrist, mid-forearm and elbow guided by ICG lymphography (23). We therefore strongly recommend avoiding the wrist incision either for LVA or lymph node placement if the hand is spared from lymphedema in order to avoid disruption of the communicating lymphatic perforator at the wrist. Moreover, sparing the wrist area from tight compression garment in these patients could be critical to preserve lymphatic drainage of the hand. Nevertheless, future detailed studies are necessary for more investigation of the deep lymphatic system and if creation of more superficial to deep bypasses at different anatomical levels through the limb could improve lymphatic drainage of the swollen limbs.
11
Conclusion Preserved lymphatic drainage in BCRL patients with spared hand is the result of communications between the superficial and deep lymphatics at the wrist region. These communications should be considered when planning the site of LVA or lymph node transfer and when applying postoperative compression therapy. Adequate imaging techniques and proper understanding of upper extremity lymphatic anatomy and its changes following mastectomy and axillary clearance are critical for individualizing surgical decisions in lymphedema management.
Conflict of Interest: The authors have no financial interest to declare in relation to the content of this article.
12
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DiSipio, T., Rye, S., Newman, B., Hayes, S. Incidence of unilateral arm
lymphoedema after breast cancer: a systematic review and meta-analysis. The lancet oncology 2013;14:500-515. 2.
Hayes, S., Sipio, T. D., Rye, S., et al. Prevalence and prognostic significance of
secondary lymphedema following breast cancer. Lymphatic research and biology 2011;9:135-141. 3.
ISL, I. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus
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Modi, S., Stanton, A. W., Mellor, R. H., Peters, A. M., Levick, J. R., Mortimer, P.
S. Regional distribution of epifascial swelling and epifascial lymph drainage rate constants in breast cancer-related lymphedema. Lymphatic research and Biology 2005;3:3-15.
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radionuclide lymphoscintigraphy in the evaluation of lymphedema. Journal of Nuclear Medicine 2003;44:43-57. 6.
Svensson, W., Glass, D., Bradley, D., Peters, A. Measurement of lymphatic
function with technetium-99m-labelled polyclonal immunoglobulin. European journal of nuclear medicine 1999;26:504-510. 7.
Stanton, A., Svensson, W., Mellor, R., Peters, A., Levick, J., Mortimer, P.
Differences in lymph drainage between swollen and non-swollen regions in arms with breast-cancer-related lymphoedema. Clinical Science 2001;101:131-140. 8.
Sappey, M. Anatomie, Physiologie des Vaisseaux Lymphatiques considérés
chez lHomme et les Vertébrés. Paris: A Dehahaye et E Lecrosnier 1874. 9.
Ma, C.-X., Pan, W.-R., Liu, Z.-A., Zeng, F.-Q., Qiu, Z.-Q. The deep lymphatic
anatomy of the hand. Annals of Anatomy-Anatomischer Anzeiger 2018;218:105-109. 10.
Edwards, J., Kinmonth, J. Lymphovenous shunts in man. Br Med J 1969;4:579-
586. 11.
Neligan, P. C., Kung, T. A., Maki, J. H. MR lymphangiography in the treatment of
lymphedema. Journal of surgical oncology 2017;115:18-22. 12.
Chang, D. W., Suami, H., Skoracki, R. A prospective analysis of 100 consecutive
lymphovenous bypass cases for treatment of extremity lymphedema. Plastic and reconstructive surgery 2013;132:1305-1314. 13.
Oliveri, J. M., Day, J. M., Alfano, C. M., et al. Arm/hand swelling and perceived
functioning among breast cancer survivors 12 years post-diagnosis: CALGB 79804. Journal of Cancer Survivorship 2008;2:233-242.
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Paskett, E. D., Naughton, M. J., McCoy, T. P., Case, L. D., Abbott, J. M. The
epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiology and Prevention Biomarkers 2007;16:775-782. 15.
Aboul-Enein, A., Eshmawy, I., Arafa, S., Abboud, A. The role of lymphovenous
communication in the development of postmastectomy lymphedema. Surgery 1984;95:562-566. 16.
Pain, S., Barber, R., Ballinger, J., et al. Tissue-to-blood transport of radiolabelled
immunoglobulin injected into the web spaces of the hands of normal subjects and patients with breast cancer-related lymphoedema. Journal of vascular research 2004;41:183-192. 17.
Suami, H., Taylor, G. I., Pan, W.-R. The lymphatic territories of the upper limb:
anatomical study and clinical implications. Plastic and reconstructive surgery 2007;119:1813-1822. 18.
Suami, H., Pan, W.-R., Taylor, G. I. Changes in the lymph structure of the upper
limb after axillary dissection: radiographic and anatomical study in a human cadaver. Plastic and reconstructive surgery 2007;120:982-991. 19.
Ma, C.-X., Pan, W.-R., Liu, Z.-A., Zeng, F.-Q., Qiu, Z.-Q., Liu, M.-Y. Deep
lymphatic anatomy of the upper limb: An anatomical study and clinical implications. Annals of Anatomy-Anatomischer Anzeiger 2019;223:32-42. 20.
Liu, N.-F., Lu, Q., Jiang, Z.-H., Wang, C.-G., Zhou, J.-G. Anatomic and functional
evaluation of the lymphatics and lymph nodes in diagnosis of lymphatic circulation disorders with contrast magnetic resonance lymphangiography. Journal of vascular surgery 2009;49:980-987.
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Liu, N., Yan, Z., Wu, X. Classification of lymphatic-system malformations in
primary lymphoedema based on MR lymphangiography. European Journal of Vascular and Endovascular Surgery 2012;44:345-349. 22.
Liu, N.-f., Wang, B.-s. Functional lymphatic collectors in breast cancer-related
lymphedema arm. Lymphatic research and biology 2014;12:232-237. 23.
Chang, D. W. Lymphaticovenular bypass for lymphedema management in breast
cancer patients: a prospective study. Plastic and reconstructive surgery 2010;126:752758.
16
Figure legends
Figure 1. MRL with sagittal multiplanar reconstruction for determining coordinates. The y-axis is defined as the center of the elbow (red arrow) and the x-axis is defined as a line from the medial epicondyle to the base of the thumb.
17
18
Figure 2. 56-year-old woman with lymphedema of the left arm without swelling of the hand. Axial (a) magnetic resonance image demonstrates the presence of one perforating lymphatic vessel (arrow) that courses first superficially then become deep. In the sagittal cut (b), the white arrow points to a deep lymphatic vessel, narrow black arrow pointing to superficial lymphatic vessel and the black bold one pointing to the communicating perforator lymphatic
19
20
Figure 3. A 50-year-old woman with lymphedema of the left arm without swelling of the hand. Axial (a) and sagittal (b) magnetic resonance images with arrows pointing to a couple of perforating lymphatic vessels.
21
Figure 4. A 53-year old woman with lymphedema of the left arm with swelling of the hand. Axial (a) and sagittal (b) magnetic resonance images clearly show the absence of any communication between superficial and deep circulation.
22
Figure 5. The communicating lymphatic vessel perforators usually located at the dorsal aspect of the distal forearm to the wrist region and its existence is responsible for the preserved lymphatic drainage of the hand in some of BCRL patients.
23
Table legend Table 1. Results of MR lymphangiography in the two groups.
Number of patients Lymphatic flow through axilla Level of Dermal backflow Forearm Wrist Arm Existence of Communicating lymphatics
Patients with Hand lymphedema 30 No
Patients without hand lymphedema 29 16 patients (55.2%)
9 patient 19 patient 2 patient No
14 patient (48.2%) 4 patient (13.7%) 11 patient (38.5%) Yes in 24 patients (82.75%)
(30%) (63.3%) (6.6%)
Table 1. Summary of the results of the two groups. Comparison of the existence of lymphatic vessel perforators, visualization of axillary lymph flow, and level of dermal back flow.
24
Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: clinical implications Usama Abdelfattah MD , Patricia M. Jaimez Msc , Juan A. Clavero MD , Vittoria Bellantonio MD , Gemma Pons MD, PhD , Jaume Masia MD PhD PII: DOI: Reference:
S1748-6815(19)30564-9 https://doi.org/10.1016/j.bjps.2019.11.053 PRAS 6359
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received date: Accepted date:
2 October 2019 23 November 2019
Please cite this article as: Usama Abdelfattah MD , Patricia M. Jaimez Msc , Juan A. Clavero MD , Vittoria Bellantonio MD , Gemma Pons MD, PhD , Jaume Masia MD PhD , Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancerrelated lymphedema: clinical implications, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.11.053
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
Correlation between superficial and deep lymphatic systems using magnetic resonance lymphangiography in breast cancer-related lymphedema: clinical implications
Authors:
Usama Abdelfattah, MD1,2 Patricia M. Jaimez, Msc3,4 Juan A. Clavero MD5 Vittoria Bellantonio, MD3,6 Gemma Pons, MD, PhD1,3 Jaume Masia, MD PhD1,3
Author Affiliations: 1
Department of Plastic and Reconstructive Surgery, Hospital de la Santa Creu I Sant
Pau, School of Medicine at Universitat Autònoma, Barcelona, Spain 2
Plastic and Reconstructive Surgery department, Al-Azhar University Hospitals, Cairo,
Egypt 3
Lymphedema and Breast Reconstructive Unit, Clinica Planas Hospital, Barcelona,
Spain 4
Nursing Department, Faculty of Medicine and Health Science, Universitat Internacional
de Catalunya, Barcelona, Spain 5
Department of Radiology, Clínica Creu Blanca, Barcelona, Spain
6
Universita degli studi di Messina, Messina, Italy
Corresponding Author:
Jaume Masià, MD PhD
1
Chief, Plastic Surgery Department, Hospital de la Santa Creu i Sant Pau; Professor of Plastic and Reconstructive Surgery, School of Medicine at Universitat Autònoma de Barcelona; Director, Microsurgery and Breast Reconstructive Unit, Clinica Planas, Barcelona, Spain Sant Quintí, 89 08041 Barcelona T: +34618779199 Fax: 5607 E-mail: [email protected]
Keywords: Lymphedema, Upper limb lymphedema, superficial lymphatics, deep lymphatics, lymphatic perforator
2
Abstract
Background: Magnetic resonance lymphangiography (MRL) has increased our knowledge of lymphatic anatomy and lymphedema pathophysiology and improved the efficacy of microsurgical procedures to manage peripheral lymphedema. The aim of this study was to investigate the ability of MRL to detect communications between superficial and deep lymphatic systems in breast cancer-related lymphedema (BRCL) and to investigate whether these communications could preserve lymphatic drainage of the hand.
Methods: Between 2008 and 2017 we used MRL imaging in 59 women with BCRL. Lymphedema of the arm and hand was detected in 30 patients while the hand was spared in 29. Using axial and coronal MRL reconstruction images we investigated the existence of any communication between the superficial and deep lymphatic systems.
Results: Among the 29 patients with spared hand, MRL revealed that 24 had at least one communicating lymphatic perforator at the wrist region (p <0.001). Lymphatic flow at the axilla was clearly visualized in 16 of the 29 patients (55.2%), no perforating lymphatic vessels were detected in the group with lymphedema in the hand (30 patients). Conclusions: Communications between the deep and superficial lymphatic systems at the wrist region in BCRL patients without hand lymphedema should be considered when planning microsurgical lymphatic procedures at the wrist and in postoperative compression therapy.
3
Introduction Lymphedema is a chronic and progressive condition in which high-protein fluid accumulating
in the interstitium induces cellular proliferation and inflammation that
results in thickening and fibrosis of lymphatic vessels and surrounding tissue. (1) The resulting swelling may have a pivotal impact on quality of life. Upper limb lymphedema is mainly the consequence of lymph node dissection for cancer treatment with or without radiotherapy. The incidence of lymphedema after breast cancer surgery ranges from 24% to 49% after mastectomy and from 4% to 28% after lumpectomy.(2) In patients requiring more aggressive surgery or radiotherapy, the risk of developing breast cancer-related lymphedema (BCRL) is greater. According to the International Society of Lymphedema, the diagnosis of lymphedema is mainly based on patient history, anamnestic data, clinical evaluation and volume differences between limbs.(3) The regional distribution of swelling along the arm is not usually uniform; it may be predominantly localized in the proximal forearm or in the distal arm, and it may or may not involve the hand.(4) BCRL is most commonly assessed using one of two diagnostic imaging techniques: indocyanine green (ICG) lymphography and lymphoscintigraphy. Both methods provide a functional assessment of the lymphatic circulation in the limb. They can show functional imaging of the lymphatic transport capacity but the anatomic definition is poor.(5) Stanton et al stated that lymph drainage in BCRL can be evaluated using quantitative lymphoscintigraphy (QL) to measure the drainage rate constant (k) for a radiotracer bound to a plasma protein injected into the subcutis (epifascial compartment) or muscle (subfascial compartment.(6) Using this approach, they found that by injecting radiotracer
4
in the second web space of the ipsilateral side spared hand, k was no lower than in the normal contralateral hand. They concluded that a collateral route of drainage from the spared hand along the subcutis possibly accounted for the preserved hand drainage.(7) The pattern of lymph channels was first described in the 19th century when Sappey injected mercury into human cadavers and dissected the lymphatic systems.(8)More recently, Chuan-Xiang et al. described the deep lymphatic system of the hand using hydrogen peroxide. They described five groups of deep lymph vessels of the hand. Each group first drained in different directions and then they all turned and ran towards the wrist in different layers.(9) Later anatomical and lymphoscintigraphic studies have suggested that connections between the superficial and deep system facilitate lymph drainage. However, as these connections were not observed in patients with a normal lymphatic system of the upper limb it was hypothesized that these connections may be found only when the lymph flow has been altered.(10) In recent years, magnetic resonance lymphangiography (MRL) has emerged as a novel non-invasive technique that can provide high-resolution three-dimensional data-set images of an entire limb with sufficient resolution to detect individual lymphatic channels and areas of dermal backflow.(11) The aim of this study was to investigate the capacity of MRL to identify communications between superficial and deep lymphatic systems at the level of the wrist in BRCL patients and to determine whether these communications could preserve the lymphatic drainage of the hand.
5
Materials and methods Patients This study included 59 women who were recruited from the Lymphedema Unit at Clinica Planas hospital (Barcelona) between 2008 and 2017 and referred for MR lymphangiography. All patients had undergone surgery for breast cancer and had been diagnosed of lymphedema of the ipsilateral upper limb in accordance with the criteria proposed by the International Society of Lymphology.(3) Thirty of the 59 patients were diagnosed with lymphedema of the ipsilateral hand, while the hand was spared from swelling in 29 patients. At examination, the volume of the lymphedematous limb was measured using the upper limb lymphedema index, calculated on the basis of a four-point circumference analysis of the limb (the olecranon, 5 cm above and 5cm below the olecranon, and the wrist) and body mass index for quantitative assessment of lymphedema severity. Imaging: Magnetic resonance lymphangiography protocol All patients were subjected to MRL using a 3T Magnetic Resonance system (MAGNETOM Verio, Siemens, Enlargen Germany). Coronal T1-3DGRE sequences with fat suppression (TR/TE 8/4; matrix of 320 x 380; flip angle 80°; FOV of 30 x 30 cm; repetition time of 5.7 ms, echo time of 2.5 ms acquisition time 120 seconds) were taken after contrast injection of “an 0.8 ml solution containing gadobenate dimeglumine (MultiHance ®, Bracco, Italy) and 0.2 ml of SCANDINIBSA (Braun Medical, SA) in the interdigital spaces of the hand. Images were processed and interpreted using MIP 6
(maximum intensity projection), a modality that shows the course of lymph vessels. Multiple projection reconstruction (MPR) is also useful to understand the anatomy, and volume rendering (VR) reconstructions provide global imaging of the limb and its lymphatics. To map the lymphatic channels, we placed hyperintense markers (vitamin A pills) on the skin surface to give a high signal intensity in the lymphography sequences. The markers were placed at fixed, predefined points along a reference line traced from the medial epicondyle of humerus to the base of the thumb (x-axis), while y-axis is defined by the central point of cubital fossa. Starting from the central point of the cubital fossa (point 0), the markers were placed every 10 cm along that X-axis (Figure.1). MRL analysis All studies were examined retrospectively. The course of the lymph vessels was studied from the dorsum of the hand to the elbow to identify at least one perforator lymphatic vessel that connected the superficial (epifascial) system with the deep (subfascial) system. The axial views and coronal reconstructions were of great help to assess and locagte the perforator lymph vessels. Results The examinations were well tolerated by all patients and no complications were reported. The lymphatic vessels visualized were considered functional because MRL enhancement of the lymphatic channels is the result of these lymphatics absorbing and transporting the intradermally-injected contrast agent. Patients with lymphedema of the hand
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Lymphatic flow to the axilla was not visualized in any of the patients with lymphedema of the hand. About 30% of these patients had dermal backflow at the forearm level, and 63.3% had backflow at the wrist level. No lymphatic vessel perforators were at the wrist or anywhere in the arm (Table 1). Patients without lymphedema of the hand Lymph flow to the axilla was visualized in 55.2% of these patients. Unlike patients with lymphedema of the hand, a high percentage (38.4%) showed backflow at the arm level (Table 1). MRL images for all 29 patients studied showed a statistically significant correlation between the absence of hand swelling and the existence of a communicating lymphatic perforator at the wrist (Chi-square, p < 0.001). In 24 (82.75%) patients, we located at least one adequate communicating lymphatic perforator vessel at the wrist. Nineteen of the 24 patients (65.5%) had only one communicating lymphatic perforator between the deep and superficial system (confusing) (Figure 2), In 3 patients (10.3%) we identified two perforator communicating lymphatic vessels (Figure 3) and in 2 other patients we identified a perforator lymphatic vessel, but we were unable to identify the superficial lymphatic vessel. In the remaining 5 patients we were unable to identify any perforator lymphatics with dermal backflow at the wrist (Figure 4). In the 11 patients with lymphedema of the left arm, the dominant perforating vessel was located at an average of 22.4 cm in the y-axis (centre of the elbow) and 0.67 cm in the x-axis (In other words for easy understanding, 22.4 cm from central point of elbow(ycoordinate) and 0.67cm posterior/dorsal to the x-axis) (Figure 1 & 5). In the 8 patients with lymphedema of the right arm, the dominant perforating vessel was 8
located at an average area of 19.7 cm in the y-axis and 0,89 cm in the x-axis. Discussion An individualized approach to the management of breast cancer-related lymphedema (BCRL) is crucial as the clinical presentation and the pattern of swelling of the upper extremity varies among individuals. Patients with spared hand should undergo a thorough evaluation because according to our findings, communications between the superficial and deep lymphatics may exist in the distal portion of the forearm in a significant number of these patients (p value< 0.001). These communications could be responsible for maintaining the lymphatic drainage of the hand. Many reports investigated the characteristics of arm and hand swelling following BCRL report a higher incidence of swelling in the upper arm than in the lower arm and hand.(13, 14) These findings have been supported by quantitative lymphoscintigraphic studies suggesting lympho-venous connections (LVC) between the superficial and deep system facilitate distal lymph drainage. It has been suggested that these LVCs act as choke vessels, possibly protecting patients from developing lymphedema of the hand. However, direct visualization of these LVC has been challenging.(15,16) Using lymphangiography, Aboul-Enein et al demonstrated the existence of a lymphaticovenous shunt in a patient with a non-edematous post-mastectomy arm.(15) According to Stanton et al, muscular lymph drainage always exceeds subcutis drainage in BCRLaffected arms and muscular lymph drainage in the ipsilateral arm is unimpaired relative to the contralateral arm. This could explain the lymphatic flow that is seen through the axilla in a significant number of our patients who had communications between the deep and superficial lymphatic system.(7) Using the Stanton technique of quantitative lymphoscintigraphy (QL), Pain et al performed QL using a scintillation detector and a 9
dual-isotope technique in women with BCRL but spared hands. They found that lymph drainage in the ipsilateral hand did not differ significantly from that in the contralateral hand.(16) New imaging techniques developed in lymphatic dissection in cadavers have helped to improve our understanding of the anatomy of the lymphatic system in extremities. Using hydrogen peroxide and a lead oxide mixture for lymphangiography Suami et al found no connections between the superficial and deep lymphatics in the hand and forearm of a normal upper limb; they found only one connection, located at the elbow along the basilic veinin one cadaver .(17) They also found several types of variations in the lymphatic pathway in the affected arm, and identified a circuitous pathway that bypassed the fibrotic obstructed lymphatics in the arm to reach the deep system. (18) In another recent cadaveric study, Chuan-Xiang et al used hydrogen peroxide and barium sulfate lymphography and found a communicating perforator at the wrist and sometimes at the elbow, but the direction of lymphatic flow was uncertain.(19) These studies, however, were performed on normal upper extremity specimens and the cadaveric lymphography techniques used cannot be applied in lymphedema patients. Furthermore, the lymphatic channels in a lymphedema arm arm cannot be clearly demonstrated either with common lymphoscintigraphy methods because of their insufficient resolution or with ICG lymphography because of its limited penetration. High-resolution magnetic resonance lymphangiography (MRL) has recently proved useful in the diagnosis of peripheral lymphatic system disorders. It is a particularly useful technique to study structural changes of peripheral lymphatic channels in both primary and secondary lymphedema.(20, 21) Using MRL in patients with BCRL, Liu and Wang found that damage to the lymphatic circulation induces alterations such as lymph
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stagnation, ectasis, stretching, and disruption. These alterations lead to fibrosis and sclerosis of the wall, with narrowing and eventual obstruction of the lumen. It is interesting to note, however, that the lymphatic collectors had not declined in number with the development of the disease but showed a trend towards increasing numbers and an extensive opening of numerous communicating branches. They also found that swelling was located only within the subcutis (the superficial lymphatics) and not in the muscle (the deep lymphatics) of the affected arm of patients, but they were unable to visualize any connections between the two systems on MRL imaging. (22) Our study demonstrates a communication branch between deep and superficial lymphatic system at the wrist in patients with BCRL with spared hand and shows that this connection can be clearly visualized with MR lymphangiography. Lymphaticovenous anastomosis (LVA) is a common supermicrosurgery procedure in the management of BCRL, usually routinely performed through 2-3 skin incisions at the wrist, mid-forearm and elbow guided by ICG lymphography (23). We therefore strongly recommend avoiding the wrist incision either for LVA or lymph node placement if the hand is spared from lymphedema in order to avoid disruption of the communicating lymphatic perforator at the wrist. Moreover, sparing the wrist area from tight compression garment in these patients could be critical to preserve lymphatic drainage of the hand. Nevertheless, future detailed studies are necessary for more investigation of the deep lymphatic system and if creation of more superficial to deep bypasses at different anatomical levels through the limb could improve lymphatic drainage of the swollen limbs.
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Conclusion Preserved lymphatic drainage in BCRL patients with spared hand is the result of communications between the superficial and deep lymphatics at the wrist region. These communications should be considered when planning the site of LVA or lymph node transfer and when applying postoperative compression therapy. Adequate imaging techniques and proper understanding of upper extremity lymphatic anatomy and its changes following mastectomy and axillary clearance are critical for individualizing surgical decisions in lymphedema management.
Conflict of Interest: The authors have no financial interest to declare in relation to the content of this article.
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Figure legends
Figure 1. MRL with sagittal multiplanar reconstruction for determining coordinates. The y-axis is defined as the center of the elbow (red arrow) and the x-axis is defined as a line from the medial epicondyle to the base of the thumb.
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Figure 2. 56-year-old woman with lymphedema of the left arm without swelling of the hand. Axial (a) magnetic resonance image demonstrates the presence of one perforating lymphatic vessel (arrow) that courses first superficially then become deep. In the sagittal cut (b), the white arrow points to a deep lymphatic vessel, narrow black arrow pointing to superficial lymphatic vessel and the black bold one pointing to the communicating perforator lymphatic
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Figure 3. A 50-year-old woman with lymphedema of the left arm without swelling of the hand. Axial (a) and sagittal (b) magnetic resonance images with arrows pointing to a couple of perforating lymphatic vessels.
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Figure 4. A 53-year old woman with lymphedema of the left arm with swelling of the hand. Axial (a) and sagittal (b) magnetic resonance images clearly show the absence of any communication between superficial and deep circulation.
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Figure 5. The communicating lymphatic vessel perforators usually located at the dorsal aspect of the distal forearm to the wrist region and its existence is responsible for the preserved lymphatic drainage of the hand in some of BCRL patients.
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Table legend Table 1. Results of MR lymphangiography in the two groups.
Number of patients Lymphatic flow through axilla Level of Dermal backflow Forearm Wrist Arm Existence of Communicating lymphatics
Patients with Hand lymphedema 30 No
Patients without hand lymphedema 29 16 patients (55.2%)
9 patient 19 patient 2 patient No
14 patient (48.2%) 4 patient (13.7%) 11 patient (38.5%) Yes in 24 patients (82.75%)
(30%) (63.3%) (6.6%)
Table 1. Summary of the results of the two groups. Comparison of the existence of lymphatic vessel perforators, visualization of axillary lymph flow, and level of dermal back flow.
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