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JSSTD Symposium
Secondary lymphedema: Pathogenesis
Smitha Ancy Varghese
Dermatology and Venereology, Government Medical College, iruvananthapuram, Kerala, India.
e lymphatic system plays two important functions in the human body. It maintains the uid
balance of the body by returning the protein deposits and extra tissue uid extravasated from
the blood capillaries to the circulation system. Besides, the lymphatic vessels carry germs and
pathogens to the lymph nodes so that the immunological defense mechanism is activated.
Understanding the normal anatomy of the lymphatic system is crucial in comprehending the
pathogenesis of lymphedema.[1]
e lymphatic vessels are categorized into lymph capillaries, pre-collectors, and lymph-collecting
vessels. e lymph capillaries have a diameter ranging from 20 μm to 70 μm. ese supercially
located vessels are placed immediately beneath the epidermis. Lymph capillaries are formed by
endothelial cells that connect loosely with each other like roof tiles (in an overlapping pattern).
ey lack valves. A brous anchoring lament joins the endothelial cell with the surrounding
tissue. In the presence of excess interstitial uid (edema), the junctions between the endothelial
cells open up. is is achieved by the action of the anchoring laments that pull the endothelial
cells outward to capture the edema uid into the lumen.
e capillaries join larger pre-collectors (70–150 μm in diameter) in the deep dermis. Pre-
collectors through their valvular structure permit lymph ow in one direction only (from the
supercial to the deep layers). Pre-collectors join together within the dermis to form larger vessels
Secondary lymphedema follows an acquired defect in the lymphatic system. e common causes leading to
a defective lymphatic function include infection, inammation, malignancy, trauma, obesity, immobility, and
therapeutic interventions. Understanding the pathogenesis of lymphedema is of prime importance in oering
eective treatment. e pathogenetic mechanisms such as lymphatic valvular insuciency, obliteration/
disruption of lymphatic vessels, and decreased lymphatic contractility aggravate lymphatic hypertension and
lymphstasis. Accumulation of lymph, interstitial uid, proteins, and glycosaminoglycans within the skin and
subcutaneous tissue eventually stimulates collagen production by broblasts, causes disruption of elastic bers,
and activates keratinocytes, broblasts, and adipocytes. ese result in thickening of skin and cause brosis of
subcutaneous tissue. However, the sequence of these pathomechanisms, their inter-relationship and progression
vary depending on the specic etiology of the lymphedema. In this article, we discuss the possible cellular
and molecular mechanisms involved in the pathogenesis. Further studies to delineate the exact sequence
of pathogenic processes surrounding the primary triggering event can help to formulate tailored therapeutic
approaches.
Inammation, Pathogenesis, Secondary lymphedema
www.jsstd.org
Journal of Skin and Sexually
Transmitted Diseases
Smitha Ancy Varghese,
Dermatology and Venereology,
Government Medical College,
iruvananthapuram, Kerala,
India.
smitharijo@gmail.com
Received : 26 January 2021
Accepted : 08 February 2021
Published : 06 April 2021
10.25259/JSSTD_3_2021
Varghese: Secondary lymphedema: Pathogenesis
called eerent pre-collectors that run vertically through the
subcutaneous tissue.
e eerent pre-collectors connect to collectors (the
lymph collecting vessels of 150–500 μm in diameter) in the
subcutaneous fat layer. e collectors are oriented horizontally
in the subcutaneous tissue and have a triple-layered wall of
endothelial cells, smooth muscle cells, and collagen bers with
broblasts. e rhythmic contraction of broblasts propels
the lymph ow. e collectors are further sub-classied
into supercial and deep vessels based on their anatomical
relationship to the deep fascia. e deep vessels follow the
arteries, while supercial vessels show no such preference.[1]
Each lymphatic vessel connects to at least one lymph node
before joining the vein. is ensures that pathogens or cancer
cells are not released into the systemic blood circulation
before the lymph nodes activate the immune system.[1]
In 2018, Suami and Scaglioni introduced the concept of
‘lymphosome’ that suggested that the lymphatic vessels in a
particular region connect to the same subgroup of regional
lymph nodes.[1]
Peripheral edema is an outcome of lymphatic failure which
can either be relative or absolute. Relative lymphatic failure
occurs when microvascular ltration overwhelms the lymph
drainage. e term “lymphedema” is reserved for absolute
lymphatic failure (edema resulting principally from a failure
in lymph drainage).[2]
Primary lymphedema refers to lymphedema due to congenital
anomalies of lymphatics while secondary lymphedema arises
from dysfunction of lymphatics due to acquired causes.[2]
e acquired causes for lymphedema range from infections
and trauma to malignancies and surgeries. Hence, not
surprisingly, secondary lymphedema is far more common
than primary lymphedema and generally develops at a later
age when compared to primary lymphedema.[2] With the
progress made in genetics and, immunology and newer
insights into the anatomy and physiology of the lymphatic
system, the pathogenetic mechanisms have been elucidated
with more clarity in recent times. is article will focus on the
pathophysiological mechanisms of secondary lymphedema.
Pathophysiology of secondary lymphedema varies depending
on the underlying conditions [Table 1]. Hence, the
pathogenesis is better discussed under the subheadings of
individual conditions causing secondary lymphedema.
In addition to lariasis (the most common cause of
secondary lymphedema), the other infections which can
lead to lymphedema are cellulitis/erysipelas, tuberculous
lymphadenitis, and lymphogranuloma venereum.
e adult forms of larial worms (Wuchereria bancroi,
Brugia malayi, and Brugia timori) living in the aerent
lymphatics and/or the lymph nodes and their larval progeny
(the microlariae, that circulate in the peripheral blood where
they infect mosquito vectors when they feed) contribute to the
pathogenesis of larial lymphedema.[3] A complex interplay of
immunologic factors, endothelial factors, genetic factors, and
superadded bacterial infections determines the outcome.
e lymphatic vessel injury and subsequent inammatory
response are attributed to specic pro-inammatory
cytokines such as tumor necrosis factor (TNF)-α, interleukin
(IL)-6, and soluble TNF receptor.[4] Endothelin-1, IL-2,
IL-8, macrophage inammatory protein (MIP)-1α, MIP-1β,
macrophage chemotactic protein-1, thymus and activation-
regulated chemokine, and interferon-inducible protein-10
in the peripheral circulation also play a role.[5,6] A pro-
inammatory milieu exists within the lymphatic vessels, with
elevated levels of gamma-globulins, α-1 acid glycoprotein,
and IL-1β in the lymph uid.[5]
Live larial parasites and their secretory products play
an important role in the early stage of the disease by
inducing activation, proliferation, and tube formation by
lymphatic endothelial cells. e serum from patients with
lariasis has shown the presence of factors that promote
signicant lymphatic endothelial cell proliferation. Active
lymphatic remodeling involving endothelial cell growth,
migration, and proliferation leads to anatomical changes in
the architecture of lymphatics ranging from lymphangiectasia
and granulomatous responses to collateral formation.[7,8]
e larial parasites induce alterations in the normal
physiology of the lymphatic endothelium. Global gene
expression analysis revealed alterations in genes involved
in junction adherence pathways that, in turn, decrease
trans-endothelial transport. A role is proposed for the
vascular endothelial growth factor (VEGF) family in
lymphangiogenesis.[9,10] Other angiogenic factors such as
angiopoietins-1 and 2 are also elevated in individuals with
lariasis.
e damaged lymphatics with leaky lymphatic endothelium
act as a potential nidus for bacterial translocation. e aected
lymphatics show increased bacterial and fungal loads.[3]
Varghese: Secondary lymphedema: Pathogenesis
Important causes and pathogenesis of secondary lymphedema.
Causes
Infections
Filariasis • Pro‑inammatory milieu and injury to lymphatic vessel
• Anatomic and physiologic alterations: Lymphangiectasia, granulomatous responses,
collateral formation and decreased trans-endothelial transport
• Promotion of lymphangiogenesis
• Secondary bacterial infection and further damage
Cellulitis/erysipelas • Further damage to the lymphatics by attendant inammation
• Local immunodeciency and reactivation of infection
Tuberculosis, Lymphogranuloma venereum • Inammation of draining lymph nodes impeding the lymph ow
Malignant disease
Large tumors •Pressure eect on lymphatic vessels
Metastases • Overexpression of lymphangiogenic growth factors:
• Induce lymphatic endothelium to produce chemokine ligand 21 that attracts tumor
cells to lymphatics
• Increase lymph ow and tumor dissemination by increasing contractility of proximal
collecting lymphatic vessels
• Tumor growth in lymph nodes/vessels causes increased ow resistance.
• Tumors lack functional lymphatic vessels within, leading to increased interstitial
pressure
Treatment for malignancy • Complete excision of a lymph node basin: Disrupts the normal return of lymphatic uid
•Radiation:
• Fibrosis of surrounding tissue compresses and blocks the lymphatic ow,
• Inhibition of proliferation of lymphatic vessels prevents compensatory growth of
lymphatic vessels
• Fibrosis of lymph nodes alters their ability to lter lymphatic uid
Trauma and tissue damage
Lymph node excision, burns, scarring,
varicose vein surgery/vein harvesting, large
wounds
• Damage to lymphatic vessels compromising the lymph ow
Venous disease
Chronic venous insuciency, venous
ulceration, post-thrombotic syndrome,
intravenous drug use
• Obliteration of parts of the lymphatic supercial capillary network
• Cutaneous reux of lymph from deep to supercial channels
• Increased lymphatic capillary permeability
• Collapse of lumen of intradermal lymphatics, loss of the open intercellular junctions,
and damage to the anchoring laments leading to impaired lymphatic function
Inammation
Rheumatoid arthritis, dermatoses including
epidermal dermatoses, psoriasis, sarcoidosis
• Inammatory mediators, such as nitric oxide and prostaglandins slow down the
frequency of the contractions in lymphatic vessels, in turn, slowing down the lymph ow
• Cytokines such as tumor necrosis factor‑a and interleukin‑1 mediate lymphatic
dysfunction
Obesity • External compression of lymphatics by adipose tissues
• Increased production of lymph
• Direct injury to the lymphatic endothelium by changes in body weight or diet
• Lymphedema‑associated fat deposition which is chronically inamed and inltrated
by macrophages and lymphocytes
• Increased production of inammatory cytokines in obese
Immobility • Lack of muscle activity(that usually massages uid into and along lymphatic vessels)
leading to stagnation of lymph ow
Pretibial myxedema • Obstruction of dermal lymphatic vessels by mucin
Factitious • Lymphatic compromise from prolonged pressure
Podoconiosis • Immune response to soil antigen/mineral(aluminum, silicon, magnesium and iron)
• Subendothelial edema and collagenization of aerent lymphatics leading to narrowing
and eventual obliteration of the lumen
Varghese: Secondary lymphedema: Pathogenesis
Lymphedema is an important predisposing factor for cellulitis.
e protein-rich lymphatic uid serves as an excellent medium
for the bacteria to grow. Besides, stagnation of the lymphatic
uid due to impaired lymph drainage and consequent
reduction in lymphatic clearance creates a state of immune
deciency locally, which, in turn, increases the risk of cellulitis.
Cellulitis and lymphedema appear to have a reciprocal
relationship – a pre-existing lymphatic defect predisposes to
cellulitis and episodes of cellulitis further damage the lymphatic
system. is vicious cycle is independent of the primary
etiology of lymphedema.[10] Mortimer et al. suggested that once
the bacteria have gained entry to edematous tissue, eradication
proves dicult and there exists the risk of reactivation of
cellulitis since the local immune system is impaired.[11]
Elephantiasis associated with tuberculosis and LGV
closely resemble each other in their association with
inguinal lymphadenitis. Tuberculosis can also produce
pseudoelephantiasis (i.e., elephantiasis of genitalia secondary
to genital pathology) with a similar clinical presentation.[12,13]
Lymphatic metastasis and subsequent functional impairment
of lymph channels leading to lymphedema are now
considered as multi-step processes that include:
In mouse models, the growth of lymph vessels in peripheral
tumors is enhanced by over-expression of lymphangiogenic
growth factors VEGF-C and VEGF which, in turn, increase
the risk of lymph node metastasis. VEGF-C also enhances
the production of chemokine ligand 21 by the lymphatic
endothelium, thereby promoting the entry of chemokine
receptor 7+ tumor cells into lymphatics.[14,15] us, tumor
cells that reach the lymphatics may enter either passively or
through the action of active signaling mechanisms.
Tumor-derived VEGF-C and VEGF-D increase the
contraction of proximal collecting lymphatic vessels, thus
potentially increasing the lymph ow and the dissemination
of tumor cells.[16] As tumors grow in lymphatic vessels or
overtake a lymph node, ow resistance increases and lymph is
diverted around these structures through collateral lymphatic
vessels.
e immune cell populations in tumor-draining lymph
nodes are altered. Several cytokines play a prominent role
in producing immunosuppression of tumor-draining lymph
nodes. e levels of IL-10, transforming growth factor-β,
and granulocyte-macrophage colony-stimulating factor are
all elevated in the tumor-draining lymph nodes. Similarly,
recruitment of myeloid immune cells from the blood favors
an immunosuppressive microenvironment in pre-metastatic
lymph nodes, facilitating cancer cell growth and expansion,
resulting in impaired recruitment of naïve lymphocytes and
the antitumor immune response.[17,18]
Cancer cells that enter the lymphatics need to survive in a low-
oxygen environment. Angiogenesis is induced in response
to hypoxic environments. Cancer cells in the subcapsular
sinus invade the lymph node, where they utilize the native
vasculature of the lymph node. As the disease progresses,
remodeling of endothelial vessels causes them to lose surface
molecules and this alters their function.[19] Although there is
angiogenesis, functional lymphatic vessels are restricted to
the tumor margin and peritumor regions surrounding the
tumors. As tumors lack functional lymphatic vessels within,
the interstitial uid pressure is elevated, which alters the
lymph ow to the tumor-draining lymph nodes resulting in
lymphedema.[20]
In Western countries, secondary lymphedema is most oen
due to lymphatic injury sustained during the course of cancer
treatment as seen following extensive lymph node dissection
or adjuvant radiation therapy.
Lymphadenectomy as part of treatment for malignancies
especially when there is complete excision of a lymph node
basin, directly disrupts the normal return of lymphatic uid
from the extremities.[21] In general, the risk of lymphedema
is proportional to the number of lymph nodes sampled, with
the excision of certain lymph nodes and lymph node basins
posing a higher risk. Apart from injury, current evidence
suggests that a variety of key players, including T helper
cells, Tregs, macrophages, and dendritic cells, play complex
roles in the pathology [Table 2] of the disease by releasing
inammatory cytokines and regulating the development of
collateral lymphatic vessels.[22,23]
Varghese: Secondary lymphedema: Pathogenesis
e immediate eect of direct radiation exposure on lymphatic
vessels is minimal as demonstrated in both in vitro and in vivo
studies, as structural and functional integrity are maintained.
Damage to the lymphatic vessels occurs in a delayed fashion
aer radiation as the surrounding tissue turns into dense
brous tissue that compresses and blocks the lymphatic ow.[24]
Moreover, the proliferation of lymphatic vessels is inhibited
by radiotherapy by prevention of compensatory lymphatic
vessel growth. is further worsens the lymphedema.[25]
Unlike lymphatic vessels which are insensitive to radiation,
lymph nodes are highly radiosensitive.[26] In response to
radiation, the initial change in lymph nodes is depletion of
lymphocytes, followed by fatty change and eventually brosis.
Fibrosis of lymph nodes signicantly alters their ability to
lter lymphatic uid, increasing the pressure proximally
which promotes lymphedema. Furthermore, there is a
stronger propensity for the lymph node to transform into
brous tissue aer radiotherapy if the nodal basin is aected
by regional metastasis.[27] erefore, patients with lymph node
metastasis undergoing radiotherapy are at an increased risk
for lymphedema compared to irradiated patients without
lymph node involvement.
Fluorescence microlymphography undertaken in patients
with severe CVI compared with that of healthy controls
demonstrated obliteration of parts of the lymphatic
supercial capillary network, cutaneous reux of lymph
from deep to supercial channels, and increased lymphatic
capillary permeability.[28] Histological studies on skin biopsies
taken from patients with CVI have demonstrated structural
changes in dermal lymphatic vessels. ere is collapse
of the lumen of intradermal lymphatics, loss of the open
intercellular junctions, and damage to the anchoring laments
which maintain the patency of the lymphatic vessel.[29] As
mentioned above, these features lead to disruption of the
normal unidirectional transport mechanism of the initial
lymphatics and consequent impairment of lymphatic
function. In severe CVI, lipodermatosclerosis may occur with
ulceration.[30] A histological study in lipodermatosclerosis has
shown a complete absence of lymphatics in the ulcer bed and
a marked decrease in the number of lymphatics surrounding
the ulcer. Additional ndings observed included destruction
of the endothelium and muscle lining of lymphatics draining
the region.[30,31] erefore, there are clinical and laboratory
evidences to suggest that in CVI, in addition to the
pathological changes in blood vessels, there is a concomitant
pathology in lymphatics which leads to a deterioration in
lymphatic function.
Well-functioning, lymphatic pumping avoids swelling. e
normal lymphatic activity ensures an adequate immune
response since lymph transports antigens and immune cells.
However, in inammatory conditions, mediators, such as
nitric oxide and prostaglandins that are abundantly produced,
alter the lymphatic pumping. Most of them slow down the
frequency of the contractions, in turn, slowing down the
lymph ow and potentially triggering the swelling.[32] Further
experimental examinations have revealed that other molecules,
namely, cytokines such as TNF-α and IL-1 that are critical in
the initial steps of an inammatory reaction play an important
role in mediating the lymphatic dysfunction.[23] Studies by
Avraham and Zampell using animal models of lymphedema
have implicated CD4+ T cells as the primary cells responsible
for more than 70% of the inammatory response.[33]
e etiological link between obesity and lymphedema is
due to the increased production of lymph from an enlarging
limb that compromises the capacity of the lymphatic system.
External compression of lymphatics by adipose tissues, or
Role of inammatory cells in the pathogenesis of
lymphedema.
1 CD4 Releases 2 cytokines that cause
progressive obliteration of the
supercial and deep lymphatic
systems with worsening lymphatic
function and inadequate collateral
lymphatic growth
2 T regs Attenuate the severity of
inammatory tissue responses,
local impaired adaptive immune
response leads to recurrent so
tissue infections
3 Macrophages Produce and activate transforming
growth factor-β1, M2 macrophages
are immunosuppressive, M2
macrophages cause regeneration
of collateral lymphatics aer
lymphatic injury, signicant
source of IL-6 which regulates
chronic inammation and adipose
metabolism and promote the
expression of inducible nitric
oxide synthase, which attenuates
lymphatic vessel contraction in
inammation
4 Dendritic cells Produce pro-inammatory
mediators that contribute to the
ongoing cycle of inammation
Varghese: Secondary lymphedema: Pathogenesis
even direct injury to the lymphatic endothelium by changes
in body weight or diet can play a role in obesity-associated
lymphedema. Obesity increases the risk of lymphedema in
patients with lymphatic injury. Recent studies have shown
that obese individuals can develop lymphedema even
without antecedent surgery or injury. It has been proposed
that body mass index, at the time of breast cancer diagnosis
is a strong indicator for developing lymphedema than
weight gain following treatment.[34] Histologic studies on
clinical samples and animal models of lymphedema have
shown that adipose deposition in the lymphedematous
tissues can be compared to fat depots in obese patients.
Similar to obesity, lymphedema-associated fat deposition
results from both proliferation and hypertrophy of
local adipocytes, and the resulting adipose depots are
chronically inamed and inltrated by macrophages and
lymphocytes.[34,35] In addition, lymphedematous tissues
exhibit evidence of adipocyte death and phagocytosis by
macrophages, producing an appearance of so-called “crown-
like structures.” is is important because the production
of inammatory cytokines by these structures is associated
with both an increased risk and aggressive behavior of a
variety of malignancies in obese patients.[35]
Movement and exercise help lymph drainage because muscle
activity surrounding the lymphatic vessels massages uid
into and along them. Reduced mobility can, therefore, lead to
lymphoedema because the uid in the lymphatic system does
not get moved along.[36]
In the systematic review conducted by Kwan et al., it was found
that in the breast cancer patients, the benets to be gained by
exercise in the prevention of post-treatment lymphedema far
outweigh the minimal adverse eects reported.[37] erefore,
the slowly progressive exercise of varying modalities is
recommended to prevent the development or exacerbation of
breast cancer-related lymphedema.[37] is again asserts the
role of movement and exercise as opposed to immobility in
the prevention of lymphedema.
is geochemical, obliterative endolymphangitis, resulting
in lymphatic obstruction and the clinical consequence of
gross lower leg lymphedema, is common in alkaline volcanic
tropical highlands. e development of podoconiosis is closely
associated with barefoot walking on irritant soils. Farmers
are at high risk, but the risk extends to any occupation that
demands prolonged contact with the soil, and the condition
has been noted among goldmine workers and weavers who sit
at a ground level loom.[38] Regarding pathogenesis, a possible
genetic predisposition has been suggested. DRB1*0701,
DQA1*0201, and DQB1*0202 alleles are suspected to have
a functional role in antigen presentation to T cells, that in
turn, induces the immune response to soil antigen or mineral
leading to development of the disease. Colloid-sized particles
of elements common in irritant clays (aluminum, silicon,
magnesium, and iron) are absorbed through the foot and
have been demonstrated in macrophages in the lymph nodes
of the lower limbs of those aected. Electron microscopy
shows local macrophage phagosomes to contain particles of
stacked kaolinite (Al2Si2O5(OH)4), while light microscopy
shows subendothelial edema and subsequent collagenization
of aerent lymphatics that cause narrowing and eventual
obliteration of the lumen.[39]
Autoantibodies directed against the thyroid-stimulating
hormone receptor on thyroid follicular cells lead to
hyperthyroidism of Graves’ disease. Pretibial myxoedema
is a manifestation of Graves’ disease and occurs due to
the deposition of glycosaminoglycans (mucin) within the
dermis. Autoimmune, cellular, and mechanical factors play
a role in the deposition of glycosaminoglycans in Grave’s
disease. Lymphedema is an outcome of the obstruction of
dermal lymphatic vessels by mucin.[2]
e lymphatic system may be aected following
closed traumatic upper limb or lower limb fractures
or following surgery (e.g., shoulder arthroplasty).[40-42]
Lymphoscintigraphy scans have shown an enlargement
of lymphatics and lymph nodes that drain the site of
injury or bone fracture (when the fracture heals without
complications). Although the pathogenesis underlying the
lymphatic response to a bone fracture is unclear, both clinical
and experimental observations indicate that an inammatory
process triggered by invading bacteria or self-antigens
exposed during trauma may lead to the persistent post-
traumatic edema.[41]
Factitious lymphedema can be caused by tourniquets, blows
to the arm or repeated skin irritation. Usually, it is seen in
patients with known psychiatric conditions.[43] Constriction
using a tourniquet initially results in a ow disorder aecting
venous return and this, in turn, causes rapid overwhelming
of the lymphatic ow leading to dermal reux. e degree of
lymphatic compromise will depend on the force and duration
of pressure exerted by the tourniquet. Prolonged pressure can
lead to complications typical of chronic lymphstasis.[44]
Varghese: Secondary lymphedema: Pathogenesis
Truncal lymphedema frequently develops following the
treatment of breast or lung cancer and can be present with
or without signicant involvement of the adjacent arm.
Disruption of the lymphatic drainage pathways can occur if
there is a complete or partial removal of the axillary lymph
nodes. is causes swelling of the breast wall and the chest
area. Scars following breast surgery such as lumpectomy,
mastectomy, or reconstructive breast surgery can further
disrupt the natural lymphatic drainage pattern. Radiation
treatments can form brotic tissues in the chest wall or
armpit and cause truncal lymphedema.[45]
A complex pathological interplay is suspected to be the
underlying mechanism of lymphatic dysfunction [Figure1]
and new research explores new theories.[46] Stimulation of
collagen production by broblasts, disruption of elastic bers,
activation of keratinocytes, and adipocytes tissue expansion
are proposed to aggravate the development of lymphedema.
Current evidence demonstrates that tissue swelling in
lymphedema is due to fat deposition and not just due to
the accumulation of uid. Adipose tissue hypertrophy
in lymphedema is accompanied by adipose remodeling,
similar to what occurs in obesity.[47] Observations show
that hypertrophic fat lobules compress and collapse their
feeding lymphatic capillaries, resulting in a vicious cycle of
disruption of uid and lipid transport, ultimately leading to
further fat accumulation in the periphery.[35,48]
Mihara et al. had demonstrated that histological and
immunohistochemical examination of skin tissues from
clinical and experimental lymphedema showed increased
amounts of collagen bers in the edematous skin.[49] Fibrosis in
lymphedema is not conned to the dermis, but may extend to the
subcutaneous tissue including the adipose tissue. Hypertrophic
adipocytes in human lymphedema patients exhibit thick
brous matrix between lobules. is hardens lymphedematous
tissues, resulting in non-pitting edema.[50] Collecting lymphatic
vessels play a role in lymphedema depending on the manner of
collagen deposition. Normal type of collecting lymphatic vessels
have collagen bers and smooth muscle cells within the medial
layer. Ectasis type lymphatics are characterized by the dilation
of the lymphatic vessel walls, with long and elongated collagen
bers. Contraction type lymphatics show the deposition of
thick collagen bers mixed with smooth muscle cells in the
medial layer. e thick collagen bers impair vessel contraction,
resulting in loss of function in the collecting lymphatic vessels.
Sclerosis-type vessels exhibit an increase in smooth muscle cells
and collagen bers and a reduction in their ability to transport
lymph uid, causing excessive lymph leakage. ese changes
in collecting vessels are consistent with the previous ndings
that show decreased lymph vessel contractility in acquired
lymphedema. In addition, brosis in the skin and subcutaneous
tissue may worsen lymphatic dysfunction by directly inhibiting
lymphatic endothelial cell proliferation leading to inhibition of
sprouting and branching of new lymphatics.[46,51]
To summarize, the multidimensional pathophysiological
mechanism of lymphedema includes processes such as
lymph stasis, lymphatic vessel remodeling, lymphatic
dysfunction, inammation, adipose tissue deposition, and
brosis. However, it is oen not possible to sequentially
arrange these events due to the complex interactions
between the pathomechanisms. Moreover, studies have
shown that certain events predominate depending on
the triggering factors such as infection, malignancy,
inammation, surgery, radiotherapy, and concomitant
venous stasis and so on. More studies focused on the
etiology of lymphedema are needed to delineate the types of
tissue changes across the stages and causes of lymphedema.
A better understanding of the pathophysiology of
lymphedema and its cellular and molecular mediators will
pave way for novel therapeutic approaches for this chronic
and debilitating condition.
Not required as there are no patients in this article.
Nil.
Complex pathomechanisms involved in secondary
lymphedema.
Varghese: Secondary lymphedema: Pathogenesis
ere are no conicts of interest.
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