| Join Our Mailing List |
9th NLN International Conference - Sept. 22-26 2010 - Breaking through the Barriers: Research, Education, and Practice
NLN Position Papers: Risk Reduction, Treatment, Exercise, Air Travel, Training
Financial Assistance for Compression Garments:
New Books: Lymphedema Caregiver's Guide
Mourning Has Broken
Updated NLN Online Patient Questionnaire
For Professionals: NLN Research Survey
Volume 21, No. 1 January ~ March 2009
- Early Diagnosis And Treatment Intervention For Lymphedema - The New Standard Of Care
Volume 20, No. 4 October ~ December 2008
- Lymphedema Of The Head And Neck: An Overview
Volume 20, No. 3 July ~ September 2008
- The Effects Of Radiation Therapy On The Lymphatic System: Acute And Latent Effects
- References for "Lymphedema Education Among Breast Cancer Survivors Undergoing Radiotherapy"
Volume 20, No. 2 April ~ June 2008
- Advances in our understanding of the Genetics of Lymphoedema: From diagnosis to treatment
By Nicole L. Stout, MPT, CLT-LANA
RELEVANCE
2.3 million women are survivors of breast cancer (BC)1. Lymphedema (LE) is a common impairment diagnosed following the treatment for cancer. Breast cancer-related lymphedema (BCLE) incidence rates are documented between 33% and 48% following axillary lymph node dissection (ALND) and radiation therapy (RT)2 and 5% to 14% after sentinel lymph node biopsy and RT.3 BCLE impacts quality of life and upper limb function and may perpetuate chronic disability considering the progressive nature of the condition when left untreated.2
DIAGNOSING LYMPHEDEMA
Traditionally, the diagnosis of LE occurs after the condition becomes clinically apparent resulting in delayed treatment and a progression of the condition. This may be due to a general lack of understanding of the pathogenesis and presentation of the condition by the medical provider as well as a lack of awareness of effective treatment modalities. Past medical dogma surrounding LE management was that of a lifetime condition with no known treatment.
Through considerable evolution in medical practice and research, today we have well-founded treatment interventions for LE, as well as a growing awareness to the condition by a more astute medical community. Despite progress made in recognizing and treating the clinically apparent condition, limitations remain in the area of riskreduction intervention and early detection. A further dearth exists in consensus as to the most appropriate diagnostic criteria and measurement methods. Evidence supports the contention that roughly 1/3 of women will develop BCLE and that there are sensory changes that occur in the limb before an overt swelling is visible.4 Therefore, a prospective surveillance method aimed at education and early detection, is the most prudent approach to preventing the manifestation of the negative consequences of cancer therapies on the lymphatic system.
Measuring and diagnosing lymphedema is a contentious issue and arguments on all sides are fraught with issues of: appropriate diagnostic criteria, inconsistent measurement technique, inconsistent utilization of measurement modalities, and over-and under-diagnosis. The clinical standard should strive to achieve diagnosis at the earliest possible point of detection and offer the most conservative, effective treatment intervention. This standard will only be achieved with a paradigm shift towards risk reduction care and surveillance methodology to enable diagnosis at the earliest possible presentation. Early detection and treatment of lymphedema will prevent the progression of the condition to an advanced stage and may prevent associated functional limitations and disabilities, in addition to rendering a cost savings to the payer.
PURPOSE
The purpose of the research trial “Preoperative assessment enables early diagnosis and treatment of lymphedema” was to investigate the efficacy of a prospective physical therapy screening method to accurately diagnose sub-clinical LE and to evaluate the effectiveness of an early intervention in patients recently treated for BC.
METHODS
A subset analysis of an intervention applied to a cohort of 34 women who developed lymphedema, drawn from a large IRB-approved study* (n=196) was conducted to evaluate its effectiveness. All patients were evaluated preoperatively and followed at 3-month intervals after surgery with repeat measures taken of bilateral arm volume. Measurement was done using the Perometer®, an optoelectronic volumeter, which scans the limb with infra-red and generates a calculated limb volume from the after-image.6
DIAGNOSTIC CRITERIA
A conservative intervention was introduced if the change in limb volume equal to approximately 100 ml or 3% compared to the pre-op inter-limb measures with consideration for the contralateral limb, the criterion for subclinical LE in this study.
When the LE criterion was met, a Ready-Made Compression Class I sleeve and gauntlet were fitted by the physical therapist and issued for daily wear. The patient was advised to follow up for repeated measures in 4 weeks to assess the limb status. Upon follow up, the volumetric assessment was repeated with the Perometer®. When volume decrease was confirmed, a modified compression intervention was prescribed. The modified compression intervention involved continued garment wear only during strenuous exercise, heavy lifting, repetitive arm activity, the appearance of visible swelling or altered sensations of heaviness, fullness or aching. Patients were then seen in 3 months for repeated measures.
RESULTS
Patients diagnosed with sub-clinical LE demonstrated a significant volume increase ( 83 ml / 6.5 % ) in the affected arm as compared to their baseline preoperative measurement (p = 0.001) at approximately 6.9 months after their breast cancer-related surgery. With the use of a compression sleeve intervention for an average of 4.4 weeks, a significant (p < 0.0001) mean volume decrease ( 46 ml / 4.1% ) was realized. Further, the cohort demonstrated the efficacy for the modified compression intervention when, at their follow-up visit, average of 4.8 months after the compression intervention, the limb volume was maintained.
DISCUSSION
Complete Decongestive Therapy (CDT) is the standard of care for patients with lymphedema. CDT involves a multi-modality intervention done daily over the course of 2-4 weeks and provides volumetric decongestion of the swollen limbs by >60%.7 This intervention is purported to be effective in patients with Stage II or Stage III lymphedema. However, when a patient is at Stage I or Stage 0 (latency) there is no clear guideline as to how treatment intervention should be undertaken to maximize effectiveness and minimize the intensity of therapy.
At the earliest stages, lymphedema is noted to be reversible with elevation. Although the swelling may exacerbate and remit at this early presentation, the constituency of the fluid congestion is still protein-rich and, with stagnation, will promote chronic swelling and fibrosis. A presentation of lymphedema that exacerbates and remits, or one that is only marginally clinically apparent, is not insignificant and must be addressed with an appropriate intervention. The intervention used in this trial effectively decreased the limb volume to a near-normal level and maintained it over time. The early intervention protocol is outlined in Table 1.
The earliest diagnosis of lymphedema will enable the most effective and least invasive intervention. This diagnosis cannot be accurately made without a pre-operative assessment of limb volume. This ‘normal’ notation of limb volume will allow the practitioner to diagnose a change in limb volume over the course of a prospective protocol. Regular interval assessment is vital to monitor limb volume and to reinforce education for risk reduction. Only when limb volume is monitored in the context of a pre-operative, pros pective surveillance protocol, will an accurate, early diagnosis of lymphedema be made.
CONCLUSIONS
Pre-operative assessment, prospective surveillance, and early intervention
may have prevented the onset of irreversible BCLE in this small cohort. The garment intervention significantly reduced the affected limb volume to nearly that of the unaffected limb and therefore provides effective treatment when sub-clinical LE (> 3 % limb volume change from baseline) is detected. Further research is warranted to confirm the long-term clinical effectiveness and cost-effectiveness of this preventive model compared to a traditional impairment-based model.
All patients undergoing cancer treatment should receive pre-operative clinical assessment of their limb volume and should be followed in a prospective manner to expedite effective diagnosis and treatment of lymphedema.
Note: This research was published in Cancer 2008:112:2809-19. Stout Gergich, N and Pfalzer, L. et al. “Preoperative Assessment Enables the Early Diagnosis and Treatment of Lymphedema.”
Nicole Stout, MPT, CLT-LANA National Naval Medical Center Breast Care Center Bethesda, Maryland
1. American Cancer Society (ACS). “Breast Cancer Facts and Figures 2006.” Retrieved from the World Wide Web on July 19, 2006 at http://www.cancer.org/downloads/STT/ CAFF2005BrF.pdf
2. Petrek JA, Pressman PI, and Smith RA. Lymphedema: current issues in research and management. CA Cancer J Clin. 2000 Sep-Oct; 50(5): pp:292-307.
3. Haid A, Koberle-Wuhrer R, Knauer M, Burtscher J, Fritzsche H, Peschina W et al. Morbidity of breast cancer patients following complete axillary dissection or sentinel node biopsy only: a comparative evaluation. Breast Cancer Res Treat 2002; 73(1):31-36.
4. Armer J, Radina M, and Culbertson S. “Predicting Breast Cancer-Related Lymphedema Using Self-Reported Symptoms.” Nursing Research. Volume 52, No.6 (2003):pp. 370-379.
5. Hayes S, Cornish B, and Newman B. “Comparison of methods to diagnose lymphedema among breast cancer survivors: 6 months follow-up.” Breast Cancer Research and Treatment. Volume 89 (2005):pp.221226.
6. Stanton AW, Northfied JW, Holroyd B, Mor-timer PS, and Levick, JR. Validation of an optoelectronic limb volumeter (Perometer). Lymphology. 1997 vol:30 (2): pp:77 -97.
7. Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment of lymphedema of the extremities. Arch.Surg. 1998;133(4):452-58
8. Cheville AL, McGarvey CL, Petrek JA, Russo SA, Thiadens SR, Taylor ME. “The Grading of Lymphedema in Oncology Clinical Trials”. Semin Radiat Oncol. 2003 Jul; 13(3): pp: 214-25.
9. American Cancer Society (ACS). “Lymphedema: What Every Woman With Breast Cancer Should Know.” Retrieved from the World Wide Web on July 01, 2006 at http:// www.cancer.org/docroot/MIT/content/ MIT_7_2x_Lymphedema_and_Breast_Cancer.asp *http://clinicaltrials.gov/ct/show/ NCT00027118?order=5
Lymphedema of the head and neck is a build-up of protein rich fluid (lymph) in any areas above the shoulders and collar bone. It is the result of obstruction of lymphatic vessels or lymph nodes; or missing or damaged lymphatic structures. Lymphedema of the head and neck should not be confused with edema that can occur in the same areas. Edema, a buildup of excessive amounts of watery fluid in cells or intercellular tissues, is not due to lymphatic dysfunction.
There are many different causes for edema and treatment of edema is based upon treating the underlying cause of the swelling. This article will not address edema. Instead, it focuses on lymphedema.
Lymphedema in the head and neck region can be either primary, due to genetic and familial abnormalities, or secondary, due to trauma to the lymphatic system. Primary lymphedema seldom occurs only in the head and neck.1 It is usually accompanied by lymphedema in the limbs or trunk. Secondary lymphedema of the head and neck is more common.
Cancer patients who have had neck surgery, lymph node removal, plastic surgery reconstruction, tumors obstructing lymph flow, and/or radiation treatment are at risk for developing lymphedema. How severe is this problem? European literature suggests that 30% to 56% of all head and neck patients develop lymphedema regardless of type of treatment, a larger percentage than those with lymphedema associated with breast cancer.2,3 There are no statistics available for rates in the United States.
Non-cancer related trauma to the head, neck or mouth from surgery or accidents, also can cause lymphedema; as can medical conditions such as rosacea, an inflammatory skin condition.4
HEAD AND NECK LYMPHATIC ANATOMY
The head and neck region of the body requires massive lymph drainage to maintain vital functions. Although small in percent of actual body area, 150 to 300 lymph nodes are located in the area.1 This is approximately one-third of the total number of lymph nodes contained in the entire body.
ASSESSMENT AND DIAGNOSIS
Similar to lymphedema occurring in other parts of the body, early diagnosis of lymphedema in the head and neck areas with prompt referral for treatment is critical to prevent or reduce the impact of distressing and potentially life threatening symptoms. However, assessment and measurement of lymphedema in HNC patients is problematic for many reasons. First, the shape of the head and neck do not lend themselves to easy tape measurement. Second, lymphedema of the head and neck areas can buildup both on the outside of the face or neck and inside the sinuses and throat. For example, people who have had cancer treatment can develop swelling inside their throat before it is ever outwardly visible. Therefore, to accurately diagnose and assess lymphedema in the head and neck areas, it may be necessary for healthcare professionals not only to monitor the visible swelling, but also monitor the internal swelling. Although there is no “gold standard” measurement method for head and neck lymphedema, ways to measure the swelling do exist. Tape measurement is used by some healthcare professionals. Photographs are also used to assess LE and to monitor response to treatment.
Recently, external digital photography of the face, head and neck has been recommended in international lymphedema best practices documents, as the method of choice for recording and monitoring lymphedema in the head and neck areas.5
Laryngoscopy (looking down the throat with a lighted instrument that has the camera attached) has been used with some success to record internal (endolaryngeal) lymphedema in cancer patients. Early attempts to develop a rating scale based on fluid distribution patterns (the number and types of internal body parts covered by fluid) seen during this procedure have been undertaken.6 The internal swelling is rated as normal, mild, moderate or severe based upon what structures it is covering in the throat.6 Results of this study were promising in that different clinicians were able to use the scale and rate the same patient’s lymphedema as being the same degree of severity. CT scans may also be helpful in some situations.
When assessing and diagnosing swelling in the head and neck region, it is extremely important to determine if the swelling is pure lymphedema, edema, or mixed-edema. Diagnosis should only be made by a physician, as an accurate assessment of the cause of the swelling is necessary to make sure the correct treatment is ordered. Accurate diagnosis requires obtaining a complete medical history and may also involve drawing blood and/or having radiological tests. If you have swelling in your head or neck areas, it is important to cooperate fully with your physician during the diagnostic phase of treatment. This will help your physician best know how to treat you.
SYMPTOMS
Research about lymphedema occurring in the head and neck region is very limited at the present time. Therefore, most information about what symptoms or problems people with head and neck lymphedema experience come from clinical observations by healthcare professionals who care for the patients or from anecdotal reports by patients themselves. Symptoms related to head and neck lymphedema are generally believed to be many in number and to differ among patients. They are both emotional and physical in nature.
Lymphedema in the head and neck area is highly visible. It can distort facial features and, in some cases, make someone almost unrecognizable to those who have known them before the swelling began. Individuals with head and neck lymphedema can become emotionally distressed and depressed. They may develop social avoidance, a reluctance to be seen by others, particularly in public settings such as restaurants. Patients may have to change the type of shirts, blouses, or dresses they wear to accommodate the swelling. Family members and caregivers also experience distress and many state that they do not know how to help.
Physically, the location of the swelling influences the type of symptoms that develop. Swelling in the throat can make it hard to swallow, create a “full” feeling in the throat, cause problems with speech (hoarseness or difficulty speaking for more than a few minutes at a time), or a cough.
Severe swelling can make it hard to breathe. It may be very hard to move the head from side to side or up and down. Eating and swallowing may also be a problem. Swelling around the eyes can make it hard to see and interferes with daily activities such as driving. Less noticeable internal swelling in the sinus areas can cause headaches, toothaches, blurred vision, scalp tingling or itching, and difficulty hearing. Occasionally, patients report feeling dizzy.
Since there is a lack of published information about head and neck lymphedema and the symptoms that arise with it, physicians and other healthcare professionals are not well-educated about this problem. They may not realize that symptoms are related to lymphedema and may fail to include referrals to lymphedema therapists in the plan of treatment. This lack of treatment can lead to increased difficulty with overall function, decreased quality of life, and worsening lymphedema which can, at times, be life-threatening.
TREATMENT
Lymphedema in the head and neck area can be treated. The current standard of care for lymphedema is manual lymphatic drainage (MLD). This treatment modality uses light massage techniques to open lymphatic pathways and move fluid into lymphatic drainage pathways and should only be undertaken by a trained, certified lymphedema therapist.7 Some patients may benefit from wearing compression garments in the head and neck areas. Care must be taken to insure that blood flow to the vital vessels located in the head and neck areas are not impaired. Compression can be used safely when a certified, experienced therapist manages the treatment.
Many people ask if there are medications available to treat lymphedema in the head and neck area and whether surgery is an option. Currently, there is no drug approved for treatment of lymphedema in the head and neck. Corticosteroids are often used in treatment of mixed edemas and to provide comfort for patients near end of life with terminal head and neck cancer. Corticosteroids should not be used to treat pure lymphedema in the head and neck. Research exploring complementary and alternative treatment methods is being examined as treatment options for lymphedema of the head and neck.
Selenium has been given to head and neck cancer patients having undergone either surgery, radiation, or both as treatment.2,3 Early studies suggest that Selenium may be helpful for a short period of time, but the long-term value remains undocumented. As with all other types of lymphedema, if infection develops in the head and neck area, antibiotic treatment is needed to address the source of the infection. Antibiotics are not effective in the treatment of lymphedema itself. Surgical treatment options are not available at this time.
It is important to remember that swelling in the head and neck area can become severe at times, especially in cancer patients. If excessive swelling (which may be edema, mixed edema, and/or lymphedema) occurs, hospitalization may be necessary to maintain breathing and improve swallowing difficulties. It is important to seek medical attention immediately if swelling makes it hard to breathe or swallow.
Adequate treatment of head and neck LE also requires addressing the symptoms and functional problems that may develop secondary to the swelling and tissue fibrosis. Patients with head and neck lymphedema may feel uncomfortable around others. If this discomfort leads to social isolation or depression supportive mental health treatment or counseling is indicated. Treatment of the emotional distress caused by this condition is as important to maintaining quality of life as is the treatment of the lymphedema itself. Speech therapy may be required to address problems related to swallowing and voice. Physical therapy may be indicated if swelling makes head and neck movement difficult.
PATIENT AND FAMILY EDUCATION
Due to there being so little information available to healthcare professionals about head and neck lymphedema, patients with lymphedema and their family members often must serve as their own healthcare advocates. Therefore, knowledgeable professionals caring for patients with LE should make sure their patients and families are well educated about the condition. Educational content will vary based upon each patient’s specific circumstances and needs. In general, education should include teaching patients and families how to care for the lymphedema at home. Observation of the patient and/or family member’s ability to correctly conduct self-care activities such as exercise and applying of compression garments is a necessary part of this education. Education should also include warning signs of infection, such as redness, heat or pain, and instruction to seek immediate medical care when breathing or swallowing becomes difficult. Therapists also need to provide instructions about when to contact them for additional treatment.
Education about the very real emotional distress that can arise when lymphedema is present in the head and neck is critical. Patients and families should be made aware that this distress is common and they are not the only ones who experience it. If patients do not want to be seen in public or have signs of depression such as feeling hopeless or sad most of the time, they should be encouraged to seek support and professional help.
If you or a family member has head and neck LE, educate yourself about the condition. The NLN Network (www.lymphnet.org), Lymph Notes (www.lymphnotes.com), American Cancer Society (www.cancer.org), National Cancer Institute (www.cancer.gov) and Support for People with Oral, Head and Neck Cancer (www.spohnc.org) are reliable sources of information. If you find yourself dealing with an uninformed healthcare provider, you may want to refer them to these resources for some self-education.
CONCLUSIONS
Early diagnosis and quick referral for treatment is needed to help reduce symptoms associated with head and neck lymphedema. Patient compliance with prescribed treatment is also of great importance. Individuals who experience emotional distress because of head and neck lymphedema may need to see a mental health professional for support. Lymphedema occurring in the head and neck area is a treatable condition, as are the symptoms
that come with it.
Sheila Ridner can be contacted at sheila dot ridner at vanderbilt dot edu
1 Twycross, R., Jenns, K., & Todd, J. (Eds.). Lymphoedema. Radcliffe Medical Press Ltd.: Abingdon, Oxon, 2000.
2 Micke, O., Bruns, F. Mucke, R., Schafer, U., Glatzel, M., & DeVries, A. F., et al. (2003). Selenium in the treatment of radiation-associated secondary lymphedema. International Journal of Radiation Oncology Biology Physics. 56, 40-49.
3 Bruns, F., Micke, O., & Bremer, M. (2003). Current status of selenium and other treatments for secondary lymphedema. Journal of Supportive Oncology, 1, 121-130.
4 Browse, N., Burnand, K. G., & Mortimer, P. S. Disease of the Lymphatics. London: Arnold, 2003
5 Lymphoedema Framework. (2006). Best Practice for the Management of Lymphoedema. International consensus. London: MEP Ltd.
6 Patterson, J. M., Hildreth, A., & Wilson, J. A. (2007). Measuring Edema in Irradiated Head and Neck Cancer Patients. Annals of Otology, Rhinology Laryngology, 116, 559-564.
7 Foldi, M., Foldi, E. (2003),Textbook of Lymphology for physicians and lymphedema therapists. In S. Subik (Ed). Muchen, Germany: Urban Fischer
By Brian D. Lawenda, MD, and Tammy E. Mondry, DPT, MSRS, CLT-LANA
*Author Disclosure:
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government
Introduction
Radiation therapy has been an effective therapeutic modality in the management of both benign and malignant tumors for over a century. The science and technology surrounding the delivery of this targeted treatment has significantly improved our ability to not only control tumors, but to also minimize the untoward complications of irradiating normal tissues. Advances in radiation and surgical techniques have significantly decreased the incidence of debilitating lymphedema (LE); however, this side effect will continue to occur in all patients who undergo surgery and/or radiation therapy on lymphatic-rich tissues. In this article, we will briefly review the pathophysiology of radiation-induced LE and discuss some of the more common radiation treatment techniques and indications employed in the management of breast, gynecologic and prostate cancers.
Etiology of Radiation-Induced Lymphedema
Radiation causes acute and chronic effects in most soft tissue subtypes. These effects are mediated by a complex process involving hormonal and oxidative changes within the tissue microenvironment. These changes persist for years, leading to apoptosis, production of free radicals, and changes in gene expression. This causes increased fibrosis, and decreased vascular/lymphatic vessel organization and function. (1) LE occurs as a result of the late effects on the lymphatic vessels and soft tissues, which cause obstruction and mechanical dysfunction due to radiation and surgical changes. If these effects are allowed to progress, they can lead to chronic dermal congestion, fibrosis, decreased limb mobility, pain and paresthesias.
Radiation late-effects are dependent on multiple factors, including: radiation dose, volume of irradiated tissue, and the histologic components of the tissue radiated. (1) The variability in these factors makes the development of generalized statements, regarding radiation side effects, a more complicated matter.
Radiation is most commonly delivered using a small daily dose, called a fraction of radiation, 5-days per week for 1-8 weeks. This as well as the total or cumulative dose is dependent on the indication, site of disease, disease type and the patient’s performance status. Late tissue effects are more likely to develop when larger daily doses and/or higher total doses are delivered. This is due to the fact that irradiated soft tissues are less able to repair the ionizing effects of larger daily doses and/or larger total doses.
The amount of tissue volume irradiated is also an important factor in the development of both acute and late effects. Even small increases in the size of the radiation field can potentially lead to a greater than expected degree of soft tissue side effects because volume increases exponentially. As larger amounts of tissue are irradiated, the degree of vascular and lymphatic injury/dysfunction, obstruction and parenchymal inflammation increases. Over time, these injuries can overwhelm the endogenous repair mechanisms and collateral vasculature of the effected tissues leading to fibrosis and/or edema.
Lymph node bearing areas to include inguinal, axillary and pelvic lymph nodes are frequently irradiated during the treatment of many cancers. There are certain high-risk indications when the regional lymphatics need to be treated with both surgery and radiation therapy. Individually, these interventions create lymphatic obstruction/disruption; however, clinically evident LE may not occur. This incidence increases dramatically when these areas are subjected to both therapeutic modalities.
Radiation Therapy in the Management of Breast Cancer
Adjuvant breast irradiation is almost always recommended following any breast conserving surgery. The breast can either be radiated with whole breast irradiation (WBI) or partial breast irradiation (PBI) techniques. The tissue at risk for local recurrence of breast cancer is the entire anatomic extent of the breast. This extends superiorly to the clavicle, inferiorly to approximately 2 cm below the inframammary fold, laterally to the mid-axillary line, and medially to the mid-sternum. The standard of care for treating breast cancer after breast conserving surgery is WBI, which includes all ipsilateral tissues within these boundaries. (2) Radiation can be delivered with external beam radiation therapy (EBRT) using a linear accelerator and/or through implantable, temporarily placed radiation sources known as brachytherapy.
The vast majority of patients who receive WBI are treated with EBRT. This technique requires a course of treatment, frequently 6-7 weeks long of daily treatment, 5 times per week. The planning for EBRT begins with a session called a simulation, where the radiation oncologist physically marks the borders of the breast on the patient. The patient then undergoes a CT scan of the chest so that the marked borders, tumor cavity, chest wall and lungs can be identified on a computer planning system. Radiation dose and beam parameters are then calculated and placed into the treatment delivery computer, which tells the linear accelerator how to deliver the daily treatment.
During the treatment, the patients will not feel or sense the radiation, and they will usually not begin to experience any side-effects until 2-3 weeks into treatment. Many patients will develop mild fatigue, skin redness/hyperpigmentation, and increased breast sensitivity as the course of treatment progresses. In some patients, the skin will develop dry or moist desquamation by the end of treatment. These effects are self-limiting and usually resolve within weeks-to-months after the completion of therapy.
The regional lymphatics in the axilla, supraclavicular fossa and internal mammary chain are only irradiated in specific circumstances when there is an increased risk of lymph node involvement or recurrence. Patients who have non-invasive breast cancer are not prescribed radiation to these regional lymphatics, as the risk of lymphatic spread is very uncommon. Invasive breast cancer is treated more aggressively due to the increased risk of lymphatic spread.
A sentinel lymph node biopsy (SLNB) is a procedure where a radioactive and / or blue dye is injected into the breast tumor or cavity and is allowed to migrate to the first echelon node(s), called the sentinel node. If the patient has a SNLB and no metastatic cancer is found, the patient will not require any further lymphatic surgery or lymphatic radiation. If however, the sentinel node is positive for cancer, the patient will require a more extensive axillary lymph node dissection (ALND). This procedure has a higher incidence of upper extremity LE than SLNB, and thus is no longer recommended as the first-line surgery in the absence of clinically involved axillary nodes.
Although there are no long-term, randomized controlled outcome data comparing WBI versus PBI, many patients with small (<3cm), low-intermediate grade breast cancers are currently being offered PBI. The rationale for PBI is that the greatest risk of a localized recurrence is within 1-2 cm of the tumor bed. PBI can be delivered either using EBRT or brachytherapy. In PBI, only the tumor bed cavity and the immediately adjacent tissues are treated. Brachytherapy can be done with either implanted catheters or a balloon implant, which is placed into the tumor cavity. Patients are then either admitted for 4-5 days, in a radiation-shielded room, while the dose is delivered or they are treated as an outpatient, using a daily radiation delivery system. The clear advantage of using brachytherapy is the convenience for the patient. The patient undergoes radiation for 4-5 days as compared to the 6-7 week EBRT course. Prospective, non-randomized data demonstrate that, in well-selected patients, this technique offers excellent local control (>95%) and cosmetic outcome. (3)
Following mastectomy, some patients will be offered radiation therapy to the chest wall, scar and/or regional lymphatics. This is almost exclusively done using EBRT, for 6-7 weeks. The regional lymphatics are irradiated based on the same criteria as in the above-mentioned sections on breast conserving treatment.
LE is a common side effect of breast and/or regional nodal irradiation. The incidence of ipsilateral upper extremity LE increases with combined surgery and radiation to the regional lymphatics. The occurrence of lymphedema after a SLNB alone is 2.6 – 3.0 percent. (4, 5) With this patient population, the tumor location in the upper outer quadrant was identified as a risk factor for the development of lymphedema. (5) If an ALND is performed alone, the incidence rate of lymphedema rises. It has been reported that after a level I/II ALND the incidence of lymphedema of the upper arm was 14 percent, 12 percent in the forearm, and 16 percent in the hand utilizing a diagnostic scale of a circumference difference greater than 5 percent. (6) The incidence rate of upper extremity lymphedema after an ALND and / or radiation therapy ranges from 6.0 – 33.5 percent. (4, 7-14)
Although no randomized data have been published, there is a suggestion from the available literature that breast edema occurs much more commonly after WBI as compared with PBI. Breast lymphedema following WBI ranges from 8 to 25 percent in patients who undergo a limited ALND. (15) In a recent study, the use of whole breast intensity modulated radiation therapy (IMRT) has been shown to possibly decrease the risk of chronic breast edema from 30 percent down to 3 percent as compared with the conventional WBI techniques. (16) A three-year median follow-up after lumpectomy and PBI using EBRT found a zero percent rate of breast edema. (17) While reports on a four-year median follow up of patients undergoing lumpectomy and PBI using intraoperative electron beam therapy found a two percent (1 out of 47 patients) rate of breast edema . (18)
Breast lymphedema is an often-overlooked area of breast cancer treatment-related side effects. Breast edema occurs in 6 – 48 percent of patients after receiving surgery and radiation therapy for breast cancer. (12, 19, 20) The incidence rate of breast lymphedema after a lumpectomy alone is six percent. (19) This rate drastically increases with nodal dissection and radiation therapy. The incidence of breast lymphedema after a sentinel lymph node biopsy and radiation therapy is 23 percent; with an axillary lymph node dissection and radiation therapy is 35 percent in node negative patients; and 48 percent in node positive patients. (20)
Radiation Therapy in the Management of Gynecologic Malignancies
Cervical cancer. Radiation is commonly used as a definitive or adjunctive treatment in patients with cervical cancer. In addition to the cervix, uterus and paracervical tissues, the regional lymphatics are often included. These consist of paracervical, pelvic sidewall / obturator and external iliac nodes (and para-aortic nodes in more advanced disease.) Total abdominal hysterectomy (TAH), with or without a pelvic lymph node dissection (PLND), is the most common surgical procedure for the earliest stages of invasive cervical cancer. As the disease becomes more extensive, a radical hysterectomy (RH) is recommended. Adjuvant radiation therapy is offered in cases when there is an increased risk of recurrence after surgery (i.e. large and/or deeply invasive tumors, lymphovascular space invasion, positive surgical margin, involved lymph nodes and parametrium.) (21) This generally involves a 5-week course of EBRT, with or without chemotherapy, to the tumor bed and pelvic lymphatics.
Definitive radiation is often recommended when there is higher probability of requiring adjuvant radiation therapy after surgery. Studies have demonstrated a greater incidence of complications and side-effects from combined surgery and radiation to the pelvis than either modality alone. (21) A single therapeutic modality is therefore preferable. In cases where definitive radiation is recommended, EBRT and brachytherapy are commonly employed. Generally, 5-weeks of EBRT are delivered to the tumor, surrounding tissues and lymphatics. This is then followed by a series of brachytherapy sessions comprised of either one or two inpatient treatments, or 1-2 weeks of multiple outpatient treatments.
The EBRT technique is delivered using either opposing anterior/posterior beams or anterior/posterior and lateral beams. Some groups are using an EBRT technique, called intensity modulated radiation therapy (IMRT), to deliver highly conformal doses of radiation to the areas at risk. IMRT uses a complex computer treatment planning system that employs multiple non-opposing beams to “paint” defined radiation doses throughout the target volume. This technique seems to reduce the unintended side effects of radiation doses to non-target tissues such as small bowel, bladder, and rectum.
Acute radiation-related side effects often occur within the first 2-4 weeks of treatment, and may include: fatigue, skin redness, loose stools, urinary frequency and dysuria. Late effects manifest months-to-years after treatment, and may include: vaginal dryness and shortening, dyspareunia, radiation proctitis or cystitis, sacral plexopathy, changes in bowel function, and lower extremity LE.
The incidence in lower extremity LE following surgery and radiation therapy in the treatment of cervical cancer ranged from 21-49 percent. (22-24) In a retrospective study of early-stage cervical carcinoma treated with preoperative radiotherapy and radical hysterectomy, LE occurred during the first year in 21 percent of the patients. (22) In another retrospective study, cervical cancer patients were treated with radical surgery and postoperative radiation therapy with 31 percent of patients presenting with lower extremity LE. (23) Patients being followed over a ten year period after undergoing radical hysterectomy followed by postoperative radiotherapy for carcinoma of the uterine cervix presented with LE at an incidence rate of 42 percent at five years, and 49 percent at ten years. (24)
Endometrial cancer. Most cases of endometrial cancer are treated with surgery alone (TAH/BSO +/- pelvic and para-aortic lymph node sampling.) However, when the risk of pelvic nodal involvement or vaginal cuff recurrence exceeds 5-10%, adjuvant radiation therapy may be recommended. The pelvic nodes are treated using a 5-week EBRT course. As with cervical cancer, some groups are using IMRT instead of the conventional opposed field radiation. The vaginal cuff (apex of the vagina) is treated using a series of outpatient brachytherapy sessions or a single inpatient session. (25)
When EBRT is used, the acute radiation-related side effects are similar to those mentioned above for cervical cancer. The use of vaginal cuff brachytherapy alone can lead to the development of acute radiation side effects, but skin redness does not occur because no external radiation beams traverse the skin. Fatigue, genitourinary and gastrointestinal side effects are less frequent due to the very short range of the brachytherapy radiation dose. Late effects from EBRT may include: vaginal dryness and shortening, dyspareunia, radiation proctitis or cystitis, changes in bowel function, and lower extremity LE. A retrospective review of 517 endometrial cancer patients undergoing surgery and postoperative radiotherapy reported LE of the lower extremity as a complication in 11 percent of all cases. (26) Vaginal cuff brachytherapy-alone can cause late vaginal cuff fibrosis, vaginal shortening, dryness and dyspareunia; rarely, vaginal cuff necrosis can also occur.
Vulvar cancer. EBRT is commonly the definitive therapeutic modality in the management of invasive vulvar cancer. The inguinal lymph nodes are the primary echelon drainage from tumors of this region and are often treated in this disease. Patients may undergo a superficial inguinal LND and/or radiation to these lymphatics. Typically, radiation is delivered with a combination of opposing anterior and posterior beams; however non co-planar (IMRT) beams may be used instead.
The acute effects of radiation usually occur within the first 2-3 weeks of treatment, and often include: skin redness, desquamation, dysuria, urinary frequency, loose stools, and proctitis. The late effects often manifest months-to-years later and include: vaginal dryness, dyspareunia, vaginal and anal stenosis (from soft tissue fibrosis), rectal urgency and other bowel movement changes. Both radiation and lymph node dissection can individually cause lower extremity LE, but the combination of the two substantially increases this risk. A retrospective review of patients undergoing bilateral groin irradiation for vulvar cancer revealed a LE incidence rate of 6 percent, as compared to 12 percent of patients undergoing bilateral or unilateral inguinofemoral dissection. (27)
Radiation Therapy in the Management of Prostate Cancer
Prostate cancer is commonly treated with either surgery (prostatectomy +/- pelvic LND) or radiation therapy (EBRT or brachytherapy.) The choice of treatment is based on a variety of factors, including: age, performance status, stage of disease, tumor grade, and prostate-specific antigen (PSA). In both management approaches of radiation or surgery, the entire prostate is treated or removed.
Radiation therapy targets the prostate only and not the lymphatics when the risk of lymph node involvement is less than 15%, whereas the pelvic lymphatics are often included when the risk exceeds 15%. The radiation fields are commonly delivered from multiple beam angles, using the non-coplanar IMRT technique. IMRT allows a higher dose to be delivered to the prostate (+/- pelvic LNs), while minimizing the dose received by the adjacent non-target tissues such as small bowel, rectum, bladder, and femurs. In circumstances where the patient either has a positive surgical margin and / or a rising postoperative PSA, adjuvant radiation therapy to the prostate bed is frequently recommended. The lymphatics are generally not intentionally treated in these circumstances.
The incidence of post irradiation lymphedema was found to be strongly dependent upon the extent of dissection performed to include biopsy only, limited / diagnostic dissection, or complete / therapeutic dissection. (28) Patients undergoing limited / diagnostic dissection followed by pelvic irradiation have a 25-30 percent risk of developing lymphedema; versus a 66 percent risk in patients undergoing complete / therapeutic dissection followed by pelvic irradiation. (28)
Conclusion
Radiation-induced LE is an untoward complication of treatment to the lymphatics as part of the management of many common malignancies. This article briefly reviewed some of the indications, techniques and side effects of radiation therapy as they pertain to a few of the more frequently encountered oncologic tumors.
All patients undergoing surgery and/or radiation therapy for the treatment of these cancers are at risk for the development of secondary lymphedema. Pre-treatment patient evaluation and education regarding lymphedema risk reduction practices should be performed. If lymphedema does develop CDT is a viable therapy for the treatment and maintenance of the condition.
1. Constine L, Milano M, Friedman D, et al. Late Effects of Cancer Treatment on Normal Tissues. In: Halperin E, Perez C, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 320-354.
2. NCCN. Practice Guidelines in Oncology (v.2.2008), Invasive Breast Cancer: Principles of Radiation Therapy. In; 2008.
3. Haffty B, Buchholz T, Perez CA. Early Stage Breast Cancer. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Therapy. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 1175-1291.
4. Golshan M, Martin W, Dowlatshahi K. Sentinel lymph node biopsy lowers the rate of lymphedema when compared with standard axillary lymph node dissection. . The American Surgeon 2003;69(3):209-211.
5. Sener SF, Winchester, D. J., Martz, C. H., Feldman, J. L., Cavanaugh, J. A., Winchester, D. P., Weigel, B., Bonnefoi, K., Kirby, K., & Morehead, C. . Lymphedema after sentinel lymphadenectomy for breast carcinoma. . Cancer 2001;92(4):748-752.
6. Querci della Rovere G, Ahmad, I., Singh, P., Ashley, S., Daniels, I. R. & Mortimer, P. An audit of the incidence of arm lymphoedema after prophylactic level I/II axillary dissection without division of the pectoralis minor muscle. . Annals of the Royal College of Surgeons of England 2003;85(3):158-161.
7. Wilke LG, McCall, L. M., Posther, K. E., Whitworth, P. W., Reintgen, D. S., Leitch, A. M., Gabram, S. G., Lucci, A., Cox, C. E., Hunt, K. K., Herndon, J. E. 2nd, & Giuliano, A. E. . Surgical complications associated with sentinel lymph node biopsy: Results from a prospective international cooperative group trial.. Annals of Surgical Oncology 2006;13(4):491-500.
8. Edwards TL. Prevalence and aetiology of lymphoedema after breast cancer treatment in southern Tasmania. The Australian and New Zealand Journal of Surgery 2000;70(6):412-418.
9. Logan V. Incidence and prevalence of lymphedema: A literature review. Journal of Clinical Nursing 1995;4(4):213-219.
10. Bani HA, Fasching, P. A., Lux, M. M., Rauh, B., Willner, M., Eder, I., Loehberg, C., Schrauder, M., Beckmann, M. W., & Bani, M. R. Lymphedema in breast cancer survivors: Assessment and information provision in a specialized breast unit. . Patient Education and Counseling 2007;66(3):311-318.
11. Hinrichs CS, Watroba, N. L., Rezaishiraz, H., Giese, W., Hurd, T., Fassl, K. A., & Edge, S. B. Lymphedema secondary to post mastectomy radiation: Incidence and risk factors. Annals of Surgical Oncology 2004;11(6):573-580.
12. Goffman TE, Laronga C, Wilson L, et al. Lymphedema of the arm and breast in irradiated breast cancer patients: risks in an era of dramatically changing axillary surgery. Breast Journal 2004;10(5):405-11.
13. Deo SV, Ray, S., Rath, G. K., Shukla, N. K., Kar, M., Asthana, S., & Raina, V. . Prevalence and risk factors for development of lymphedema following breast cancer treatment. Indian Journal of Cancer 2004;41(1):8-12.
14. Petrek JA, & Heelan, M. C. Incidence of breast carcinoma-related lymphedema. Cancer 1998;83(Supplement):2776-2781.
15. Meek AG. Breast radiotherapy and lymphedema. Cancer 1998;83(12 Suppl American):2788-97.
16. Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy. International Journal of Radiation Oncology, Biology, Physics 2007;68(5):1375-80.
17. Vicini FA, Chen P, Wallace M, et al. Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy. International Journal of Radiation Oncology, Biology, Physics 2007;69(4):1124-30.
18. Mussari S, Sabino Della Sala W, Busana L, et al. Full-dose intraoperative radiotherapy with electrons in breast cancer. First report on late toxicity and cosmetic results from a single-institution experience. Strahlentherapie und Onkologie 2006;182(10):589-95.
19. O'Brien PJ. Integrated survivorship care. . In: The Fourth Annual Orlando Breast Cancer Conference; 2007; Orlando, FL; 2007.
20. Ronka RH, Pamilo MS, von Smitten KA, et al. Breast lymphedema after breast conserving treatment. Acta Oncologica 2004;43(6):551-7.
21. Perez CA, Kavanagh B. Uterine Cervix. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 1532-1609.
22. Gerdin E, Cnattingius, S. & Johnson, P. . Complications after radiotherapy and radical hysterectomy in early-stage cervical carcinoma. Acta Obstetricia et Gynecologica Scandinavica 1995;74(7):554-561.
23. Hong JH, Tsai, C. S., Lai, C. H., Chang, T. C., Wang, C. C., Lee, S. P., Tseng, C. J. & Hsueh, S. . Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis. International Journal of Radiation Oncology, Biology, Physics 2002;53(5):1284-1290.
24. Chatani M, Nose, T., Masaki, N. & Inoue, T. . Adjuvant radiotherapy after radical hysterectomy of cervical cancer. Prognostic factors and complications. . Strahlentherapie und Onkologie 1998;174(10):504-509.
25. Cardenes H, Look K, Michael H, et al. Endometrium. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 1610-1628.
26. Nunns D, Williamson, K., Swaney, L. & Davy, M. The morbidity of surgery and adjuvant radiotherapy in the management of endometrial carcinoma. . International Journal of Gynecological Cancer 2000;10(3):233-238.
27. Petereit DG, Mehta, M. P., Buchler, D. A. & Kinsella, T. J. . A retrospective review of nodal treatment for vulvar cancer. . American Journal of Clinical Oncology 1993;16(1):38-42.
28. Pilepich MV, Asbell, S. O., Mulholland, G. S. & Pajak, T. Surgical staging in carcinoma of the prostate: The Radiation Therapy Oncology Group Experience. . Prostate 1984;5(5):471-476.
By Mei R. Fu, PhD, RN, ACNS-BC; Judith Haber, PhD, APRN-BC, FAAN; Amber A. Guth, MD, FACS; Deborah Axelrod, MD, FACS
Armer, J.M., Radina , M.E. , Porock, D., & Culbertson , S.D. (2003). Predicting breast cancer-related lymphedema using self-reported symptoms. Nursing Research, 52(6), 370-379.
American Cancer Society (ACS). (2006). Lymphedema: What Every Woman With Breast Cancer Should Know. http://www.cancer.org/docroot/MIT/content/Lymphedema_and_Breast_Cancer.asp Accessed on January 7, 2006.
National Lymphedema Network (NLN) (2006). Position Paper on Lymphedema Risk Reduction Practices. http://www.lymphnet.org/lymphedemaFAQs/positionPapers.htm Accessed on January 7, 2006.
National Cancer Institute (NCI). (2006). Lymphedema [Patient Version]. http://www.cancer.gov/search/results.aspx Accessed on January 7, 2006.
La nger, I. , Guller, U,. Berclaz, G., Koechli, O.R., Schaer, G., Fehr, M.K., Hess, T., Oertli, D., Bronz, L., Schnarwyler, B., Wight, E., Uehlinger, U., Infanger, E., Burger, D., Zuber, M. (2007). Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Annals of Surgery, 245 (3):452-61.
Paskett, E.D., Naughton, M.J., McCoy, T.P., Case, L.D., Abbott, J.M. (2007). The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiology, Biomarkers & Prevention, 16(4), 75-82.
Soran, A., D'Angelo, G., Begovic, M., Ardic, F., Harlak, A., Samuel, Wieand, H., Vogel, V.G., Johnson, R.R. (2006). Breast cancer-related lymphedema--what are the significant predictors and how they affect the severity of lymphedema? Breast Journal, 12(6), 536-543.
By Professor Neil B. Piller
Summary
A patient presents with no real cause for their lymphoedema; we call it “primary”. We superficially examine the patient, see if there are any clinically manifest external signs of lymph vascular malformation, ask them about the nature of their swollen limb, when it started, how it progressed, if there is a family history, make some measurements and if they are lucky, they may be able to be referred to a genetic specialist. In the examination, we may find (or be told of) other associated angio-dysplasias or associated syndromes such as distachiasis, webbed neck, or others. We classify and then begin treatment of the outwardly appearing symptoms of a dysfunctional lymphatic system. In reality, we have little idea of what has happened or is happening at the genetic, molecular and biochemical levels. We often cannot be sure of whether what we suggest will work. There is little or no pro-activity in this. We react and then treat in a “shotgun” approach with little knowledge or ability to target the real issues – that is the structure and functional aberrations of the lympho-vascular system. The time is right for change. Our better understanding of genetics and of molecular biology, specifically molecular lymphology will soon hopefully mean a change to this. We will be able to act on sound knowledge to change and improve the structure and/or function of the lymphatic system.
We are not there yet, but in the meantime the best we can do is early detection, recognition, and acknowledgement of a dysfunctional lymphatic system, hopefully leading to some prophylactic intervention (for those who have been lucky enough to gain an early referral) and an offering of the best treatment targeting the range of problems using a multidisciplinary team.
Article
Our genes are the blueprint for the body’s development, growth and functioning. However, sometimes there is an error in the code we get from each of our parents, sometimes the code is read wrongly, and sometimes the code changes as we move through life. These changes can affect our biochemical and physiological events which can lead to the manifestation of lymphoedema.
In the world of lymphoedemas and associated syndromes, these code and misreading errors are what can form the basis of a range of dysplasias of the lympho-vascular systems, the end point of which, for some, is the development of one of a range of what we currently call primary lymphoedemas. Lately it seems that the proportion of primary lymphoedemas compared to secondary ones seems to be declining. Perhaps this is a consequence of our ability now to more accurately determine the causes and paths of lymphoedemas than previously. Not withstanding this, when a primary lymphoedema (and its associated co-morbidities) manifest it is a situation which needs to be reacted to. It is important, to look back at the family history of the disorder, examine family members with clinical, sub-clinical or latent forms of lymphatic dysfunction, and then glance into the future for potential offspring who may also be at risk.
Sometimes these genetic errors are severe and the embryo fails to thrive, while on other occasions the errors are small. Depending on the nature of these errors and on the impact of this misreading or wrong reading of coded information, there can be aberrations to the structure and thus function of the lympho-vascular system and associated structures. The more wide spread these are across the lympho-vascular structures of the body, the earlier they present.
An example, is those surviving embryos with the earliest congenital form of lymphoedema (hereditary/type 1/Nonne-Milroy). It seems to affect boys and girls equally, is more common in the legs, but certainly occurs in the genitalia, arms, trunk and face at times. Its incidence is about 1 in 6000 births; in real terms it’s a fairly common genetic disorder. In this form of lymphoedema, the fault seems to be on chromosome 5 and with the VEGFR-3 (also known as FLT-4) gene for a majority of families.
For the later types of primary lymphoedema (juvenile and later onset/Meige), it’s different in that mostly girls are affected and then usually in one limb (or more so in one limb than the other). While the exact genes here are not certain, many of those who have it do not express it (develop lymphoedema), but there is still the risk that it will be passed to their children.
Often the genetic coding or transcription error which leads to lymphoedema (or to an increased risk of it) are associated with other disorders (commonly also with a genetic basis). Under these conditions the term “syndromic lymphoedema” is sometimes used. Examples of when lymphoedema occurs with other syndromes include, yellow nail syndrome (adults), distichiasis (teenagers mostly), choleostasis, intestinal lymphangiectasia, hypoparathyroidism, Noonan’s syndrome, microcephaly and a range of other infrequent but often significant conditions. In the case of distichiasis, there is a haplo-insufficiency due to a mutation in one allele of the gene which encodes the FOXC2 transcription factor (Erickson, 2001). An excellent paper to read about the syndromic classification of heritable lymphoedema is by Northup et al (2003).
What is clear is that a dysplasia of the lymphatic system often is associated with a range of other malformations in other structures and systems of the body. The severity of these malformations will often determine the timing of their appearance. (Chaft et al 2003). One gets the impression that a really pure primary lymphoedema is rare given the strong association of lymphangiopathies with carriers of chromosomal aberrations, Because of this, if one comes across a person with just a lymphangiopathic aberration (no matter what the age), there should perhaps be an attempt to screen for symptoms of chromosomal aberrations as described above.
Individuals with lymphangiopathies want to know what has gone wrong, what the future for those with these conditions is, and what may be done in the future to prevent or remediate them. Our best chance seems to be linked to our expansion of our knowledge of factors affecting the growth and development of the lympho-vascular system to the extent that we can use it to suppress abnormal growth of the lymph vascular system, grow functional vessels (where they previously did not grow) and repair lymphatic damage caused by surgery, radiotherapy, tissue trauma and other diseases/disorders.
There are proteins that circulate in the body called vascular endothelial growth factors (one is VEGF-A for short). When VEGF-A meets a special receptor (in this case VEGFR-1 or 2), blood vessels grow. However, too much growth can be bad (as occurs in tumors). Of course the opposite extreme can also be bad – undergrowth or poorly organized growth – which results in insufficient functional vessels to supply cell and tissue demands.
There are also growth factors (VEGF-C and D) and their receptors (VEGFR-2 and 3) in the lymphatic vessels. As in the blood vascular system, high levels of these factors may be associated with higher risk of tumor spread. Lower levels of these growth factors may be associated with hypoplastic conditions such as primary lymphoedemas. The importance of VEGF-C and D in the sprouting and guidance in the migration of lymphatic vessels is crucial; if levels are low then growth is poor.
There are some indications of an anti-VEGFR-3 neutralising antibody which seems to be able to inhibit lymph vascular regeneration. This will be fantastic in situations where there is pathological overgrowth such as Klippel-Trenauney syndrome and others. There are many actions and interactions between the range of growth factors and receptors and the endothelium of the lymph and vascular systems leading to significant debate about which system developed first (Wilting et al 2004). This part of the argument is far from settled, but it’s clear that when there are vascular issues there are often associated lymphatic ones as well (and vice versa!). So does it really matter which was first, as long as we have better identified the growth factors, their receptors and the switches?
Of course the whole issue is not as simple as this. Looking at it simplistically is often dangerous, but it can at least help us understand some of the inter-relationships between our genes on one extreme and the lymphatic system and cell and tissue health, and lymphoedema on the other. What will be important to help us make better clinical decisions will be a close look at the relationships between our clinical descriptions of the range of lymph vascular dysplasias which confront us (which most often are nothing more fancy than a description of what we see externally) and what is actually going on at the genetic, molecular and biochemical levels (Witte et al., 2003).
Also as suggested earlier, tied in with lymphatic vessel development issues are other dysfunctionalities such those indicated in the papers of Harvey et al and Harvey (2005) who indicated that the inactivation of a single allele of the homeobox gene (Prox1) could lead to adult onset obesity seemingly due to abnormal leakage from poorly structured lymph vessels. Maybe this is in part the reason for the unique increase in epifascial adiposity in middle and latter stage lymphoedema! Or course it might not be just this since lymph flow is slow in lymphoedemas and slow lymph flow (due to possible adipogenic factors in it) might also help in the deposition of fatty tissue!
We also need to consider the other crucial roles of the lymphatic system and associated structures in tumor metastases and specific immunity. High levels of VGEF-C and D correlate with high numbers of intra tumoral vessels and appear to increase tumor metastasis. (Well at least that is one view and others disagree!). Again a detailed genetic interrogation and the use of the tools of molecular biology will have a lot to offer our understanding in this area.
Even further along the pathway, we should have the genetic basis of how patients will respond to pharmacological treatment. Some time ago coumarin (Lodema) was used as a common treatment for lymphoedemas, however the discovery of significant hepatotoxity effects and possible linked death of some patients meant it was taken from the market. And yet now it seems that the problem of hepatotoxity could have been related to reductions in CYP2A6 activity (the major enzyme involved in coumarin metabolism). Individuals with poor CYP2A6 metabolisers metabolised coumarin via a cytotoxic pathway. There are multiple CYP2A6 variants and some of these are alleles which express the enzyme with reduced or no activity. Those who are homozygous for these alleles are poor metabolizers and thus are the ones possibly more susceptible to coumarin toxicity. (Farinola and Piller, 2007)
There are genetic factors (some of which remain to be clearly identified) which will affect the development of lymphoedema, its inter-relationship with vascular development and a wide range of other syndromes, and which may affect the response to pharmacological means to manage the lymphoedema. At the present time, we do not have an adequate understanding to intervene and achieve better outcomes for individuals. We do hope that soon we will be able to tailor medicines to a patient, based on what we know of their genetic presentation.
Researchers have begun to switch genes on and off to control growth of small capillary-like lymphatics as the work of Stacker, Achen and others have shown experimentally (Stacker et al., 2006). There are quite a few steps that still need to be perfected before we can apply this practically, but we are well on the way. One very interesting step will be the application of this knowledge to tissue engineering (Neumann et al., 2003). Once scientists have control over lymph vascular proliferation, they may be able to build three dimensional tissues with a functional lymph vascular system and have an array of not only lymphatic capillaries but also collectors and nodes (Piller, 2003).
Harvey (2005) has indicated our most important questions of the moment relate to the nature of the signals that separate the lymphatic and blood vasculature, why there are different responses of the superficial and visceral lymphatic networks to growth factors and which signals determine endothelial cell growth and its fate. In the meantime we must encourage and participate in further research into primary lymphoedemas and their associated syndromes and of how best to treat and manage them. But what we can all do today is to work toward early recognition and identification of these syndromes, initiate appropriate treatment, and at least show that we can have some control over them even if we have an incomplete knowledge of all the reasons for their presentation. Some of our current research strategies here in Australia involve measurement of the structural and functional changes of the lympho-vascular systems both generally and locally and early detection of their symptoms (such as subtle fluid accumulation through bio-impedance spectroscopy). In addition, we are looking at the functional status of the lymphatic system through lymphoscintigraphy, since it is the blood-tissue lymph interface, the pre-lymphatic fluid and the lymph which carry the signals, mediate the response and the site of action of every thing we have been talking about. Optimal flow, physio-chemical properties, and communication with other entities are crucial irrespective of all of the issues of genetic transcription or coding errors. We must recognize and react to physical and structural changes while we wait for our knowledge at the genomic and molecular level to reach the level of expertise where we can begin to seriously influence the development, structure and function of the lymphatic system.
Definitions
Angiodysplasia: Abnormal growth of the lymph and blood vessels
Distichiasis: Double row of eyelashes. Seen in lymphedema-distichaisis patients with a FOXC2 gene mutation and often associated with other congenital anomalies.
Choleostasis: Blockage or slowing of bile flow from liver.
Lymphangiectasia: Malformation and disorder of the lymphatic capillaries or collectors
Allele: A range of DNA codings which occupy a particular position on a chromosome, variation (mutation) of which leads to a range of different outward expressions.
FOXC2: A gene which is a member of the forkhead family; an important developmental gene.
Homeobox gene: Gene that encodes proteins and is very important developmentally.
Epifascial Adiposity: Accumulation of fat above the deep fascia of the limb possibly due to slow lymph flow (lymphoedema) or a malformed lymphatic system with microaneurysms (lipoedema)
Key References :
Farinola N, N Piller.(2007) CYP2A6 polymorphisms: Is there a role for pharmocogenomics in preventing coumarin induced hepatotoxity in lymphoedema patients? Pharmogenomics 8(2):151-158.
Harvey N. (2005) Embryonic Lymphatic Development: Recent Advances and Unanswered Questions. Lymphatic Research and Biology 3(3):157-165.
Erickson R. (2001) Lymphoedema-Distichiasis and FOXC2 gene mutations. Lymphology 34(1): 1.
Harvey N, RS Srinivasan, M Dillard, et al. (2005) Lymphatic vascular defects promoted by Prox1 haploinsuffficiency cause adult onset obesity. Nature Genetics Advance on Line Publication 18 th sept 2005 doi:10.1038/ng1642
Piller N. (2003) Literature watch: Tissue Engineering. Lymphatic Research and Biology 1(4):337-341.
Witte M, M Bernas, K Northup, C Witte.(2003) Molecular Lymphology and genetics of lymphedema-angiodysplasia syndromes In Text book of Lymphology (Foeldi, M, Foeldi, I and Kubik, S Eds) Urban and Fisher, Munich.
Newmann T, B Nicholson, J Sanders.(2003) Tissue engineering of perfused microvessels. Microvascular Res. 66:59-67.
Wilting J, M Papoutsi, J Bekcer.(2004) The lymphatic vascular system: Secondary or Primary? Lymphology 37(3):98-106.
Northup K, M Witte, CWitte. (2003) Syndromic classification of hereditary lymphoedema. Lymphology 36(3):162-189.
Chaft J, D Steckman, F Blei. (2003) Genetics of vascular anomalies: An update Lymphatic Research and Biology 1(4):283-289.
Stacker SA, RA Hughes, RA Williams, MG Achen (2006) Current Strategies for modulating lymphangiogenesis signalling pathways in human disease. Curr. Med. Chem., 13:783-792.
Professor Neil Piller
Director Lymphoedema Assessment Clinic
Flinders University and Medical Centre
President of 2009 International Society of Lymphology Congress
South Australia
About Us | Privacy Policy |
Contact Us
©2005 National Lymphedema Network. All rights reserved.
Permission to print and duplicate this page for personal and educational purposes only, not for sale. Reprint Permission Request Form (pdf format, 86kb). For more information, call 510-208-3200.