Introduction
Anatomy and Pathophysiology of the Lymphatic System
Clinical Manifestations
        Psychological symptoms
Epidemiology
Risk Factors
        Axillary node removal
        Sentinel node biopsy
        Obesity
        Other
Diagnosis and Evaluation

Introduction

Lymphedema is swelling that occurs when protein-rich lymph fluid accumulates in the interstitial tissue. This lymph fluid may contain plasma proteins, extravascular blood cells, excess water, and parenchymal products.[1] Lymphedema is one of the most poorly understood, relatively underestimated, and least researched complications of cancer or its treatment. The Institute of Medicine of the National Academies published a report in 2006 recommending a “survivorship care plan” for cancer patients that incorporates information about late effects of treatment, health management behaviors, disease management, and recurrence monitoring.[2] The Institute of Medicine also highlighted critical shortfalls in the transition to survivorship, particularly in providing education about late effects of treatment.

Lymphedema is an important consideration for clinicians who care for cancer patients because of its relatively high frequency and significant functional and quality of life implications for patients. Lymphedema is an independent predictor of decreased quality of life, even when other predictive factors such as socioeconomic status, decreased range of motion, age, and obesity are taken into account.[3]

This summary will review issues related to anatomy and pathophysiology of lymphedema related to cancer, its clinical manifestations, diagnosis, and treatment. Primary (congenital) lymphedema and non–cancer-related lymphedema (i.e., recurrent cellulitis, connective tissue disease, and infection) will not be reviewed here.

The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillarylike channels that drain into larger, secondary lymphatic vessels located in the subdermal space. These primary and secondary lymphatic vessels parallel the superficial veins and drain into a deeper third layer of lymphatic vessels located in the subcutaneous fat adjacent to the fascia. A muscular wall and numerous valves aid active, unidirectional lymphatic flow in secondary and subcutaneous lymphatic vessels. Primary lymphatic vessels lack a muscular wall and do not have valves. An intramuscular system of lymphatic vessels that parallels the deep arteries and drains the muscular compartment, joints, and synovium also exists. The superficial and deep lymphatic systems probably function independently, except in abnormal states, although there is evidence that they communicate near lymph nodes.[4] Lymph drains from the lower limbs into the lumbar lymphatic trunk, which joins the intestinal lymphatic trunk and cisterna chyli to form the thoracic duct that empties into the left subclavian vein. The lymphatic vessels of the left arm drain into the left subclavian lymphatic trunk and then into the left subclavian vein. Lymph channels of the right arm drain into the right subclavian lymphatic trunk and then into the right subclavian vein.

One function of the lymphatic system is to return excess fluid and protein from interstitial spaces to the blood vascular system. Because lymphatic vessels often lack a basement membrane, they can resorb molecules too large for venous uptake. Mechanisms of clinical edema include increased arteriovenous capillary filtration and reduced interstitial fluid absorption. Causes of increased capillary filtration include increased hydrostatic pressure in capillaries, decreased tissue pressure, and increased membrane permeability. Reduced interstitial fluid resorption can be caused by decreased plasma oncotic pressure, increased oncotic pressure of tissue fluid, and lymphatic obstruction.

The onset of secondary lymphedema is often insidious. However, it may be suddenly provoked by local inflammation from causes such as infection or limb injury. Therefore, patients should be evaluated for evidence of cellulitis. Classically, lymphedema is characterized by nonpitting swelling of an extremity, usually with involvement of the digits. Early stages of lymphedema manifest with pitting edema until fibrosis develops. The distribution of the swelling may be restricted only in the proximal or distal portion of the limb. Lymphedema may also predispose to recurrent skin infections.[5]

Patients with lymphedema may report a wide variety of complaints: heaviness or fullness related to the weight of the limb, a tight sensation of the skin, or decreased flexibility of the affected joint. The texture of the skin may become hyperkeratotic, with verrucous and vesicular skin lesions. With upper extremity involvement, the patient may have difficulty fitting the affected area into clothing or wearing previously well-fitting rings, watches, or bracelets. Similar difficulties with lower extremity lymphedema include a sensation of tightness or difficulty wearing shoes, itching of the legs or toes, burning sensation in the legs, or sleep disturbance and loss of hair. Ambulation can be affected because of the increased size and weight of the affected limb. Activities of daily living, hobbies, and the ability to perform previous work tasks may also be affected.

Breast cancer survivors with arm lymphedema have been found to be more disabled, experience a poorer quality of life, and have more psychological distress than do survivors without lymphedema.[6,7] In addition, women reporting swelling have reported significantly lower quality of life with multiple functional assessments.[8]

Lymphedema can occur after any cancer or its treatment that affects lymph node drainage. It has been reported to occur within days and up to 30 years after treatment for breast cancer.[9] Eighty percent of patients experience onset within 3 years of surgery; the remainder develop edema at a rate of 1% per year.[10] Upper-extremity lymphedema most often occurs after breast cancer; lower-extremity lymphedema most often occurs with uterine cancer, prostate cancer, lymphoma, or melanoma.[1] A large population-based study supports the evidence that lower-limb lymphedema is experienced by a significant proportion of women after treatment for gynecological cancer, with the highest prevalence (36%) among vulvar cancer survivors and lowest prevalence (5%) among ovarian cancer survivors.[11]

There is no consistency in the data on the incidence and prevalence of lymphedema after breast cancer, probably because of differences in diagnosis, the different characteristics of the patients studied, and inadequate follow-up to capture delayed development of the disorder. The overall incidence of arm lymphedema can range from 8% to 56% at 2 years postsurgery.[8]

Patients undergoing axillary surgery and/or axillary radiation therapy for breast cancer are at higher risk for developing lymphedema of the arm. Previous convention suggested that nodal positivity was a predisposing factor for the development of lymphedema in breast cancer patients.[12] Controlling for axillary radiation, one study actually found an inverse relationship between nodal positivity and arm volume.[12]

Compared with axillary sampling alone, partial or total mastectomy followed by full axillary lymph node dissection significantly increases a patient’s chance of developing arm edema. For example, in one series of 100 women who underwent partial or total mastectomy and then full axillary lymph node dissection or axillary sampling, arm edema developed in more patients who underwent axillary lymph node dissection compared with sampling alone (30% vs. none).[13] In addition, the extent of axillary lymph node dissection increases the risk for developing arm edema. For example, in one series involving 381 women undergoing segmental mastectomy and axillary lymph node dissection, women who had ten or more lymph nodes removed were more likely than women who had few lymph nodes in the specimen to develop arm symptoms within the first year (53% vs. 33%) and within the next 2 years (33% vs. 20%).[14]

For patients with breast cancer, sentinel lymph node dissection has gained favor over axillary lymph node dissection for the axillary staging of early disease because of decreased morbidity and because of the questionable survival benefits of axillary lymph node dissection, as shown in a phase III randomized study (ACOSOG-Z0011) of axillary lymph node dissection in women who had stage I or IIA breast cancer and a positive sentinel node.[15] Several studies have shown that lymphedema is more prevalent in breast cancer patients who undergo axillary lymph node dissection than in those who undergo sentinel lymph node biopsy.[16] One study evaluated 30 patients with unilateral invasive breast carcinoma who underwent sentinel lymph node biopsy and 30 patients who underwent axillary lymph node dissection. This study found a 20% rate of developing lymphedema in the axillary lymph node dissection group compared with none in the sentinel lymph node biopsy group.[16]

Among all breast cancer patients, being obese or overweight may predispose women to developing lymphedema after treatment for breast cancer.[9] Some studies have correlated the degree of lymphedema with the level of obesity.[9] Similarly, among young breast cancer survivors, persistent swelling was related to having more lymph nodes removed and being obese.[8]

Other risk factors for developing lymphedema include the following:

• Extent of local surgery.



• Local radiation (axillary, inguinal, pelvic, or supraclavicular regions).



• Delayed wound healing.



• Tumor causing lymphatic obstruction of the anterior cervical, thoracic, axillary, pelvic, or abdominal nodes.



• Scarring of the left or right subclavian lymphatic ducts by either surgery or radiation.



• Intrapelvic or intra-abdominal tumors that involve or directly compress lymphatic vessels and/or the cisterna chyli and thoracic duct.

Lymphedema is typically evident by clinical findings such as nonpitting edema, usually with involvement of the digits, in a patient with known risk factors such as previous axillary dissection. Other causes of limb swelling, including deep venous thrombosis, malignancy, and infection, should be considered in the differential diagnosis and excluded with appropriate studies, if indicated.

If the diagnosis is not evident on the basis of clinical assessment, imaging of the lymphatic system with lymphoscintigraphy (radionuclide imaging) may be necessary. Lymphangiography is generally no longer a favored diagnostic test and may be contraindicated in patients with malignancy because of concern that it may contribute to metastatic spread of tumor. Additional imaging techniques such as magnetic resonance imaging may complement information obtained via lymphoscintigraphy by providing anatomic and nodal detail.[17]

The wide variety of methods described in the literature for evaluating limb volume and lack of standardization makes it difficult for the clinician to assess the at-risk limb. Options include water displacement, tape measurement, infrared scanning, and bioelectrical impedance measures.[18]

The most widely used method to diagnose upper extremity lymphedema is circumferential upper extremity measurement using specific anatomical landmarks.[5] Arm circumference measures are used to estimate volume differences between the affected and unaffected arms. Sequential measurements are taken at four points on both arms: the metacarpal-phalangeal joints, the wrist, 10 cm distal to the lateral epicondyles, and 15 cm proximal to the lateral epicondyles. Differences of 2 cm or more at any point compared with the contralateral arm are considered by some experts to be clinically significant. However, measuring specific differences between arms may have limited clinical relevance because of implications, for example, of a 3-cm difference between the arm of an obese woman and the arm of a thin woman. In addition, there can be inherent anatomic variations in circumference between the dominant and nondominant limb related to differences in muscle mass and variations after breast cancer treatment that may occur with atrophy of the ipsilateral arm or hypertrophy of the contralateral arm.[3] A small study comparing various methods of assessing upper limb lymphedema did not show any superiority of any one method.[18] Sequential measurements over time, including pretreatment measurements, may prove to be more clinically meaningful.

The water displacement method is another way to evaluate arm edema. A volume difference of 200 mL or more between the affected and opposite arms is typically considered to be a cutoff point to define lymphedema.[19]

One common method of lymphedema classification uses three stages based on severity.[5] Stage I is spontaneously reversible and typically is marked by pitting edema, increase in upper extremity girth, and heaviness. Stage II is characterized by a spongy consistency of the tissue without signs of pitting edema. Tissue fibrosis can then cause the limbs to harden and increase in size.[5] Stage III, also called lymphostatic elephantiasis, is the most advanced stage, but is rarely seen following breast cancer treatment.[5]

References

1. Meneses KD, McNees MP: Upper extremity lymphedema after treatment for breast cancer: a review of the literature. Ostomy Wound Manage 53 (5): 16-29, 2007.  [PUBMED Abstract]
   
   
2. Hewitt M, Ganz PA, eds.: From Cancer Patient to Cancer Survivor - Lost in Transition: An American Society of Clinical Oncology and Institute of Medicine Symposium. Washington, DC: The National Academies Press, 2006. 
   
   
3. Petrek JA: Commentary: prospective trial of complete decongestive therapy for upper extremity lymphedema after breast cancer therapy. Cancer J 10 (1): 17-9, 2004. 
   
   
4. Horsley JS, Styblo T: Lymphedema in the postmastectomy patient. In: Bland KI, Copeland EM, eds.: The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia, Pa: Saunders, 1991, pp 701-6. 
   
   
5. Bicego D, Brown K, Ruddick M, et al.: Exercise for women with or at risk for breast cancer-related lymphedema. Phys Ther 86 (10): 1398-405, 2006.  [PUBMED Abstract]
   
   
6. Pyszel A, Malyszczak K, Pyszel K, et al.: Disability, psychological distress and quality of life in breast cancer survivors with arm lymphedema. Lymphology 39 (4): 185-92, 2006.  [PUBMED Abstract]
   
   
7. Ridner SH: Quality of life and a symptom cluster associated with breast cancer treatment-related lymphedema. Support Care Cancer 13 (11): 904-11, 2005.  [PUBMED Abstract]
   
   
8. Paskett ED, Naughton MJ, McCoy TP, et al.: The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiol Biomarkers Prev 16 (4): 775-82, 2007.  [PUBMED Abstract]
   
   
9. Shaw C, Mortimer P, Judd PA: Randomized controlled trial comparing a low-fat diet with a weight-reduction diet in breast cancer-related lymphedema. Cancer 109 (10): 1949-56, 2007.  [PUBMED Abstract]
   
   
10. Petrek JA, Senie RT, Peters M, et al.: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92 (6): 1368-77, 2001.  [PUBMED Abstract]
    
    
11. Beesley V, Janda M, Eakin E, et al.: Lymphedema after gynecological cancer treatment : prevalence, correlates, and supportive care needs. Cancer 109 (12): 2607-14, 2007.  [PUBMED Abstract]
    
    
12. Purushotham AD, Bennett Britton TM, Klevesath MB, et al.: Lymph node status and breast cancer-related lymphedema. Ann Surg 246 (1): 42-5, 2007.  [PUBMED Abstract]
    
    
13. Borup Christensen S, Lundgren E: Sequelae of axillary dissection vs. axillary sampling with or without irradiation for breast cancer. A randomized trial. Acta Chir Scand 155 (10): 515-9, 1989.  [PUBMED Abstract]
    
    
14. Liljegren G, Holmberg L: Arm morbidity after sector resection and axillary dissection with or without postoperative radiotherapy in breast cancer stage I. Results from a randomised trial. Uppsala-Orebro Breast Cancer Study Group. Eur J Cancer 33 (2): 193-9, 1997.  [PUBMED Abstract]
    
    
15. Lucci A, McCall LM, Beitsch PD, et al.: Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 25 (24): 3657-63, 2007.  [PUBMED Abstract]
    
    
16. Celebioglu F, Perbeck L, Frisell J, et al.: Lymph drainage studied by lymphoscintigraphy in the arms after sentinel node biopsy compared with axillary lymph node dissection following conservative breast cancer surgery. Acta Radiol 48 (5): 488-95, 2007.  [PUBMED Abstract]
    
    
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18. Ridner SH, Montgomery LD, Hepworth JT, et al.: Comparison of upper limb volume measurement techniques and arm symptoms between healthy volunteers and individuals with known lymphedema. Lymphology 40 (1): 35-46, 2007.  [PUBMED Abstract]
    
    
19. Mondry TE, Riffenburgh RH, Johnstone PA: Prospective trial of complete decongestive therapy for upper extremity lymphedema after breast cancer therapy. Cancer J 10 (1): 42-8; discussion 17-9, 2004 Jan-Feb.  [PUBMED Abstract]
    
    

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