Lymphoscintigraphy to confirm the diagnosis of lymphedema

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1 Lymphoscintigraphy to confirm the diagnosis of lymphedema clinical Peter J. Golueke, MD, Robert A. Montgomery, MD, John D. Petronis, MD,* Stanley L. Minken, MD, Bruce A. Perler, MD, and G. Melville Williams, MD, Baltimore, Md. Confirmation of the diagnosis of lymphedema often requires l~anphangiography, a procedure that is painful for the patient and technically demanding. Radioisotope lymphoscintigraphy is a relatively new technique that uses technetium 99m antimony trisulfide colloid to produce a diagnostic image similar to a lymphangiogram. The procedure requires a single subcutaneous injection in the involved extremity, and images are obtained 3 hours later. It is technically easy to perform, produces minimal discomfort for the patient, and has no adverse effects. We have recently used radioisotope lymphoscintigraphy to evaluate 17 patients with extremity edema. These patients initially had a presumed diagnosis of lymphedema involving the upper or lower extremity. Lymphoscintigraphy confirmed the diagnosis of lymphedema in 12 (70.6%) patients. In five of the I7 patients (29.4%) the clinical impression oflymphedema was not supported by lymphoscintigraphy, leading to alternative diagnoses such as tipomatosis, venous insufficiency (two patients), congestive heart failure, and disuse edema. In all patients with secondary lymphedema the lymphatic system in the involved extremity could be partially visualized. Conversely, three of four patients with primary lymphedema had no ascent of the tracer from the foot and no lymphatic channels could be visualized. Lymphoscintigraphy is relatively easy to perform, safe, minimally invasive, and not uncomfortable for the patient. It is useful in differentiating lymphedema from other causes of extremity edema, allowing institution of appropriate therapy. (J VASC SURG 1989;10: ) Vascular surgeons are frequently asked to establish the cause of extremity, edema. Whcn formal evaluation reveals a lack of venous disease or systemic causes of extremity edema, the diagnosis of lymphedema is suggested. Conventional lymphangiography is performed with reluctance because it is technically difficult, painful, and associated with a moderate number of complications. For this reason thc diagnosis oflymphedema is often assumed on clinical grounds and therapy is instituted. Recent advances in the technique of radioisotope lymphangiography (lymphoscintigraphy) have improved the image quality and the reproducibility of the scans. The clearer detail of lymphatic anatomy and the ability to evaluate lymphatic function are the assets of this minimally invasive confirmatory test for From the Division of Vascular Surgery and the Division of Nuclear Medicine, ~ The Johns Hopkins Medical Institutions. Presented at the Thirteenth Annual Meeting of the Southern Association for Vascular Surgery, Key West, Fla., Jan , Reprint requests: Peter I. Golueke, MD, Department of Surgery, Francis Scott Key Medical Center, 4940 Eastern Ave., Baltimore, MD /6/14117 lymphedema. 1,2 Herein we describe the use of this technique in the routine evaluation of patients with suspected lymphedema. PATIENTS Seventeen patients had extremity, edema consistent with a diagnosis oflymphedema and underwent radioisotope lymphoscintigraphy between 1978 and Eleven of the 17 (64.7%) were evaluatcd within the last 2 years when it became apparcnt that this technique was useful in establishing the diagnosis of lymphedema. The technique has been under limited approval by the Food and Drug Administration, and until recently it was used primarily for the mapping of lymph node drainage pattcrns of tumors, a,4 The average age of the patients studied was 48 years (range 4 to 84 years). There were eight males and nine females. Edema involved the upper extremity in 29.4% (5/17) and the lower extremity in 70.6% (12/17). Additional diagnostic testing included contrast venography in 58.8% (10/17), venous plethysmography in 47.1% (8/17), CT scanning to look for 306

2 Volume 10 Number 3 September 1989 Lymphoscintigraphy for lymphedema Fig. 1. Normal lymphoscintigram. A, Marked radioactivity at site of injection of radiotracer in both feet, with lymph channels ascending calf. Marker ~ in midcalf, region (arrow). B, Ilia c region shows iliac and femoral nodes bilaterally. C, Paraaortic nodes and normal liver activity 3 hours after injection. (Note: Extremity scans usually separated by 24-. to 48-hour interval to evaluate hepatic uptal~e individually by each limb injection.) malignancy in 41.2% (7/17), lymph node biopsy in 23.5% (4/17), and conventional contrast lymphangiography in 5.9% (1 / 17) of patients. TECHNIQUE The technique of radioisotope lymphoscintigraphy was performed with technetium 99m-antimony trisulfide (gvmtc-sb2sa) colloid (Cadema Medical Products, Inc., Middletown, N.Y.) with a particle size of 4 to 11 ~m. The imaging protocol consisted of a single 1 ~Ci dose of the isotope injected subcutaneously in the foot or hand of the involved extremity. Care was taken to avoid intravascular injection by aspirating for blood before injection. The

3 308 Journal of VASCULAR SURGERY Golueke et al. Fig. 2. Photograph and lymphoscintigram of patient with lymphedema praecox. A, Front view shows involvement of right leg. B, Scintiscan of right lateral foot shows absence of normal lymphatic channels, with moderate dermal backflow; marked tracer activity at injection site (arrow). C, No lymphatic channels noted in right knee region; note l<nee marker (arrow). D, No lymph channels or inguinal nodes (large arrow) in right groin region; note bladder activitt (small arrow). E, Abdomen scan 3 hours after injection of radiotracer in right foot; no liver tracer activity noted. paticnts were instructed to return 3 hours after injection for imaging, and no specific instructions regarding exercise during this time interval were given. After 3 hours, images of the involved extremity and liver were obtained with a gamma camera for 100,000 cotmts or 10 minutes. The patients thcn returned 24 to 48 hours later for an identical injection and scanning in the uninvolved extremity, which was used as a basis for comparison. Qualitative scintigraphic images were considered normal when dis- crete lymphatic channels draining the extremity, lymph node chains, and liver activity could be visualized (Fig. 1). Upper extremity images were similar in appearance, delineating the lymphatic drainagc of the arm and normal uptake by the liver at 3 hours. Studies were considered abnormal when the radiotracer failed to ascend the extremity, when discrete lymph channels or regional lymph node chains were not identified, or when no activity was noted in the liver 3 hours after injection of contrast material. The

4 Volume 10 Number 3 September 1989 Lymphoscintigraphy for lymphedema 309 Table I. Causes of secondary lymphedcma Cause Cancer metastatic to regional nodes Venom thrombosis Surgical lymphadenectomy Modified radical mastectomy Inguinal node dissection Radiation therapy Chronic osteomyelitis, lymphadenitis No. Table II. Diagnosis established in patients with normal lymphoscintigraphy resuks Diagnosis No, Lipomatosis 1 Venous insufficiency Deep I Superficial 1 Right-sided heart failure 1 Disuse (dependent) edema 1 radiation dose with this isotope is maximal at the injection site and is approximately 400 to 500 mrad, which is much less than the radiation dose in routine hepatic scintiscanning. Quantitative lymphoscintigraphic data were not obtained in this study. On completion of the scintigraphic study the scan data were reviewed in the context of the clinical history, physical examination, and other ancillary diagnostic results, and a diagnosis was formulated. RESULTS In 12 (70.6%) of the 17 patients who had extremity edema, qualitative lymphoseintigraphy confirmed the diagnosis of lymphedema. In each of the I2 cases the scan results were clearly abnormal, with faint (n = 3) or absent (n = 9) liver activity 3 hours after injection in the edematous extremity. In addition, each study displayed either gross reduction in normal lymphatic channels (n = 11), significant collateralization of lymph flow (n = 2), absence of one or more groups of regional lymph nodes (n = 10), or complete absence of tracer movement from the site of injection (n = 3). In each case the contralateral comparison extremity was qualitatively normal. Secondary lymphedema was the most common diagnosis in this series (7/i2), and the causes are listed in Table I. All of the patients with secondary lymphedema had at least partial visualization of the lymphatic system in the involved extremity. Four patients, all with lower extremity edema, were thought to have primary lymphedema (praecox, two; tarda, two), since no secondary cause could be identified. Three of the four patients with primary lymphedema had scans showing no movement of tracer from the foot after injection (Fig. 2). In one patient, a 33-year-old white man, the differentiation between primary and secondary lymphedema was difficult because he had had an ipsilateral-right ureteral reimplantation for uretero-vesical junction obstruction 6 years before experiencing edema. Despite the fact that the operation was not a nodal ablative procedure, the lymphoscintigram was consistent with high-grade partial obstruction near the right iliac vessels with relatively normal appearing nodal distribution above this area. It is interesting to note that results of venous plethysmography were positive or equivocal in each of the six patients with lymphedema in whom it was performed, despite a negative venographic study (contrast or isotope) in each case. Only one patient underwent conventional lymphangiography and lymphoscintigraphy. This 12-year-old girl with lymphedema praecox involving the right leg had normal appearing lymphatics in the left leg on the conventional lymphangiogram, although the number of lymph channels were slightly decreased in the left thigh. Lymphoscintigraphy showed normal lymphatic fimction on the left. Lymphangiography could not be performed on the right because a lymphatic channel could not be cannulated. Lymphoscintigraphy showed severe dermal backflow without ascent of isotope tracer from the foot, confirming the diagnosis of lymphedema. In five patients with suspected lymphedema (5/17) the diagnosis was not confirmed by lymphoscintigraphy since the studies showed normal lymphatic channels and nodes, with normal liver activity at 3 hours. In each case, review of the collected clinical data and scintiscans led to a subsequent diagnosis (Table II). One patient with massively enlarged lower extremities was originally thought to have lymphedema. However, lymphosdntigraphy resuits were entirely normal and a diagnosis of severe lipomatosis was established. The patient was treated by a plastic surgery consultant who used a combination of liposuction and surgical excision. Two other patients had clear photoplethysmographic evidence of venous insufficiency despite a clinical resemblance to lymphedema. Another patient with bipedal edema was diagnosed as having mild rightsided heart failure after completely normal results on lymphoscintigraphy. The fifth patient had stage II Hodgkins lymphoma treated with radiation and chemotherapy and had right leg edema and right hip

5 310 Golueke et al Journal o~ VASCULAR SURGERY pain. Completely normal right leg lymphoscintigraphy results ruled out local minor invasion, leading to the diagnosis of disuse (dependent) edema. No adverse side effects were noted in the patients who underwent lymphoscintigraphy. DISCUSSION Our experience with radioisotope lymphoscintigraphy and recent data from other investigators S,6 suggest that the technique is useful in confirming the clinical diagnosis of lymphedema. A normal scintigraphic scan outcome with clearly defined lymph channels, regional nodes, and obvious tracer activity in the liver at 2 to 3 hours after injection in the foot or hand virtually rules out significant lymphatic obstruction. This enables the physician to redirect his diagnostic evaluation toward systemic or venous causes of limb edema without making unsupported assumptions. Conventional oily contrast lymphangiography, as originally described by Kinmonth, 7 remains the "gold standard" for definition of the anatomy of the peripheral lymphatic system, against which lymphoscintigraphy is compared. Radioisotope lymphoscintigraphy, although less precise anatomically than conventional lymphangiography, often gives adequate morphologic information and additionally evaluates lymphatic function by following the ascent of a microcolloid as it is handled by the lymphatic system. Conversely, conventional lymphangiography gives little fianctional assessment, since the study is obtained by forceful injection of oily contrast media directly into a cannulated lymphatic channel. The conventional technique requires a minor surgical procedure to cannulate a very small lymphatic vessel with a 27- to 30-gauge catheter with magni~ing loupes or an operating microscope. This technique is painful and can be technically tedious, especially in edematous extremities, leading Kinmonth and others 8 to suggest using a general anesthetic for the procedure. In addition, complications of conventional lymphangiography include local skin necrosis or sterile abscess, which can result in a poorly healing wound, exacerbation of lymphedema by direct damage from oily contrast injection into cannulated lymph channels, and pulmonary embotization of oily contrast media. For all of these reasons, conventional contrast lymphangiography is seldom performed. ~9 In contrast, radioisotope lymphoscintigraphy is technically easy to perform, produces minimal discomfort for the patient, and has no associated adverse side effects. The information gained from this study is clearly worth the time and risk involved to perform it. Lymphoscintigraphy is based on the transport of a colloidal radiotracer that is injected subcutaneously, phagocytized by macrophages, and carried to local lymphatics, on to regional lymph nodes, and evenreally to the liver. An~ng that alters the integrity of this system fimctionally or anatomically will disrupt the normal flow of the radiotracer. If a radiotracer is injected intravenously instead of subcutaneously, it will rapidly localize within the reticuloendothelial system of the liver, spleen, and bone marrow, without lymph channel or nodal visualization. Colloid particle size is an important aspect in the uniformity of test results. Historically, early efforts at lymphoscintigraphy, which began in the 1940s, used radioactive gold or iodinated aggregated serum albumin. These radiotracers had significant disadvantages including delivery of a high dose of radiation to the patient, relatively long half-lifes, and high ener~" of emissions producing poor-quality scan images. Modern lymphoscintigraphy with the introduction of new radiopharmaceuticals and modifications in instrumentation obviates the problems of earlier techniques. Currently, the 99mTc-Sb2S3 radiotracer is being evaluated at 350 medical centers within the United States, and approval by the Food and Drug Administration is expected soon. It is not always possible to discern the exact cause of the lymphatic obstruction seen on lymphoscintigraphy, but in most cases the cause is clear from the clinical presentation. The pathophysiologic characteristic of edema in secondary lymphedema is thought to be obstruction (infection, tumor infiltration, surgical removal of nodes). The pathophysiologic characteristic of edema in patients with primat T lymphedema is less well understood. There are severn anatomic classifications based on studies with conventional lymphangiography. 9 One classification divides patients by hypoplastic, hyperplastic, or varicose type thought to be a result of incompetent lymphatic valves and an aplastic variety. Another classification suggests that there may be a proximal and a distal obliterative form of primary lymphedema. Our small series of patients with primary lymphedema merely showed severe lymphatic dysfunction, making it difficult for us to make any assumptions regarding the pathophysiologic characteristics or anatomic classification of the tymphedema. Possibly, if these patients arestudied earlier in their course, these determinations can be made. However, since lymphoscintigraphy studies the lymphatic system in a different manner than conventional lymphangiography, these comparisons may not be possible. Ad-

6 Volume 10 Number 3 September I989 Lymphoscintigraphy for lymphedema 311 ditionally, it appears that further evaluation and classification of the lymphedematous limb in severely affected individuals may require several injections ha each limb at different sites. A web space injection in the foot may only evaluate the superficial lymphatics that do not usually communicate with the deep system. 9 Deep lymphatic evaluation requires access injection near and posterior to the bony malleoli. In addition, an injection in the proximal leg or thigh may be required to evaluate the proximal lymphatics in cases of severe distal lymphatic dysfunction. These refinements in the technique of radioisotope lymphoscintigraphy may give more information regarding pathophysiologic characteristics than the anatomic studies performed from only one site with conventional lymphangiography and pressure injection. The ability of lymphoscintigraphy to guide therapy is currently being investigated, l 'n Gloviczki et al. 10 have used lymphoscintigraphy preoperatively and postoperatively in a number of patients who underwent lymphovenous anastomoses (LVA), and they found a high correlation between the presence of visible lymph channels on scintiscan and the ability to locate these lymph vessels at operation. As in our series, they found that in patients with secondary lymphedema the lymphatic system often could be partially visualized, whereas often no lymph channels were visualized in patients with primary lymphedema. This may suggest that secondary lymphedema, which is usually obstructive in nature, is not associated with dysfunction of the entire lymphatic drainage of the extremity. Conversely, the lack of any visualization of the lymphatic system fia most patients with primary lymphedema suggests a more generalized or severe lymphatic dysfunction and not simple proximal obstruction. In the study by Gloviczki et al.~ the results obtained with LVA were better in the secondary lymphedema group, but the improvement was not well sustained in long-term follow-up. Further investigations are warranted and will be aided by lymphoscintigraphy. Conventional lymphangiography is relatively contraindicated in this setting, since it damages the remaining lymphatic channels, which could be used for LVA. 1'9 Collins et al. I2 have recently reported the use of lymphoscintigraphy to evaluate the contribution of abnormal lymphatic function to the edema found in patients with known venous disease. They found that abnormal lymphatic function was commonly present in this setting. We had one patient with obvious abnormal lymphatic drainage involving the upper extremity associated with venous thrombosis. It is as- sumed that the lymphatic obstruction (dysfunction) ha this case is caused by inadequate flow at the proximal lymphovenous connection, but this is not entirely clear. However, it appears that lymphoscintigraphy can play an increasing role in investigations of lymphatic dysfunction, as in patients with venous disease, especially as the technique is further refined. Several authors have clearly shown that quantitation of the lymphoscintigraphic data improves the diagnostic accuracy in borderline cases, s'13 For instance, in patients with primary lymphedema they have shown that the contralateral extremity, thought to be normal by clinical examination and qualitative scanning, is often quantitatively abnormal compared to normal controls. However, in patients with enough lymphatic dysfunction to cause clinically evident edema, qualitative lymphoscintigraphy is accurate and will establish the diagnosis. Quantitative lymphoscintigraphy requires a uniform colloid particle size, which is a benefit of the SbgS s colloid used in this study. For quantitative studies, normal controis should probably be established in each nuclear medicine department. In conclusion, modern radioisotope lymphoscintigraphy with 99mTc-gb2Sa colloid is a useful test that will confirm the clinical diagnosis of lymphedema. Thus early institution of conservative compression therapy can be undertaken with the hope of controlling the process in the edematous phase before tissue fibrosis ensues. 1~ The procedure is simple, has no adverse side effects, and can be performed on an outpatient basis. It would appear that use of this technique for research into lymphatic dysfunction is in its infancy. The authors thank Mrs. Leslie Stoll McKee for her technical assistance in preparing the manuscript for publication. REFERENCES 1. Vaqueiro M, Gloviczki P, Fisher J, et al. Lymphoscintigraphy in lymphedema: an aid to microsurgery. J Nud Med 1986;27: Petronis }', Lalarance N, Kaelin W. Lymphoscintigraphy. Eur J Nucl Med 1985;I0: Dufresne E, Kaplan W, Zimmcrman R, et al. The application of internal mammary lymphoscintigraphy to planning in radiation therapy. J Nud Med 1980;21: Ege G. Lymphoscintigraphy--techniques and applications in the management of breast carcinoma. Semin Nucl Med 1983;13" Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lymphoscinrigraphy in 238 patients. Radiology 1988;167: Jackson F, Bowen P, Lentle B. Scintilymphangiography with 99mTc-antimony sulfide colloid in hereditary lymphedema (Nonne-Milroy disease). Clin Nucl Med 1978;3:296-8.

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