CONTINUING EDUCATION The Third Circulation: Radionuclide Lymphoscintigraphy in the Evaluation of Lymphedema* Andrzej Szuba, MD, PhD1; William S. Shin1; H. William Strauss, MD2; and Stanley Rockson, MD1 1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California; and 2Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, California all. Lymphedema results from impaired lymphatic transport Lymphedema—edema that results from chronic lymphatic in- caused by injury to the lymphatics, infection, or congenital sufficiency—is a chronic debilitating disease that is frequently abnormality. Patients often suffer in silence when their misdiagnosed, treated too late, or not treated at all. There are, primary physician or surgeon suggests that the problem is however, effective therapies for lymphedema that can be im- plemented, particularly after the disorder is properly diagnosed mild and that little can be done. Fortunately, there are and characterized with lymphoscintigraphy. On the basis of the effective therapies for lymphedema that can be imple- lymphoscintigraphic image pattern, it is often possible to deter- mented, particularly after the disorder is characterized with mine whether the limb swelling is due to lymphedema and, if so, lymphoscintigraphy. whether compression garments, massage, or surgery is indi- At the Stanford Lymphedema Center, about 200 new cated. Effective use of lymphoscintigraphy to plan therapy re- cases of lymphedema are diagnosed each year (from a quires an understanding of the pathophysiology of lymphedema and the influence of technical factors such as selection of the catchment area of about 500,000 patients). Evidence that the radiopharmaceutical, imaging times after injection, and patient disease is often overlooked by physicians caring for the activity after injection on the images. In addition to reviewing the patient is seen by the fact that about 60% of the patients are anatomy and physiology of the lymphatic system, we review self-referred for initial evaluation and treatment, even if physiologic principles of lymphatic imaging with lymphoscintig- they have had lymphedema for years. raphy, discuss different qualitative and quantitative lymphoscin- tigraphic techniques and their clinical applications, and present Lymphedema is a prevalent disease. Approximately 10 clinical cases depicting typical lymphoscintigraphic findings. million people have lymphedema secondary to breast and Key Words: lymphatic system; radiotracers; lymphatic insuffi- pelvic cancer therapy, recurrent infections, injuries, or vas- ciency cular surgery. Worldwide, about 90 million people have J Nucl Med 2003; 44:43–57 lymphedema, primarily because of parasitic infection. When chronic venous insufficiency is added as a cause, there may be as many as many as 300 million cases (1–4). In our clinic, about 75% of the patients have lymphedema Effective use of lymphoscintigraphy to plan therapy for because of malignancy or its therapy, with about half of lymphedema requires an understanding of its pathophysiol- these related to breast cancer surgery. ogy and the influence of technical factors such as selection of the radiopharmaceutical, imaging times after injection, Arm Lymphedema and patient activity after injection on the images. Arm lymphedema is a frequent complication of breast cancer therapy and axillary lymph node dissection, with an CHARACTERISTICS OF LYMPHEDEMA estimated frequency of 5%–30%. This incidence is based Lymphedema is a chronic debilitating disease that is primarily on studies that use volume and circumference frequently misdiagnosed, treated too late, or not treated at criteria in the first 2–5 y after surgery. Arm volume differ- ences above 100–200 cm3 or a circumference difference above 2 cm is used as a cutoff point for the diagnosis of Received Jan. 29, 2002; revision accepted Aug. 8, 2002. For correspondence or reprints contact: H. William Strauss, MD, Memorial lymphedema. All these studies disregard milder forms of Sloan Kettering Cancer Center, 1275 York Ave., Room S212, New York, NY lymphedema and miss a significant number of patients with 10021. E-mail: [email protected] mild lymphedema, especially in the nondominant arm, *NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH which could be 200 cm3 smaller than the dominant arm THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) THROUGH JANUARY 2004. before surgery. Unfortunately, almost all studies are retro- RADIONUCLIDE LYMPHOSCINTIGRAPHY • Szuba et al. 43 spective and do not include arm measurements before sur- “mild” lymphedema of the leg may cause chronic leg discom- gery (5,6). fort and problems with walking, running, and fitting shoes. One prospective study, by Goltner et al., of 360 women Advanced lymphedema of the leg causes severe lifelong dis- undergoing breast cancer surgery found that arm lymphe- ability. Genital lymphedema, frequently secondary to therapy dema developed after surgery in 42% of women (7). for pelvic cancer, can be devastating for the patient (18,19). Even clinically “mild” lymphedema may cause a signif- In summary, noninfectious lymphedema is a common icant disability, especially if it affects the hand. A hand disease and one can expect an increase in the number of volume increase of 100 cm3 causes substantial impairment patients rather than a disappearance of this condition over of function, because any work requiring fine movements of the next decade. Many of these patients suffer because they the hand, such as typing, writing, or playing piano, are were not properly diagnosed and treated. Early diagnosis difficult to perform. can lead to effective treatment and prevention of secondary A combination of conservative surgery and careful pa- effects, including extremity deformity, disuse atrophy, and tient selection for nodal radiotherapy may reduce the inci- increased susceptibility to recurrent infections. dence of postmastectomy lymphedema (8), particularly when these therapies are combined with sentinel node bi- Diagnosis opsy, but their impact on the incidence of postsurgical Lymphedema can be surprisingly difficult to diagnose, lymphatic insufficiency has not yet been adequately as- especially in its early stages. Without a proper diagnosis, sessed. Although axillary surgical staging, with or without therapy is often delayed, allowing secondary fibrosis and breast conservation techniques, is characterized as relatively lipid deposition to take place. Early treatment often results free of significant complications (9), a postoperative study in rapid clinical improvement and prevents progression to the chronic phase of the disease. of 200 patients suggested that lymphatic complications still Lymphoscintigraphy offers an objective and reliable ap- occur. Statistically significant changes in ipsilateral arm proach to diagnose and characterize the severity of volume were detected at the mid biceps, antecubital fossa, lymphedema. The following sections review the anatomy and mid forearm; furthermore, clinically significant arm and pathophysiology of the lymphatic system and the tech- edema (arm circumference difference Ͼ 2 cm) was detected nique and interpretation of the lymphoscintigram. in 13% of patients at1yormore after surgery, whereas 76.5% experienced postoperative sensorineural dysfunction LYMPHATIC ANATOMY, PHYSIOLOGY, of the medial arm or axilla (9). AND PATHOLOGY Axillary lymph node dissection, because it correlates positively with 10-y survival in breast cancer patients (10), Components of the Lymphatic System is still applied to most patients with early breast cancer (10). The lymphatic system is a component of both the circu- Sentinel node biopsy, however, is gaining clinical accep- latory and the immune systems. The lymphatic system con- tance and offers a chance to avoid axillary node dissection sists of a series of conduits (the lymphatic vasculature), in patients with early breast cancer. Sentinel node biopsy lymphoid cells, and organized lymphoid tissues. Lymphoid will not eliminate the necessity of axillary node dissection tissues include the lymph nodes, spleen, thymus, Peyer’s in patients with positive sentinel nodes (28%–46% of eli- patches in the intestine, and lymphoid tissue in the liver, gible patients (11)) and in patients with advanced breast lungs, and parts of the bone marrow (20). Lymphatics are cancer. One cautionary note about sentinel node biopsy is found throughout the body, with the exception of the central the limited utility of this procedure in patients with preop- nervous system, where cerebrospinal fluid fulfills the nor- erative chemotherapy; up to 33% of patients may have mal role of lymph. Lymphatic vasculature and lymphoid false-negative results (12). tissue are prevalent in organs that come into direct contact The incidence of breast cancer in the United States is with the external environment, such as the skin, gastroin- projected to increase from 185,000 patients per year to testinal tract, and lungs. This distribution is probably a 420,000 per year in the next 20 y (11). The higher incidence reflection of the protective role of the lymphatics against of breast cancer is likely to increase the incidence of infectious agents and alien particles. Absorption of fat from lymphedema despite the developments of breast-conserving the intestine occurs through the lymphatic system, which surgery and sentinel node biopsy. In addition, the longer transports the lipids (chyle) to the liver. The lymphatic survival of breast