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LYMPHEDEMA DEVELOPMENT: Why do some get lymphedema after breast cancer treatment and others do not ?

WHY IS THIS INFORMATION IMPORTANT?

· Because, if you have not started treatment yet, it arms you with information about some of the factors involved in lymphedema development.

· Because, if you have lymphedema, you can better understand what factors may have been involved in your situation and perhaps alleviate some of the guilt that I see in some people who feel that they have done something wrong to cause their lymphedema.

· Because being proactive and informed is better than being in the dark and surprised. As overused as the saying is……knowledge IS power.




WHY DO SOME WOMEN DEVELOP LYMPHEDEMA AFTER BREAST CANCER TREATMENT AND OTHERS DO NOT?


This question has plagued doctors and researchers for many years. It is just within about the last ten to fifteen years, due to newer research interest in the lymphatic system and the fine tuning of lymphatic system assessment and visualization technology, that some theories are coming to light. Lymphedema is a chronic condition of swelling, and for many breast cancer survivors, an unwanted reminder of the disease and its treatment. Of all the questions I am asked, “Why did I get lymphedema?” is the most common and difficult one to answer. As I try and help my clients understand lymphedema, we take a look at their individual risk factors and discuss what the newer research about the lymphatic system and lymphedema is finding.


RISK FACTORS


The risk of developing breast cancer-related lymphedema rises with a combination of many factors. For many years the big three included surgery, lymph node removal in the axilla (armpit) and radiation therapy. Newer research from the past ten to fifteen years has added obesity, advanced stage of cancer at diagnosis and seroma formation after surgery (an accumulation of fluid where tissue has been removed) to the risk factor list. The combination of these factors puts breast cancer patients at higher risk for lymphedema development. [2,3,4] A prospective observational study of over 900 women published in 2017 [5] found that lymphedema was observed in 13.5% of women at two years of follow-up, 30.2% at five years and 41.1% at ten years. Obesity, seroma formation, chemotherapy in the at-risk limb and radiation therapy were common risk factors among this study group.


SURGERY, AXILLARY LYMPH NODE DISSECTION AND RADIATION


Surgery alone, whether lumpectomy or mastectomy, has a lower risk of developing lymphedema. However, some studies have related that the more extensive mastectomy surgery has a bit higher risk. [4] Adding ALND (axillary lymph node dissection- removal of lymph nodes in the armpit) and radiation therapy increases this risk. A combination of all three poses the highest risk. Sentinal lymph node biopsy involves removal of the closest lymph nodes to the tumour site and has a lower incidence rate of lymphedema than ALND and the preferred surgical method if at all possible [2]. A lymph node is responsible for filtering lymph fluid, protein and waste products from the tissues in addition to its immune function of fighting off bacteria, viruses and other pathogenic cells such as cancer cells. When a group of lymph nodes are removed during ALND congestion occurs as a natural swelling after surgery. The drain(s) put in place during surgery help to remove fluids from the site and allow for regeneration of lymphatic vessels and healing to occur. When a higher number of lymph nodes are removed the more work the lymphatic vessels must work to remove the fluid. More research is needed to provide information about the relationship between number of lymph nodes removed and lymphedema risk.[3]

Radiation has long been part of treatment for cancer with a purpose to increase survival rates and decrease reoccurrence at the original site of the cancer. [1] Lymphedema is noted to be the most common complication of radiation treatment and affects 1 in 4 patients who have radiation treatment. [1] The lymphatic vessels are less sensitive to radiation energy, but the lymph nodes are highly sensitive. Lymphedema results from changes that occur in the lymph node structure after radiation and with the tissue changes that occur over time to affect the lymphatic vessels. [1] Radiation of the lymph nodes causes a decrease in the immune cells within them, creates fatty changes to occur and eventually scarring or fibrosis. The fibrotic changes in the nodes alters their ability to filter lymph fluid and increases pressures and clearance capabilities which promotes lymphedema. [1] Radiation effects on the tissue are cumulative and fibrotic changes in lead to tissue thickening within the radiation field. This blocks lymphatic flow and impairs new growth of lymphatic vessels (lymphangiogenesis).[1] Post surgical inflammation, infection, removal of lymph nodes in axilla (armpit), radiation dose and technique as well as obesity are sited as other contributing factors.[1]


DIFFERENCES BETWEEN INDIVIDUALS

Lymphatic anatomy research has been sparse, but in recent years, to understand lymphedema, researchers have noticed some changes that occur to the lymphatic system after surgery. Using imaging studies like lymphoscintigraphy and indocyanine green (ICG) fluorescent lymphography they have noted backflow of fluid from the lymphatics into the tissue (dermal backflow), re-growth of lymphatic vessels (lymphangiogenesis) and the use by the body of deeper lymphatics as alternative pathways. [6]


Dermal backflow (DB)




DB occurs when the lymph fluid within the lymphatic system stays in lymphatic vessels closest to the surface of the skin. It shows up on lymphoscintigraphy imaging as a splotchy white patch and is indicative of lymphedema. It is a natural way for the body to reroute fluid to other areas but when the body is unable to do so, fluid will stay in the tissues causing the signs and symptoms of lymphedema. However, if there are open connections to the deeper lymphatic system vessels they may compensate, and the fluid will be shunted to these vessels.

(picture adapted from Suami (2020) [6]




Lymphangiogenesis and rerouting to alternate lymph nodes


Growth factors are released in response to lymphatic vessel damage that occurs with surgery and lymph node dissection. The lymph nodes themselves do not grow again, but new pathways are created to help maintain lymph drainage from the surgical site and at-risk limb.[6] This is where it gets interesting. In Dr. Hiroo Suami’s research he found that regeneration and attachment to lymph nodes can occur in the axilla (armpit), the lymph nodes above the collar bone and the chest nodes on the surgical side or even the opposite side axillary (armpit) nodes essentially rerouting lymph fluid to other drainage pathways. Some arm swelling can be noted after surgery as the lymph vessels are reorganizing and Dr. Suami’s article suggests that the regeneration process can take about a month. If the vessels mature successfully lymphedema may not develop, but scar formation, delayed wound-healing with seroma, radiation and cellulitis infection can adversely impact the regeneration process to cause lymphedema.[6] This could explain why some women develop lymphedema, whether immediately after surgery or years after, it depends on how well these new connections are made, if at all.


Rerouting to deeper alternate pathways


According to Suami (2020) the lymphatic system is divided into superficial and deep channel systems that normally function independently. However, changes have been found to occur after surgery that connect the two in in certain places to preserve lymphatic drainage from the arm and help prevent lymphedema. [6] Does this happen in all cases? More research is definitely needed and may be another reason why some people develop lymphedema and others do not.


Genetics


A paper by Visser et al. (2018), Breast Cancer-Related Lymphedema and Genetic Predisposition: A Systematic Review of the Literature [7] found that a similar genetic variation in 18 genes had been identified in patients with breast cancer related lymphedema. Indicating a possible non-treatment, personal risk factor for the development of lymphedema.


Age


Lymphatic vessels and lymph nodes change as we age. The muscles located in the walls of the lymph vessels become thinner affecting the force of fluid pumped through and creating weaker valves that are meant to keep the fluid moving in one direction toward the “main drain” in the neck and back to the blood stream. The combination of the two changes creates a more sluggish flow and congestion. See my blog on Ageing and the Lymphatic System for more details.


There are still so many questions regarding the factors that play a role in the development of lymphedema and since we all are unique, it will take much more research to answer the question “why do some people develop lymphedema and others do not?”



SUMMARY OF CONTENT




References


[1] Allam, O., Park, K., E, Chandler, L, et al. (2020). The impact of radiation on lymphedema: a review of the literature. Gland Surgery, 9(2). 596-602. Doi: 10.21037/gs.2020.02.02. Retrieved from: https//dx.doi.org/10.21037/gs.2020.03.02


[2] Ayre, K., Parker, C. (2019). Lymphedema after treatment of breast cancer: a comprehensive review. Unexplored Med Data. 4:5.


[3] McLaughlin, S., A. (2013). Lymp0edema: Separating fact from fiction. Oncology, 26(3). Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22545305/#:~:text=Although%20the%20true%20etiology%20of,lymphedema%20is%20not%20clearly%20correlated.


[4] Miller, C., L. et al. (2014). Risk of lymphedema after mastectomy-potential benefit of applying ACOSOG Z0011 protocol to mastectomy patients. Breast Cancer Res Treat. 144(1);71-77. Doi.10.1007/a10549-014-2856-3. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011490/


[5] Ribeiro Pereira, A. C. P., Koifman, R. J., & Bergmann, A. (2017). Incidence and risk factors of lymphedema after breast cancer treatment: 10 years of follow-up. Breast (Edinburgh, Scotland), 36, 67–73. https://doi.org/10.1016/j.breast.2017.09.006


[6] Suami H. (2020). Anatomical Theories of the Pathophysiology of Cancer-Related Lymphoedema. Cancers, 12(5), 1338. https://doi.org/10.3390/cancers12051338


[7] Visser, J., van Geel, M., Cornelissen, A. J. M., van der Hulst, R. R. W. J., & Qiu, S. S. (2019). Breast Cancer-Related Lymphedema and Genetic Predisposition: A Systematic Review of the Literature. Lymphatic research and biology, 17(3), 288–293. https://doi.org/10.1089/lrb.2017.0083

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