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Chapter 51
Primary Lymphedema as a Truncular
Lymphatic Malformation
Byung-Boong Lee, James Laredo, and Richard F. Neville
Definition
Primary lymphedema has been treated successfully for many decades and is one of
the two main types of chronic lymphedema; the other is secondary lymphedema.
1,2
Primary and secondary lymphedema are two different diseases with different etiologies, clinical behavior, response to treatment, and prognosis. Throughout the last
decade, substantial progress has been made in the understanding of the true nature
of primary lymphedema as a type of congenital vascular malformation (CVM)
3,4
affecting the lymphatic system.
Primary lymphedema has been classified as a “congenital” disorder because the
majority of patients present with a congenital defect of the lymph-transporting system. This lymphatic congenital defect is often a hypoplastic, hyperplastic, or aplastic lesion of the lymph vessels and/or lymph nodes.
5,6
Indeed, the majority of “primary” lymphedema patients present with the clinical
manifestations of a “truncular” type of lymphatic malformation (LM) that arises
during the later stages of lymphangiogenesis.
7,8
Nevertheless, not all primary lymphedema patients have anatomically evident
truncular defects in the lymphatic system. For example, “hereditary familial lymphedema,” known as Milroy’s disease,9 does not have a gross macrostructural defect
of the lymphatic vessels. Initial and collecting lymphatics are present, but there is
impairment of absorption at the level of the initial lymphatics reflecting a functional
defect. “Lymphedema–distichiasis syndrome”10 lacks only intraluminal valves of
the lymphatic collectors, resulting in lymph reflux. These conditions are further
discussed in detail in Section II – Embryology, Anatomy, and Histology.
B.-B. Lee (*)
Department of Surgery, Division of Vascular Surgery,
George Washington University School of Medicine, Washington, DC, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_51, © Springer-Verlag London Limited 2011
419
420 B.-B. Lee et al.
There is also some controversy about the current classification of primary lymphedemas based on the time of onset of clinical manifestations: congenital, praecox,
and tarda to constitute one spectrum of the disease where an arbitrary end point of
age 35 is used to separate tarda from praecox. However, there are some conditions
classified as tarda that can hardly fit as a primary disorder (see Chap. 3).
11
By the same token, some congenital lymphedemas by classification are not true
congenital defects but postnatal obliterations of lymph collectors/lymph nodes that
simply mimic the congenital/prenatal condition. In a true sense, these are not malformations of the lymphatic system, but nonetheless they are classified as congenital lymphedema since they are found at birth.
12,13
Nevertheless, primary lymphedema should be considered as an LM until proven
otherwise, not only for its clinical management, but also from the point of view of
its prognosis.
Classification
LM is one of the two most common forms of CVM,
14,15
the other being venous malformations. LM exists either as an independent lesion, or as a combined lesion with other
CVMs: venous malformations,
16,17
arteriovenous malformations (AVMs),
18,19
and capillary malformations.20 Such a combined condition is classified separately in the Hamburg
Classification21 as a hemolymphatic malformation (HLM).
22,23
LM is further classified into two subgroups based on the embryological stage
when developmental arrest occurred. “Extratruncular” lesions develop at an earlier
stage of embryogenesis and “truncular” lesions originate at a later stage. The truncular LM is better known as primary lymphedema, whereas extratruncular lesions
are known as cystic/cavernous lymphangiomas.
5,24
These two different types of LMs resulting from different embryological stages
are often mistakenly identified as two different disease entities without relationship.
However, extratruncular LM lesions and truncular LM lesions are inseparable and
often coexist, affecting each other in a profound manner.
Extratruncular Lymphatic Malformation Lesions
Extratruncular lesions are the result of premature embryonic tissue that fails to involute and remains in the condition of earlier stages of embryonic life (e.g., the reticular stage). The extratruncular lesion represents the pretruncal embryonic tissue
remnant before the lymphatic trunks are formed.
Therefore, extratruncular lesions maintain the unique embryonic characteristics
of the mesenchymal cells that respond/grow when provoked or stimulated by various conditions such as trauma, menarche, pregnancy, surgery, or hormonal changes.
They will never disappear and will remain throughout adult life and, because of
their origin, and will continue to grow.
25,26
51 Primary Lymphedema as a Truncular Lymphatic Malformation
421
Clinically, extratruncular lesions present as diffuse infiltrating conditions that
exert mechanical pressure on surrounding tissues and organs, including nerves and
muscles (e.g., cystic hygroma). Such lesions usually form a closed system independent of normal lymph-conducting pathways without direct communications,
although they could coexist with lymphedema-causing truncular lesions.
Truncular Lymphatic Malformation Lesions
In contrast, truncular lesions are the result of developmental arrest occurring at later
stages of fetal development during the formation of the lymphatic trunks, vessels,
and nodes long after the reticular stages of vascular development have ceased. These
are termed posttruncal fetal lesions (cf. pretruncal extratruncular lesions).
Truncular lesions, therefore, no longer have the evolutional power to grow or
recur. They have lost the embryonic characteristics of mesenchymal cells and bear
no risk of recurrence, but they have a significant lymphodynamic impact on the
lymph transport system involved.
Truncular lesions occur in various clinical conditions as the result of an incomplete development of the axial or truncal lymphatic vessels. Depending on the severity or extent of the abnormality occurring during the last maturation period of the
lymphatic system, various conditions may result, such as aplasia, hypoplasia, or
hyperplasia of lymphatic vessels and/or lymph nodes. These may clinically manifest as obstruction or dilatation. When the endoluminal valves are absent or defective, lymphatic reflux becomes the most important clinical manifestation.
25,26
Clinical Evaluation
Detailed information about the clinical evaluation of primary lymphedema as
a chronic lymphedema together with secondary lymphedema is presented in
Section IV – Clinical Diagnosis, Section V – Laboratory/Imaging Diagnosis, and
Section VI – Infection.
Once the differential diagnosis has excluded secondary lymphedema, further
evaluation of primary lymphedema as a truncular LM is required in addition to staging of the condition as a chronic lymphedema.
Clinical evaluation should begin with a basic evaluation of the CVM as a whole,
followed by a more focused, separate investigation into the possible coexistence of
an extratruncular LM. Further evaluation of the potential risk of other occurring
CVM lesions should be considered when the overall results of the investigation are
suggestive (e.g., Klippel–Trenaunay syndrome).
Based on the initial assessment with history and physical examination, an appropriate combination of non- to minimally invasive tests can be performed.
Usually, a few basic tests (e.g., lymphoscintigraphy [LSG]) will provide all the
information necessary to ensure an adequate diagnosis and lead to a correct
27,28
22,23
29-32
422 B.-B. Lee et al.
multidisciplinary treatment strategy. However, a few additional tests can be
added to provide more specific and detailed information.
Radionuclide (LSG)
35,36
is the most essential test and remains the gold standard
33,34
for evaluation of lymphatic function. Periodic LSG findings provide adequate laboratory staging, which is essential to supplement clinical staging necessary for proper
clinical management.
Together with LSG, Duplex ultrasound31 for evaluation of venous function/status
is indicated in every case of primary lymphedema. Accurate assessment of venous
function is essential to rule out accompanying abnormal venous conditions that
often act as predisposing factors for deterioration of the LM condition (e.g., aplasia/
hypoplasia of the ilio-femoral-venous system).
Invasive tests are necessary in certain situations and provide more information
for an accurate differential diagnosis among the CVMs. These tests should be considered to help guide subsequent therapy.
11
Direct puncture percutaneous lymphangiography to verify the status of an
extratruncular LM can be generally deferred until needed to refine the diagnosis
or to provide information if surgical or other invasive therapeutic measures are
considered.
11
Conventional oil contrast lymphangiography is useful in selecting patients with
chylous dysplasia and gravitational reflux disorders to better define the extent of the
pathological alterations and sites of lymphatic and chylous leakage.
11
Lymphedema in children can be a part of the syndrome if there are other concomitant phenotypic abnormalities. Detailed information about the genetic testing
and related evaluation is presented in Chaps. 3 and 59.
Clinical Management
Primary lymphedema management is essentially the same as that for secondary
lymphedema when it is due to an independent truncular LM. Detailed information
has been presented in Section VII through Section X.
However, when both truncular LM (primary lymphedema) and extratruncular
LM (lymphangioma) lesions occur together, treatment should be focused on the
extratruncular LM lesion. The extratruncular lesion often accelerates the deterioration of the truncular lesion by increasing the lymphatic burden to an already jeopardized lymphatic system.
When the two different LM lesions coexist with other CVMs, the treatment
should be focused on the other malformation such as the venous malformation or
AVM if they are clinically significant “major” lesions. Further detailed information
on combined CVM conditions is presented in Chap. 52.
Conservative (Physical) Therapy
Detailed discussion is presented in Section VII – Physical and Medical Management,
and Section VIII – Practical issue on Physical Therapy.
51 Primary Lymphedema as a Truncular Lymphatic Malformation
423
The management of truncular LM aims to control the clinical manifestation as
primary lymphedema. Complex decongestive therapy (CDT) is still the most effective form of therapy for truncular LM lesions, whether alone or combined with
extratruncular LM lesions.
Surgical Therapy: Reconstructive Surgery
Although ample discussion on the role of reconstructive surgery in chronic lymphedema is presented in Section IX – Surgical treatment – Reconstructive Surgery,
there is one critical and unique issue where primary lymphedema is caused by truncular LM.37 Truncular LMs have an extremely variable number and type of lymph
vessels and lymph nodes, as exemplified by the various forms of dysplasias such as
lymphangiodysplasia, lymphadenodysplasia, and lymphangioadenodysplasia.
Candidates for reconstructive surgery are, therefore, rare among primary lymphedemas because of the variable anatomy involved with the truncular defect,
although some colleagues reported different findings.39 Surgery outcomes are
also variable, but generally not as successful as those of secondary lymphedema
patients who have surgically correctable lesions along the major lymphatics/
collectors.
8,33
Hence, the role of reconstructive surgery is further limited in patients with primary lymphedema, even as an adjunctive therapy to CDT at best with a specific
indication.
38
Surgical Therapy: Ablative/Excisional Surgery
As discussed in Section X – Surgical treatment – Excisional/Cytoreductive Surgery
thoroughly for the role of excisional surgery in chronic lymphedema when the condition reaches the later/end stage (stages III and IV), most of the normal tissues have
become fibrosclerotic and all the remaining lymph vessels are severely damaged,
leading to an unsalvageable condition. Therefore, the etiology/cause does not matter
from a treatment/excision point of view at this stage.
11,40
Excisional surgery becomes a treatment of last resort in such a condition once the
CDT-based therapy fails to arrest lymphedema progression toward the end stages
with evidence of steady deterioration despite maximum treatment.
Liposuction: Circumferential Suction-Assisted Lipectomy
As presented in Section X – Surgical treatment – Excisional/Cytoreductive Surgery,
this procedure has been used for treatment of secondary lymphedema following
mastectomy. The procedure utilized liposuction to remove excessive, overgrown
adipose tissue. However, this less-invasive approach is only effective when performed in the early stage of secondary lymphedema. It is not effective in advanced
424 B.-B. Lee et al.
cases of lymphedema where tissue fibrosis predominates. Circumferential suctionassisted lipectomy requires intensive compression therapy post-procedure and its
results are short-lived when compression therapy is discontinued. Its role in the
treatment of primary lymphedema is still unknown and its efficacy remains to be
proven.
Prospect: Primary Lymphedema as Lymphatic Malformation
This critical part was also presented in Section XIV: Chap. 59.
Conclusion
The primary lymphedema represents a clinical manifestation of the truncular type
of lymphatic malformation (LM) arising during the later stages of lymphangiogenesis. A clear understanding of its contemporary classification as a vascular malformation is necessary, because embryological staging information of the LM is critical
for proper management of the primary lymphedema as one of the CVMs.
References
1. Lee BB, Villavicencio JL. Primary lymphedema and lymphatic malformation: Are they the
two sides of the same coin? Eur J Vasc Endovasc Surg. 2010;39:646-653.
2. Lee BB. Lymphedema-angiodysplasia syndrome: a prodigal form of lymphatic malformation
(LM). Phlebolymphology. 2005;47:324-332.
3. Lee BB, Kim YW, Seo JM, et al. Current concepts in lymphatic malformation (LM). Vasc
Endovascular Surg. 2005;39(1):67-81.
4. Lee BB. Lymphatic malformation. In: Tredbar LL, Morgan CL, Lee BB, Simonian SJ, Blondeau B,
eds. Lymphedema—Diagnosis and Treatment. London: Springer; 2008: 31-42, chap 4.
5. Lee BB, Laredo J, Lee TS, Huh S, Neville R. Terminology and classification of congenital
vascular malformations. Phlebology. 2007;22(6):249-252.
6. Lee BB, Laredo J, Seo JM, Neville R. Treatment of lymphatic malformations. In: Mattassi R,
Loose DA, Vaghi M, eds. Hemangiomas and Vascular Malformations. Milan: Springer;
2009:231-250. chap. 29.
7. Lee BB. Critical issues on the management of congenital vascular malformation. Ann Vasc
Surg. 2004;18(3):380-392.
8. Lee BB, Kim DI, Whang JH, Lee KW. Contemporary management of chronic lymphedema –
personal experiences. Lymphology. 2002;35(Suppl):450-455.
9. Eliachar E, Servelle M, Tassy R, Gamerman H. Hereditary lymphedema (Milroy’s disease).
Ann Pediatr (Paris). 1970;17(11):750-753.
10. Erickson RP. Lymphedema-distichiasis and FOXC2 gene mutations. Lymphology. 2001;
34(1):1.
51 Primary Lymphedema as a Truncular Lymphatic Malformation
11. Lee BB, Andrade M, Bergan J, et al. Diagnosis and treatment of primary lymphedema: con-
sensus document of the International Union of Phlebology (IUP)-2009. Int Angiol. 2010;29(5):
454-470.
12. Witte MH, Jones K, Wilting J, et al. Structure function relationships in the lymphatic system
and implications for cancer biology. Cancer Metastasis Rev. 2006;25(2):159-184.
13. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol.
2008;52:799-806.
14. Lee BB, Laredo J, Lee SJ, Huh SH, Joe JH, Neville R. Congenital vascular malformations:
general diagnostic principles. Phlebology. 2007;22(6):253-257.
15. Lee BB. Statues of new approaches to the treatment of congenital vascular malformations
(CVMs) – single center experiences – (editorial review). Eur J Vasc Endovasc Surg. 2005;
30(2):184-197.
16. Lee BB, Kim DI, Huh S, et al. New experiences with absolute ethanol sclerotherapy in the man-
agement of a complex form of congenital venous malformation. J Vasc Surg. 2001;33:764-772.
17. Lee BB, Do YS, Byun HS, Choo IW, Kim DI, Huh SH. Advanced management of venous
malformation with ethanol sclerotherapy: mid-term results. J Vasc Surg. 2003;37(3):533-538.
18. Lee BB, Do YS, Yakes W, et al. Management of arterial-venous shunting malformations
(AVM) by surgery and embolosclerotherapy. A multidisciplinary approach. J Vasc Surg.
2004;39(3):590-600.
19. Lee BB, Laredo J, Deaton DH, Neville RF. Arteriovenous malformations: evaluation and treat-
ment. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American Venous
Forum. 3rd ed. London: A Hodder Arnold Ltd; 2009.
20. Berwald C, Salazard B, Bardot J, Casanova D, Magalon G. Port wine stains or capillary malfor-
mations: surgical treatment. Ann Chir Plast Esthét. 2006;51(4–5):369-372. Epub 2006 Sep 26.
21. St B. Classification of congenital vascular defects. Int Angiol. 1990;9:141-146.
22. Glovczki P, Driscoll DJ. Klippel-Trenaunay syndrome: current management. Phlebology.
2007;22(6):291-298.
23. Villavicencio JL. Congenital vascular malformations – Predominantly venous? The syndrome
of Klippel-Trenaunay. Scope Phlebology Lymphology. 2000;71(1):116-125.
24. Lee BB. Classification and staging of lymphedema. In: Tredbar LL, Morgan CL, Lee BB,
Simonian SJ, Blondeau B, eds. Lymphedema—Diagnosis and Treatment. London: Springer;
2008; 21-30, chap. 3.
25. Bastide G, Lefebvre D. Anatomy and organogenesis and vascular malformations. In: Belov
ST, Weber J, eds. Vascular Malformations. Reinbek: Einhorn-Presse; 1989:20-22.
26. Leu HJ. Pathoanatomy of congenital vascular malformations. In: Belov S, Loose DA, Weber
J, eds. Vascular Malformations, vol. 16. Reinbek: Einhorn-Presse; 1989:37-46.
27. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema.
2009 Consensus document of the International Society of Lymphology. Lymphology.
2009;42:51-60.
28. Lee BB, Bergan JJ. New clinical and laboratory staging systems to improve management of
chronic lymphedema. Lymphology. 2005;38(3):122-129.
29. Lee BB, Mattassi R, Kim BT, Kim DI, Ahn JM, Choi JY. Contemporary diagnosis and man-
agement of venous and AV shunting malformation by whole body blood pool scintigraphy
(WBBPS). Int Angiol. 2004;23(4):355-367.
30. Lee BB, Mattassi R, Kim BT, Park JM. Advanced management of arteriovenous shunting
malformation with transarterial lung perfusion scintigraphy (TLPS) for follow up assessment.
Int Angiol. 2005;24(2):173-184.
31. Lee BB, Mattassi R, Choe YH, et al. Critical role of Duplex ultrasonography for the advanced
management of a venous malformation (VM). Phlebology. 2005;20:28-37.
32. Lee BB, Choe YH, Ahn JM, et al. The new role of MRI (Magnetic Resonance Imaging) in the
contemporary diagnosis of venous malformation: Can it replace angiography? J Am Coll Surg.
2004;198(4):549-558.
425
426 B.-B. Lee et al.
33. Lee BB. Current issue in management of chronic lymphedema: personal reflection on an expe-
rience with 1065 patients. Lymphology. 2005;38:28.
34. Lee BB, Villavicencio L. General considerations. Congenital vascular malformations. Arterio-
venous anomalies (Sect 9). In: Cronenwett JL, Johnston KW, eds. Rutherford’s Vascular
Surgery. 7th ed. Philadelphia: Saunders Elsevier; 2010: 1046-1064, chap. 68.
35. Olszewski WL. Lymphoscintigraphy helps to differentiate edema of various etiologies (inflam-
matory, obstructive, posttraumatic, venous). Lymphology. 2002;35(Suppl):233-235.
36. Choi JY, Hwang JH, Park JM, Kim DI, Lee BB, Kim BT. Risk assessment of dermatolymp-
hangioadenitis by lymphoscintigraphy in patients with lower extremity lymphedema. Korean
J Nucl Med. 1999;33(2):143-151.
37. Lee BB. Surgical management of lymphedema. In: Tredbar LL, Morgan CL, Lee BB, Simonian SJ,
Blondeau B, eds. Lymphedema—Diagnosis and Treatment. London: Springer; 2008: 55-63,
chap. 6.
38. Papendieck CM. Lymphangiomatosis and dermoepidermal disturbances of lymphangioadeno-
dysplasias. Lymphology. 2002;35(Suppl):478.
39. Campisi C, Da Rin E, Bellini C, Bonioli E, Boccardo F. Pediatric lymphedema and correlated
syndromes: role of microsurgery. Microsurgery. 2008;28(2):138-142.
40. Lee BB, Kim YW, Kim DI, Hwang JH, Laredo J, Neville R. Supplemental surgical treatment
to end stage (stage IV –V) of chronic lymphedema. Int Angiol. 2008;27(5):389-395.
Chapter 52
Primary Lymphedema and Klippel-Trénaunay
Syndrome
Byung-Boong Lee, James Laredo, Richard F. Neville, and Raul Mattassi
The majority of primary lymphedemas
1,2
are due to a congenital, independent lesion
of the lymphatic system resulting in dysfunction. Primary lymphedema due to a
truncular lymphatic malformation (LM) has been thoroughly reviewed in Chap. 51.
Primary lymphedema less commonly presents as a component of multiple
congenital vascular malformations (CVMs) producing a clinical condition. One
such condition was named after Maurice Klippel and Paul Trenaunay, based on their
description in 1900 of a complex CVM. Klippel–Trenaunay syndrome (KTS)
became a synonym for a complicated condition due to CVMs for more than a
century.
3,4
This old eponym originally described a clinical triad: port wine stain, soft tissue,
and bone hypertrophy of the lower limb, and atypical, mostly lateral varicosities.
These various soft tissue, bone, and vein lesions are due to the underlying vascular
malformations involved. This original description failed to specify the type of vascular malformations involved (Fig. 52.1).
The vascular malformation components of KTS are venous malformation
5,6
(VM),
mation (AVM)
7,8
LM,
and capillary malformation (CM).9 When an arteriovenous malfor-
10,11
is further involved, it is known as Parkes–Weber Syndrome
(PWS; Fig. 52.2).
Such eponyms like KTS or PWS failed to meet the requirements for advanced
management of various CVMs based on a new contemporary concept. These eponyms
have been replaced with new terminology based on the Hamburg Classification
(Table 52.1).
12,13
The VM component of the KTS is classified as a hemolymphatic malformation
(HLM) and represents a combined condition of VM, LM, and CM, resulting in the
various presentations seen in patients with KTS.
14,15
B.-B. Lee (*)
Department of Surgery, Division of Vascular Surgery,
George Washington University School of Medicine, Washington, DC, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_52, © Springer-Verlag London Limited 2011
427
428 B.-B. Lee et al.
Rt
30 min1Hr 2Hrs
Update (x) : 13.93
Update (x) : 4.53
Clearance (x) : 26.03
Lt
0.47 0.48 0.57
32.28
40.95
16.14
3.41
45.00
30.06
30.32
16.50
4.68
37.27
24.31
12.99
a
b
Fig. 52.1 Klippel–Trenaunay syndrome (KTS). (a) Clinical appearance of KTS involving the left
lower extremity. Various non-invasive tests confirmed all four different vascular malformation
components: truncular LM (primary lymphedema) by radionuclide lymphoscintigraphy (b) and
MR-T2 weighted image (d), extratruncular LM by direct puncture lymphangiography (g),
extratruncular VM by whole-body blood pool scintigraphy (c), and truncular VM (marginal vein)
by Duplex ultrasound (e) and MR venography (f)