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Chapter 18
Laboratory/Imaging Diagnosis:
General Guidelines
Mauro Andrade
General Considerations
The perfect diagnostic method employed for any disease evaluation should provide
good anatomical definition, relevant pathophysiological information, be non-invasive,
and must be reproducible, offering reliable data on evolution and treatment. As for
most human diseases, there are many different diagnostic methods to study lymphatic
insufficiency, all of them with their advantages and disadvantages, all of them fulfilling specific aspects regarding investigation of lymphatic disorders, but none of them
possessing all of the required features to be considered ideal.
Historically, direct oil lymphography, developed by Kinmonth in the 1950s, was
a cornerstone in the field of lymphology.1 This diagnostic method provided most of
the basis for our current knowledge and systematization about lymphatic diseases,
but, even if lymphography must be honored for its significance, it is no longer a useful test for routine lymphatic examination, because it is not a practical method and
complications may be severe.2 Radiological lymphography, currently reserved for
exceptional clinical situations, like chylous reflux and thoracic duct injuries, has
been largely replaced by less invasive diagnostic explorations, even though its anatomical definition remains unparalleled.
Almost simultaneously, the first reports regarding functional studies of the lymphatic system through measurements of peripheral uptake of injected radioactive
particles and their appearance in regional lymph nodes3 established the foundation
of the current use and techniques of lymphoscintigraphy for exploration of lymphatic disorders.
As outlined in the Clinical Diagnosis chapter (Part 6), lymphedema is a result
of deranged lymph flow secondary to abnormalities in lymph absorption and/or
M. Andrade
Department of Surgery,
University of São Paulo Medical School,
São Paulo, Brazil
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_18, © Springer-Verlag London Limited 2011
139
140 M. Andrade
transport, leading to edema and tissue changes. Selected diagnostic methods can be
aimed at the structure and function of lymph vessels and lymph nodes and can
provide estimation of tissue alterations caused by lymph stasis.
When Clinical Examination Should Be Complemented by Imaging
Not considering differential diagnosis, medicolegal issues, and research protocols,
which may require supplementary studies, a decision about whether any additional
investigation should be undertaken for an individual patient, and which one(s),
depends mostly on clinical judgment. Clearly, history and physical examination are
usually sufficient to make a correct diagnosis of the subjacent lymphatic disorder
and to choose the initial therapeutic approach. Only occasionally will diagnostic
methods change the initial clinical impression or offer a reliable prognosis tool better than careful clinical evaluation and close follow-up.
Imaging methods to further explore affected limbs are mandatory whenever the
diagnosis of lymphedema is not clear or other associated diseases may mask the
relevance or concomitance of lymphatic involvement.
The preferred imaging method to depict lymphatic abnormalities is lymphoscintigraphy or radionuclide lymphography.
2,4
In fact, lymphoscintigraphy is considered
to be an essential part of the primary evaluation of any lymphedema patient (level
of evidence 1B),4 even though its usefulness regarding etiological diagnosis (primary or secondary),5 initial therapeutic choice or prognostic value may be controversial in most cases.
In lower limb lymphedemas, duplex ultrasound examination of the venous system
is advisable.
2,4
Beyond differential diagnosis, unsuspected venous insufficiency may
aggravate lymphatic load and once diagnosed, may change proposed treatments.
2
Methods to Evaluate Lymph Flow, Lymphatic Vessels, and Lymph Nodes
Lymphochromy or the blue dye test, examination of initial uptake and lymphatic
transport, consists of subdermal or intradermal injection of a vital dye and is an
essential step for direct oil lymphography. Along with Landis’ test, its elegant functional radionuclide successor, lymphochromy may be used to assess local lymph
flow, but has little relevance in daily clinical practice for the evaluation of
lymphedemas.
Peritumoral injection of patent blue, either alone or coupled with radioactive
tracers, is another method derived from classical lymphochromy. This anatomical
test is very useful for identifying sentinel lymph nodes, most commonly in breast
18 Laboratory/Imaging Diagnosis: General Guidelines
141
cancer and melanoma operations. Interestingly, a method developed in the past to
explore lymphedemas is currently essential to avoid unnecessary lymphadenectomies, thus playing an important role in preventing lymphedema development.
Quantitative and semi-quantitative analysis of lymphatic drainage are best
achieved with lymphoscintigraphy. Quantitative studies are obtained by quantitative
nuclear imaging in selected regions of interest using a time curve graphic. By
assigning predetermined grades to some observed morphological characteristics
analyzed by visual interpretation, the semi-quantitative evaluation6 avoids unnecessary problems related to physical properties of the radiotracer. In clinical practice,
lymphatic transport and structure are more often estimated by qualitative analysis.
This is a reliable method to evaluate the lymphatic system and, even if qualitative
evaluation always relies upon subjective interpretation, it fulfills most diagnostic
needs. Qualitative lymphoscintigraphy uses detailed description of many characteristics that may be observed: local spread of the radiotracer, dermal flow in the
absence of patent collector vessels, and dermal back flow in proximal obstructions;
appearance, quantity, and location of the lymph collectors; number, location, and
time of appearance of lymph nodes. Either way, an important concept to keep in
mind is that images obtained in lymphoscintigraphy will only represent the lymphatic drainage of the injection site and not the entire lymphatic system of the
affected limb. Injection in the interdigital spaces of the feet will preferentially show
the greater saphenous pathway, which is the normal drainage for that region. If, for
instance, the collectors accompanying the lesser saphenous vein and popliteal nodes
are visible, deranged lymph drainage of the superficial system is diagnosed, as this
deviation to the deep system of the popliteal area is not the expected pathway emerging from the injection point. Patients with leg swelling may display completely
different patterns of lymph vessels and lymph flow if injection is performed between
the toes or in the medial aspect of the knee. As a corollary, lack of patent lymphatic
collectors after interdigital injection of radiotracer does not always mean that no
collectors are patent. Additionally, there is no direct relationship between qualitative or quantitative lymphoscintigraphy and the clinical severity of lymphedema.
Lymphoscintigraphy also has its drawbacks: lack of standardization regarding
various radiotracers with variable radioactivity and volumes, choice of subcutaneous or intradermal injection sites, exercise protocols that vary according to the diagnostic center, different imaging times, dynamic or static acquisition of the images.2
All these variables prevent this useful examination from being a universal language
for defining lymphatic function.
Chylous disorders or thoracic duct fistulas require a more accurate anatomical
definition than the one that can be provided by lymphoscintigraphy and are best
demonstrated by conventional oil contrast lymphangiography,7 especially if coupled
with CT. Special techniques of lymphoscintigraphy, e.g., unilateral injection and
demonstration of reflux to the contralateral side, may be useful for chylous reflux
patients.8 Since these challenging problems are rare in clinical practice and should
be managed by experienced lymphatic disease specialists, it is unlikely that a general practitioner will even request a conventional lymphography during routine
clinical activity.
142 M. Andrade
Imaging of enlarged lymph nodes (or tumoral masses, as part of a complete diagnostic evaluation of lymph stasis) can be very important in lymphedema patients,
especially when malignant lymphedema is suspected. For this purpose, ultrasound
or, more usefully, MRI and CT, may unveil subjacent obstruction or compression of
the lymphatic pathways.
Excisional lymph node biopsy, except for sentinel node biopsy in the groin or
axilla for staging malignancy, should be avoided in peripheral lymphedema patients,
for it risks aggravating distal swelling.2 Moreover, histological information is seldom helpful. Where pathological specimens are judged necessary, fine needle aspiration can be diagnostic if malignancy is suspected.
Methods of Evaluating Tissue Changes
Chronic lymph stasis leads to several modifications in the affected limb that may be
variable in their severity, but are unique in aggregate, as they are not seen in any
other cause of edema.
Skin thickening, fibrosis, fat changes, and fluid retention, together and in various
proportions, account for the volume change observed in these patients. Mostly, lymphedema interferes with suprafascial tissues and the muscular compartment remains
unchanged. Due to overuse or disuse of the affected limb, muscular hypertrophy or
atrophy can be respectively observed in some patients.
Evaluation of suprafascial tissues includes magnetic resonance imaging, computed
tomography, ultrasound, DEXA, or bi-photonic absorptiometry, among other possible
but less useful methods. MRI and CT offer remarkable insight into tissue fibrosis,
fluid accumulation, skin thickness, and cross-sectional area. The “honeycomb” pattern observed in the subcutaneous tissue is specific to lymphedema.9 Both can also be
used to evaluate volumetric and tissue density reduction after treatment.
Although still investigational, technological development of MRI will offer the
possibility to evaluate lymphatic collectors, lymph nodes, and tissue changes at the
same time.11 This would seem to be a promising and complete method of studying
most lymphatic disorders in the future.
Considering the recent and growing interest in the relationship of lymph stasis to
fat formation, dual-energy X-ray absorptiometry (DEXA), or bi-photonic absorptiometry, has great potential for use in estimating the contribution of the fat component to the overall volumetric increase.12 Such knowledge may prove to be useful for
therapeutic purposes13 or prognosis.
10
References
1. Kinmonth JB, Taylor G, Tracy C, Marsh J. Primary lymphedema clinical and lymphographic stud-
ies of a series of 107 patients in which he lower limbs were affected. Br J Surg. 1957;45:1-11.
18 Laboratory/Imaging Diagnosis: General Guidelines
2. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema.
Lymphology. 2009;42:51-60.
3. Sherman AI, Ter-Pogassian M. Lymph node concentration of radioactive colloidal gold fol-
lowing interstitial injection. Cancer. 1953;6:1238-1240.
4. Lee BB, Andrade M, Bergan J, et al. Diagnosis and treatment of primary lymphedema.
Consensus Document of the International Union of Phlebology (IUP)-2009. Int Angiol.
2010;29:454-470.
5. Weissleder H, Weissleder R. Lymphedema: evaluation of qualitative and quantitative lympho-
scintigraphy in 238 patients. Radiology. 1988;167:729-735.
6. Cambria RA, Gloviczki P, Naessens JM, Waher HW. Noninvasive evaluation of the lymphatic
system with lymphoscintigraphy: a prospective, semiquantitative analysisin 386 extremities.
J Vasc Surg. 1993;18:775-782.
7. Campisi C, Bellini C, Eretta C, et al. Diagnosis and management of primary chylous ascites.
J Vasc Surg. 2006;43:1244-1248.
8. Andrade M, Puech-Leao P. Surgical treatment of primary chylous reflux to the lower limbs. In:
Jamal S, Shenoy J, Manokaran G, eds. XVII International Congress of Lymphology; 1999;
Chennai – India. 36.
9. Hadjis NS, Carr DH, Banks L, Pflug JJ. The role of CT in the diagnosis of primary lym-
phedema of the lower limb. AJR. 1985;144:361-363.
10. Andrade M, Almeida MT, Puech-Leão P. Standard CT assessment of lymphedematous limbs.
Radiological pattern change after conservative treatment. Lymphology. 1996;29(suppl):
97-100.
11. Dimakakos E, Koureas A, Koutoulidis V, et al. Interstitial magnetic resonance lymphography:
the clinical effectiveness of a new method. Lymphology. 2008;41:116-125.
12. Brorson H, Ohlin K, Olsson G, Karlsson MK. Breast cancer-related chronic arm lymphedema
is associated with excess adipose and muscle tissue. Lymphat Res Biol. 2009;7:3-10.
13. Brorson H, Svensson H, Norrgren K, Thorsson O. Liposuction reduces arm lymphedema
without significantly altering the already impaired lymph transport. Lymphology. 1998;31:
156-172.
143
Chapter 19
Radionuclide Lymphoscintigraphy
Walter H. Williams, Magdalene Ochart, Michael J. Bernas,
Charles L. Witte, and Marlys H. Witte
Brief Historical Note
After McMaster1 used intracutaneous injection of vital dyes to visualize streamers
and to follow lymph flow in patients with heart failure and other edematous conditions, Kinmonth et al.2 developed conventional lymphography by incising skin over
the blue-stained streamers seen on the dorsum of the foot or hand and exposing tiny
skin lymphatics. Subsequent cannulation of the larger lymphatic draining collectors
was followed by pump-controlled infusion of oily contrast. Kaindl and Servelle3
directly cannulated pathologically dilated, often delicate fragile peripheral and central lymphatics and those associated with the viscera and injected them with iodinated contrast material.
For the next 40 years, conventional lymphography was the gold standard for
the definitive delineation of the lymphatic system – both peripheral and central
channels – and nodes. This time-consuming, tedious procedure requires an incision
for visualization, and the cannulation of often tiny lymphatics is challenging and
commonly unsuccessful. Moreover, iodinated contrast material is irritating to the
lymphatic endothelial lining, and this contrast agent remains in the lymphatics, particularly in the lymph nodes, for an extended period of time. Uptake in the lung,
heart, liver, and spleen obscures the upper abdominal and mediastinal lymphatics.
Conventional lymphography may also cause symptomatic oil (fat) embolism, particularly to the lungs, and local wound infection at the injection site.4 This procedure
is now rarely used in everyday practice, except when specifically indicated
(Fig. 19.1).
M.H. Witte ()
Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_19, © Springer-Verlag London Limited 2011
145
146 C.L. Witte et al.
Techniques of
lymphatic system imaging
Direct
lymphography
Indirect
lymphography
Lymphangioscintigraphy
CT
US
MRI
Central
lymphatic
Central vein
Lymph node
Fig. 19.1 Scheme illustrating different approaches to imaging the lymphatic system
Sherman and Ter-Pogossian5 first showed radioisotopic colloidal uptake in lymph
nodes. The improvement in isotope lymphography (also called lymphangioscintigraphy [LAS]) with whole-body modification (WB-LAS) using technetium
99m-labeled macromolecules, such as albumin6 or colloid as the radioactive tracer,
has transformed the field.
Materials and Methods
A large molecule, such as sulfur colloid, dextran, hetastarch, or preferably human
serum albumin (HSA), is linked to radioactive technetium (Tc)-99m. Tc-99m is
nearly completely decayed with gamma radiation in 24 h (half-life 6 h).
We have found the following protocol optimal for obtaining clear, comprehensive, and consistent LAS images. Tc-99m HSA and Tc-99m sulfur colloid have
been evaluated using dynamic LAS. 550 uCi (18.5 MBq) Tc-99m labeled colloid or
human serum albumin is instilled intradermally to create a wheal in the second web
space of the hand or foot for upper or lower extremity studies respectively (single
injection per limb). Both arms and legs are examined to provide a normal control in
unilateral lymphedema. After mild exercise (flexion of the hands or feet [often
walking]), the patient returns for WB-LAS at 3–4 h post-injection.
19 Radionuclide Lymphoscintigraphy
147
Fig. 19.2 Common patterns of lymphangioscintigrams of arms (upper row) and legs (lower row).
(a, and f ), Normal lymphatics and regional nodes. (c–e, h, and i) Unilateral limb lymphatic obstruction
(radical mastectomy or groin dissection). (b, g, and j) Left limb primary lymphedema. (j) A tracer
(technetium-99m-labeled human serum albumin) was injected only into the right foot and refluxes
into the left leg. Round midline markers denote sternal notch, xiphoid, pubis, and knees (superior to
inferior) (Reprinted with permission from Witte et al.
7
)
Interpretation and Comments
Lymphangioscintigraphy is a safe, single, non-invasive, and rapidly repeatable
technique. WB-LAS provides clear dynamic images of lymphatic transport and
peripheral and central lymphatic structures and function, often in complex settings
(Fig. 19.2a, f). A variety of structural and functional changes in lymphatic flow
dynamics can be visualized. Delayed imaging with Tc-99m HSA or sulfur colloid
shows lymph node uptake, albeit without detailed structural features seen on conventional lymphography. HSA migrates more rapidly from the distal limb injection
sites and shows better defined deep lymphatic trunks than observed with colloids.
Axillary or inguinal lymph nodes are typically visualized within 15–25 min.
148 C.L. Witte et al.
=++ ++TIS K D 0.04 T N V
The transport index score (TIS)8 allows semi-quantification of peripheral lymphatic
radiotracer transport by means of a relative value score (0–9) for each marker. The
scores are added together to arrive at an overall numeric index derived from objective
and subjective criteria based on lymphatic and nodal temporal and spatial distribution
of the radionuclide and its rate of appearance in regional lymph nodes (groin or axilla).
The TIS ranges from 0 to severely pathological (45) and is calculated as follows:
where K = lymphatic transport kinetics (degree of transport delay); D = radionuclide
distribution pattern (degree of dermal extravasation), T = timing of radionuclide
appearance in regional lymph nodes (in minutes normalized for 200 min, the maximum delay accepted for lymph node appearance), N = demonstration and intensity
of lymph nodes, and V = demonstration and intensity of lymphatic collectors.8
Although variable, a high TIS supports either congenital or acquired lymphatic disease. Retarded lymph transport or faint or absent nodal visualization typically contribute to the abnormally high TIS.
9,10
Whole-body lymphangioscintigraphy (WB-LAS) is a reliable screening technique to evaluate the etiology and pathophysiology of upper and lower extremity
edema. For example, confinement to a wheelchair or other sedentary conditions
causing disuse may be associated with peripheral swelling. WB-LAS demonstrates
sluggish flow, but eventual clearance of the radiotracer because the lymphatic vessels are intact and not the primary cause of edema. Morbid obesity, and specifically
lipedema, is a condition worthy of special consideration. Affected patients often
present with large, heavy legs, corpulent buttocks and bulky upper arms. The feet
show no definite abnormality and may even be small, and there is no dorsal hump.
WB-LAS usually shows normal deep lymphatic trunks without obstruction, and
tracer transport may be within normal limits (Fig. 19.3). Occasionally, however,
repeated cellulitis and trauma may lead to areas of lipolymphedema with corresponding WB-LAS alterations.
Most importantly, WB-LAS is a rapid, non-invasive, dynamic, and definitive
means of assessing the nature and distribution and pinpointing the specific anatomical
and functional features of pure or mixed lymphatic disorders (as indicated in the
following sections). In addition, lymphatic abnormalities may be revealed before
edema becomes manifest, allowing early preventive or precautionary measures to
be undertaken.
Primary Lymphedema
An intrinsic inborn abnormality in the lymphatic conducting pathways underlies
primary lymphedema (Fig. 19.2b, g, j). Most patients with this condition have unilateral or bilateral lower limb swelling, but less commonly, arms, viscera, face, or