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Cancers
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Cancer Related Lymphedema
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Cancer Related Lymphedema

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 56257

Special Issue Editors

Dr. Babak J. Mehrara

E-Mail Website
Guest Editor
Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: autologous breast reconstruction; lymphedema; patient-reported outcomes
Special Issues, Collections and Topics in MDPI journals
Dr. Raghu P. Kataru

E-Mail Website
Guest Editor
Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: lymphangiogenesis; inflammatory regulation; immune responses; fibrosis; secondary lymphedema; T cells; lymphatic trafficking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last decade has been notable in terms of advances in medical and surgical treatment of lymphedema resulting from cancer treatment (secondary lymphedema). This is particularly important since secondary lymphedema is a morbid and life-long disease that affects a large number of patients treated for solid cancers including breast cancer, melanoma, urologic malignancies, gynecological tumors, and sarcomas. More than 1 in 5 patients treated for these conditions develop secondary lymphedema making lymphedema the most common long-term complication of solid cancer treatment. In fact, it is estimated that nearly 6 million Americans suffer from this disease with resultant significant morbidity and biomedical costs.

The advances in medical and surgical treatments of this disease have been made possible by improvements in surgical techniques and key discoveries that have shed light on the pathophysiology of lymphedema. Understanding the mechanisms that regulate lymphatic degeneration following lymphatic injury has led to clinical trials of medical therapies aiming to reverse these pathways. Indeed, preclinical studies have shown the important role of chronic inflammation, changes in lymphatic smooth muscle cells, tissue fibrosis, lymphatic pumping, and regulation of collateral lymphatic channels.

Similarly, surgical therapies such as lymph node transplantation and lymphovenous bypass have been developed to reverse the pathologic changes of lymphedema and show promise in some settings. These studies have highlighted the importance of presurgical lymphatic imaging, development of novel surgical techniques, and unique challenges in quantifying outcomes following surgery.

This Special Issue aims to summarize our current understanding of the pathophysiology of secondary lymphedema and how this knowledge is used in designing novel medical and surgical therapies for this disease.

You may choose our Joint Special Issue in Biology.

Dr. Babak J. Mehrara
Dr. Raghu P. Kataru
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • secondary lymphedema
  • breast cancer related lymphedema
  • cancer related lymphedema
  • lymph node dissection
  • iatrogenic lymphatic injury
  • pathophysiology
  • inflammation
  • lymphangiogenesis
  • lymphatic pumping
  • lymphatic leakiness
  • lymphatic smooth muscle cells
  • fibrosis
  • T cells
  • surgical treatment of lymphedema
  • lymphovenous bypass
  • lymph node transplantation
  • liposuction
  • surgical outcomes of lymphedema

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Related Special Issue

Published Papers (9 papers)

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Research

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16 pages, 9242 KiB  
Article
Prospective Validation of Indocyanine Green Lymphangiography Staging of Breast Cancer-Related Lymphedema
by Mads Gustaf Jørgensen, Navid Mohamadpour Toyserkani, Frederik Christopher Gulmark Hansen, Jørn Bo Thomsen and Jens Ahm Sørensen
Cancers 2021, 13(7), 1540; https://doi.org/10.3390/cancers13071540 - 26 Mar 2021
Cited by 24 | Viewed by 3232
Abstract
Indocyanine green lymphangiography (ICG-L) allows real-time investigation of lymphatics. Plastic surgeons performing lymphatic reconstruction use the ICG-L for patient selection and stratification using the MD Anderson (MDA) and the Arm Dermal Backflow (ADB) grading systems. However, the applicability of ICG-L in evaluating breast [...] Read more.
Indocyanine green lymphangiography (ICG-L) allows real-time investigation of lymphatics. Plastic surgeons performing lymphatic reconstruction use the ICG-L for patient selection and stratification using the MD Anderson (MDA) and the Arm Dermal Backflow (ADB) grading systems. However, the applicability of ICG-L in evaluating breast cancer-related lymphedema (BCRL) is sparse and not well established. This study comprehensively examines the usability of ICG-L in the assessment of BCRL. We prospectively performed ICG-L in 237 BCRL patients between January 2019 and February 2020. The aim of this study was to assess the interrater and intrarater agreement and interscale consensus of ratings made using the MDA and ADB scales. Three independent raters performed a total of 2607 ICG-L assessments. The ICG-L stage for each grading system was correlated to the lymphedema volume to assess the agreement between the ICG-L stage and clinical severity. The interrater agreement was near perfect for the MDA scale (kappa 0.82–0.90) and the ADB scale (kappa 0.80–0.91). Similarly, we found a near-perfect intrarater agreement for the MDA scale (kappa 0.84–0.94) and the ADB scale (kappa 0.88–0.89). The agreement between the MDA and the ADB scales was substantial (kappa 0.65–0.68); however, the ADB scale systematically overestimated lower ICG-L stages compared to the MDA scale. The volume of lymphedema correlated slightly with MDA stage (Spearmans rho = 0.44, p < 0.001) and ADB stage (rs = 0.35, p < 0.001). No serious adverse events occurred. The staging of BCRL with ICG-L is reliable, safe, and provides unique disease information unobtainable with clinical measurements alone. The MDA scale seems to provide better disease stratification compared to the ADB scale. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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7 pages, 5153 KiB  
Article
Real-Time Visualization of the Mascagni-Sappey Pathway Utilizing ICG Lymphography
by Anna Rose Johnson, Melisa D. Granoff, Hiroo Suami, Bernard T. Lee and Dhruv Singhal
Cancers 2020, 12(5), 1195; https://doi.org/10.3390/cancers12051195 - 8 May 2020
Cited by 18 | Viewed by 3683
Abstract
Background: Anatomic variations in lymphatic drainage pathways of the upper arm may have an important role in the pathophysiology of lymphedema development. The Mascagni–Sappey (M–S) pathway, initially described in 1787 by Mascagni and then again in 1874 by Sappey, is a lymphatic drainage [...] Read more.
Background: Anatomic variations in lymphatic drainage pathways of the upper arm may have an important role in the pathophysiology of lymphedema development. The Mascagni–Sappey (M–S) pathway, initially described in 1787 by Mascagni and then again in 1874 by Sappey, is a lymphatic drainage pathway of the upper arm that normally bypasses the axilla. Utilizing modern lymphatic imaging modalities, there is an opportunity to better visualize this pathway and its potential clinical implications. Methods: A retrospective review of preoperative indocyanine green (ICG) lymphangiograms of consecutive node-positive breast cancer patients undergoing nodal resection was performed. Lymphography targeted the M-S pathway with an ICG injection over the cephalic vein in the lateral upper arm. Results: In our experience, the M-S pathway was not visualized in 22% (n = 5) of patients. In the 78% (n = 18) of patients where the pathway was visualized, the most frequent anatomic destination of the channel was the deltopectoral groove in 83% of patients and the axilla in the remaining 17%. Conclusion: Our study supports that ICG injections over the cephalic vein reliably visualizes the M-S pathway when present. Further study to characterize this pathway may help elucidate its potential role in the prevention or development of upper extremity lymphedema. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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18 pages, 3277 KiB  
Article
Preoperative Assessment of Upper Extremity Secondary Lymphedema
by Itay Wiser, Babak J. Mehrara, Michelle Coriddi, Elizabeth Kenworthy, Michele Cavalli, Elizabeth Encarnacion and Joseph H. Dayan
Cancers 2020, 12(1), 135; https://doi.org/10.3390/cancers12010135 - 6 Jan 2020
Cited by 38 | Viewed by 4778
Abstract
Introduction: The purpose of this study was to evaluate the most commonly used preoperative assessment tools for patients undergoing surgical treatment for secondary upper extremity lymphedema. Methods: This was a prospective cohort study performed at a tertiary cancer center specializing in the treatment [...] Read more.
Introduction: The purpose of this study was to evaluate the most commonly used preoperative assessment tools for patients undergoing surgical treatment for secondary upper extremity lymphedema. Methods: This was a prospective cohort study performed at a tertiary cancer center specializing in the treatment of secondary lymphedema. Lymphedema evaluation included limb volume measurements, bio-impedance, indocyanine green lymphography, lymphoscintigraphy, magnetic resonance angiography, lymphedema life impact scale (LLIS) and upper limb lymphedema 27 (ULL-27) questionnaires. Results: 118 patients were evaluated. Limb circumference underestimated lymphedema compared to limb volume. Bioimpedance (L-Dex) scores highly correlated with limb volume excess (r2 = 0.714, p < 0.001). L-Dex scores were highly sensitive and had a high positive predictive value for diagnosing lymphedema in patients with a volume excess of 10% or more. ICG was highly sensitive in identifying lymphedema. Lymphoscintigraphy had an overall low sensitivity and specificity for the diagnosis of lymphedema. MRA was highly sensitive in diagnosing lymphedema and adipose hypertrophy as well as useful in identifying axillary vein obstruction and occult metastasis. Patients with minimal limb volume difference still demonstrated significantly impaired quality of life. Conclusion: Preoperative assessment of lymphedema is complex and requires multimodal assessment. MRA, L-Dex, ICG, and PROMs are all valuable components of preoperative assessment. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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10 pages, 746 KiB  
Article
Lower Extremity Lymphedema in Gynecologic Cancer Patients: Propensity Score Matching Analysis of External Beam Radiation versus Brachytherapy
by Won Ick Chang, Hyun-Cheol Kang, Hong-Gyun Wu, Hak Jae Kim, Seung Hyuck Jeon, Maria Lee, Hee Seung Kim, Hyun Hoon Chung, Jae Weon Kim, Noh Hyun Park, Yong Sang Song and Kwan-Sik Seo
Cancers 2019, 11(10), 1471; https://doi.org/10.3390/cancers11101471 - 30 Sep 2019
Cited by 10 | Viewed by 3887
Abstract
The goal of this study is to compare the risk of lower extremity lymphedema (LEL) between pelvic external beam radiation therapy (EBRT) and vaginal brachytherapy, and to identify risk factors for LEL in gynecologic cancer patients treated with adjuvant radiation therapy (RT) after [...] Read more.
The goal of this study is to compare the risk of lower extremity lymphedema (LEL) between pelvic external beam radiation therapy (EBRT) and vaginal brachytherapy, and to identify risk factors for LEL in gynecologic cancer patients treated with adjuvant radiation therapy (RT) after radical surgery. A total of 263 stage I–III gynecologic cancer patients who underwent adjuvant RT were retrospectively reviewed. One-to-one case-matched analysis was conducted with propensity scores generated from patient, tumor, and treatment characteristics. Using the risk factors found in this study, high- and low-risk groups were identified. With a median follow-up of 36.0 months, 35 of 263 (13.3%) patients developed LEL. In multivariate analysis, laparoscopic surgery (HR 2.548; p = 0.024), harvesting more than 30 pelvic lymph nodes (HR 2.246; p = 0.028), and para-aortic lymph node dissection (PALND, HR 2.305; p = 0.014) were identified as independent risk factors for LEL. After propensity score matching, the LEL incidence of the brachytherapy group was significantly lower than the EBRT group (p = 0.025). In conclusion, high-risk patients with risk factors such as laparoscopic surgery, harvesting more than 30 pelvic lymph nodes, PALND, and adjuvant pelvic EBRT require closer observation for LEL. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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Review

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15 pages, 1228 KiB  
Review
Sex Hormones in Lymphedema
by Florent Morfoisse, Audrey Zamora, Emmanuelle Marchaud, Manon Nougue, Leila H. Diallo, Florian David, Emilie Roussel, Eric Lacazette, Anne-Catherine Prats, Florence Tatin and Barbara Garmy-Susini
Cancers 2021, 13(3), 530; https://doi.org/10.3390/cancers13030530 - 30 Jan 2021
Cited by 18 | Viewed by 5461
Abstract
Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return resulting in swelling of the extremities and accumulation of undrained interstitial fluid/lymph that results in fibrosis and adipose tissue deposition in the limb. Whereas it is clearly established that [...] Read more.
Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return resulting in swelling of the extremities and accumulation of undrained interstitial fluid/lymph that results in fibrosis and adipose tissue deposition in the limb. Whereas it is clearly established that primary lymphedema is sex-linked with an average ratio of one male for three females, the role of female hormones, in particular estrogens, has been poorly explored. In addition, secondary lymphedema in Western countries affects mainly women who developed the pathology after breast cancer and undergo through hormone therapy up to five years after cancer surgery. Although lymphadenectomy is identified as a trigger factor, the effect of co-morbidities associated to lymphedema remains elusive, in particular, estrogen receptor antagonists or aromatase inhibitors. In addition, the role of sex hormones and gender has been poorly investigated in the etiology of the pathology. Therefore, this review aims to recapitulate the effect of sex hormones on the physiology of the lymphatic system and to investigate whetherhormone therapy could promote a lymphatic dysfunction leading to lymphedema. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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18 pages, 527 KiB  
Review
Lymphatic Valves and Lymph Flow in Cancer-Related Lymphedema
by Drishya Iyer, Melanie Jannaway, Ying Yang and Joshua P. Scallan
Cancers 2020, 12(8), 2297; https://doi.org/10.3390/cancers12082297 - 15 Aug 2020
Cited by 34 | Viewed by 8512
Abstract
Lymphedema is a complex disease caused by the accumulation of fluid in the tissues resulting from a dysfunctional or damaged lymphatic vasculature. In developed countries, lymphedema most commonly occurs as a result of cancer treatment. Initially, impaired lymph flow causes edema, but over [...] Read more.
Lymphedema is a complex disease caused by the accumulation of fluid in the tissues resulting from a dysfunctional or damaged lymphatic vasculature. In developed countries, lymphedema most commonly occurs as a result of cancer treatment. Initially, impaired lymph flow causes edema, but over time this results in inflammation, fibrotic and fatty tissue deposition, limited mobility, and bacterial infections that can lead to sepsis. While chronically impaired lymph flow is generally believed to be the instigating factor, little is known about what pathophysiological changes occur in the lymphatic vessels to inhibit lymph flow. Lymphatic vessels not only regulate lymph flow through a variety of physiologic mechanisms, but also respond to lymph flow itself. One of the fascinating ways that lymphatic vessels respond to flow is by growing bicuspid valves that close to prevent the backward movement of lymph. However, lymphatic valves have not been investigated in cancer-related lymphedema patients, even though the mutations that cause congenital lymphedema regulate genes involved in valve development. Here, we review current knowledge of the regulation of lymphatic function and development by lymph flow, including newly identified genetic regulators of lymphatic valves, and provide evidence for lymphatic valve involvement in cancer-related lymphedema. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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25 pages, 11741 KiB  
Review
The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors
by Melissa B. Aldrich, John C. Rasmussen, Caroline E. Fife, Simona F. Shaitelman and Eva M. Sevick-Muraca
Cancers 2020, 12(8), 2280; https://doi.org/10.3390/cancers12082280 - 14 Aug 2020
Cited by 24 | Viewed by 6682
Abstract
Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. [...] Read more.
Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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18 pages, 642 KiB  
Review
Systematic Review of Patient-Reported Outcomes following Surgical Treatment of Lymphedema
by Michelle Coriddi, Joseph Dayan, Nikhil Sobti, David Nash, Johanna Goldberg, Anne Klassen, Andrea Pusic and Babak Mehrara
Cancers 2020, 12(3), 565; https://doi.org/10.3390/cancers12030565 - 29 Feb 2020
Cited by 53 | Viewed by 7703
Abstract
Introduction: Analysis of quality of life (QOL) outcomes is an important aspect of lymphedema treatment since this disease can substantially impact QOL in affected individuals. There are a growing number of studies reporting patient-reported outcomes (PROMs) for patients with lymphedema. The purpose of [...] Read more.
Introduction: Analysis of quality of life (QOL) outcomes is an important aspect of lymphedema treatment since this disease can substantially impact QOL in affected individuals. There are a growing number of studies reporting patient-reported outcomes (PROMs) for patients with lymphedema. The purpose of this study was to conduct a systematic review of outcomes and utilization of PROMs following surgical treatment of lymphedema. Methods: A literature search of four databases was performed up to and including March, 2019. Studies included reported on QOL outcomes after physiologic procedures, defined as either lymphovenous bypass (LVB) or vascularized lymph node transplant (VLNT), to treat upper and/or lower extremity primary or secondary lymphedema. Results: In total, 850 studies were screened—of which, 32 studies were included in this review. Lymphovenous bypass was the surgical intervention in 16 studies, VLNT in 11 studies, and both in 5 studies. Of the 32 total studies, 16 used validated survey tools. The most commonly used PROM was the lymph quality of life measure for limb lymphedema (LYMQOL) (12 studies). In the remaining four studies, the upper limb lymphedema 27 scale (ULL27), the short form 36 questionnaire (SF-36), the lymphedema functioning, disability and health questionnaire (Lymph-ICF), and lymphedema life impact scale (LLIS) were each used once. QOL improvement following surgical treatment was noted in all studies. Conclusions: Physiologic surgical treatment of lymphedema results in improved QOL outcomes in most patients. The use of validated PROM tools is increasing but there is no current consensus on use. Future research to evaluate the psychometric properties of PROMs in lymphedema is needed to guide the development and use of lymphedema-specific tools. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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Other

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13 pages, 6132 KiB  
Commentary
Anatomical Theories of the Pathophysiology of Cancer-Related Lymphoedema
by Hiroo Suami
Cancers 2020, 12(5), 1338; https://doi.org/10.3390/cancers12051338 - 23 May 2020
Cited by 33 | Viewed by 10806
Abstract
Lymphoedema is a well-known concern for cancer survivors. A crucial issue in lymphoedema is that we cannot predict who will be affected, and onset can occur many years after initial cancer treatment. The variability of time between cancer treatment and lymphoedema onset is [...] Read more.
Lymphoedema is a well-known concern for cancer survivors. A crucial issue in lymphoedema is that we cannot predict who will be affected, and onset can occur many years after initial cancer treatment. The variability of time between cancer treatment and lymphoedema onset is an unexplained mystery. Retrospective cohort studies have investigated the risk factors for lymphoedema development, with extensive surgery and the combination of radiation and surgery identified as common high-risk factors. However, these studies could not predict lymphoedema risk in each individual patient in the early stages, nor could they explain the timing of onset. The study of anatomy is one promising tool to help shed light on the pathophysiology of lymphoedema. While the lymphatic system is the area least investigated in the field of anatomical science, some studies have described anatomical changes in the lymphatic system after lymph node dissection. Clinical imaging studies in lymphangiography, lymphoscintigraphy and indocyanine green (ICG) fluorescent lymphography have reported post-operative anatomical changes in the lymphatic system, including dermal backflow, lymphangiogenesis and creation of alternative pathways via the deep and torso lymphatics, demonstrating that such dynamic anatomical changes contribute to the maintenance of lymphatic drainage pathways. This article presents a descriptive review of the anatomical and imaging studies of the lymphatic system in the normal and post-operative conditions and attempts to answer the questions of why some people develop lymphoedema after cancer and some do not, and what causes the variability in lymphoedema onset timing. Full article
(This article belongs to the Special Issue Cancer Related Lymphedema)
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