Keywords 99mTc-HSA - intradermal - lipedema - lymphoscintigraphy - stress
Introduction
Lipedema was first described by Allen and Hines in 1940.[1 ] It is a chronic and progressive painful disease due to a disproportionate hyperplasia
and hypertrophy of adipocytes in the subcutaneous tissue of the lower limbs. The cause
and pathogenesis of lipedema are thought to be a genetic disorder with an autosomal
dominant inheritance with presentation being limited to the female gender.[2 ] Lipedema is characterized by a symmetrical and bilateral swelling of the lower extremities
(sometimes also upper limbs), extending from hips to ankles classically sparing the
dorsum of the feet and hands. Lipedema is characterized by a symmetrical and bilateral
swelling of the lower extremities (sometimes also upper limbs), extending from hips
to ankles classically sparing the dorsum of the feet and hands [Figure 1 ].
Figure 1 Lower limbs lipedema in anterior and posterior views. The subcutaneous fat is increased
above all in the area of buttocks and hips
Women with early lipedema report a rapid growth of the subcutaneous adipose tissue
frequently activated by puberty, pregnancy, or menopause. Women in later stages of
lipedema have a classic “column leg” appearance, with masses of nodular fat.[3 ] As lipedema worsens, chronic fatty redistribution may be associated with heaviness,
bruising, burning, itching, and pain. In later stages, the disease might progress
to secondary lymphedema, known as lipolymphedema.
Lipedema is believed to affect nearly 1 in 9 adult women worldwide.[4 ]
Despite this relatively common disease, there are few physicians who are aware of
it. The diagnosis of lipedema is clinical and mainly relies on history and clinical
evaluation.[5 ] Lymphatic flow is usually preserved, and lipedema patients usually have normal lymphoscintigrams,
in early stages. However, lipedema is underdiagnosed, and often confused with primary
lymphedema, obesity, or chronic venous insufficiency.
In our study, we propose rest/stress lymphoscintigraphy in early stage of lipedema
to confirm diagnosis, or to evaluate altered lymphatic drainage in clinically advanced
stages of lipolymphedema.
Materials and Methods
We consecutively studied 54 women (aged 46 ± 19 years) with a clinical diagnosis of
lower limb lipedema.
Tight and elastic clothes were removed before examination. Two doses of 99mTc-HSA
nanocolloidal, 50–80 MBq in 0.3 mL, were injected intradermally at the first intermetatarsal
space and in the lateral malleolar area. This was followed by a soft massage around
the injection site. We used a dual-head gamma camera (Infinia-Xeleris GP3; GE Medical
System, Milwaukee, WI, USA), equipped with low-energy general-purpose parallel-hole
collimators, to increase gamma-camera sensitivity.
The lower limbs were scanned in a supine position reducing the distance between the
collimator and limbs to improve resolution. We used following parameters: Preset time
180” to 300”, matrix 128 × 128,140 keV ± 10%. Usually, the injection points were positioned
outside of the field of view. Two static planar scans taken in anterior and posterior
views were acquired at rest immediately following the injection (one for the legs
and one for the thighs).
Subsequently, all patients were asked to perform an isotonic muscular exercise (stepping)
for 2 min. The exercise is followed by post exercise scans to monitor the tracer pathway.
Subsequently, the patient performed 30–40 min walking exercise.
A series of new limb images including iliac and abdominal area for lower limbs were
acquired at 60 min. This technique was used to evaluate the effect of prolonged exercise
and visualize the lymph nodes, lymphatic pathways starting from the injection points.[6 ],[7 ]
The time in minutes was evaluated from injection to the appearance of the tracer (tracer
appearance time [TAT]) in the inguinal or axillary lymph nodes. Normally, TAT is <10
min. All scintigraphic images were evaluated qualitatively by two independent observers,
and TATs were recorded. In order to quantify the visual scintigraphic findings, a
numeric transport index (TI), combining a visual assessment of five criteria (temporal
and spatial distribution of the radionuclide, appearance time of lymph nodes, and
graded visualization of lymph nodes and vessels) was applied into a modified method
as previously described by Kleinhans et al.[8 ] In normal cases, TI ranges from 0 to 10. A minimum of 3 points were assigned when
the scan at rest showed no flow or delayed flow. Higher values describe a more severe
degree of lymphatic disorders.
Results
We scanned consecutively 54 consecutive women, mean age 47.1 years (± 19.3), range
17–86 years.
The mean body mass index (BMI) was 32.3, with a range 21.7–58.5 (normal value: 18.5–24.9).
The rest scan showed a normal visualization of lymphatic vessel along the great saphenous
vein in 36 out of 108 limbs (33.3%). Stress scan showed a complete visualization of
lymphatic pathways from injection sites to inguinal lymph nodes in 100 of 108 limbs
(92.5%). A tortuous course of the lymph pathway of the legs, together with some visualization
of collateral flow was observed in 75% of legs. The presence of collaterals and/or
popliteal node uptake occurred in 53 out of 108 limbs (49.1%). Delayed scan showed
tracer stagnation areas in 16 out of 108 limbs (14.8%), dermal backflow in 3 out of
108 limbs (2.8%) (both major sign of a lymphatic disorder). Deep lymphatic vessels
and popliteal node uptake, a minor sign of lymphatic disorder, were observed in 39
out of 108 limbs (36%). The TAT in the inguinal lymph node was <10 min in 100 out
of 108 Limbs (92.5%). The mean trasport index was 9, with a range 3–16 (normal value
<10). Age, height, weight, BMI, and TI for single limb are summarized in [Table 1 ].
Table 1 Age, height, weight, body mass index, right lower limb transport index, left lower
limb transport index
Discussion
Lipedema is frequently misdiagnosed or confused with primary lymphedema, obesity,
and chronic venous insufficiency.[9 ] Lipedema almost exclusively appears in women, is symmetric and spares feet, whereas
lymphedema is usually asymmetric, swelling may interest the entire limb, including
the feet. Lipedema may change minimally with elevation or compression. Lipedema is
painful and associated with easy bruising. Obesity is characterized by an increase
fat all over the body. Cellulite may cause a disproportionate amount of fat accumulation
in the legs but is not associated to pain. Chronic venous insufficiency can cause
swelling and pain, however, it is not usually symmetric and commonly presents varicose
veins. Nevertheless, lipedema is mostly unknown, therefore resulting in a lack of
recognition. A 2012 survey of lipedema patients, conducted by the British Lymphology
Society and Lipoedema, UK, found that only 9% of patients were diagnosed with lipedema
the first time they reported their symptoms.[10 ]
An online survey questionnaire, conducted on 209 female patients with lipedema who
had undergone tumescent liposuction in a single center in Germany, found that most
of the patients (mean age, 38.5 years) noticed the first manifestation of the disease
at the age of 16 years, followed by a mean of 15 years to reach the diagnosis.[11 ]
Lipedema is related to eating habits. This can be seen in advanced stages of lipedema
which are more frequently linked to being overweight and obesity. A patient with unhealthy
eating habits may undergo more advanced stages of lipedema. An increased intake of
energy-dense foods, high fat content foods, a sedentary lifestyle and genetic susceptibility
may result in an associated obesity, that worse the symptoms of lipedema. The prevalence
of being overweight and obesity among children and adolescents aged 5–19 years has
risen dramatically from 4% in 1975 to over 18% in 2016.[12 ] Recently, in a paper by Faerber resulted that more than 50% of lipedema patients
in Germany are also obese. Lipedema and obesity may reinforce each other, this leading
an accelerated deterioration of disease.[13 ]
In a recent statistic from Lymphedema Center in Santa Monica, CA concluded that 50%
of their patients in the last decade (2010–2019) had lipedema (vs. the 21% in the
decade 2000–2009).[14 ]
In the previous studies, the most common method used to perform lymphoscintigraphy
of the extremities was to inject 74–296 MBq of millipore-filtered 99mTc sulfur colloid
or 99mTc-nanocolloids suspended in 0.10 mL of saline subcutaneously into the interdigital
web spaces. Previous studies on lipedema patients showed a delayed lymph flow in the
absence of major signs of lymphedema.[15 ],[16 ],[17 ],[18 ],[19 ],[20 ]
This innovative technique rest/stress intradermal lymphoscintigraphy consists of an
intradermal administration of a radiotracer and a different tracer injection site.
The intradermal injection allows a better absorption of the tracer by the lymphatic
capillary network of the dermis, this allows for a better visualization of lymphatic
pathways and regional lymph nodes in shorter time. The tracer injection sites used
in this study were the first intermetatarsal space and the lateral malleolar area.
The intradermal rest/stress intradermal lymphoscintigraphy in lipedema patients shows
a complete visualization of lymphatic pathways and inguinal lymph nodes after a brief
exercise (2 min) in almost all cases. On the contrary to lymphedema patients, we may
observe a scarce resistance to the tracer injection by the intradermal way in all
lipedema patients. Probably, this depends on a normal pressure in the peripheral lymphatic
system. A normal TAT and an early visualization of lymphatic pathways and regional
lymph nodes allows for an easy differential diagnosis between lipedema and primary
lymphedema. The presence of collateral pathways and/or uptake of popliteal nodes may
be considered minor signs of a lymphatic disorder. By injecting radiotracer intradermally,
we visualized a tortuous course of the lymph pathway in the legs of 75% of lipedema
patients, [Figure 2 ],[Figure 3 ],[Figure 4 ] combined with a normal inguinal node TAT in 92.5% of limbs imaged.
Figure 2 66-year-old woman, body mass index = 0.32. Resting scan shows a "tortuous course"
of lymphatic pathways of legs, as a typical pattern of lipedema
Figure 3 (Same patient) Stress scan shows a clear and complete visualization of lymphatic
pathways from injection sites on the feet to inguinal lymph nodes (tracer appearance
time < 10 min). The scan confirms a bilateral tortuous course of lymphatic vessels
of legs and the presence of collaterals
Figure 4 (Same patient) Delayed scan shows an unusual uptake of the right popliteal node (demonstrating
the involvement of deeper lymphatic drainage), and a normal uptake of inguinal, ileal
and periaortic lymph nodes
In our experience, we observed the same pattern in 10%–15% of patients with primary
or secondary lymphedema. A delayed TAT, a higher TI, and the presence of major signs
of lymphedema allow for a differential diagnosis of lymphatic disorders.
A tortuous course of lymph pathway may also be observed in patients with filarial
lymphedema, a pathology endemic in West and Central Africa. The worms responsible
for disease progressively occupy the subcutaneous tissue provoking lymphedema in the
years after infection. When lymphatic filariasis develops into chronic conditions,
it leads to secondary lymphedema. Until very recently, diagnosing lymphatic filariasis
had been extremely difficult, since parasites could only be microscopically detected
in the blood. The development of a card test to detect high levels of circulating
parasite antigens in the blood may clarify diagnosis.[21 ]
Analogs scintigraphic patterns have been observed in patients with Prader–Willi syndrome.
This rare genetic syndrome is characterized by excessive eating and gradual development
of morbid obesity.[22 ]
Probably, lymph adapts its course to the increasing presence of subcutaneous fat.
A tortuous lymphatic pathway may be considered a typical pattern of lipedema and of
diseases involving subcutaneous tissue [Figure 2 ],[Figure 3 ],[Figure 4 ].
In clinically advanced stages of lipedema, we observed tracer stagnation areas or
lymphangiectasia. In this case, the chronic buildup of fat most likely damages the
lymph collector determining a secondary lymphedema (lipolymphedema) [Figure 5 ].
Figure 5 64-year-old woman, body mass index = 0.53. Delayed scan shows a tracer stagnation
area at third medium of the left leg in a patient with an advanced clinical stage
of lipolymphedema
Conclusion
Rest/stress intradermal lymphoscintigraphy shows a normal lymphatic drainage, a normal
uptake of regional lymph node, absence of lymph stagnation area after muscular exercise
and normal TI value, in early and intermediate clinical stages of lipedema. Using
our method, we observed a tortuous course of lymphatic pathways in 75% of legs of
women with lipedema.
Tracer stagnation areas or dermal backflow, an expression of secondary damage to lymphatic
vessels (lipolymphedema) was observed in only few patients with and advanced stage
of lipedema.
Distinct from other forms of fatty deposition, diet, or exercise are ineffective as
treatment for the fat deposition in lipedema patient. Combined decongestive therapy
may reduce symptoms and may be recommended for patients with a demonstrable lymphatic
disfunction and is recommended in the all patients to avoid significant weight gain.[22 ]
Surgical treatment of lipedema should be based on the features of each patient. For
patients without lymphatic functional impairment, liposculpture of affected areas
represent a valid solution in reducing the fat accumulation while shaping the entire
leg and ankle. Liposuction nowadays is a safe and well-established procedure.[23 ],[24 ],[25 ],[26 ]
Being a blind procedure, liposuction might lead to injures of microvascular structures
of the adipose tissue (including lymphatic channels), which are usually not clinically
relevant.
However, in the setting of an impaired lymphatic drainage, microvascular injuries
lead to a clinically relevant lymphatic impairment, ultimately leading to secondary
lymphedema.
As for now, in our center, we are prospectively evaluating lipedema patients undergoing
liposculpture according to our surgical inclusive criteria and use of intraoperative
Indocyanine Green fluorescence-navigated surgery, to evaluate the liposuction safety
for those with an impaired lymphatic function.[27 ]
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
