Why is lymphedema so hard to diagnose? Let's talk about lymphedema imaging technologies

Diagnostic Tools

Why is lymphedema so hard to diagnose?

Let’s talk about lymphedema imaging technologies

By Savannah Paetzel and Melissa Aldrich

Introduction When looking to predict postsurgical lymphatic complications or diagnose lymphedema, a condition caused by the abnormal functioning of the lymphatic system, it is highly beneficial to image a patient’s lymphatic system.

The lymphatic system has been ignored by medical school curricula; the average time spent teaching students about lymphatics is less than 30 minutes.1 The resulting chasm of lymphatics knowledge in the medical community is compounded by the fact that a central tenet of human fluid homeostasis, the Starling principle, states that “spent” blood fluid/cellular waste returns through the venular system.

In 2010, Levick, et al. showed that this waste actually returns through the lymphatics—in fact, 1-2 gallons of fluid must return each day through lymphatic vessels.2 Unfortunately, many curricula have yet to include this information, so medical students may carry misbeliefs into the clinic, where lymphedema is frequently mistaken for edema or even obesity. The Stemmer’s sign, basically a pinch test, is often the only tool used by physicians to discern whether lymphedema is present.3 With all the misinformation and lack of knowl-

edge on lymphedema, it may not be surprising that the disease often takes years to diagnose.4 Patients, especially those with early-stage lymphedema, often leave the doctor’s office unclear on the state of their own health and without proper guidance on how to proceed.

Even when doctors are competent in office examination for lymphedema, classic physical signs of lymphedema may not be discernible.5 Lymphatic imaging can help physicians accurately diagnose lymphedema and subsequently decide how to proceed with treatment. Imaging also helps scientific researchers learn how the lymphatic system interacts with other bodily systems, paving the way for work towards alternative treatment options for those with lymphatic diseases.

Lymphatic imaging has also been used to prove to health insurance companies that certain treatment options, such as complete decongestive therapy (CDT), are necessary in improving lymphedema and thus must be covered financially.6-8 Numerous imaging techniques exist,9 each with benefits and limitations for visualizing lymphatics, sometimes making it difficult for doctors to reach a clear lymphedema

Savannah Paetzel is a senior at Round Rock High School in Round Rock, Texas. A primary lymphie, she founded Project Lymph, an online platform where she interviews lymphedema patients and specialists. She also serves as the Ambassador for the ILWTI’s Lymphie LARA. Melissa B. Aldrich is an assistant professor at UTHealth in Houston, Texas.

She directs several clinical studies of breast cancer-related lymphedema.

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diagnosis regardless of which modality they use. This article outlines the difficulties of imaging lymphatics and reviews various lymphatic imaging technologies available in order to understand why it is so difficult to accurately diagnose lymphedema and examine how we can move forward.

The lymphatic system and lymphedema The lymphatic system is a drainage network essential for the maintenance of fluid homeostasis and immunocompetence.6,7 Beginning in the interstitial spaces and ending in the great veins of the neck or thorax10, the system consists of small lymphatic capillaries that absorb interstitial fluid and cells to create lymph. Initial lymphatics bring lymph to the collecting lymphatic vessels, which transport lymph over long distances through lymph nodes and eventually to the blood. To achieve a continuous lymphatic output, periodic stress needs to be applied to the tissue (e.g., through arterial pressure pulsations, intestinal smooth muscle contractions, external compression).11 Lymphedema is an incurable, progressive dysfunction of the draining lymphatics that can be caused by inherited abnormalities in the lymphatic system (primary lymphedema) but is more often caused by acquired damage (secondary lymphedema). Lymphedema frequently occurs after cancer treatment, developing usually within 18 months, but sometimes even five or more years after, cancer treatment. With edema progressing Wi n t e r 2 0 2 0

slowly, a definite diagnosis of early-stage lymphedema is difficult to achieve.13 The condition, once in its later stages, results in swollen limbs, often paired with pain, fibrosis, recurrent infections, arthritis, and depression, complicating the patient’s day-to-day functioning and sometimes prohibiting their ability to work.14 Lymphatic vessels are generally difficult to visualize because they contain few cells, carrying mainly clear lymph fluid. This makes them difficult to locate and cannulate for angiographic techniques, so most visualization techniques rely on the natural ability of lymphatic vessels to absorb tracers injected into the tissue space. The tracer is then transported and concentrated into the proximal network, allowing detection by a variety of imaging modalities.9

been shown to be particularly useful for this.

Lymphoscintigraphy can see deep vessels, the “collectors,” while MRL can see cisterna chyli, which is of great interest in chylothorax (chest swelling). In the past, lymphoscintigraphy was the gold standard for lymphatic imaging despite very low-resolution images and limited usefulness. Many physicians, in fact, may only be familiar with this “old-school” method. Of note, the contrast agent traditionally used for lymphoscintigraphy is now largely unavailable in the US and Korea, and replacements may yield less-than-optimal images.15 Some applications of Indocyanine Green (ICG) Lymphography can show lymph nodes and mostly superficial vessels. This imaging technique is particularly used by microsurgeons, whose concern is which shallow vessels to work with rather than the deep vessels.

Lymphatic imaging technologies Table 1 (included in the online references) summarizes some of the modalities that can be used to image lymphatics and aid in diagnosis, each with their own advantages and limitations.

Although this paper highlights their individual applications, several imaging methods might optimally be used together to provide the most complete picture of lymphatic dysfunction.

Reliability The most reliable modalities for imaging lymphatics (i.e., those most likely to provide an accurate diagnosis consistently) are lymphoscintigraphy, ICG lymphography, and any modalities when they can show backflow.

MRL and photoacoustic imaging can deliver high-resolution lymphatic vessel anatomy images, as long as veins are avoided. NIRFLI can show whether lymph is flowing and pumping, and lymphoscintigraphy can take snapshots at different times in order to indirectly show you if lymph is moving (at least through the large vessels).

Editor’s Note: Because of space restrictions, we encourage readers to review the comprehensive Table 1 moved to the online references (www. lymphedemapathways.com).

Canadian readers should note that not all these techniques are available in Canada and it will depend on the province where they live, whether they are covered or not under their applicable Provincial Health Plan.

Uses, advantages, and disadvantages of different modalities The most common purpose of lymphatic imaging across all modalities is to determine cancer patient susceptibility to postsurgical lymphatic complications. Near-infrared lymphatic fluorescence imaging (NIRF-LI) and magnetic resonance lymphography (MRL) have Wi n t e r 2 0 2 0

Availability Computerized tomography (CT) scans which can pick up cancerous lymph nodes (which start to accumulate calcium), and magnetic resonance imaging (MRI), which can pick up changes in water content in tissues, are easy to perform and widely available in the USA, but neither can provide a diagnosis of lymphedema based on their images alone.

Recently, magnetic resonance imaging (MRI) without contrast was used to show water and fat accumulation in lymphedematous arms.16 Surprisingly, muscle layers were found to accumulate fluid; previously, only fluid-filled skin and subdermal fat were known features of lymphedema.

NIRF-LI and photoacoustics, the two most

Several imaging methods might optimally be used together to provide the most complete picture of lymphatic dysfunction. promising modalities for the objective diagnosis of lymphedema, are not yet commercially available. Since most general physicians (GPs) and other primary care providers do not have any version of NIRF-LI or photoacoustics, and may not be aware of these modalities, patients in the USA, seeking a lymphedema diagnosis typically only get lymphoscintigraphy as a firstline diagnostic tool. Lymphatic microsurgeons, who use ICG lymphography routinely to identify amenable vessels before surgery, see only established lymphedema patients, not those who are seeking a diagnosis. NIRF-LI is currently available only to volunteers in NIRF-LI research studies. ICG lymphography, NIRF-LI, and photoacoustics are not routinely used by practitioners trying to make an initial lymphedema diagnosis. In short, the tools that provide the most reliable diagnosis available are the hardest to come by, making it much less likely that a patient will receive a proper diagnosis through a lymphatic imaging process.

Of primary importance for cancer patients are baseline limb measurements, preferably before neoadjuvant chemo, to establish a benchmark for swelling detection. Unfortunately, many cancer treatment providers do not take said measurements or even perform posttreatment surveillance to detect lymphedema, which would enable patients who test positive for lymphedema to receive early treatment.

Non-imaging methods for lymphedema detection Perometry, Bioimpedance Spectroscopy (BIS), and Tissue Dielectric Constant (TDC) are non-imaging methods for the detection and diagnosis of lymphedema. Perometry shoots near-infrared beams onto the skin, measuring bounce-back and absorption to calculate limb volume as an alternative to tape measurements. Perometry detects swelling, is easy to perform, however the L y m p h e d e m a p a t h w a y s . c a 11

Editor’s Note: Many experienced clinicians still deem the traditional circumferential measurement method to be the most accurate hands-on clinical assessment tool.

Summary Lymphoscintigraphy is commonly prescribed by physicians in the USA needing an initial lymphedema diagnosis. When lymphoscintigraphy does not provide a clear answer, perhaps because shallow, not deep, lymphatic vessels are primarily affected, then ICG lymphography or MRL may be used, with the caveat that MRL may unintentionally show veins. Photoacoustic imaging, using ICG as contrast, can provide high-resolution vessel images, but cannot tell physicians if lymph is pumping, may unintentionally show veins, and is still investigational. A near-commercialized version of ICG lymphography, NIRF-LI, can show near real-time pumping, as well as shallow lymphatic vessel anatomy. Of note, very little longitudinal lymphatic imaging has been done to show the progression of lymphedema, with the exception of a few recent NIRF-LI studies.

The future Recognizing that patients with lymphatic disorders are undercounted, poorly served, and frustrated by the difficulty in receiving an accu-

Photoacoustic image.

rate diagnosis and finding adequate treatment, in 2018, the Lymphatic Education & Research Network (LE&RN) began developing standards for Centers of Excellence in the Diagnosis and Treatment of lymphatic disorders. LE&RN Centers of Excellence (COE) are a network of multidisciplinary clinical care and service centers spanning the world. The Centers will provide clinical and social services, professional and lay education in the geographic areas they serve, and are involved in lymphatic disorders clinical research.19 Lymphatic imaging capability is one of the considered criteria. (Table 2 is included in the online references). LP A full set of references can be found at www.lymphedemapathways.ca

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Wi n t e r 2 0 2 0

Image: Matsumoto – Scientific Reports

machine itself is expensive. Measurement accuracy can depend on user skill unless one is using LymphaTech, an at-home scanning system, which is fast, easy to use, and more accessible to patients.

BIS involves passing a low-strength electrical current through the affected area and measuring how the flow of the current is slowed by the fluid in the body. BIS measurements are not available everywhere.17 TDC measurements characterize localized tissue water in arms of women with and without breast cancer treatment-related lymphedema.18 BIS and TDC have been found to have a potential for early diagnosis, are widely used, and can be an important part of the diagnosis toolbox, though they have their limitations.17