Diagnosis of Lymphedema

Patients with limb swelling are often commonly described with the term lymphedema regardless of the underlying cause. However, lymphedema, which may be primary or secondary, is a unique disease with specific clinical and imaging findings. Nonetheless, 25% of patients referred to a lymphedema service with the diagnosis of “lymphedema” have another disease.

The differential diagnosis of lymphedema is broad, which includes obesity, lipedema, infection, primary/recurrent malignancy, vascular anomalies, and systemic diseases such as congestive heart failure, hepatic failure, renal failure, hypoproteinemia, electrolyte imbalances, and peripheral neuropathies. The astute clinician should be able to accurately diagnose extremity swelling among multiple etiologies. Providing a correct diagnosis of the limb swelling is key before starting a treatment plan and establishing an objective baseline.

A thorough history and physical examination are the essential first steps to establishing a correct diagnosis of lymphedema. In most cases, the causes of primary and secondary lymphedema can be easily identified in the patient’s history. The clinical presentation is characterized by limb heaviness, swelling, tissue thickening, paresthesia, and recurrent cellulitis accompanied occasionally by localized pain. Initially, pitting edema is present in the distal limb and changes to non-pitting edema with the progression of the disease due to the collection of subcutaneous adipose and fibrosis. The Stemmer sign is commonly used for the clinical diagnosis of lymphedema. Noticeably, these clinical findings could result from a variety of diseases, and the diagnosis of lymphedema is not always correct.

Simultaneous assessment of the venous and lymphatic system is essential for a precise diagnosis. Duplex ultrasonography should be performed first in all forms of lymphedema to differentiate between lymphatic and venous etiologic factors or for the diagnosis of concomitant vascular anomalies. In the senior author’s routine practice, computed tomography (CT) angiography is used to diagnose vascular lesions if there is a suspicious clinical examination finding (e.g., cutaneous evidence of hemangioma, vascular malformation, or a palpable thrill).

Since 2018, in our lymphedema center, single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have been added for the diagnosis of chylous ascites secondary to retroperitoneal lymphangiomatosis.

Lymphoscintigraphic Criteria for the Diagnosis of Lymphatic Dysfunction: Qualitative and Quantitative Analyses

Several imaging modalities can be used to aid in the diagnosis of lymphedema, such as lymphoscintigraphy, CT, MRI, and indocyanine green (ICG) lymphography. Both the ISL and the International Union of Phlebology recommended lymphoscintigraphy as the standard criterion for the diagnosis of lymphedema. This imaging modality is crucial not only to confirm whether lymphedema is present but also to document the severity of the lymphatic obstruction, which is critical for patient selection regarding treatment and for follow-up evaluation.

Radionuclide lymphoscintigraphy enables both qualitative and quantitative analyses to be performed. Visual qualitative information primarily aims to demonstrate the morphology of the lymphatic system by visualizing the lymph nodes and lymphatic ducts. Common qualitative findings for identifying lymphatic dysfunction include (1) symmetry, uptake intensity, number, and appearance timing of proximal lymph nodes (e.g., axillary or inguinal), (2) number and course of lymphatic ducts, (3) collateral lymphatic channels, (4) visualization of deep lymph nodes (e.g., elbow, popliteal), and (5) presence of dermal backflow.

Some authors have suggested 10–30 minutes as the standard time taken by the radiotracer to symmetrically reach the proximal axillary lymph nodes from the injection site. Delayed transport is considered at 60 minutes, and very compromised transport is considered at 120 minutes. However, a recent study showed that 120 minutes was the most frequent time necessary to visualize axillary lymph nodes in both melanoma patients before lymph node dissection and healthy volunteers.

Vaqueiro et al. showed the usefulness of lymphoscintigraphy for the visualization of patent lymphatic ducts. Lymphoscintigraphy is able to visualize the number and course of lymphatic ducts. The detection of linear, engorged, or absent distal linear lymphatic ducts is a useful finding for planning lymphovenous anastomosis (LVA).

Dermal backflow findings are considered to be the abnormal extravasation of lymphatic fluid from the lymphatics into the interstitial space as a result of the incompetence of the deep lymphatic valves. Attempts have been made to grade the severity of dermal backflow. If untreated, dermal backflow with long symptom duration can extend from the distal limb to the entire limb as a sign of progressive limb lymphedema.

Visualization of lymph nodes in the elbow or knee is commonly considered an abnormal finding due to the routing of lymph flow from the superficial system to the deep system. However, other studies have described the presence of popliteal or epitrochlear nodes in “normal” subjects following the subcutaneous injection of radiotracer.

Hassanein et al. reported 96% sensitivity and 100% specificity for the diagnosis of lymphedema using qualitative information. In cases with a high suspicion of primary lymphedema and negative lymphoscintigraphies, the authors suggested repeating the test at least 1 year later.

Quantitative lymphoscintigraphy commonly focuses on (1) proximal lymph node uptake, (2) clearance of the radiopharmaceutical from the injection site or from anatomic limbs, and (3) appearance of the soluble molecules in the blood and various other calculations. Previous studies have used quantitative analyses to assess the severity of lymphatic obstruction following breast cancer treatment as well as to evaluate the treatment outcome in patients with lower limb lymphedema. The quantification is particularly useful when comparing the affected limb with the contralateral limb to verify if a preexisting lymphatic obstruction is already present due to a primary impairment. However, quantitative lymphoscintigraphy has often been criticized for inconsistent results and being time-consuming.

Lymphoscintigraphy Findings in Primary and Secondary Lymphedema

Different patterns of lymphoscintigraphy findings were found in primary and secondary lymphedema. Common patterns observed in primary lymphedema are high accumulation of radiotracer in the injection site, poor definition of the lymphatic vessels, delayed or absent visualization in the proximal lymph nodes, and, rarely, accumulation of radiotracer in soft tissue or lymphatic vessels in cases of hypoplasia or absence of radiotracer accumulation in case of aplasia. In secondary lymphedema, decreased or absent lymphatic transport and accumulation of radiotracer in soft tissue and lymphatic channels are the most common lymphoscintigraphic patterns. Some authors reported that lymphoscintigraphy cannot differentiate primary and secondary lymphedema.