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Chronic Lymphedema:
Etiology & Classification
The 30th Annual Congress, American College of Phlebology
November 3 - 6, 2016
Anaheim, California
Track C: Lymphedema and Wound Care
B. B. Lee, MD, PhD, FACS
Professor of Surgery, George Washington University, Washington DC, USA
Adjunct Professor of Surgery, Uniformed Services University, Bethesda, MD, USA
Visiting Professor of Surgery, Johns Hopkins University, Baltimore, MD, USA
DISCLOSURE OF
CONFLICTS OF INTEREST
BYUNG-BOONG LEE,MD, PhD, FACS
Chronic Lymphedema: Etiology & Classification
I do not have any relevant financial relationships
with any commercial interests.
Chronic Lymphedema
Chronic lymphedema is the most commonly encountered
lymphatic dosorder in the form of a progressive and a
relatively painless swelling of any peripheral tissue –
limbs, head and neck, breast, trunk or genitals.
They represent a clinical condition of diffuse swelling of
affected limb/region as the result of a less-than-optimal
transport capacity of the lymphatic system as the result of
the blockage of lymph-transport/collection caused by
various conditions of primary or secondary origin.
B.B. Lee, MD
GWU
Chronic Lymphedema
Etiology – classification
Primary lymphedema
Congenital lymphedema
Lymphedema praecox
Lymphedema tarda
Secondary lymphedema
Iatrogenic; post-surgical and/or
post-radiation
Infections; filariasis
Tumor, trauma, etc.
B.B. Lee, MD
GWU
Primary Lymphedema
The majority of chronic lymphedema cases classified as
primary lymphedema are due to inborn abnormalities of
the lymphatic system, present at birth by definition.
In patients with primary lymphedema the cause of
decreased lymphatic transport can be an intrinsic ”defect”
or a malfunction of the lymph conducting elements, and
generally considered as the outcome of a genetically
determined abnormality of lymphatic anatomy or function
caused by abnormal (mutant) genes.
Hence, primary lymphedemas encompass both the
sporadic and hereditary forms, as well as those that are
syndrome-associated.
B.B. Lee, MD
GWU
Primary Lymphedema
B.B. Lee, MD
GWU
Primary lymphedema represents the clinical expression of
heritable abnormal structural development, and defined as a
‘truncular’ lymphatic malformation (LM).
LMs are a common type of congenital vascular malformation.
They occur as independent malformations in its majority but it
also coexist with other CVMs such as venous malformation,
arterio-venous malformations, and/or capillary malformation.
The LM to cause primary lymphedema is involved to the 'later'
stage of lymphangiogenesis while lymphatic vessel trunks are
formed.
Primary Lymphedema
B.B. Lee, MD
GWU
This type of the LM lesions from the 'later' stage is named
/classified to 'truncular' lesions based on direct involvement
to the matured lymphatic vessels/nodes in various extents of
defective condition: hypoplasia, hyper-plasia, and aplasia.
In these circumstances, a malformation is clinically
manifest as a macroscopically irregular or abnormal
structural development, but some primary lymphedemas
have very little structural derangement and represent a
functional defect that is molecular in origin.
Therefore, a malformation may not necessarily have
attributes that can be imaged but may ultimately require
detection in molecular or other functional terms.
Primary Lymphedema
For such condition/milieu to cause defective development in
the ‘later’ stage of lymphangiogenesis to result in 'primary'
lymphedema, there is always a good risk to have similar
defective development in the ‘earlier’ stage of the
lymphangiogenesis to result in 'lymphangioma’ as well.
When the developmental arrest should occur in the 'earlier'
stage before (the stage of) vessel trunk formation, it
maintains the primitive structure of reticular network and
remains as a amorphous vascular cluster. They were named/
classified to 'extratruncular' LM lesions.
B.B. Lee, MD
GWU
Primary Lymphedema
Therefore, extratruncular LM lesions represent the
embryonic tissue remnant before evolving to mature
structures through the later stage of lymphatic vessel trunk
formation.
Extratruncular LM lesions are therefore, morphologically
distinctive as a premature or pretruncal embryonic lesion
occurred prior to maturation of the lymphatic system to
form lymphatic vessel trunks.
They maintain primitive lymphatic structures of macrocystic/micro-cystic tissues; they have been called
as “lymphangioma”.
B.B. Lee, MD
GWU
Primary Lymphedema
On contrary, truncular LM lesion is the result of a defective
development of the main lymphatic vessels during vascular
trunk maturation/formation along the later truncal/truncular
stage of fetal development.
Hence, the defective development in this stage after the
reticular stage of vascular development will results in
the formation of a “mature lesion”.
The term: 'truncular' describes such unique anatomical
condition of this malformation lesion involved to the main
vessel trunks, distinguishing its morphological difference from
the (‘extratruncular’) lesion which remained peripherally with
no direct involvement of the vessel trunk itself.
B.B. Lee, MD
GWU
Primary Lymphedema
Primary lymphedema represents mainly a clinical condition of truncular
malformations of the lymphatic system with lymphatic truncular hypoplasia
(89%), aplasia, numerical hyperplasia, or dilation (lymphangiectasia-10%)
with valvular incompetence. Selective lymph node
dysplasia rarely predisposes an individual to primary
lymphedema (e.g., ilio-inguinal nodal sclerosis).
There is some controversy whether all lymphedema and
lymphatic malformations are genetically derived.
Nevertheless, primary lymphedema includes all those
manifestations of lymphedema that represent an inherited
condition.
B.B. Lee, MD
GWU
Primary Lymphedema
B.B. Lee, MD
GWU
A disease-causing mutation of any of the genes involved in the development
of the lymphatic system, can result in a familial distribution of primary
lymphedema. Representative identified genetic mutations
can affect FLT4 , FOXC2, and GJC2. All these forms of
genetically determined lymphedema are collectively classified
as “primary” lymphedema.
Such conditions have been reported among multigeneration
families where the lymphedema is the major clinical sign as
primary phenotype and shows an autosomal dominant pattern
of inheritance; various genes strongly associated with this
pattern of inheritance have been demonstrated with variable
expression and variable age at onset.
Primary Lymphedema
B.B. Lee, MD
GWU
Milroy disease is one example of an inherited lymphedema. Many of the
family cohorts examined demonstrate a gene mutation at the locus 5q35.3:
the gene mutated is FLT4, which encodes for the Vascular
Endothelial Growth Factor Receptor 3 (VEGFR3) receptor.
Milroy disease is an autosomal dominant single gene disorder
inherited as a germline mutation, whereas most asymmetrical
and regionally limited genetic disorders (e.g. malformations)
are due to a somatic mutation. In this situation, some tissue
(e.g. skin) may be unaffected while the adjacent tissue (skin)
may carry the mutation, an example of “mosaicism."
Primary Lymphedema
Although a family history was thought to be a prerequisite
for diagnosis of (Nonne) Milroy syndrome (or FLT4-related
lymphedema), the description of “de novo FLT4 mutations”
suggests that FLT4 inactivating mutations are even found in
sporadic cases.
Nevertheless, the 'hereditary' type of primary lymphedema
accounts for the minority of cases, while the 'sporadic' type
represents the majority although both have a genetic basis.
Primary lymphedemas have been classified into three groups
depending on the age of onset: Congenital (before age 2),
Praecox (between age 2 and 25) and Tarda (after age 35).
B.B. Lee, MD
GWU
Primary Lymphedema
There is much doubt in classifying all lymphedema ‘tarda’ as a
primary disorder on the basis of conventional classification based
on the age of the onset: congenital, praecox and tarda as one
spectrum of the disease.
Congenital type of primary lymphedema is frequently associated
with other malformations (heart, mental, renal etc) while praecox
and tarda never show these features.
Tarda is bilateral in most patients while bilateral involvement
occurs in only 30% of patients with praecox, even though 70% of
praecox patients have bilateral anomalies. This is likely due to
mozaicism where a patient may clinically have only unilateral
clinical symptoms with underlying bilateral pathology.
B.B. Lee, MD
GWU
Primary Lymphedema
B.B. Lee, MD
GWU
Therefore, there is some objection to classifying all
lymphedema ‘tarda’ as a primary disorder on the basis of
the conventional spectrum based on the age of the onset.
The arbitrary age of 35 used to separate ‘tarda’ from
‘precox’ is not clinically useful because this classification
does not imply a mechanism or pathogenesis.
In addition, there is some concern about the current
definition of the primary lymphedemas; some may
represent post-natal obliterations of lymph collectors and
lymph nodes, thus mimicking congenital and prenatal
pathology.
Primary Lymphedema
B.B. Lee, MD
GWU
Lymphedema-distichiasis syndrome caused by mutations in
the FOXC2 gene is associated with congenital distichiasis
(extra eyelashes arising from the Meibomian gland) (95%)
and congenital heart disease (8%) but lymphedema never
manifests at birth, although true malformations, by definition,
are present at birth.
Lymphedema usually presents in late childhood or puberty
among lymphedema-distichiasis syndrome and may be
delayed until the 5th decade.
Therefore, terms like tarda and precox are outdated terms,
potentially misleading as sole criteria for classification.
Primary Lymphedema
Not all gene mutations will result in a phenotype that reflects a major
impact on lymphatic function. A minor impact among patients with primary
lymphedema has been also reported for HGF and MET genes. Due to
incomplete penetrance, some individuals of the same family can remain as
(healthy) carriers of the genetic mutation and do not develop the disease.
However, This 'sub-clinical' condition of lymphedema suggests the potential
risk of such varying degrees of developmental error to trigger clinically
significant lymphatic transport insufficiency later in the life when the trigger
ing conditions are met. This unique group of subclinical presentation merits
special consideration in the realm of lymphedema prevention.
B.B. Lee, MD
GWU
Secondary Lymphedema
In patients with secondary lymphedema, there is a specific external
cause to impact on a presumed previously normally functioning lymphatic
system to be identified. Hence, secondary lymphedema includes all those
manifestations of lymphedema occasioned by acquired lymph transport
abnormalities triggered by an external event such as a parasite infection/
filariasis, previous surgery, trauma, radiation therapy, malignancy/tumors
or inflammatory processes.
Courtesy of G Manokaran
B.B. Lee, MD
GWU
Secondary Lymphedema
Lymphatic filariasis: Globally, more than 129 million patients are afflicted
by. This condition is characterized by markedly impaired lymphatic
function and lymphangiectasia. Patients are infected by filariae, or
parasitic worms, which take up residence in the lymphatic structures. As a
result, the lymphatics become compromised; the formation of new lymph
channels is impaired by the adenolymphangitis, fibrosis and stenosis of
the lymph nodes.
B.B. Lee, MD
GWU
Courtesy of G Manokaran
Secondary Lymphedema
B.B. Lee, MD
GWU
Lymphangitis is, in general, a consequence of the inflammation of
lymphatic channels through tissue infection. Pathogenic organisms can
include bacteria, fungi, viruses, and protozoa.
Therefore, the majority of secondary lymphedema associated either with
malignant, i.e., direct neoplastic invasion and/or obstruction of the vascular
channels and nodes, or benign, i.e., acquired as a consequence of infection,
trauma, obesity or iatrogenic causes, including the surgical and
radiotherapeutic treatment of malignancies.
Secondary Lymphedema
However, ‘post-surgical/radiation’ lymphedema remains
the most frequent form of secondary lymphedema in
developed countries (e.g. post-mastectomy lymphedema)
while ‘post-infectious’ lymphedema is most important
form in third world countries (e.g. filariasis-induced
lymphedema).
Radical mastectomy - 6 to 60%
Modified radical mastectomy - 15.4%
Extensive axillary dissection followed by
radiotherapy - 38.3%
Radical hysterectomy and pelvic
lymphadenectomy for cervical cancer 28.4%
B.B. Lee, MD
GWU
Secondary Lymphedema
Further, more recent studies suggest that the boundaries that
separate the seemingly distinct categories of primary and
secondary lymphedema may, in fact, be indistinct: primary
cases often declare themselves after a “secondary” provocation,
and evolving clinical data suggests that there might be a genetic
predisposition for the development of lymphedema, even when
the inciting secondary events are easy to identify.
Indeed, very recent data suggests that secondary lymphedema
is not exclusively due to environmental insult but can be linked
to a heritable factors according to a model of genetic
susceptibility; a single heterozygous mutation of the gene,
GJC2 has been found to promote lymphedema.
B.B. Lee, MD
GWU
Chronic Lymphedema
B.B. Lee, MD
GWU
Conclusion
There is a spectrum of human disease that directly or indirectly alters
lymphatic structure and function. The symptomatic and objective
presentation of these patients is quite heterogeneous. Diagnosis and
differential diagnosis pose distinct challenges.
Current classification of the lymphedema based on morpho-etiology
is not accurate enough to meet its role as a contemporary classification.
But new classification based on evolving insights into molecular
embryology of lymphatic vascular development is needed as a new
mandate.
Thank you for your Attention!