Phẫu Thuật Tạo Hình (Tập 1): Nguyên Lý Cơ Bản – Neligan (Ấn bản 4)

489
Treatment and surgical technique
there is wound breakdown at the mastectomy incision, the
implant, rather than muscle, will be exposed.
The inferior border of the pectoralis major is identified, the
pectoralis fascia is incised if it has been preserved, and the
muscle is elevated while preserving the origin of the serratus
anterior and rectus abdominis muscle. The expander is intro­
duced so that it lies in a dual plane with its upper pole covered
by muscle and its lower pole solely by subcutaneous tissue.
Subpectoral position with an ADM
An ADM can be used to extend the subpectoral pocket, creat­
ing a hammock effect below the implant that provides an
aesthetic inferior pole and inframammary fold, as well as
soft-tissue coverage (Fig. 25.12).51–56 The hammock, or sling,
optimization of skin-sparing mastectomy and development of
nipple-sparing mastectomy, general surgeons are much more
conscientious in preservation of the skin. If too much skin is
spared, the plastic surgeon will need to trim excess skin that
could cause dog-ears and sagging; this is done after placing
the expander.
After completion of the mastectomy, the expander is placed
in one of three locations, depending on the surgeon’s prefer­
ence and experiences. These are the total submuscular posi­
tion, the subpectoral (dual-plane) position, and the subpectoral
position with supplementation with an ADM.
Complete muscle coverage is more important in immediate
than in secondary breast reconstruction because it completely
isolates the implant from the overlying mastectomy wound.
Should there be skin necrosis with a loss of mastectomy flaps,
wound dehiscence, delayed healing – especially in previously
irradiated chest walls – or cellulitis, a totally submuscular
implant may be salvaged, whereas a partially submuscular
implant will be lost.
After placement of the implant by one of these three
methods, suction drains are placed in the subcutaneous space
and in the axilla if a lymph node dissection has also been
completed. The wounds are closed in layers and the expander
filled with enough fluid to obliterate dead space, but avoiding
excessive tension on the wound closure.
Submuscular position
When the submuscular position is used for expansion, a
submuscular pocket is dissected for placement of the tissue
expander. The muscle incision can be made in one of two
locations. If a musculofascial layer has been preserved after
mastectomy, the incision can be made parallel to the pectoralis
major fibers. Using sharp and blunt dissection, the pectoralis
major muscle is lifted off the underlying chest wall and the
pectoralis minor muscle. Dissection is continued inferiorly
beneath the origin of the rectus abdominis muscle and later­
ally beneath the serratus anterior muscle.
Alternatively, an incision can be made at the lateral border
of the pectoralis major or parallel to the fibers of the serratus
anterior muscle. This dissection is continued down to the rib,
and from the lateral position, a pocket is dissected inferiorly,
superiorly, and medially, lifting the pectoralis major origin off
the rectus abdominis muscle and the origin of the serratus
anterior muscle.
It is important to avoid dissecting the serratus anterior
muscle too far laterally, regardless of the location of the muscle
incision, for this would allow displacement of the implant into
the axilla. If the fascia at the junction of the pectoralis major
and rectus abdominis muscles has been violated during
mastectomy, complete submuscular closure can be difficult.
In general, a small exposure of the implant is of no conse­
quence. A large exposure can be covered with a transposition
or rotation of anterior rectus abdominis fascia.
Subpectoral (dual-plane) position
Only the upper two-thirds of the expander in the subpectoral
(dual-plane) position is covered by muscle. Advantages
include less postoperative discomfort and less discomfort
during expansions. Criticisms of this technique include the
risk of upward migration of the pectoralis major, which results
in even less coverage of the lower portion of the implant. If
Fig. 25.12  (A) Tissue expanders for breast reconstruction are usually placed
beneath the pectoralis and serratus muscles. (B) It is possible to place the
prosthesis under the pectoralis major, where the muscle covers only the top half of
the prosthesis, when a dermal matrix is sutured to the lower half of the pectoral
muscle and the chest wall to cover the lower half of the prosthesis.
A
Tissue expander
B
Tissue expander
Acellular dermal matrix

490
CHAPTER 25 • Principles and applications of tissue expansion
with an integrated port. Care is taken not to overinflate
the expander, causing unnecessary discomfort. The expander
should be inflated until the overlying skin and subcutaneous
tissues feel firm. If the patient experiences significant discom­
fort, saline is withdrawn until the patient is comfortable. With
each inflation, the overlying skin frequently becomes hyper­
emic, but the problem usually resolves after inflation has been
completed. After volumetric symmetry with the opposite side
is achieved, hyperinflation of the expander is often carried
out. If a large amount of ptosis is to be developed or extensive
repositioning of the breast is necessary, additional hyperinfla­
tion may be required. Expanders may be left in place for many
months or even years before being exchanged for permanent
implants and this principle is also applied in the management
of adolescent hypomastia.13
Repositioning of the inframammary fold can influence
breast ptosis and definition. Increased ptosis is created by
infolding and uplifting the expanded tissue and advancing a
lower abdominal flap.58,59 After removing excess saline to
determine the appropriate, symmetrical volume of the recon­
structed breast, the inframammary fold is moved up or down
so that the apices of the breasts are at an equal level. The new
position of the fold is marked so that the reconstruction can
be accomplished through an incision at the desired inframam­
mary fold (Fig. 25.13). The capsule is left intact unless the
prosthesis needs to be repositioned. Stable reconstruction of
the inframammary fold can be achieved by tacking the interior
capsule to the posterior chest wall capsule at the same
level where the earlier, symmetrical marking was made. The
abdominal skin is undermined above the fascia and is
advanced superiorly into the inframammary cleavage to close
the posterior wall defect (Fig. 25.14).
Tissue expansion in cases of chest wall irradiation
Studies suggest that previous chest wall irradiation negatively
affects success with tissue expansion and subsequent implant
placement.60,61 The complication rate due to infection, extru­
sion, and wound complications is higher. Furthermore, the
Fig. 25.13  The technique of designing a ptotic breast by moving the inframammary fold. (A) The prosthesis is over-expanded to make an excess amount of tissue. (B) The
position of the desired breast fold (point B) is determined on the thoracic wall. (C) Through an inframammary incision at point C, the expander is removed and a permanent
device is placed. The skin and soft tissue (point A) are moved superiorly and sutured to point B. (D) The abdominal wall is undermined above the fascia and advanced into
the inframammary defect.
A
Fold
B
Expander
B
A
C
Fold
C
B A
Fold
D
holds the expander in place, minimizing the risk of downward
migration of the implant. Further, the expander is less
restricted than when it is completely submuscular, so expan­
sion can progress more rapidly before placement of the per­
manent implant. In non-irradiated patients, human acellular
dermis is re-vascularized and remodeled into the host tissues.57
A number of human ADMs are commercially available. The
ADMs are expensive and their cost must be considered when
planning the best reconstructive course. Another disadvan­
tage of using ADMs is that they also promote serous drainage,
requiring drains to be maintained until serous drainage is less
than 30 cc/day.
The pectoralis major muscle is elevated as described above.
A sheet of ADM is sutured to the fascia overlying the rectus
abdominis muscle at the planned inframammary fold. The
size of the matrix is determined by the diameter of the chest
wall and elasticity of the chosen dermal matrix. Typical sheet
sizes vary from 4 × 12 cm to 6 × 16 cm. The expander is intro­
duced beneath the pectoralis superiorly and the ADM inferi­
orly and the muscle and superior edge of the ADM are
approximated. Drains are placed to accommodate serous
drainage. If there is breakdown of the mastectomy wound, the
underlying matrices will become exposed. Our preferred
management of this complication is early excision of ischemic
skin and re-closure of the wound.
Delayed breast reconstruction with tissue expansion
As with immediate reconstruction, it is important to mark the
inframammary fold and the extent of undermining while the
patient is sitting in an upright position before induction of
anesthesia. The tissue expander may be placed in one of the
three pockets described above for immediate placement after
mastectomy.
Inflation follows the general plan for expansion as previ­
ously described. Inflation of the expander is initiated 10–14
days after placement. The patient returns weekly or biweekly
for serial percutaneous inflations. A 23-gauge butterfly needle
is used with a distal port and a 21-gauge needle is used

491
Treatment and surgical technique
Fig. 25.14  (A) A patient after modified
radical mastectomy with preservation of the
pectoralis muscle. (B) An expander was
placed beneath the pectoralis and serratus
muscles and then gradually over-expanded.
At a second procedure, a permanent
implant was placed and a ptosis procedure
was performed on the opposite side.
A
B
hypoplasia. Management of the deformity depends on the
degree of breast asymmetry, the nature of the deformity, the
quality of the chest wall soft tissue, and the age of the patient
at presentation.
Unilateral hypoplasia varies from a smaller, well-formed
breast to total absence of the breast. These cases further have
variable hypoplasia or aplasia of the nipple and areola. If a
hypoplastic nipple–areola complex is present, it will usually
lie in a cephalad position relative to that of the contralateral
breast.
The degree of breast hypoplasia is determined and charac­
terized as minor hypoplasia with a normal nipple–areola
complex, moderate to severe hypoplasia, or total breast
aplasia. The nipple–areola complex is characterized separately
as normal, hypoplastic, displaced, or aplastic. Mild breast
hypoplasias may be corrected with simple placement of a
breast implant, but more severe hypoplasias and aplasias with
nipple–areola displacement are best treated with initial place­
ment of a tissue expander. If pre-surgical examination reveals
that the pectoralis muscle is absent, the deformity is probably
associated with Poland syndrome (see below).
A tissue expander is placed through either an inframam­
mary or axillary incision into the subpectoral space. The
surgeon may choose from many expanders: these include
smooth and textured implants, implants with integrated
valves, and expanders with distal ports. The prosthesis is
initially expanded at 2-week intervals. As the expander is
inflated and the overlying skin relaxes, the cephalad-
displaced nipple–areola complex will descend. The more
slowly the expander is inflated, the better the nipple–areola
will descend. A slow expansion also minimizes development
of striae. The expander is ultimately overinflated to a volume
that is at least 40% larger than the desired volume of the
permanent implant. The expander is left in place for several
months after the final inflation to allow development of
additional ptosis.
The permanent implant is introduced at a second proce­
dure. An incision is made through the original incision that
was made to place the expander. The expander is removed,
and a capsulectomy is carried out, if needed. If capsulectomy
is not needed, the inferior portion of the capsule may be
tacked to the rib periosteum to delineate the inframammary
fold better. A permanent implant is selected to achieve sym­
metry with the contralateral side.
final aesthetic result is frequently compromised by capsular
contracture.
Two groups of patients are probably best managed with
autologous tissue transfers instead of with tissue expansion.
They are those undergoing: (1) mastectomy for recurrence of
disease after previous lumpectomy and radiation; and (2)
secondary reconstruction after mastectomy and radiation. In
selected patients with excellent-quality chest wall skin and
soft tissue, tissue expansion may be considered even though
the incidence of complications and a compromised aesthetic
result are high.
Chest wall irradiation treatment is increasingly frequent in
post-mastectomy patients. A large number of women who
have undergone placement of a tissue expander at the time of
mastectomy now have to deal with postoperative radiation.
There is no consensus at this time on how to manage these
patients. Alternatives that have been presented include the
following:
1. Continue expansion until the time of irradiation, but
cease inflating the expander during and for several
months after irradiation; then resume expander inflation
once the radiation dermatitis has resolved and follow
with placement of the permanent implant.
2. Complete expansion and exchange with the permanent
implant and then proceed with radiation.
3. Remove the fluid in the expander, initiate and complete
radiation therapy, and then re-inflate the expander once
tissues have begun to heal.
4. Remove or maintain the tissue expander and make
plans for autologous tissue reconstruction after radiation
is complete.
Despite the above risks, more than 50% of patients are reported
to have satisfactory results if tissue expansion is completed
alongside treatment with radiation.61 Patient education about
risks and alternatives is critical and there must be an under­
standing of these different options/strategies before any
reconstruction is initiated in patients receiving radiation for
breast cancer treatment.
The hypoplastic breast
Tissue expansion has played an important role in the
reconstruction of both acquired and congenital breast

492
CHAPTER 25 • Principles and applications of tissue expansion
Reconstruction with a permanent expander prosthesis is
also possible. This prosthesis is inflated to a size several
hundred milliliters larger than the desired final volume. The
expander prosthesis is allowed to remain overinflated for
several months. In the office, saline is then withdrawn to
achieve symmetry with the contralateral breast. When desired,
the port with its attached tubing is removed through an inci­
sion made over the distal port.
The tuberous breast
Expansion is a useful technique in the correction of the
hypoplastic tuberous breast. Through an inframammary or
periareolar approach, the tuberous breast is lifted off the
underlying pectoralis fascia. Radial cuts are made through the
breast tissue to expand the base of the breast, and a tissue
expander is introduced in the submammary plane. Inflation
and expansion are achieved as previously discussed. Once
adequate expansion has been achieved, the expander is
removed and replaced with the permanent prosthesis. Alter­
natively, a permanent expander device is used and overin­
flated by several hundred milliliters. Several months after
completion of the inflation, fluid is removed to achieve sym­
metry with the contralateral side, and the port and attached
tubing are removed.
The immature breast
The use of tissue expanders has been beneficial in the manage­
ment of young adolescents presenting with breast asymme­
try.62 Adolescence is a critical time that is characterized by
intense social pressures and self-awareness of a developing
physique, so failure to address the problem of breast asym­
metry can result in psychological problems. These patients do
not need full maturity for reconstruction.
A subpectoral muscle plane is elevated through a small
axillary incision. An expander with an integrated valve or
distal port is placed in the subpectoral plane beneath the
hypoplastic breast. If a distal-port prosthesis is used, the infla­
tion reservoir is placed in the lateral thoracic wall or in the
upper abdomen below the inframammary fold. The prosthesis
is then inflated at intervals appropriate to maintain symmetry
with the developing breast on the contralateral side. The slow
expansion will cause the areola to enlarge, and the nipple–
areola complex will progressively be displaced caudally to a
more normal position. The adolescent can continue with
normal activities, participation in sports, and other physical
endeavors.
Once development of the contralateral breast has stabilized,
usually between 18 and 19 years of age, the expander is
removed. Definitive reconstruction is achieved as previously
described for correction of the mature breast.
Correction of Poland syndrome
Poland syndrome involves not only abnormal development
of the breast but also thoracic wall deformities, deformities of
the upper extremity, and vertebral anomalies. Poland syn­
drome exhibits a uniform absence of the sternal head of the
pectoralis major muscle. Further structural problems may be
seen and include abnormalities in the anterior ribs and costal
cartilages and deficiencies of the muscles of the scapular area,
including the latissimus dorsi. Other findings include defi­
ciency of subcutaneous tissue, hypoplasia, aplasia, or
malposition of the nipple–areola complex, and deficiency of
breast tissue.
A mild deformity characterized by breast hypoplasia or
aplasia is corrected with the initial placement of a tissue
expander through a transaxillary approach. A 700-mL or
larger expander may be required to achieve full expansion
over a 3–4-month period. Then the tissue expander is removed
and a permanent breast implant is placed. Ideally, if there is
an inadequate anterior axillary fold and adequate latissimus
dorsi muscle, it may be transposed to cover the breast pros­
thesis. Its insertion is taken down and transposed anteriorly
on the humerus to form an anterior, axillary fold. Alterna­
tively, the tissue expander can be placed at an initial operation
and covered immediately with a latissimus dorsi muscle
transposition. Once expansion has been completed, the
expander is removed and the permanent breast implant
introduced.
More severe cases of Poland syndrome that are character­
ized by contour depression of the ribs will require either an
osteotomy and repositioning of the ribs or the use of a custom,
solid, silastic implant. The anterior axillary fold is recon­
structed by transposition of the insertion of the latissimus
dorsi muscle over the custom silastic implant. The breast
contour is reconstructed with tissue expansion and the subse­
quent use of a permanent breast implant.
In the immature girl with Poland syndrome, expanders are
placed at the onset of contralateral breast development
through a small incision in the axilla. To maintain aesthetically
pleasing symmetry, the implant is gradually inflated until
development of the contralateral breast has stabilized. In the
final months of treatment, the expander is overinflated by
200–300 mL and then replaced with the permanent implant.
If a latissimus dorsi muscle is available, it is transposed at this
time to cover the breast prosthesis (Fig. 25.15).62
Expansion of the trunk
The trunk and abdomen are well suited to tissue expansion
in individuals of all ages. Because of the large adjoining
surface area from which tissue can be recruited, large prosthe­
ses can be placed and flaps quickly expanded (Fig. 25.16).
Expansion of the trunk with large prostheses may produce
significant deformity and discomfort. Expansions of the back
and buttocks are particularly difficult for the patient because
of their interference with activities of daily living. Fortunately,
using multiple prostheses in such areas produces sufficient
tissue for completion of the reconstruction, minimizes distor­
tion, and allows rapidly expedited expansion.
Large prostheses can be either placed above the fascia or
incorporated between fascia and muscle planes in the abdomen
or on the back. Incorporation of any of the latissimus dorsi,
pectoralis major, or rectus muscles allows development of an
expanded myocutaneous flap. Prostheses placed between
layers of the abdominal wall have been used to develop large
flaps for abdominal wall reconstruction (Fig. 25.17).63
Large deformities, such as burns, giant hairy nevi, and
other congenital anomalies, may require multiple serial
expansions. In such cases as these, the expanders are inflated
maximally and the flaps are advanced. The prostheses are left
in place and re-expansion is carried out in the subsequent
weeks. In the abdomen, two or three serial expansions are
usually well tolerated, even in children.

493
Treatment and surgical technique
Fig. 25.15  (A) This 17-year-old patient presented with severe right breast hypoplasia with nipple hypoplasia and superior malposition of the right nipple as a feature of her
Poland syndrome. (B) She underwent the subcutaneous placement of a tissue expander beneath the skin and soft tissues of the right breast to expand the soft-tissue
envelope and increase the distance from the clavicle to the nipple. A latissimus dorsi muscle flap was harvested using two small incisions on the back and single incisions
in the axilla and inframammary region of the breast. (C, D) The muscle was transposed to the chest through a high axillary tunnel and placed beneath the expanded
soft-tissue envelope and anchored to the parasternal area and inferior aspect of the expanded breast envelope. (E) An implant was placed beneath the muscle to provide the
necessary volume to the breast reconstruction, producing an immediate and (F) long-term improvement of the breast appearance at 3-year postoperative follow-up. (G) This
produced an excellent change in the breast appearance at 3-year follow-up after surgery. (This case courtesy of Julian J. Pribaz MD. Reproduced from Hall Findlay E, Evans
G. Aesthetic and Reconstructive Surgery of Breast. Edinburgh: Elsevier Saunders, 2010. © Elsevier 2010.)
A
B
C
D
E
F
G

494
CHAPTER 25 • Principles and applications of tissue expansion
Fig. 25.16  (A) Separation of ischiopagus twins was aided by first expanding both the anterior and posterior trunk skin. (B) At a second procedure, the hemipelvis of each
side was brought together with the opposite side by closing the pelvic ring over expanded soft tissue. Soft tissue was adequate to achieve total closure in both infants. The
children have now survived over 10 years since separation and are doing well.
A
B
Fig. 25.17  (A) A ruptured omphalocele including the liver had failed reconstruction on two attempts. (B) The abdominal contents were enclosed in Alloderm™ and a
vacuum-assisted closure dressing placed over it to colonize it with granulation tissue. When adequate granulation tissue had been developed, a cultured split-thickness skin
graft was placed over the entire defect. (C) At 4 years of age, expanders were placed beneath and lateral to the rectus muscle to generate adequate skin and muscles for
abdominal closure. (D) The viscera was reduced to the abdominal cavity and the rectus muscles were brought together in the midline to create a stable abdominal wall. The
patient has remained stable for 7 years without further surgery.
A
B
C
D

495
Treatment and surgical technique
and 31 acute wounds over a nine-year period in conjunction
with their animal study experience over the same period. Clini­
cally, the application of negative pressure causes the dressing
sponge to collapse towards its center producing deformation
and traction forces applied to the wound perimeter pulling the
wound edges together which progressively make the wound
smaller. In addition, NPWT removes wound edema, appears
to increase circulation and decrease bacterial counts, and sig­
nificantly increases the rate of granulation tissue formation.69
Cellular and molecular basis of NPWT
The mechanical effects of NPWT on wounded tissues and
their subsequent cellular and molecular effects are actively
being studied. At a cellular level, NPWT alters wound bed
gene expression with resultant changes in cytokine/chemo­
kine/growth factor expression and matrix metalloproteinase
(MMP) expression. In human and animal models, increases in
anti-inflammatory cytokines (IL-10) and pro-angiogenic
growth factors (VEGF, FGF, PDGF) have been demonstrated
with the use of NPWT. The above, in conjunction with reduc­
tion in MMP expression, indicates that NPWT may promote
healing by modulation of cytokines to an anti-inflammatory
profile and alteration in mechanoreceptor- and chemoreceptor-
mediated signaling to culminate in angiogenesis and extracel­
lular matrix remodeling for the deposition of granulation
tissue.18
The vacuum-assisted closure (VAC) device
The basic VAC system consists of sponge material composed
of reticulated polyurethane or polyvinyl alcohol (white foam)
cut to fit the wound, an occlusive drape, suction tubing, and
adjustable vacuum pump with a collection canister. Since its
introduction, many technologic improvements have been
made, making this technique more user-friendly. Advances
include smaller device and battery, the ability to modulate
pressures applied to the wound, improved fluid management
capabilities, the availability of different types of foams to be
tailored to wound characteristics, and the addition of safety
precautions/leak alerts to the device.65
Patient selection
Vacuum-assisted closure devices were initially designed for
the management of chronic wounds such as diabetic ulcers,
venous stasis ulcers, and pressure ulcers in order to simplify
wound care in this patient population or bridge wounds until
factors preventing definitive wound reconstruction could be
resolved or improved. Today, this technique can be safely
applied to all patient populations and in a wide range of acute
or traumatic soft tissue injuries including wounds with com­
promised soft tissues, contaminated wounds, hematomas,
and gunshot wounds.
Despite the myriad of clinical scenarios where a VAC can
be utilized, there are specific contraindications to its use. It
should not be used when hemostasis is inadequate as the
negative pressure may continue to remove blood from an
actively bleeding or oozing wound. NPWT application should
be avoided if necrotic or sloughing tissue is present. In general,
prior to application of NPWT, aggressive surgical debride­
ment of all nonviable tissue and any foreign body is performed,
appropriate coverage of critical structures is completed (major
Expansion in the extremities
Skin and soft tissues of the extremities tolerate tissue expansion
well,64 so tissue defects resulting from congenital abnormalities,
tumor, or trauma may be corrected. The capsule that develops
adjacent to the expander has a resilient surface that can be
transposed over joints and tendons to decrease adhesions.
The use of multiple expanders in the extremity has the
advantages of less distortion, less compromise of everyday
life activity, and more rapid development of tissue. Standard
rectangular and round prostheses usually suffice and they are
best placed axially to the defect. Functional impairment, even
when the prostheses are placed directly over vessels and
nerves, is unusual. Occasional transitory neuropraxias have
been described in the lower extremity but are uncommon in
the upper extremity. If such discomfort or neuropraxia devel­
ops, the prostheses should be deflated and then re-inflated at
a much slower rate.
In areas such as the hand or foot, custom implants may be
fabricated. The dorsum of the hand or foot lends itself well to
expansion, whereas the palm and plantar areas are particu­
larly painful during, and resistant to, expansion. Expanded
full-thickness grafts harvested from the abdomen are extremely
versatile in reconstruction of the foot and hand. These grafts
are stable and can be harvested as a single graft. Reasonable
protective sensation returns to these grafts over time.
The upper leg is easily expanded because of the thickness
of skin and its underlying subcutaneous tissue: one large
expander or multiple smaller expanders may be used. Com­
plications are infrequent. However, below the knee, inflation
carries major risks. Clean, isolated defects, such as those that
follow local tumor excisions, are more amenable to expansion
than sites where large areas of previously traumatized skin
surround the defect. Multiple small expanders are recom­
mended to minimize the risks of implant loss. If cellulitis or
tissue compromise occurs during expansion, the prosthesis
should be deflated or removed.
Lower leg expansion after crush injuries carries particularly
high risk. Individuals who have suffered major crush or
degloving trauma to the extremity are better treated with
function-restoring microvascular and myocutaneous flaps
than with attempts at excessive aesthetic reconstructions
using tissue expansion.
Wound management with negative
pressure therapy
Negative pressure wound therapy (NPWT) uses the principle
of applying mechanical force to cells surrounding a wound to
stimulate the induction of new tissue development that will
subsequently aid in closure of that wound.3
Historical perspective
The use of vacuum forces on wounds was described in 1995
by Fleischmann who employed the technique of placing
suction drains wrapped in porous polyvinyl alcohol foam
into wounds.68 These wounds were sealed with polyurethane
drapes and then the drains were attached to a suction appa­
ratus at 600 mmHg. In 1997, Drs. Argenta and Morykwas
at Wake Forest University presented their experience with
vacuum-assisted closure (VAC) devices.3 They presented the
use of the VAC in 175 chronic wounds, 94 subacute wounds,

496
CHAPTER 25 • Principles and applications of tissue expansion
closure the wound is not yet sealed, and the VAC is beneficial
in drawing serous fluid from between the sutures of the
closure. It may be applied over a fresh flap and does not result
in any compromise to the underlying flap. Recently, applica­
tion of NPWT to incision closure has been more frequently
employed. There is a growing body of literature that demon­
strates reduced incidence of wound healing complications
with the use of incisional wound VAC application for a period
of 3–5 days.73,74
Postoperative care
In general, expanders should be partially inflated immediately
after wound closure. This allows closure of “dead space” to
minimize seroma and hematoma formation. It also smooths
out the implant wall to minimize risk of fold extrusion.
Enough saline is placed to fill the entire dissection space
without placing undue tension on the suture line.
Serial inflation usually starts 1–2 weeks after initial place­
ment, although inflation schedules can be individualized to the
specific case and the tolerance of the patient. Inflation reser­
voirs seal best when a 23-gauge or smaller needle is used. A
23-gauge butterfly intravenous needle is especially useful; it
allows the patient to move slightly without dislocating the
needle. Frequent small-volume inflations are better tolerated
and are physiologically more suited to the development of
adequate overlying tissue than are large infrequent inflations.
For practical purposes, most prostheses are inflated at
weekly intervals. On occasion, accelerated inflation schedules
may be followed.41 In children who have devices with external
ports, small-volume inflation at 2–3-day intervals is well toler­
ated. Individual inflations proceed until the patient experi­
ences discomfort or blanching of the overlying skin. In
hypoesthetic areas, objective changes in flap vascularity must
be evaluated with particular care. Although a variety of
devices such as pressure transducers and oxygen tension
monitors are available to help determine proper inflation, an
objective evaluation of the patient’s response is usually a
reliable indicator of appropriate inflation. Serial inflations
proceed until an adequate amount of soft tissue has been
generated to accomplish the specific surgical goal.
Specific to breast tissue expansion, the frequent visits
required to inflate the expansion device fully create some
inconvenience for patients, who are seen every 7–14 days.
This process usually continues for 2–3 months, depending on
the desired final size of the implant. Overinflation is helpful
when permanent breast implants are to be placed. Inflation of
breast expanders by 20% over capacity is commonly per­
formed so that after the permanent implant is placed, some
ptosis of the breast can be developed.
Complications and their management
Initial attempts at tissue expansion were associated with a
high rate of complication which included, but were not limited
to, implant failure due to either puncture during inflation
or mechanical problems. As more experience accumulated,
however, the incidence of complications dramatically
decreased. Complication rates are directly proportional to the
number of expansion procedures performed and the experi­
ence of the individual surgeon.66 Most complications incurred
vessels, viscera, nerves) utilizing local muscle or soft tissues,
and then NPWT initiated.
NPWT technique
Negative pressure wound therapy requires placement of a
sponge material on or into the wound. An occlusive drape is
then placed over the sponge and onto the surrounding skin.
An opening is made in the occlusive drape, and the suction
tubing is fixed to the exposed sponge with an occlusive seal.
The suction tube is attached to the collection canister which
is attached to the adjustable vacuum pump. The vacuum
pump can be used as continuous or intermittent vacuum
using pressures of 75 to 125 mmHg when using polyurethane
foam and as higher continuous pressures of 125 to 175 mmHg
when using polyvinyl alcohol foam. VAC foam dressing can
safely be changed at 2 to 3 day intervals. At the time of foam
change, other traditional wound healing modalities, such as
pulse lavage, can be used. Silver-impregnated foam sponge
has been introduced to provide a bactericidal sponge in
patient with colonized wounds. This technique is continued
until the goal of wound closure is achieved or the wound
undergoes elective reconstruction with standard techniques.
Special considerations
Decompressive fasciotomy wounds
NPWT may be employed in the management of wounds fol­
lowing decompressive fasciotomy. With negative pressure,
the edematous muscle and soft tissues are decompressed
rapidly over a period of 2–3 days. The interval between fas­
ciotomy and wound closure may be lessened with this tech­
nique and may increase the likelihood of primary closure
rather than skin grafting, which has been the traditional
method of management of fasciotomy wounds treated with
daily saline dressing changes.
Skin grafting/dermal substitutes
Vacuum-assisted closure provides an alternative method with
which to bolster a skin graft or dermal substitute.70 The sponge
is cut to conform to the wound and, when the air is withdrawn
from the sponge, the firm sponge serves as a stent that main­
tains the graft/ substitute in place during the process of
revascularization. Furthermore, the negative pressure therapy
aids in neovascularization providing a better wound bed for
full thickness skin grafts, dermal substitutes,71 and grafts on
the diploic layer of bone with little granulation.
Acute burns
Morykwas showed in a swine model that NPWT decreases
burn wound progression.72 This is likely due to the removal
of edema fluid allowing for improved blood flow into the
burn wound environment. This in turn minimizes tissues in
the zone of stasis progressing to the zone of coagulation with
subsequent tissue necrosis. When applied to hand burns,
NPWT results in more rapid reduction of hand edema allow­
ing improved physical therapy and hand mobility.
Incisional VAC application
The collapsed VAC sponge does not traumatize a fresh wound
closure or a fresh flap. During the first 24 hours after wound

497
Complications and their management
6. Neumann CG. The expansion of an area of skin by the progressive
distention of a subcutaneous balloon. Plast Reconstr Surg.
1957;19:124–130. This classic article describes mastoid skin expansion as
a first stage in the reconstruction of an amputated ear. It is a landmark
case report more than 20 years before tissue expansion became an
accepted reconstructive modality.
7. Radovan C. Breast reconstruction after mastectomy using the
temporary expander. Plast Reconstr Surg. 1982;69:195–208. This
article is a follow-up to Dr. Radovan’s original article on tissue
expansion and breast reconstruction and a review of his experience in 68
patients.
11. Argenta LC, Watanabe MJ, Grabb WC. The use of tissue expansion
in head and neck reconstruction. Ann Plast Surg. 1983;11:31–37.
12. Manders EK, Schenden MJ, Furrey JA, et al. Soft-tissue expansion:
concepts and complications. Plast Reconstr Surg. 1984;74:493–507.
This is an article by Dr. Manders, one of the earliest surgeons to review
a large series of patients treated with tissue expansion in multiple areas.
It is an excellent overview of the technique and a look forward to its use
for the next 25 years.
31. Chummun S, Addison P, Stewart KJ. The osmotic tissue expander:
a 5-year experience. J Plast Reconstr Aesthet Surg. 2011;63:2128–
2132. Inflation through a port is a cumbersome technique requiring
multiple office visits for the patient. Since Dr. Austad first reported the
self-inflating tissue expander in 1982 there has been little progress. Drs.
Chummun, Addison and Stewart present an excellent experience on the
modern use of self-inflating expanders.
42. Manders EK, Graham WP 3rd, Schenden MJ, et al. Skin expansion
to eliminate large scalp defects. Ann Plast Surg. 1984;12:305–312.
50. Spear SL, Pelletiere CV. Immediate breast reconstruction in two
stages using textured, integrated-valve tissue expanders and breast
implants. Plast Reconstr Surg. 2004;113:2098–2103. This is an
excellent article and follow-up to the 1998 article on immediate breast
reconstruction using integrated valve tissue expanders. It presents the
refinements and improved aesthetic results now achievable.
61. Cordeiro PG, Pusic AL, Disa JJ, et al. Irradiation after immediate
tissue expander/implant breast reconstruction: outcomes,
complications, aesthetic results, and satisfaction among 156
patients. Plast Reconstr Surg. 2004;113:877–881.
62. Argenta LC, VanderKolk C, Friedman RJ, et al. Refinements in
reconstruction of congenital breast deformities. Plast Reconstr Surg.
1985;76:73–82.
67. Adler N, Dorafshar AH, Bauer BS, et al. Tissue expander infections
in pediatric patients: management and outcomes. Plast Reconstr
Surg. 2009;124:484–489.
Access the complete reference list online at

during tissue expansion are relatively minor and do not
interfere with completion of multistage procedures.
Implant failure
Despite design improvements, the use of an excessively large
needle or the inadvertent puncture of the implant can lead
to implant deflation. To maximize sealing of the valve, the
implant reservoir should be entered at a 90° angle. If there is
any question about the location of the inflation reservoir,
radiologic or sonographic techniques may be helpful.
Infection
As with the placement of any prosthetic device in the human
body, infection is possible. The introduction of bacteria to the
wound in the perioperative period is the most common cause
of early infection. The area to be reconstructed should be
stable, and there should be no open wounds at the time that
the procedure is undertaken. Areas susceptible to lymph­
edema, such as traumatized lower extremities, carry a signifi­
cantly higher rate of infection. An area of copious lymphatic
drainage, such as the neck or the groin, also tends to accumu­
late lymphatic fluid around a prosthesis and is more suscep­
tible to infection. These areas should be drained with suction
drains until all excess drainage stops. Antibiotics are given as
long as the drain remains in place.
Late infections are usually caused by iatrogenic introduc­
tion of bacteria during the course of inflation. The inflation
procedure should be performed under sterile conditions in
the office. Povidone-iodine (Betadine®) is used to prepare the
injection site. Externalized distal ports carry a high coloniza­
tion rate, but the resultant contamination produces little
complication. Many infections can be difficult to detect and
can be tolerated well by the patient.67
Some erythema may occur over all expansion prostheses;
however, pain, warmth, and systemic symptoms such as fever
and chills suggest clinical infection. If the infection occurs in
the perioperative period or early course of expansion, the
prosthesis should be removed and the wound irrigated. The
procedure is aborted, and a second attempt is made 3 or 4
months after healing. If infection occurs late in the course of
expansion, the prosthesis can be removed and the expanded
tissue advanced after irrigation of the infected cavity. Perma­
nent implants should not be placed when Gram stain of the
expander space reveals bacteria.
Implant exposure
Implant exposure can occur both early in the postoperative
period and after a protracted course of expansion. Treatment
of the exposed implant depends on the timing of exposure.
Exposure early after placement is usually related to inadequate
dissection or use of an excessively large prosthesis that abuts
on wound closure. If the prosthesis becomes exposed soon
after placement, it is best to remove it and re-operate 3–4
months later.
Late exposure is usually related to excessively rapid or
overzealous inflation. Rapid expansion is medically necessary
only in few instances. Tissue expansion should be carried out
judiciously to achieve optimal cosmetic results. If minimal or
late exposure occurs during the course of expansion, the
procedure can continue with the use of antibiotic creams on
the exposed area. In this situation, multiple, rapid fillings are
done to generate adequate tissue. Reinforcement of the com­
promised overlying skin with paper tape is sometimes helpful.
Most flaps survive and do well even with some exposure of
the implant.
In compromised tissues, such as grossly traumatized lower
extremities or irradiated and burned tissues, the use of tissue
expansion can more easily result in implant exposure – a
cautious approach is warranted.
Compromise and loss of flap tissue
Tissue expansion exerts changes on living tissue similar to
those seen in the phenomenon of conventional flap delay.29
Expanded flaps are almost universally more robust than non-
expanded flaps. To ensure vascularity, one should attempt to
maintain a major axial vessel in the expanded tissue.

497.e1
References
References
1. McCarthy JG, Schreiber J, Karp N. Lengthening the human
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2. Ilizarov GA, Soybelman L, Chirkov AM. Some roentgenologic
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3. Argenta LC, Morykwas MJ. Vaccum-assisted closure: a new
method for wound control and treatment: clinical experience. Ann
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4. Codvilla A. On the means of lengthening in the lower limbs, the
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5. Matev IB. Thumb reconstruction after amputation at the
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phalanx. A case report. Hand. 1979;11:302–305.
6. Neumann CG. The expansion of an area of skin by the progressive
distention of a subcutaneous balloon. Plast Reconstr Surg.
1957;19:124–130. This classic article describes mastoid skin expansion as
a first stage in the reconstruction of an amputated ear. It is a landmark
case report more than 20 years before tissue expansion became an
accepted reconstructive modality.
7. Radovan C. Breast reconstruction after mastectomy using the
temporary expander. Plast Reconstr Surg. 1982;69:195–208. This
article is a follow-up to Dr. Radovan’s original article on tissue
expansion and breast reconstruction and a review of his experience in 68
patients.
8. Austad ED, Rose GL. A self-inflating tissue expander. Plast
Reconstr Surg. 1982;70:588–594.
9. Austad ED, Pasyk KA, McClatchey KD. Histomorphologic
evaluation of guinea pig skin and soft tissue after controlled tissue
expansion. Plast Reconstr Surg. 1982;70:704–710.
10. Radovan C. Tissue expansion in soft-tissue reconstruction. Plast
Reconstr Surg. 1984;74:482–492.
11. Argenta LC, Watanabe MJ, Grabb WC. The use of tissue expansion
in head and neck reconstruction. Ann Plast Surg. 1983;11:31–37.
12. Manders EK, Schenden MJ, Furrey JA, et al. Soft-tissue expansion:
concepts and complications. Plast Reconstr Surg. 1984;74:493–507.
This is an article by Dr. Manders, one of the earliest surgeons to review
a large series of patients treated with tissue expansion in multiple areas.
It is an excellent overview of the technique and a look forward to its use
for the next 25 years.
13. Versaci AD. Reconstruction of a pendulous breast utilizing a tissue
expander. Clin Plast Surg. 1987;14:499–508.
14. Gibney J. The long-term results of tissue expansion for breast
reconstruction. Clin Plast Surg. 1987;14:509–518.
15. Takei T, Rivas-Gotz C, Delling CA. Effect of strain on human
keratinocytes in vitro. J Cell Physiol. 1997;173:64–72.
16. Takei T, Mills I, Arai K, Sumpio BE. Molecular basis for tissue
expansion: clinical implications for the surgeon. Plast Reconstr
Surg. 1998;102:247–258.
17. Osol G. Mechanotransduction by vascular smooth muscle. J Vasc
Res. 1995;32:275–292.
18. Glass GE, Murphy GF, Esmaeili A, et al. Systematic review of
molecular mechanism of action of negative-pressure wound
therapy. Br J Surg. 2014;101:1627–1636.
19. Pasyk KA, Austad ED, Cherry GW. Intracellular collagen fibers in
the capsule around silicone expander in guinea pigs. J Surg Res.
1984;36:125–133.
20. Pasyk KA, Argenta LC, Austad ED. Histopathology of human
expanded tissue. Plast Reconstr Surg. 1987;14:435–445.
21. Brobmann GF, Huber J. Effects of different-shaped tissue
expanders on transluminal pressure, oxygen tension,
histopathologic changes, and skin expansion in pigs. Plast Reconstr
Surg. 1985;76:731–736.
22. Johnson PE, Kernahan DA, Bauer BS. Dermal and epidermal
response to soft-tissue expansion in the pig. Plast Reconstr Surg.
1988;81:390–397.
23. Leong M, Basu CB, Hicks MJ. Further evidence that human
acellular dermal matrix decreases inflammatory markers of
capsule formation in implant-based breast reconstruction. Aesthet
Surg J. 2015;35:40–47.
24. Gur E, Hanna W, Andrighetti L, Semple JL. Light and electron
microscopic evaluation of the pectoralis major muscle following
tissue expansion for breast reconstruction. Plast Reconstr Surg.
1998;102:1046–1051.
25. Kim KH, Hong C, Futrell JW. Histomorphologic changes in
expanded skeletal muscle in rats. Plast Reconstr Surg.
1993;92:710–716.
26. Ricciardelli EJ, Goding GS, Bright DA, Cummings CW. Acute
blood flow changes in rapidly expanded and adjacent skin. Arch
Otolaryngol Head Neck Surg. 1989;115:182–186.
27. Lantieri LA, Martin-Garcia N, Wechsler J, et al. Vascular
endothelial growth factor expression in expanded tissue: a possible
mechanism of angiogenesis in tissue expansion. Plast Reconstr
Surg. 1998;101:392–398.
28. Sasaki GH, Pang CY. Pathophysiology of skin flaps raised on
expanded pig skin. Plast Reconstr Surg. 1984;74:59–67.
29. Cherry GW, Austad E, Pasyk K, et al. Increased survival and
vascularity of random pattern skin flaps elevated in controlled,
expanded skin. Plast Reconstr Surg. 1983;72:680–687.
30. Fischer JP, Nelson JA, Au A, et al. Complications and morbidity
following breast reconstruction–a review of 16,063 cases from the
2005–2010 NSQIP datasets. J Plast Surg Hand Surg. 2014;48:104–114.
31. Chummun S, Addison P, Stewart KJ. The osmotic tissue expander:
a 5-year experience. J Plast Reconstr Aesthet Surg. 2011;63:2128–
2132. Inflation through a port is a cumbersome technique requiring
multiple office visits for the patient. Since Dr. Austad first reported the
self-inflating tissue expander in 1982 there has been little progress. Drs.
Chummun, Addison and Stewart present an excellent experience on the
modern use of self-inflating expanders.
32. Bergé SJ, Wiese KG, von Lindern JJ, et al. Tissue expansion using
osmotically active hydrogel systems for direct closure of the donor
defect of the radial forearm flap. Plast Reconstr Surg. 2001;108:1–5,
discussion 6–7.
33. Connell AF. Patient-activated controlled expansion for breast
reconstruction with controlled carbon dioxide inflation: a
feasibility study. Plast Reconstr Surg. 2011;128:848–852.
34. Connell TF. Patient-activated controlled expansion for breast
reconstruction using controlled carbon dioxide inflation:
confirmation of a feasibility study. Plast Reconstr Surg.
2014;134:503e–511e.
35. Lozano S, Drucker M. Use of tissue expanders with external ports.
Ann Plast Surg. 2000;44:14–17.
36. Neale HW, High RM, Billmire DA, et al. Complications of
controlled tissue expansion in the pediatric burn patient. Plast
Reconstr Surg. 1988;82:840–848.
37. Hudson DA, Lazarus D, Silfen R. The use of serial tissue
expansion in pediatric plastic surgery. Ann Plast Surg. 2000;45:589–
593, discussion 593–594.
38. Forte V, Middleton WG, Briant TD. Expansion of myocutaneous
flaps. Arch Otolaryngol. 1985;111:371–374.
39. Thornton JW, Marks MW, Izenberg PH, Argenta LC. Expanded
myocutaneous flaps: their clinical use. Clin Plast Surg.
1987;14:529–534.
40. Baumeister S, Follmar KE, Erdmann D, et al. Tissue expansion of
free and pedicled flaps after transfer: possibilities and indications.
J Reconstr Microsurg. 2007;23:63–68.
41. Argenta LC, Marks MW, Pasyk KA. Advances in tissue expansion.
Clin Plast Surg. 1985;12:159–171.
42. Manders EK, Graham WP 3rd, Schenden MJ, et al. Skin expansion
to eliminate large scalp defects. Ann Plast Surg. 1984;12:305–312.
43. Argenta LC, Dingman RO. Total reconstruction of aplasia cutis
congenita involving scalp, skull, and dura. Plast Reconstr Surg.
1986;77:650–653.
44. Adson MH, Anderson RD, Argenta LC. Scalp expansion in the
treatment of male pattern baldness. Plast Reconstr Surg.
1987;79:906–914.

497.e2
CHAPTER 25 • Principles and applications of tissue expansion
45. Anderson RD, Argenta LC. Tissue expansion for treatment of
alopecia. In: Unger DP, Nordstrom RA, eds. Hair Transplantation.
2nd ed. New York: M. Dekker; 1988:519–561.
46. Juri J, Juri C. Temporo-parieto-occipital flap for the treatment of
baldness. Clin Plast Surg. 1982;9:255–261.
47. Anderson RD. The expanded “BAT” flap for treatment of male
pattern baldness. Ann Plast Surg. 1993;31:385–391.
48. Tanino R, Miyasaka M. Reconstruction of microtia using tissue
expander. Clin Plast Surg. 1990;17:339–353.
49. Breuing KH, Warren SM. Immediate bilateral breast reconstruction
with implants and inferolateral AlloDerm slings. Ann Plast Surg.
2005;55:232–239.
50. Spear SL, Pelletiere CV. Immediate breast reconstruction in two
stages using textured, integrated-valve tissue expanders and breast
implants. Plast Reconstr Surg. 2004;113:2098–2103. This is an
excellent article and follow-up to the 1998 article on immediate breast
reconstruction using integrated valve tissue expanders. It presents the
refinements and improved aesthetic results now achievable.
51. Spear SL, Parikh PM, Reisin E, Menon NG. Acellular dermis-
assisted breast reconstruction. Aesthetic Plast Surg. 2008;32:418–425.
52. Bindingnavele V, Gaon M, Ota KS, et al. Use of acellular cadaveric
dermis and tissue expansion in postmastectomy breast
reconstruction. J Plast Reconstr Aesthet Surg. 2007;60:1214–1218.
53. Nahabedian MY. Does AlloDerm stretch? Plast Reconstr Surg.
2007;120:1276–1280.
54. Preminger BA, McCarthy CM, Hu QY, et al. The influence of
AlloDerm on expander dynamics and complications in the setting
of immediate tissue expander/implant reconstruction: a matched-
cohort study. Ann Plast Surg. 2008;60:510–513.
55. Nahabedian MY. AlloDerm performance in the setting of
prosthetic breast surgery, infection, and irradiation. Plast Reconstr
Surg. 2009;124:1743–1753.
56. Namnoum JD. Expander/implant reconstruction with AlloDerm:
recent experience. Plast Reconstr Surg. 2009;124:387–394.
57. Menon NG, Rodriguez ED, Byrnes CK, et al. Revascularization of
human acellular dermis in full-thickness abdominal wall
reconstruction in the rabbit model. Ann Plast Surg.
2003;50:523–527.
58. Pennisi VR. Making a definite inframammary fold under a
reconstructed breast. Plast Reconstr Surg. 1977;60:523–525.
59. Ryan JJ. A lower thoracic advancement flap in breast
reconstruction after mastectomy. Plast Reconstr Surg.
1982;70:153–160.
60. Spear SL, Onyewu C. Staged breast reconstruction with saline-
filled implants in the irradiated breast: recent trends and
therapeutic implications. Plast Reconstr Surg. 2000;105:930–942.
61. Cordeiro PG, Pusic AL, Disa JJ, et al. Irradiation after immediate
tissue expander/implant breast reconstruction: outcomes,
complications, aesthetic results, and satisfaction among 156
patients. Plast Reconstr Surg. 2004;113:877–881.
62. Argenta LC, VanderKolk C, Friedman RJ, et al. Refinements in
reconstruction of congenital breast deformities. Plast Reconstr Surg.
1985;76:73–82.
63. Rohrich RJ, Lowe JB, Hackney FL, et al. An algorithm for
abdominal wall reconstruction. Plast Reconstr Surg. 2000;105:202–
216, quiz 217.
64. Mackinnon SE, Gruss JS. Soft tissue expanders in upper limb
surgery. J Hand Surg Am. 1985;10:749–754.
65. Argenta LC, Morykwas MJ, Marks MW, et al. Vacuum-assisted
closure: state of clinic art. Plast Reconstr Surg. 2006;117:127S–142S.
66. Manders EK, Schenden MJ, Furrey JA, et al. Soft-tissue expansion:
concepts and complications. Plast Reconstr Surg. 1984;74:493–507.
67. Adler N, Dorafshar AH, Bauer BS, et al. Tissue expander infections
in pediatric patients: management and outcomes. Plast Reconstr
Surg. 2009;124:484–489.
68. Fleischmann W, Becker U, Bischoff M, et al. Vacuum sealing:
indication, technique, and results. Eur J Orthop Surg Traumatol.
1995;5:37–40.
69. Morykwas MJ, Argenta LC, Shelton-Brown EI, et al. Vacuum-
assisted closure: a new method for wound control and treatment:
animal studies and basic foundation. Ann Plast Surg.
1997;38:553–562.
70. Scherer LA, Shiver S, Chang M, et al. The vacuum assisted closure
device: a method of securing skin grafts and improving graft
survival. Arch Surg. 2002;137:930–933, discussion 3–4.
71. Molnar JA, DeFranzo AJ, Hadaegh A, et al. Acceleration of Integra
incorporation in complex tissue defects with subatmospheric
pressure. Plast Reconstr Surg. 2004;113:1339–1346.
72. Morykwas MJ, David LR, Schneider AM, et al. Use of
subatmospheric pressure to prevent progression of partial-
thickness burns in a swine model. J Burn Care Rehabil.
1999;20:15–21.
73. Stannard JP, Robinson JT, Anderson ER, et al. Negative pressure
wound therapy to treat hematomas and surgical incisions
following high-energy trauma. J Trauma. 2006;60:1301–1306.
74. Grauhan O, Navasardyan A, Hofmann M, et al. Prevention of
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pressure wound therapy. J Thorac Cardiovasc Surg.
2013;145:1387–1392.

26 
Principles of radiation
Gabrielle M. Kane and Gurleen Dhami
SYNOPSIS
■ Radiation therapy (RT) can be used as a primary or adjuvant treatment
for many cancers.
■ The unit of dose measurement is the gray (Gy).
■ Side effects are characterized as acute and late toxicities.
■ Acute toxicities are temporary and reversible.
■ Late toxicities are permanent.
■ The primary mechanism of action of radiation is through breakage of
DNA strands.
■ Treatment planning is achieved through use of three-dimensional
computed tomography (CT) planning.
■ Delivery of radiation can be very precise with the use of intensity-
modulated radiation therapy (IMRT) as well as with image-guided
radiation therapy (IGRT).
Access the Historical Perspective section online at

Introduction
Radiation therapy (RT) requires an understanding of physics.
A multidisciplinary team, including radiation oncologists,
physicists, dosimetrists, and radiotherapists, is required for
the delivery of radiation. Delivery of radiation can be achieved
using different modalities, including kilovoltage, orthovolt­
age, megavoltage, electrons, protons, and brachytherapy.
RT utilizes ionizing radiation to treat malignant tumors
and some benign disorders. Nearly two-thirds of cancer
patients receive RT as part or all of their treatment. Radiation
oncology is the discipline of medicine that addresses the
causes, prevention, and treatment of human cancer with
special emphasis on the role of ionizing radiation.4 Radiation
oncologists work in a multiprofessional team with radiation
therapists, nursing, dosimetry, and medical physics, along
with dieticians, social workers, and counselors. Radiation
therapists are the technologists who deliver the RT; they
spend not only considerable time on the technical components
of treatment (treatment delivery, quality assurance, and veri­
fication), but also interact with and support cancer patients
throughout the duration of their therapy. Radiation oncolo­
gists work with surgical and medical oncologists, diagnostic
radiologists and pathologists, and are essential participants at
tumor board for multidisciplinary decision-making. Outside
the immediate team, it is rare for other physicians to know
much about the technology, process, rationale, and issues
around RT, and even less about the risks and causes of toxicity.
This chapter is designed as a primer, or virtual elective in the
topic, and aims to improve communication and understand­
ing between plastic surgeons and radiation oncologists so that
they can better appreciate some of the common issues faced
when caring for cancer patients. This chapter starts with a
brief description of the basics of radiation technology, modali­
ties, medical physics, and radiobiology. It then outlines
practical applications, with a description of RT planning and
process, and clinical treatment issues for select cancers. The
final section describes specific toxicity syndromes.
Radiation technology
RT has consistently relied on technology. Although much of the
equipment that has been the mainstay of RT is being replaced
by newer technology, some of it remains in effective and effi­
cient use. For example, kilovoltage therapy can be effectively
used for very superficial treatments. It delivers 100% of the
prescribed dose at the skin, has rapid fall-off below the skin,
and a tight penumbra (edge of the beam). In the 50–150-kV
range, penetration provides useful coverage only to a depth of
5 mm; orthovoltage therapy (150–500 kV) provides better
penetration, but is not capable of treating much more than 3 cm
below the skin. With kV energies, skin dose becomes the rate-
limiting step. At the orthovoltage range of energy, interaction
between radiation and matter is strongly dependent on the
atomic number (Z) of the attenuating material. For the photo­
electric effect, high Z tissue, such as bone, attenuates more
  Access video lecture content for this chapter online at expertconsult.com

498.e1
Historical perspective
Historical perspective
In November 1895, Wilhelm Conrad von Roentgen discov­
ered a new type of ray that was generated from a stream
of electrons in a cathode gas discharge tube and had the
ability to pass though tissues with different degrees of pen­
etration. Because the composition of the rays was unknown,
they were called X-rays. His subsequent presentation to the
Wurzburg Society on the ability of his rays to generate an
image of structures inside the body gave birth to diagnostic
radiology. The following year, in France, Henri Becquerel
discovered that fluorescent materials made of uranium also
emitted constant radiation.1 Marie and Pierre Curie used
ionization to measure becquerel rays and quantify radiation
intensity against uranium. Marie Curie first used the word
“radioactivity” in 1898. The couple isolated two new radio­
active elements from pitchblende, polonium, named for
Marie’s native Poland, and radium, Latin for ray. Today,
these pioneers’ names are in constant use as measures of
radioactivity.2
The earliest oncologic brachytherapy procedure was in
1902, when a radium applicator was used to treat a tumor of
the palate and pharynx. Within a few years, there were clinical
studies of effectiveness, and radium tubes were inserted
directly into tumors, and by the 1920s, radium had become
the standard of care in oncology,3 as well as the treatment for
many benign conditions. The use of Roentgen’s rays to palli­
ate advanced cancer was first described in 1903,4 and this was
the forerunner of external-beam radiation treatment.
Until the 1950s, most radiation machines were very similar
to diagnostic radiology ones, and generated X-rays at poten­
tials of up to 300 kV. Superficial therapy (50–150 kV) could
treat to a depth of 5 mm, and thus was useful for superficial
skin cancers. Orthovoltage (or deep) therapy (150–500 kV)
provided greater penetration, but was not capable of treating
much more than 3 cm below the skin, with 100% of the dose
at the skin. At this range of energy, interaction between radia­
tion and matter is strongly dependent on the atomic number
(Z) of the attenuating material – in other words, in this process,
known as the photoelectric effect, tissue such as bone, which
has a high Z, attenuates more radiation; fat and soft tissue
(lower Z) attenuate less; and air (for example, in the lungs)
hardly at all, thus producing the contrast necessary for diag­
nostic imaging. Unfortunately, this higher absorbed dose in
bone resulted in many more problems from osteoradionecro­
sis (ORN).
The development in Canada of the cobalt-60 unit in 1951
introduced the new era of megavoltage (MV) radiotherapy to
the world, allowing greater penetration of tissue and, with
maximal dose not achieved until a depth of 0.5 cm, resulting
in better skin-sparing and improved dose homogeneity. Since
then, computer-controlled megavoltage linear accelerators
have been developed, providing increasing penetration and
skin-sparing, and a rapid accumulation of technologies to
verify, deliver, and record increasingly precise RT.

499
Particle therapy
and other sensitive structures in that region, and would other­
wise cause severe toxicity, or for spinal cord tumors, such as
ependymoma (Fig. 26.1). Another indication for protons is to
deliver craniospinal irradiation for pediatric cancers such as
medulloblastoma, because the proton dose distribution signifi­
cantly reduces the exit dose to anterior structures (kidneys,
bowel, lungs) when compared to conventional photon therapy
(Fig. 26.2). Proton beam radiotherapy is useful for reirradiation
as it often can reduce dose to critical structures that have
radiation than lower Z tissue, such as fat and lungs, producing
the contrast necessary for diagnostic imaging. Unfortunately,
this higher absorbed dose in bone resulted in many more
problems from osteoradionecrosis (ORN).
Megavoltage radiotherapy allows even greater penetration
of tissue, resulting in better skin-sparing and improved dose
homogeneity. It is not influenced by the atomic number of the
absorbing medium, as Compton scattering is predominant in
this energy range.
Cobalt units deliver MV radiation, and have a 60Co source
that generates gamma (γ) rays with average megavoltage
energy of 1.25 MV. 60Co has a half-life of 5.26 years, and as a
result of this decay and subsequent drop in output, the source
needs to be replaced every few years. Maximum dose (Dmax) is
not achieved until 0.5 cm beyond the surface of the skin and
the intrinsic scatter of the beam and ionized particles means
that the penumbra, or dose fall-off at the edge of a beam, is not
very tight. Despite this, cobalt is still a prevalent and important
external-beam radiotherapy modality, as it still provides an
excellent low-maintenance, reliable, safe, and effective alterna­
tive in many low- and middle-income countries.
Photons are the most commonly used RT modality. They
are generated by a linear accelerator, or linac, which uses
high-frequency electromagnetic waves to accelerate electrons
to a very high energy through an accelerator tube and beam
transport system. When the accelerated electrons hit a high
Z target at the end of this, they produce megavoltage X-ray
beams that have sharper edges and can penetrate deep tissue.
Typical photon energies produced by linacs are 4, 6, 10, and
18 MV that result in increasing maximum depth doses.
Particle therapy
Electrons are the most commonly used particle therapy. They
are also generated by linacs by removal of the target in the
beam’s path for production of electron beams. Most linacs can
produce a range of electron energies from 4 to 17 MeV. They
deposit their energy superficially, sparing structures deeper
in the body, with fairly steep dose distribution curves. Elec­
trons produce more side scatter than photons and have wider
penumbras. They are typically used to treat skin cancers,
“boosts” to breast tumor cavities, and for intraoperative
radiotherapy. They are also used to spare sensitive organs that
may otherwise reach maximum tolerance, for example, pro­
tecting the spinal cord when treating posterior neck nodes.
Many new proton facilities are opening nationwide; they are
expensive and cumbersome to construct and maintain, requir­
ing a cyclotron or a synchrotron to accelerate protons, which
have a mass nearly 2000 times that of an electron. Protons have
similar biologic activity as photons; their advantage is that they
have a unique shape to their dose distribution, with low
steady-dose deposition until near the end of their clearly
defined range when the dose peaks then falls sharply to nearly
zero. This is the Bragg peak phenomenon, which allows very
precise dose distribution, protection of critical structures, and
dose intensification. By combining different beam energies, a
spread-out Bragg peak (SOBP) is created which is able to
encompass the target in its entirety to the prescribed dose.
Protons are ideal for treating structures in the base of skull,
such as the clivus, especially for chordomas, where the neces­
sary dose is far above the tolerance of the sensitive optic chiasm
Fig. 26.1  Axial proton treatment plan for a spinal myxopapillary ependymoma with
sparing of the bone marrow and anterior-lying organs. (Courtesy, Jason K. Rockhill MD
PhD.)
Fig. 26.2  Comparison of photon and proton craniospinal radiation treatment plans
for pediatric medulloblastoma. Both techniques use a single posterior beam, but
the proton plan has significantly less exit dose. (Courtesy, Ralph Ermoian MD.)

500
CHAPTER 26 • Principles of radiation
The radioactive sources are housed in a shielded safe in a
remote-controlled after-loading unit, which looks very much
like a small heating furnace. After a final verification of posi­
tioning, the applicator, catheters, cylinders, or trocars are
connected with tubes to the after-loading unit. After all per­
sonnel have left the room, the active sources, which look like
small beads, are remotely loaded through a pressurized
system. The unit is programmed to control the position of the
sources and the duration of the sources in any position to
achieve the prescribed dose in a homogeneous fashion over
the three-dimensional dose distribution. The unit can be
paused, and the active sources retract temporarily into the
safe within the after-loading unit, making it possible for
personnel to enter the room to provide care.
Low-energy radionuclides such as 131I, 103Pd, and 198Au do
not pose the same concerns for radioprotection, and thus are
used as permanent implants in the form of seeds, most com­
monly for prostate cancer.
Physics
An explanation of RT techniques and dosimetry requires a
basic understanding of physics. The photons generated by the
linac are very high-energy X-rays that do not have any charged
particles in them. When a photon beam enters the body, it uses
the Compton process to deposit energy. This means that it
interacts with tissue by colliding with an atom’s loosely bound
outer shell electron (Fig. 26.3). The photon continues along its
path, but the electron is knocked off, like a billiard ball, at an
angle that depends on the speed and angle with which it was
hit. The electron travels (scatters) a distance that is proportional
to the energy with which it was hit, meaning that higher
photon energies propel electrons more in a forward direction
than lower energies can do, before the electron is deposited,
and the dose absorbed into the tissues. This triggers down­
stream free radical interactions, and these can cause DNA
single-strand or double-strand breaks, or other injuries, includ­
ing damage to base pairs and protein cross-links. The chromo­
somal aberrations that result from double-strand breaks mean
that the cancerous cell cannot repair or duplicate at the end of
its life cycle, leading to the principal cause of cell death.
If all of these electron energy deposits are added up, then a
distribution curve showing absorbed dose and depth can be
plotted (Fig. 26.4A) that shows that skin absorbed dose is less
than 40%, and 100% or Dmax occurs some distance into the skin
at a depth that is consistent with the energy of the photon
beam. The commonest energy used is 6 MV, which has a Dmax
of 1.5 cm beyond skin. The dose then falls off at a steady rate
Fig. 26.3  Incident photon knocks an electron off the outer ring and scatters it
along a pathway through a distance before the electron energy is absorbed.
Air
Skin
Incident photon
Tissue
–
–
–
–
+
already been exposed to prior radiation. Proton beam radio­
therapy is also utilized for the treatment of prostate cancer and
shown to have high efficacy with minimal bowel and bladder
toxicity,5 but long-term data are needed to compare late toxicity
rates with photon beam RT. However, changes in tissue hetero­
geneity can affect where the particle stops and the positon of
the Bragg peak, leading to some uncertainty in dosing. Cur­
rently, there are several ongoing randomized trials that are
evaluating the role of protons versus photons in respect to
survival, toxicity, and quality of life outcomes. Some currently
accruing trials include RTOG 1308 for inoperable non-small
cell lung cancer and NRG-BN001 for glioblastoma.
Neutron RT, first used for cancer therapy in the 1930s, offers
the advantage of high linear energy transfer, a property that
allows the delivery of 20–100 times more energy along their
path than photons, thus being biologically more effective in
treating radioresistant tumors such as sarcomas and salivary
gland tumors.1 Their use requires a careful balance of risk and
benefit as they can lead to more severe late toxicities.6
Carbon, neon, and heavier ions hold promise as they
combine the radiobiological advantages of neutrons with the
dose distribution and Bragg peak of protons, but are only
available in select centers.
Brachytherapy
Brachytherapy, meaning “short distance” in Greek, is a method
of delivering radiation treatment near or within a target using
radioactive sealed sources. There are three main ways of
delivering this type of radiation: (1) an applicator can be used
to deliver dose to the surface of a thin tumor, for example, an
eye plaque used to treat ocular melanoma; (2) intracavitary –
inserting the sealed source into the cavity of an organ, e.g., in
the treatment of cervical cancer, a combination (tandem) appa­
ratus is used consisting of a cylindrical rod inserted into the
cervical os and through the cervical canal into the uterus, with
two ovoids placed in the lateral fornices; and (3) interstitial,
when the source is either implanted directly into the tumor or
postoperative bed, for example, for postoperative treatment of
sarcoma, or when radioactive gold seeds are implanted directly
into an organ, e.g., in the treatment of early-stage prostate
cancer. Brachytherapy is often used in conjunction with exter­
nal beam, usually to increase the total dose to a smaller volume
at the site of greatest risk of recurrence, for example, in the
postoperative management of cervical cancer.
Following the work done by Marie Curie and others,
radium needles were initially used, until the importance of
radioprotection was realized. In the modern era, artificially
produced radionuclides are used, most commonly those
derived from cesium (137Cs), iridium (192Ir), iodine (131I), pal­
ladium (103Pd), and gold (198Au). The activity of these radio­
nuclides is still calculated relative to that of radium. To protect
health professionals and the patient, the process of using
high-energy sources, such as 137Cs and 192Ir, has evolved con­
siderably, most notably with the use of after-loading. Empty
cylinders (for intracavity) or catheters and trocars (for inter­
stitial brachytherapy) are inserted, and loaded with inert
metal “dummy” sources that are visualized on radiologic
imaging; this is done to verify the position and calculate the
dose distribution. The patient is treated in a shielded room,
either as an inpatient over several days, or in an outpatient
brachytherapy suite, for shorter high dose rate treatments.

501
Physics
Fig. 26.5  Multileaf collimators (photographed looking into the head of the
machine) are used to provide static shielding, or, when programmed dynamically,
differential dose absorption for intensity-modulated radiation therapy.
Fig. 26.4  (A) Depth dose distribution for 6 MV photons: only approximately 30%
of the dose is absorbed at the skin surface; the maximum dose (100%) is absorbed
at a depth of 1.5 cm, and then attenuates by less than 5% per cm. (B) When two
beams are opposed, depth doses can be added, resulting in an even distribution
across the target volume. (C) If a higher dose is required at the skin surface, a strip
of bolus material is placed on the skin.
100%
50%
cm
Attenuation
0
10
5%/cm on 6MV
Dmax
20
A
100%
50%
cm
Attenuation
0
10
Parallel opposed pair
Dmax
Skin sparing
20
B
100%
1 cm
bolus
50%
cm
Attenuation
0
10
Parallel opposed pair
Dmax
Skin sparing
20
C
that is just less than 5%/cm, meaning that 50% of the dose has
been deposited approximately 11 cm into the body. If a tumor
is situated centrally, this means that there is too much of a
gradient of dose across it. To overcome this heterogeneity
within the target volume, a second beam can enter the body
(assuming a diameter of 20 cm) from the opposite side, again
depositing its maximal energy at 1.5 cm, then attenuating at
<5%/cm. The energy deposits from each side are added, a
homogeneous distribution is achieved across the target volume
(Fig. 26.4B), and the skin does not receive a therapeutic dose,
unless bolus is used (Fig. 26.4C). The addition of right and left
lateral beams (four-field box technique) would give an even
tighter homogeneous distribution to the target volume, and,
since the entrance and exit doses are shared between four
beams, further skin dose reduction. This is the basis for using
multiple fields, or beams, from different angles, to “focus” (a
misleading term, since the beam does not focus on a spot, as
light does through a lens) and deposit maximal dose to a target.
In conventional RT, most beams are delivered with uniform
intensity across the field. Beam-modifying devices are acces­
sories such as shielding blocks, wedges, and compensators,
which are placed in the head of the machine to differentially
absorb dose proportionally to the thickness of the device (i.e.,
more dose is absorbed through thicker regions, and less
through thin), to improve dose homogeneity within the target.
In modern linacs, blocking is done by a system of multileaf
collimators (MLCs), which are narrow strips of metal in the
head of the linac that act like miniblocks. Their shape can be
programmed for shielding (Fig. 26.5). Three-dimensional con­
formal therapy uses multiple beams to be shaped in such a way
that a significant amount of normal tissue can be excluded.
MLCs can also be programmed to move dynamically in
and out of the beam, so that the amount of time in each
position is adjusted to allow a variable amount of dose
through each leaf, compensates for irregular shapes with
great precision, and can control the dose to specified targets
within a volume. This is the basis for intensity-modulated
radiation therapy (IMRT), which involves identifying doses
for individual or multiple target volumes and constraints for
normal organs that need to be protected from the effect of
radiation, and then using a sophisticated RT planning program
that modulates the intensity across multiple individual beams
or arcs with dynamic MLC, using an inverse planning system.
This allows the creation of a very conformal plan that can
even have convex and concave shapes to avoid a critical

502
CHAPTER 26 • Principles of radiation
Fig. 26.6  (A) Axial intensity-modulated radiation therapy plan of a sarcoma
involving the mediastinum extending into a thoracic vertebral body. The technique
allowed a radical dose (66 Gy) to be delivered to the target volume, but constrained
the cord dose to a safe dose of 52 Gy. (B,C) Coronal and sagittal distributions.
A
B
C
structure, for example, avoiding the spinal cord in a way that
conventional beams may not achieve (Fig. 26.6). It is also
possible to “dose paint” so that different areas receive differ­
ent doses at the same time, and also to reduce volumes,
adapting to reduction in the tumor size. A similar result is
obtained with tomotherapy, which uses principles of CT scan­
ning to deliver intensity-modulated beams slice by slice. An
advantage of IMRT over this system is that IMRT is delivered
on a normal linac rather than a dedicated machine.
Image-guidance is essential for high precision in RT deliv­
ery (IGRT). Electronic portal imaging (digital MV or KV
X-rays taken on the RT machine) can take both orthogonal
views of the target, e.g., anterior and lateral beams, and
beam’s eye view images. The utility of this is enhanced when
there are recognizable and stable landmarks, for example,
some part of the bony anatomy. However, when the target is
mobile, then fiducial markers, such as gold seeds placed in
the prostate gland or along the cervical os for brachytherapy,
can serve as a surrogate for target location. The cone beam CT
(CBCT) uses KV three-dimensional imaging to verify posi­
tioning for IGRT on the treatment couch.
Stereotactic techniques like radiosurgery deliver hypofrac­
tionated RT to small lesions in structures such as the brain. A
linac-based process involves the use of multiple very small
beams that cover a small target (2–5 cm) to a large dose of RT,
delivering a therapeutically radical equivalent dose in just a
few, or even just one, fraction. It has primarily been used on
central nervous system tumors, including benign conditions
such as arteriovenous malformations or schwannomas, immo­
bilizing the head in a frame. Gamma knife uses a 60Co source
with similar principles. With the advent of IGRT, this principle
is now applied to stereotactic body RT (SBRT) for sites else­
where in the body, such as lung, liver, and paraspinal tumors.
Large doses, for example 10–18 Gy, are higher depending on
tumor size and location, are given 2–3 times weekly over fewer
fractions than conventional fractionation to an ablative dose,
but with much greater precision, and potentially less toxicity.
It is well tolerated even by frail and ill patients.
Intraoperative RT (IORT) is used to treat small areas
(3–10 cm) that are at high risk for recurrence immediately
after the tumor has been resected, such as a retroperitoneal
sarcoma, on the same day. An advantage of IORT is that criti­
cal structures, such as bowel, can be physically moved out of
the beam’s pathway. The radiation oncologist positions elec­
tron applicators (also known as cones) into the wound to
cover the tissue at risk for microscopic residual disease that
has been localized by the surgical oncologist (Fig. 26.7). The
Fig. 26.7  Intraoperative radiotherapy (IORT) delivering a large single fraction of
XRT to the operative bed in the retroperitoneum. This photograph shows the cone,
or electron applicator (the metal cylinder), after it has been positioned over the
target volume. It will now be secured into place, the position verified, the monitor
units and dose rate calculated, before personnel leave the room and XRT is
delivered. Set-up takes approximately 15–20 minutes, but the treatment is delivered
in only 2–3 minutes. (Courtesy, Edward Y Kim MD.)

503
Radiobiology
Fig. 26.8  Therapeutic ratio curves. (A) In an ideal situation, a tumor response
would be almost complete before causing any tissue reaction. (B) More commonly,
the dose required to achieve adequate tumor response also causes an unacceptably
high risk of normal tissue reaction. (C) An acceptable trade-off is one that allows
adequate tumor control and less than 5% probability of normal tissue complications
(NTC).
% response
100
Dose
0
Tumor
Normal tissue
A
% response
100
Dose
0
50%
Tumor
Normal tissue
B
% response
100
Dose
0
5%
Tumor
Normal tissue
Probability of NTC
C
cone position is stabilized and verified before being aligned
with the head of the machine. Medical physicists calculate
and verify the delivery. Personnel then leave the room, the
beam is switched on, and the dose is delivered in less than 2
minutes. The cone is removed, and the surgeon closes up.
Radiobiology
Radiation injury can be viewed from two perspectives: the
radiation effect on tumor cells, and the radiation toxicity on
normal cells. The therapeutic ratio is a dose–response relation­
ship between tumor control and normal tissue complications,
and helps balance these two perspectives. In an ideal world,
the curves representing tumor response and normal tissue
complications would be well separated (Fig. 26.8A). Far too
often, they are so close together that it is not possible to
achieve a high enough dose to eradicate the tumor without
causing harmful complications (Fig. 26.8B). Usually in clinical
practice there is some degree of compromise, and tradition­
ally, less than 5% risk of normal tissue complications is
accepted (Fig. 26.8C), taking into account the specific risks of
the situation.
Radiation toxicity is expressed during mitosis of normal
cells. Acute toxicity occurs during treatment course or shortly
afterwards. It is related to the total dose, the size of the volume
irradiated, and radiosensitizing drugs such as chemotherapy.
It occurs in cells with a rapid turnover, such as oral mucosa
or skin epithelium, where cell division is necessary to main­
tain function. Even though these cells may be affected within
a few days of starting fractionated treatment, their damage
does not become manifest for at least 2 weeks as the progeni­
tor stem cells do not have as rapid a turnover. Examples are
skin erythema and desquamation, oral mucositis, and esopha­
gitis. Even quite brisk reactions can heal fast once RT is
completed (Figs. 26.9 & 26.10). Acute toxicity is reversible and
does not predict for permanent damage. The exception is if
there is consequential damage, i.e., there is persistent injury
due to the destruction of the basement membrane zone with
complete depletion of stem cells due to very high dose, and
usually an additional factor such as chemotherapy, infection,
or trauma. This can be found in chronic ulcers in the skin,
bladder, or gastrointestinal tract. Delayed acute toxicity occurs
6 weeks to 6 months after the completion of treatment; it is
also reversible. As with acute toxicity, it is dose-, volume-,
and drug-related. Examples are radiation pneumonitis and
Lhermitte’s syndrome (a transient demyelination syndrome
of the spinal cord, which does not predict for subsequent
radiation myelitis).
Late toxicity occurs 6 months or later after the completion
of RT. It represents damage that is expressed at the end of the
life cycle of parenchymal cells that have slow cell renewal and
a relative inability to repopulate from stem cells. It occurs in
organs that have less dependence on cell turnover and have
both proliferative and functional cell populations, primarily
connective and nervous tissue. Examples are the endothelium
of blood vessels, and osteoblasts and chondroblasts of bone.
These injuries are characterized by fibrosis, often over many
years, and are not reversible, thus of serious consequence. It
is essential to factor these risks into dose limitations. They are
strongly correlated with fraction size, and the type of radia­
tion used (Fig. 26.11).
A method of quantifying the risk of permanent tissue
damage is the concept of TD5/5, which is the total dose, given
in standard fraction sizes, that produces a 5% risk of damage
to a specified organ at 5 years.7 These figures have been
updated to reflect modern conformal treatments8 and provide
a working model based on pooled data to constrain the dose
to an organ at risk during the treatment-planning process, as
well as for guiding informed consent.
Ionizing radiation kills cells by damaging DNA either
directly or indirectly. Direct action disrupts DNA, and can

504
CHAPTER 26 • Principles of radiation
hematopoietic cells, primarily undergo apoptotic death. The
commonest mechanism of cell death from radiation is through
mitotic death when cells cannot divide because of damaged
chromosomes. Another cellular response after radiation is
senescence, in which cells survive and continue to function,
but lose their capacity to reproduce and proliferate.
All organized tissues mount repair in response to injury.
Radiation injury prompts the body to respond in a similar
way as it does to other trauma, for example, surgery. However,
there are three important differences. Firstly, radiation deliv­
ers a repetitive, daily injury during the course of fractionated
cause lethal double-strand breaks. Indirectly ionizing radia­
tion, which includes photons and neutrons, can cause damage
by producing charged particles that then disrupt the DNA,
but the damage is generally through indirect action, caused
by the release of reactive oxygen species. Cell death can take
several forms. Lethal chromosome damage can result in cel­
lular death or loss of reproductive capacity. Apoptosis is a
type of programmed cell death associated with activation of
the tumor suppressor gene p53 and is rapid, inducing no
inflammatory response. Although it has been described in
many different tissues, only certain tumors, such as
Fig. 26.9  Acute skin reactions can be severe, depending on multiple factors, including the volume and total dose. (A) Clinical photograph of the posterior thigh of a
woman with a large (28 cm) sarcoma, treated with postoperative radiation to a total dose of 66 Gy. She had a history of over 240 lb (109 kg) intentional weight loss, and
had marked skin redundancy, resulting in multiple folds, exacerbating her acute reaction. (B) Rapid improvement after just 7 days of conservative management with
application of saline soaks. The white patches are healthy islands of new skin. (C) 14 days post completion of XRT.
A
B
C
A
Fig. 26.10  Acute skin reaction in the neck.
(A) An acute skin reaction at the base of
the neck at a completion dose of 70 Gy,
(B) 1 week later, again demonstrating rapid
recovery and the skin islands. This reaction
at the base of the neck is fairly typical, and
is a result of the obliquity of the surface
and narrowness of the shoulder.
B

505
Applications
wound healing, with decreased wound-breaking strength
because of the damage to the microvasculature and the
decreased cellular elements.11 These problems are related to
the total dose, the dose per fraction, the timing of the surgery,
and the extent of the surgery. The optimal time to operate on
irradiated skin is the window provided once the acute reac­
tion has resolved and before the development of excessive
fibrosis, generally 3–10 weeks after completion of X-ray
therapy (XRT).
Applications
Radiation treatment-planning and process
The preparation for radiation treatment, or planning, starts
with a decision on the treatment intention – curative, pallia­
tive, or optimization of local control (complex palliation) – and
the probable dose prescription. Following informed consent,
the patient is simulated for the treatment. Simulation is the
radiation oncologist’s equivalent to the operative day, allow­
ing dedicated time to accurately map out the areas for treat­
ment. Two-dimensional planning with fluoroscopy has now
been mostly replaced by a three-dimensional approach, using
diagnostic-quality CT scan with contrast (intravenous and
oral as necessary). The scanners are equipped with a flat, as
opposed to concave, couch, and the bore is often extra-wide,
to accommodate the proposed treatment position, such as
arms above the head, or legs separated in a frog-leg position.
To achieve a reproducible position, immobilization devices
are made. The type of device depends very much on the
treatment site. To treat the head and neck region, a mesh
acrylic mask, similar to the type of mask worn by burn patients
requiring compression treatment, is formed exactly to the
patient’s face and head with eye, nares, and mouth openings
(Fig. 26.12). This not only allows reproducible positioning but
also obviates the need for tattoos or other skin markings in
visible areas. Extremities are immobilized using casts of the
treatment. Secondly, the injury caused by the release in the
tissue of free radicals affects all cellular and extracellular
components within the volume of tissue irradiated. Thirdly,
radiation causes damage to the DNA.
Response to radiation injury causes a signal transduction
pathway that is mediated by the ataxia telangiectasia mutated
(ATM) gene to instigate DNA repair and to regulate cell cycle
checkpoints, giving the cells additional time to repair. A
cascade of cytokines is an immediate response, and may lead
to both radiosensitization and protection.9 Interleukin-1 and
6, and tumor necrosis factor-α cause an inflammatory response
and coagulation effect. Transforming growth factor-β (TGF-β)
is one of the most widely studied radiation-induced cytokines,
and plays multiple roles.10 It causes fibroblast differentiation
as well as stimulating the production of collagen. It is involved
in the synthesis and regulation of extracellular matrix mol­
ecules. Following radiation, the extracellular matrix is both
quantitatively and qualitatively modified – degrading pro­
cesses are altered and production of collagen synthesis
increases. TGF-β also down-regulates thrombomodulin activ­
ity in endothelium, leading to platelet aggregation, and, from
the platelets, release of more TGF-β, thus setting up a self-
perpetuation production of TGF-β that contributes to the
chronicity of radiation injury. However, it is primarily the
sustained activity of TGF-β-driven myofibroblasts that causes
the fibrotic reactions to radiation. Fibrosis is not an endpoint,
but a dynamic process of fibroblast activity. In traumatic
wounds, remodeling happens over years, but this capacity to
remodel is lost in irradiated tissue and instead there is self-
perpetuating reactive fibrosis. As a result, irradiated skin and
soft tissue are susceptible to minimal trauma, creating a
problem for surgical intervention. Radiation causes delayed
Fig. 26.11  A severe late skin reaction as a result of fast neutron therapy 22 years
earlier following excision of a large dermatofibrosarcoma protuberans (DFSP) tumor
from the shoulder. It demonstrates characteristic telangiectasia, hypopigmentation,
subcutaneous fibrosis and, medially, delayed healing of a minor skin abrasion.
Fig. 26.12  A mask to immobilize the head and neck in a reproducible position.

506
CHAPTER 26 • Principles of radiation
Clinical applications
Units of radiation
The unit of absorbed radiation dose is the gray (Gy), corre­
sponding to 1 joule of energy per kilogram of tissue. One gray
equals 100 cGy. SI units that are named after people are, by SI
convention, lower case when the whole name is used, but
capitalized when the abbreviation is used. The gray replaced
the older unit rad. One rad is equivalent to 1 cGy.
Treatment intention and dosing
The dose is determined by the intention of the treatment.
Radiation can be used as the primary modality of therapy or
combined with surgery and chemotherapy. When the treat­
ment intent is curative, radical doses, such as 66 Gy for early
(and 70 Gy for late) laryngeal cancer or 80 Gy for prostate
cancer, are delivered in standard fractionation sizes of
1.8–2.0 Gy per daily fraction, 5 days a week, over periods of
7 weeks or more. Typically, the maximum dose is applied to
known tumor, but lower doses (45–50 cGy) are used to treat
tissues that have the potential for microscopic disease, for
example, the peritumoral edema around a soft tissue sarcoma.
However, when resection margins are histologically positive,
a higher dose is needed, e.g., to 70 Gy, and the context is no
longer adjuvant.
In noncurative situations, treatment may be used to palliate
symptoms such as pain or bleeding, employing hypofraction­
ated regimens that use smaller total doses but a larger dose
per fraction. A common palliative course would be 20 Gy
delivered in 5 fractions of 4 Gy. However, there are also
noncurative situations when a patient has known metastatic
disease, but bulky or aggressive tumor at the primary site that
is, or will shortly become, very symptomatic and impair
quality of life. Radical radiation approaches are used to opti­
mize local control, for example, an unresectable fungating
breast cancer even in the presence of bone metastases.
Dose can also be hyperfractionated, when smaller fractions
are given twice a day, so that treatment can be accelerated,
potentially improving tumor cell kill and causing less repopu­
lation of very fast-growing tumors. This can also be a way to
protect normal structures from late irreversible toxicity, espe­
cially in high-risk situations like retreatment. Hypofraction­
ated RT with a large dose per fraction, but fewer fractions, has
traditionally been reserved for palliative RT, as described
above. However, when the volume is small, the risk of late
toxicity is low, and the high dose is ablative, treatment can be
curative, as in SBRT, described earlier. It is also increasingly
used in oligometastatic situations for patients with good
performance status and a small burden of metastatic disease
that is chemosensitive, as this approach can improve survival,
and may have an abscopal effect.12,13
Patient selection
As in any branch of medicine, careful patient selection and
informed consent are essential. Patients are often referred to
radiation oncology when surgery or chemotherapy options
are not feasible because of comorbidities or poor performance
status. There are some basic principles to follow. For all
patients, but particularly for young people, potential benefit
of radiation must be weighed against the late sequelae of
same material and body immobilization is achieved with the
use of vacuum splints and bags. All of these devices are ref­
erenced to the couch position. Once the position is confirmed,
immobilized, and referenced, the patient then has a CT scan
in this position and goes home. These images are imported
into a radiation treatment-planning system.
Using the original diagnostic scans, and often fusing them
with the planning CT, the radiation oncologist starts delineat­
ing all the structures of interest on every CT slice as it is
displayed on the workstation. Any visible tumor is delineated
as one or several gross tumor volumes (GTV). These are then
encompassed by one or more clinical target volumes (CTV),
which include normal-looking tissue considered by the radia­
tion oncologist to be at high risk of containing tumor cells.
Defining this volume, and deciding on its dose, require judg­
ment of risks and benefits, and are central to the discipline of
radiation oncology. It is possible to have several CTVs that
require different doses, depending on the likelihood of tumor
burden. The CTV is then expanded to a form a planning
target volume (PTV) that accounts for measured movement
of the tumor or organs, for example, to account for a lung
mass moving with respiration, as well as other calculated
variations.
The next step is to identify and contour all organs at risk
(OAR), that is, those normal tissues that are sensitive to
radiation – examples include kidneys, spinal cord, and
femoral head. Each of these sensitive structures is identified
with a dose constraint. The result is a three-dimensional
digital representation of the patient, tumor, and organs at
risk. Working with dosimetrists, a treatment technique is
decided by placing multiple beams through a series of pro­
tocols to determine the optimal beam arrangement to cover
the target volumes homogeneously to the prescribed dose
while sparing critical structures. Dose volume histograms
calculate constraints for the OAR, for example, in the thorax,
the V20 refers to the percentage of cancer-free lung (i.e.,
without the CTV) that receives >20 Gy; if this is above 35%,
it is strongly predictive for radiation pneumonitis. This
aspect of radiation treatment planning, rather than just posi­
tioning the patient on the CT bed, is the heart of the simula­
tion process.
Once the radiation treatment plan has been designed, it is
checked by a physicist for quality assurance to ensure that the
plan is technically feasible on the treatment unit, and that no
further beam modification is necessary. The patient returns
for a dry run of the plan, and verification of set up. During
this session the patient is repositioned in the immobilization
device on the treatment machine, and, using light beams,
the geometric parameters are checked. Verification includes
comparison of the portal imaging to the digitally recon­
structed radiographs (DRR) from simulation to ensure that
the isocenter of the fields, the field shapes, and the shielding
are consistent with the plan. If all parameters set up correctly,
the patient is tattooed to facilitate accurate placement on the
machine on subsequent visits. If there are any problems,
adjustments are made before the patient returns the next day
for the start of actual treatment. Further verification is done
with cone beam CT, and adjustments, or shifts, are made
as necessary, and usually repeated on a daily basis. Image-
guided radiation therapy (IGRT) thus verifies that highly con­
formal plans are delivered not only accurately, but also with
precision.

507
Applications
are all strong predictors of chest wall recurrence. Radiation
should also be considered when the lymph node status is
uncertain, and the histology shows that the tumor has evidence
of lymphovascular involvement, which predicts for local
recurrence.25,26 Conversely, it is not indicated when the tumor
size is less than 5 cm with negative margins and without
spread to the lymph nodes. There is even evidence to suggest
that tumors of 5 cm that are N0 do not benefit from PMRT.27
Radiation of the nodal draining areas
Nodal irradiation is indicated when four or more lymph
nodes are positive; RT for 1–3 nodes is still a gray area, even
though it has become fairly routine practice. When there has
been an adequate sampling, the upper axilla is usually not
included in the volume, although the supraclavicular area,
i.e., the next echelon of nodes, is included. Internal mammary
(IM) nodal RT is controversial, and subject to institutional
bias.28 IM nodal involvement is known to be more common
in medial and central breast cancers, and to be present when
axillary lymph nodes are positive,29 although IM clinical
failure is rare. Positive IM nodes detected on imaging such as
positron emission tomography (PET) fludeoxyglucose scan
are rarely resectable, unlike axillary nodes, and thus need a
higher dose of RT,30 as this situation is no longer one of adju­
vant therapy.
RT techniques
The target volume includes the breast, subcutaneous tissues,
and chest wall. In any technique used to cover these tissues,
the lower axilla is usually within the high dose volume. The
classic technique is breast “tangents”, using medial and lateral
beams (Fig. 26.13) that are either angled or blocked to reduce
the dose to the heart and lungs. The beam can be modified
radiation, including the risk of second malignancy. Poor
performance status and patient preferences can shift a poten­
tially curative scenario into one of observation, or nonradical
radiotherapy. However, chromosomal fragility syndromes
such as Li–Fraumeni syndrome and Rb or ATM gene carriers
are contraindications to radical or curative RT. Previous RT is
only a relative contraindication, in that it may be possible to
give a palliative dose, or even to treat to radical doses using
stereotactic techniques to treat small volumes.
Hints and tips
• For all patients, but particularly for young people, potential
benefit of radiation must be weighed against the late
sequelae of radiation, including the risk of second
malignancy.
• Chromosomal fragility syndromes such as Li–Fraumeni
syndrome, and Rb or ATM gene carriers, are
contraindications to radical or curative radiation therapy.
• Previous radiation therapy is a relative contraindication.
Fig. 26.13  Conserved breast treated with classic breast tangents, internal
mammary chain (IMC) not covered.
Breast cancer
Until 1997, it was widely believed that XRT for breast cancer
only offered local control, and that any improvement in sur­
vival was related to the effect of adjuvant systemic therapy.
Any survival advantage of radiation was negated by deaths
that may have been caused by cardiotoxicity from large frac­
tions and older, less precise techniques. Two landmark studies
examining the role of RT in node-positive breast cancer
demonstrated significantly improved survival with RT and
changed breast cancer practice dramatically.14–16 The impact
on overall survival has been confirmed in subsequent meta-
analyses.17,18 Although not as dramatic a finding as for nodal
XRT, radiation to the intact breast alone also confers a small
survival advantage.19
Breast conservation
Adjuvant breast irradiation allows breast conservation by
reducing the risk of breast cancer recurrence. The evidence for
the effectiveness of postlumpectomy radiation is strong, and
derived from many randomized clinical trials,20 and provides
equivalent21 or even improved22 survival for younger women
in modern series. It is one of the commonest radiotherapy
treatments in RT practice. Cosmesis was also found to be
satisfactory in a large European study that used rigorous
assessment methods.23 It is contraindicated when there has
been previous radiation treatment to the breast or chest wall
(e.g., in the treatment of Hodgkin’s lymphoma), during preg­
nancy, or when the margins are positive. Women with active
connective tissue disease, especially scleroderma,24 may have
an increased risk of acute and late toxicities, and woman with
large tumors may have poorer cosmesis as a result of a larger
defect. These, however, are only relative contraindications.
Indications for postmastectomy radiation (PMRT)
PMRT is indicated for circumstances where the tumor is 5 cm
or larger; when the margins are positive, or closer than 1 mm;
or where there are regional lymph node metastases, since these

508
CHAPTER 26 • Principles of radiation
Apart from the lower axilla, which is incidentally covered
in breast or chest wall techniques, additional planning is
required to ensure that the targeted lymph node areas match
carefully to the breast/chest wall volumes to avoid overlap
and increased toxicity to the normal tissues, including the
brachial plexus. The small apex of the ipsilateral lung receives
a full dose when treating the supraclavicular lymph node. If
overlap of fields happens, a portion of the brachial plexus may
receive almost a double dose of radiation, and thus be at very
high risk of brachial plexopathy. If treating the IM nodal
chains, there are two main techniques: the first uses an extra-
wide tangent arrangement, which can result in a significantly
larger volume of lung tissue being damaged. The addition of
an electron field patched on to the medial aspect of the tangent
fields delivers a fairly homogeneous dose over the IM nodes,
despite increasing lung and also cardiac dose, if the tumor is
located on the left side. Getting adequate dosing into the IM
nodes, and avoiding critical structures, can be especially chal­
lenging when an expander has already been placed in the
chest wall prior to using this technique (Fig. 26.15), sometimes
causing the electron dose to “splash” on to the contralateral
breast. This does not happen often on the flat chest wall of
PMRT, or when the breasts are natural and fall to the side,
leaving the ipsilateral parasternal area flat.
The standard adjuvant dose to the chest wall or breast
ranges from 45 to 60 Gy, given in 1.8–2 Gy/fraction, depend­
ing on practice, with the same dose used for the nodal areas.
As a result of a Canadian study in early-stage breast cancer,
hypofractionated RT prescribing 42.5 Gy at 2.66 Gy/fraction
provides the same local control as more prolonged treatment
schedules. Despite the larger dose per fraction, cosmesis
remains acceptable on long-term follow-up.31,32
Even in the absence of positive margins, local recurrence is
most likely to occur in the operative bed, or tumor cavity. The
use of a boost to this volume can reduce this risk, and is rec­
ommended in patients at higher risk for local failure (age <50
years, positive axillary nodes, lymphovascular invasion, or
close margins). A European study33 showed that women aged
40 or younger benefited significantly from extra treatment to
the tumor cavity, halving their risk of local recurrence from
19.5% to 10.2%. The benefit was less striking in women aged
over 40. Boost doses of 2 Gy/fraction usually bring the total
dose to the tumor cavity to a minimum of 60 Gy, and can be
delivered with photons, including using conformal or IMRT
techniques, electrons, a combination of photons and electrons,
brachytherapy, or, more recently, with protons. The technique
again depends on institutional experience and operator skill.
Addition of a boost can result in fibrosis and compromise
cosmesis.33
Another approach has been to treat only the area most at
risk, i.e., the cavity plus a margin, and not treat the whole
breast. Accelerated partial breast irradiation seems to provide
equivalent local control in patients over age 60 years, with low
risk features, in a very convenient fashion with 10 b.i.d. treat­
ments of either brachytherapy (total 34 Gy) or external-beam
photon therapy (total 38.5 Gy) to the tumor bed.
Head and neck cancer
Head and neck cancers are mostly squamous cell carcinomas
(HNSCCs). Radiation has an important role in the primary,
postoperative, and palliative aspect of their management.
with a wedge-shaped device to reduce the “hot spot” of radia­
tion dose that can result from this technique. IMRT and other
conformal approaches are frequently used now, obviating the
need for wedges, providing homogeneous dose distribution
and reducing treatment time.
The same techniques are used to treat the chest wall, although
the scar and drains have traditionally been in the high-dose
volume, necessitating bolus to ensure that the scar receives an
adequate dose (Fig. 26.14). The use of bolus on the entire chest
wall is debatable, except in the case of inflammatory breast
cancer, where tumor cells, by definition, invade the dermis,
and so it is essential to achieve full dose on the chest wall skin.
Fig. 26.14  Post mastectomy XRT plan. (A) Including the IMC nodal area using a
wide tangent technique, resulting in a larger volume of irradiated lung. (B) The use
of bolus to bring the surface dose to 100%, and losing the skin sparing effect.
A
B

509
Applications
a smaller dose per fraction over the same time period (hyper­
fractionation) can improve outcome but result in severe acute
toxicity so that breaks in treatment may be necessary, thus
negating the benefit of altering the fractionation schedule.
Doses used for gross tumor are in the 66–72 Gy range.
Subclinical disease is treated to 50–60 Gy. Before the introduc­
tion of IMRT, these areas were usually treated sequentially,
covering the larger volume to a “microscopic” dose, before
boosting the smaller volume or volumes containing gross
disease, although a concomitant boost was sometimes used.
However, IMRT allows a technique of “dose painting” or
differential dosing so that the areas at higher risk are pro­
grammed to receive a slightly higher dose per day than the
areas of low risk. It can also reduce the dose to the parotid,
reducing the risk of permanent xerostomia.37 Submandibular
gland-sparing IMRT has also been utilized in select patients
to reduce xerostomia with excellent locoregional control.38
Acute toxicities occur during the course of treatment and
resolve 2–3 months following completion of treatment. They
are reversible unless the acute damage is confluent, causing
damage to the basal membrane and depleting the supply of
stem cells. Mucositis, which is exacerbated by smoking and
alcohol, starts during weeks 2–3, becoming confluent by the
end. It affects the mucous membranes within the high-dose
volume and results in difficulty in swallowing. Because of
concerns about nutritional status, percutaneous endoscopic
gastrostomy tubes are inserted before the start of treatment.
Mucositis is painful and mouthwashes containing local anes­
thetic help this, but usually narcotics are also required. The
skin develops erythema by weeks 3–4, even with the aggres­
sive use of topical aloe vera gels, other unguents, and steroids.
Reaction is inevitably brisk with moist desquamation by
completion of treatment. Because of dose to the parotid,
patients will also experience change in taste; radiation causes
xerostomia, changing the consistency of saliva by drying the
water component, which results in thick mucoid secretions
Previously, a general principle of minimizing toxicity by using
either surgery or radiation, and keeping the other modality for
salvage, was preferred. However, increasingly, especially in
locally advanced disease, combined modality, particularly
postoperative radiation treatment, is used because it has been
shown to reduce the incidence of recurrence, especially in the
cervical lymph nodes. The use of concurrent chemotherapy has
also changed the practice over the last 10–15 years. Several
studies have shown a benefit in both survival and local control;34
as a result, platinum-based therapy has become the standard
of care in the management of all but the most favorable – early
disease that has a high cure rate with RT alone. However acute
toxicity is considerably worsened by concurrent chemotherapy,
and some patients are not optimal candidates for cisplatin due
to competing comorbidities or poor performance status. In
RTOG 9501,35 cetuximab concurrently with radiotherapy for
locally advanced head and neck squamous cell carcinomas
showed an improvement in survival and local control com­
pared to radiation alone and appeared to have less toxicity
compared to cisplatin based on historical trials.
The incidence of HPV-associated oropharyngeal cancers
has been increasing, with a decrease in rates in smokers. HPV-
associated oropharyngeal SCC clinically behaves differently
with a better prognosis. De-intensification of therapy for HPV-
positive tumors is being investigated in multiple ongoing
trials with the overall goal to reduce morbidity in HPV-related
HNSCC without a detriment in survival and local control.
Data from these studies will help guide optimal treatment in
this patient population.
SCC head and neck cancers have lower local control rates if
treatment time is extended, due to repopulation of tumor
cells.36 In order to overcome this effect, efforts have to be made
to deliver five fractions per week even if it requires treating
twice a day to do so. Approaches that intensify the course of
treatment by giving it over a shorter period of time (accelerated
fractionation) or giving treatment more than once a dayusing
Fig. 26.15  (A) Treating a right breast mound with inflated expander in place can mean that the medial aspect of the contralateral breast may be “splashed”. (B) The
expander in situ is more problematic for the contralateral breast when the IMC lymph nodes are treated.
A
B

510
CHAPTER 26 • Principles of radiation
the radiologically visible tumor and the CTV covers peritu­
moral edema as seen on MRI T2 imaging, or CT or PET CT
volume plus 2–3 cm. If the margins are positive after resec­
tion, a further 16 Gy is usually given, although this practice
may not be necessary.41
Optimal immobilization is important in the RT planning
process. It is also necessary to delineate bones, joints, and
perineum so that dose to these sites can be minimized. It is
also necessary to spare a longitudinal strip of skin and sub­
cutaneous tissue so that lymphatic drainage remains intact
to reduce the risk of chronic lymphedema. Conformal tech­
niques, including IMRT, are often needed to meet these
constraints.
The issue of whether pre- or postoperative XRT is used
remains controversial. Certainly the preoperative advantages
of an early start of XRT, a smaller irradiated volume and likely
lower dose, and, as a result of these features, less fibrosis and
better functional outcome42 are compelling. However, the
delay to definitive surgical treatment and the doubling of risk
of wound complications (17–35% in the Canadian random­
ized trial) are also serious issues to consider.42
Skin cancers
Nonmelanoma skin cancers
This group encompasses basal cell carcinoma (BCC), SCC,
Merkel cell carcinoma, and cutaneous angiosarcoma. Of
these, the commonest are BCC and SCC. The majority are
radiation-related, albeit mostly solar radiation! Due to their
chronic immunosuppression, patients who have undergone
transplantation are more likely to develop SCC, which tends
to behave more aggressively. Primary radiation is indicated
when the patient is not a surgical candidate (due to comor­
bidities, anticoagulation, or patient preference) or when
surgery may risk function or cosmesis, and in the adjuvant
setting to reduce the risk of local recurrence. It can provide
good palliation for locally advanced unresectable disease,
often with high doses to optimize local control. Decisions
about the extent of the RT target volume are based on the risk
of lymph node metastases, and inclusion of the regional nodes
in high-risk disease. An important consideration is the pres­
ence of perineural invasion, which may involve treating
extended volumes along neural pathways. In all, 30–40% of
incompletely incised BCCs recur but they can be salvaged
equally with surgery or radiation.43 Doses for the primary
treatment of BCC are in the range of 40–50 Gy delivered in
10–20 fractions, but higher doses are needed for SCC, similar
to those for head and neck squamous cell cancers. Small
lesions without risk for nodal or perineural involvement can
be treated with hypofractionation.
When delivering radiotherapy for skin cancers one has to
be able to achieve a high dose superficially. One of the best
ways to do this is to use superficial kV equipment that pro­
vides 100% of the dose at the surface and a very tight penum­
bra resulting in smaller fields. However, this equipment has
now been largely supplanted by electrons, which have a
larger penumbra due to their propensity to scatter. Further­
more, low-energy electrons do not provide 100% of the dose
at the surface, which is corrected with the use of bolus.
Although treatment with XRT is highly curative, late toxici­
ties of treatment result in cosmetic changes related to change
that are difficult to clear. During treatment patients often lose
weight and experience fatigue.
Late toxicities depend on the size of dose per fraction given.
They occur 6 months to 3 years following the completion of
treatment and unfortunately are permanent and progressive.
The primary problem is fibrosis that can affect the subcutane­
ous tissues, musculature, and joints. The patient can experi­
ence trismus, neck stiffness, aching, and swallowing difficulties
as a result. If the parotid has been treated to more than 26 Gy
the patient may be left with permanent xerostomia, which can
exacerbate dental problems. The patient may also experience
voice changes due to chronic laryngeal edema and/or carti­
lage damage. Patients are also at risk of osteoradionecrosis
(ORN), as described later.
Soft-tissue sarcoma
Sarcomas comprise a heterogeneous group of more than 100
bone and soft-tissue mesenchymal subtypes. Soft-tissue sarco­
mas (STS) are rare mesenchymal malignancies arising from
connective tissue. They can arise anywhere in the body but
most commonly affect the extremities and trunk. In the pedi­
atric population, 7% of tumors are STS,39 with half of these
being rhabdomyosarcoma, and, especially in younger children,
these tumors are more responsive to chemotherapy, so radia­
tion is either spared or used at lower doses to avoid arresting
growth or increasing the risk of a second malignancy.
Because of the rarity of STS (only about 10 000 are diagnosed
per year in the US) and the numerous locations and subtypes,
they are best managed in specialized multidisciplinary groups
that include dedicated sarcoma radiation oncologists. Progno­
sis depends on size, grade, histological subtype, and superfi­
ciality of the tumor. Location is also important; retroperitoneal
sarcomas have an independently worse outcome, but usually
do not present until tumors are very large.
Although the primary treatment of STS is surgery, adjuvant
radiation is important for limb and function conservation in
extremity sarcoma and reducing the risk of local recurrence.
Overall, local control rates are approximately 80% at 5 years.40
If the patient is unfit for surgery, primary RT can provide
useful local control. The role of XRT in adjuvant treatment of
osteosarcoma, chondrosarcoma, and chordoma is minimal,
although it can be a useful modality for palliation.
Doses and techniques in adults
Postoperative adjuvant XRT is indicated after resection of
high-grade or large tumors with negative margins, or any
tumor with positive margins.
Standard adjuvant postoperative radiation doses for STS
are 60–66 Gy in 30–33 fractions, or higher if any gross disease
remains, with reduction in the size of the volume after 50 Gy.
The CTV is often large, encompassing the entire operative
bed, which is determined with postoperative magnetic reso­
nance imaging (MRI) to visualize the operative “footprint”,
or by reconstructing preoperative imaging (e.g., fusing with
diagnostic MR scan) and using surgical clips, operating room
report, and guidance from the surgeon to determine the extent
of the target volume. Generous margins are used to cover any
uncertainty.
The standard preoperative neoadjuvant XRT dose is 50 Gy
given in 25 fractions of 2 Gy over 5 weeks. The GTV covers

511
Specific toxicities and complications
tumor recurrence.49 It presents as clinically exposed bone,
sometimes without any pain, and radiologic evidence of
necrosis on both CT and MRI between 1 and 3 years following
radiation. Radiologic findings may mimic disease recurrence.
ORN is mostly seen as a result of treating head and neck
cancer and most frequently affects the mandible. Radiation-
related risk factors include fraction size (>200 cGy), the volume
of bone irradiated, a total dose to the bone of >6000 cGy, and
re-irradiation. The modality of radiation used is also impor­
tant, because particle therapy (electrons, neutrons, and
protons), brachytherapy, and kilovoltage energy can result in
higher absorbed doses within bone than from megavoltage
XRT, e.g., photons. The use of three-dimensional treatment-
planning systems, improvements in immobilization, as well
as conformal techniques such as IMRT and higher precision
with IGRT for localization, help to minimize the volume of
bone in the target, as well as the dose. Other risk factors in
the head and neck region include poor oral hygiene and
dental extraction, making careful dental preparation an inte­
gral part of treatment planning. Prior to initiation of radiation
therapy, patients undergo dental clearance. Dental extractions,
if indicated, are done prior to the start of RT. During RT
planning, the radiation oncologist delineates the mandible,
maxilla, and salivary glands and identifies dose constraints.
After completion of radiotherapy, patients proceed with life-
long daily fluoride treatments and maintain a pristine dental
hygiene regimen. Concurrent chemotherapy causes mucositis
and xerostomia, further increasing the risk, as does the xero­
stomia resulting from relatively low doses to the parotid.
ORN arising in other sites can also be associated with trauma
and surgery.
Although ORN in the head and neck region had an inci­
dence of 6.8% in 1968,50 it is fortunately now quite rare, with
recent series reporting incidences of 0–2%.51,52 Bisphospho­
nates can cause osteonecrosis without radiation,53 but it is still
unclear what increased risks are incurred with concurrent
radiation and bisphosphonate therapies.
Bone fractures occurring within the irradiated volume are
more common. Rib fractures tend to be the result of coughing.
Limb fractures can happen with minimal trauma. No inter­
vention is necessary for clavicles or ribs, but long bones
usually require an intramedullary nail and there can be long
delays in union. An analysis of fractures associated with soft-
tissue sarcoma identified that the total dose to the bone and
the volume irradiated were critical factors, leading to recom­
mendations that the maximum dose to the bone should be
5900 cGy, and that the volume of bone receiving >4000 cGy be
limited to 64%.54
Bone growth in children
Prior to the development of effective chemotherapies, radio­
therapy was the main modality in the treatment of pediatric
tumors, so it was widely recognized early on that radiation
impedes bone development in children, leading to limb
shortening, asymmetry (including scoliosis), deformity and
functional impairment. It was difficult initially to quantify
dose constraints as treatments and dosimetry were very het­
erogeneous. Radiologically, there are changes on the growth
plate that resemble rickets, with metaphyseal sclerosis, meta­
physeal fraying, and epiphyseal plate widening, reflecting the
radiosensitivity of rapidly proliferating cells in this region.
in pigmentation, fatty necrosis, subcutaneous fibrosis, and
dermal telangectasia. These tend not to arise for 2 years or
more after treatment and not all patients suffer these effects.
These risks are increased with larger volumes and larger frac­
tion size. Fortunately, since many of these cancers are small,
and the patient population is, by and large, elderly and frail,
one can still get away with using hypofractionated treatment
over a shorter period of time.
Merkel cell carcinoma is a rare neuroendocrine skin tumor
that has a lethal potential for spread. Both the local disease
and the regional lymph nodes need to be treated. Inclusion of
nodal areas means that radiotherapy volumes become larger
and smaller fraction sizes are necessary. However, hypofrac­
tionation with single fraction has been shown to provide
excellent control with possible abscopal effects.44
Angiosarcoma is primarily treated with surgery. When this
is not possible or when there is recurrence or presence of posi­
tive margins, radiation is necessary with higher doses between
66 and 70 Gy. Tumor location can be an important issue in
planning treatment. Treating the entire scalp but avoiding the
brain requires sophisticated treatment planning. One tech­
nique is called the “German helmet”, in which a combination
of photons and electrons is used to minimize penetration to
the brain and subsequent cognitive dysfunction.
Malignant melanoma is generally thought to be relatively
radioresistant. In vivo studies show that the cell survival curve
has a very broad shoulder, indicating that these cells have a
large capacity to repair sublethal damage. The way to over­
come this is to hypofractionate with large doses per fraction.
Adjuvant radiation can reduce the risk of local recurrence in
high-risk adjuvant situations. At the MD Anderson Cancer
Center, criteria for this include desmoplastic histology, depth
>4 mm with ulceration or satellite lesions, positive margins,
or recurrent disease.45 Radiation to involved or high-risk but
clinically negative lymph nodes can improve control. Hypo­
fractionated radiotherapy is effective, 6 Gy twice a week for
a total of 30–36 Gy regimens such as are commonly used,46
albeit with a higher risk of lymphedema, improving local
control from 50% to 87%47 without affecting survival. Radia­
tion also plays a major role in palliation of brain and bone
metastases, and uncontrolled tumor.
Benign disorders
RT was historically used to treat many benign conditions,
such as ankylosing spondylitis, tinea capita, and eczema, that
fortunately now are treated with other therapies. However, it
is still used in the treatment of noncancerous conditions such
as prevention of heterotopic ossification after hip replacement
surgery and keloid scars.48 Doses used are low, so unlikely to
cause significant problems with fibrosis. However, especially
in a younger person, the concerns about development of a
radiation-induced malignancy must be weighed against the
potential gain of using radiation for benign disease.
Specific toxicities and complications
Bony injury
ORN is a necrotic wound manifested in irradiated bone that
persists without healing for 3–6 months, in the absence of

512
CHAPTER 26 • Principles of radiation
Independent risk factors for breast cancer-associated
lymphedema include radiation treatment of the axilla, the
extent of axillary lymph node dissection, the type of breast
surgery, and the presence of regional lymph node metastases.62
A history of infection and injuries, and the patient’s body
mass index are also associated factors. The combination of
XRT and axillary lymph node dissection confers the greatest
risk.61 A large series from Massachusetts General Hospital
reported lymphedema rates of 10% in women who had
breast-conserving surgery and XRT to the axilla,62 although
historically, higher rates have been reported. It has also been
suggested58 that, with survival and longevity, this late toxicity
becomes more prevalent. However, as sentinel lymph node
dissection has become the standard of care in early breast
cancer, this will result in a lower risk of lymphedema than
conventional axillary lymph node dissection risks.63 ACOSOG
Z0011 demonstrated that complete axillary lymph node dis­
section could be omitted in select patients with limited sentinel
node-positive disease. This trial compared sentinel lymph
node resection with versus without axillary lymph node dis­
section in patients with T1–2 tumors with up to 3 positive
sentinel lymph nodes. All of the patients underwent
The child’s age at the time of radiation is important, since
most bone growth occurs in the first 5 years. The most impor­
tant radiotherapy factors are the total dose and volume of
bone irradiated. Although 30 Gy is considered the tolerance
threshold dose, growth effects are seen with as low a dose as
15 Gy, suggesting a very steep dose–response curve in this
range.55 If the spine is within the high-dose volume, uniform
dose across the whole vertebral body is recommended to
reduce the risk of scoliosis.39
Craniofacial growth is different to long bones, since these
bones develop through intramembranous ossification, result­
ing in a complex three-dimensional pattern of growth.56 Dis­
ruption of this growth by radiation in all or any part of the
head and face can cause significant clinical problems, includ­
ing distorted appearance and functional problems related to
eating. Dentition is also affected.
Cranial irradiation is used for prophylaxis against central
nervous system relapse in leukemia. Not only can this affect
cognition and bone growth, it can also impair the production
of growth hormone, which results in decreased bone miner­
alization.57 Genetic factors are important, for example, in the
treatment of retinoblastoma, where there may be much greater
sensitivity to XRT. Biological factors that are disrupted by XRT
include remodeling of the extracellular matrix in response to
paracrine and endocrine signaling that affects chondrocyte
production. Radioprotective agents, such as amifostine, have
been studied in vivo and found to protect a number of cell
lines, such as osteoblast-like, endothelial, and fibroblastic,
from harmful effects of radiation.58
Cardiovascular disease
There has been a well-established correlation between radia­
tion and risk of cardiac morbidity and mortality, particularly
associated with treatment of breast cancer and Hodgkin’s
lymphoma. Radiation therapy for left-sided breast tumors
increases risk of subsequent ischemic cardiac disease by 7.4%
per Gy mean heart dose that follows a linear, no-threshold
relationship.59 Several techniques have been developed to
reduce heart and coronary vessel dose. Deep inspiratory
breath hold (DIBH) is a technique to reduce the heart dose for
left-sided breast cancer irradiation, with current data showing
clinical benefit based on modeled risk estimates, most notably
in patients with high baseline cardiac risk.60 This technique
displaces the heart away from the chest wall (Fig. 26.16). CT
simulation involves both DIBH and free breathing scans for
dosimetric comparisons of the heart and chest wall separation
with breath hold technique.
Lymphedema
The mechanics of RT-related lymphedema are due to the
radiation-induced fibrosis causing compression of the lymph
vessels. When assessing lymphedema in someone who has
had a previous cancer diagnosis, it is important to exclude
recurrent disease before assuming that the edema is related
to treatment. However, lymphedema after breast cancer is
common. Norman et al. identified 42% 5-year accumulative
incidence in a 5-year prospective, population-based study of
breast cancer survivors. However, the majority (23%) described
only mild lymphedema, and only 2% had developed chronic,
severe edema.61
Fig. 26.16  Reducing dose to the heart in left-sided breast tumors. (A) Radiation
treatment CT simulation for whole-breast irradiation with deep inspiratory
breath-hold technique avoids the heart and coronary arteries in comparison to using
standard free breathing (B). (Courtesy, L. Christine Fang MD.)
A
B

513
Specific toxicities and complications
volumes and can minimize dose to critical structures, there
is a large lower-dose volume from the multiple-beam entry
through normal tissues.71,73 Thyroid cancer is unlikely when
the gland has received doses over 30 Gy. Conversely, sarco­
mas tend to arise in heavily irradiated tissues, and appear to
have a dose–response effect. Survivors of Hodgkin’s disease
treated with mantle radiation (i.e., mediastinal, cervical, and
axillary nodal XRT with shields over the lungs) have four
times the risk of developing breast cancer. The woman’s age
at the time of XRT is extremely important: adolescent girls
aged 10–16 years have a 136-fold greater risk of developing
breast cancer than their nonirradiated peers.74 Factors such
as smoking can markedly increase the risk of developing
primary lung cancer, even in parts of the lung that received
only a tiny scattered dose. Some genetic predispositions,
such as Li–Fraumeni syndrome, which is linked to germline
mutations of the p53 suppressor gene, or ATM and RB gene
carriers, are exquisitely susceptible to any form of radiation.
Exposure to radiation
Radiation accident studies have shown that there is a propor­
tional relationship between the amount of radiation exposure
and the risk of developing cancer.75 The sievert (Sv) is the SI
unit that measures the biological effect of absorbed dose, taking
into consideration the relative biological effectiveness of the
radiation (e.g., 1 for photons and electrons, 20 for high-dose
neutrons and α-particles) and the biological effect on different
organs. When all of these weightings are 1, then 1 Sv = 1 Gy.
The gray is a unit of absorbed dose in any material defined
only by physical, not biological, properties of radiation. The
sievert is used to quantify risk of radiation damage, including
cancer. To put this into perspective, on average, a chest X-ray
is 0.34 mSv, mammogram 0.48 mSv, and CT thorax 6 mSv. The
biggest contributor of background radiation source is radon,
which is approximately 2 mSv annually. There is background
cosmic radiation of 0.24 mSv per year, and a passenger on a
return flight between Seattle, WA and Toronto, ON would
be exposed to 0.085 mSv. Radiation oncologists are limited
to an occupational exposure of 50 mSv per year, excluding
medical and background sources of radiation, but after the
March 2011 earthquake and subsequent explosion in a nuclear
reactor, the emergency nuclear workers at Fukushima, Japan
were exposed to up to 400 mSv per hour. The Japanese public
already has a 20–25% lifetime risk of cancer, and exposure to
400 mSv increases that risk by 2–4%. Survivors of the atom
bombs in Hiroshima and Nagasaki have an excess risk of
cancer (RR 1.42 at 1 Sv) that persists through their lifetime.
Exposure to 1 Sv increases the lifetime risk of fatal cancer
by approximately 5%. The most sensitive organs to this sort
of accidental exposure are bone marrow and thyroid, and
leukemia is the most common resulting malignancy. Radia­
tion sickness is an acute effect of radiation exposure, causing
nausea, headache, and bone marrow suppression, and is
rarely experienced at exposures of less than 1 Sv.
Regardless of the regulatory safety requirements, the
ALARA (As Low As Reasonably Achievable) principle is
the mantra of all who work with ionizing radiation in their
efforts to reduce the risk of harm. Ways to minimize radiation
exposure include reducing time of exposure, increasing the
distance from the radiation source, and utilizing adequate
shielding.
breast-conserving surgery with whole breast irradiation. The
study required no dedicated axillary lymph node irradiation.
There was no difference in local or regional recurrence, sup­
porting omission of axillary lymph node dissection in this
population.64 Initial results of the AMAROS trial (which ran­
domized patients with a positive sentinel lymph node to
ALND or axillary RT) show excellent 5-year local control and
survival with less lymphedema in the radiotherapy arm.65
Brachial plexopathy
Brachial plexopathy is most commonly due to metastatic
disease involving the brachial plexus, and it can be very dif­
ficult to distinguish between the late side effect of XRT versus
recurrence. PET has been reported to be helpful.66 However,
it is also a rare (1%) complication of radiation treatment.67 Its
development is dependent not just on total dose, with a
marked increase above 6000 cGy, but also on the dose per
fraction. RT technique is also a very important factor, as older
breast RT techniques that extended to the lymph nodes could
result in overlapping fields just above the clavicle immediately
above the brachial plexus, meaning that the plexus received
up to twice the prescribed dose. Concurrent chemotherapy
also increased the risk.
Radiation-induced malignancies
Radiation has been shown to induce malignant transforma­
tion in vitro, for example, in laboratory mice, and in vivo, for
example, from atom bomb survivors, as well as long-term
follow-up studies. Three mechanisms for radiation-induced
malignancy have been suggested: (1) DNA damage and sub­
sequent mutation; (2) disturbances of multiple defense or
control mechanisms within the cell at the molecular level; and
(3) the chronic ongoing damage of irradiated tissue.68
Radiation-induced malignancies are rare within the first 5
years after treatment, and usually present many years after
treatment. As more cancers are cured, and the number of
long-term survivors increases, so does the risk of radiation-
induced malignancies.69 Although a second malignancy rate
of 1 per 100 000 patients treated is often cited, this figure is
only an estimate, and may be misleading. Many different
mathematical models are used to standardize the doses, dose
per fraction and quality of radiation, as well as the volume
of the target, the organs treated, and the age of the patient.
Second primary tumors are more common in those who
have already had a malignancy, with a RR of 1.12, regardless
of treatment. Chemotherapy, especially alkylating agents, is
also carcinogenic, although more likely to induce leukemia
than a solid tumor, and within a much shorter latency period.
The addition of chemotherapy during RT also increases the
risk. Some of the best data come from follow-up of child­
hood survivors,70 although also identifying large variations
in findings. In children, susceptibility varies according to age
and the type of tissue irradiated, with leukemia developing
after 5–8 years, and solid tumors, the commonest of which
are thyroid cancers, breast cancers, and bone and central
nervous system malignancies, usually occurring many years
later.71,72 Some second primary malignancies, especially carci­
nomas, arise around the periphery of the high-dose volume.
Concerns have been expressed about the risk of techniques
such as IMRT: although they have very conformal high-dose

514
CHAPTER 26 • Principles of radiation
and reducing the risk of radiation injury by sparing more
normal tissue. Improvements in RT-planning systems
provide not only the ability to apply dose constraints to
specified structures, but also to provide data that help quan­
tify risk of toxicity, in tandem with better reporting and col­
lection of data and outcomes. These approaches all
contribute to improving the prevention of radiation injury.
Radioprotection also occurs by reducing risk of radiation
damage through modification of delivery techniques, but
modulating radiation cellular response is of greater impor­
tance. Although this concept has been studied for years,
clinical results have been disappointing; nevertheless, a new
generation of biological modifiers offers greater hope.
However, the future of radiation oncology lies in biology,
and specifically bioengineering and tissue regeneration, and
the imperative to repair the damage that has already
been caused.
Conclusion and future trends
Radiation treatment uses ionizing radiation to treat malignan­
cies as a primary therapy, or, more importantly now, as part
of a planned collaborative multidisciplinary approach, used
in combination with systemic therapy and surgery. Like
surgery, it is a local therapy, and has a curative, adjuvant, or
palliative role in managing most cancers. Although acute
toxicities are reversible, late toxicities are not, and are related
mostly to the loss of normal fibrosis mechanisms. The risk of
radiation-induced malignancy, as well as other late side
effects, becomes more important as more cancers are cured,
and the proportion of survivors grows.
Dramatic advances in radiation treatment planning, deliv­
ery, and verification technology have increased the accuracy
and precision of treatment, allowing higher doses to tumor,
7. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to
therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122.
8. Bentzen SM, Constine LS, Deasy JO, et al. Quantitative Analyses of
Normal Tissue Effects in the Clinic (QUANTEC): an introduction to
the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76:S3–S9. The
QUANTEC project was to update classic modeling of normal tissue
complication probability (NTCP) described by Emami in 1991 to include
new data and models, and more specifically, data acquired from more
modern 3-dimensional dosimetry techniques. They also identified the
inherent methodological problems of modeling from very heterogeneous
sources and variable quality of data, and the need to include new
biological and pharmaceutical knowledge into the relationship between
dose and volume, and proposed a structure for future research priorities.
10. Straub JM, New J, Hamilton CD, et al. Radiation-induced fibrosis:
mechanisms and implications for therapy. J Cancer Res Clin Oncol.
2015;141:1985–1994. This comprehensive literature review of radiation-
induced fibrosis describes the complex reaction of normal tissues to
ionizing radiation on a cellular level, including the acute inflammatory
response mediated by numerous cytokines and growth factors, including
growth factor beta, in an attempt to heal the injury. The outcome is a
progressive fibrotic reaction that is quite different to scarring from surgery
or trauma.
11. Denham JW, Hauer-Jensen M. The radiotherapeutic injury–a
complex ‘wound’. Radiother Oncol. 2002;63:129–145. The complexity of
radiotherapeutic injury within the irradiated volume is compared to
traumatic wound healing; the biggest difference is the injury is repeated
with the delivery of each fraction. The response to radiotherapy is an
organized process that can also be affected by the dose and scheduling of
radiotherapy, as well as several clinical factors.
12. Prasanna A, Ahmed MM, Mohiuddin M, Coleman CN. Exploiting
sensitization windows of opportunity in hyper and hypo-
fractionated radiation therapy. J Thorac Dis. 2014;6:287–302.
28. Taghian A, Jagsi R, Makris A, et al. Results of a survey regarding
irradiation of internal mammary chain in patients with breast
cancer: practice is culture driven rather than evidence based. Int J
Radiat Oncol Biol Phys. 2004;60:706–714. There is great variation in the
use of radiation to treat the internal mammary chain (IMC) of lymph
nodes in patients with breast cancer. There is little definitive data, making
this a controversial issue. These patterns of practice were examined in a
case-based survey of radiation oncologists across North America and
Europe. All respondents were more likely to treat the IMC if the axillary
nodes were involved, and European and Academics in North America
were also more likely to treat the IMC. However, the study also
demonstrated how the greatest influence on decision-making was the local
culture, and the value and preference that was placed on interpretation of
local data.
32. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of
hypofractionated radiation therapy for breast cancer. N Engl J Med.
2010;362:513–520.
42. Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity
following randomization to preoperative versus postoperative
radiotherapy in extremity soft tissue sarcoma. Radiother Oncol.
2005;75:48–53.
57. Norman SA, Localio AR, Potashnik SL, et al. Lymphedema in breast
cancer survivors: incidence, degree, time course, treatment, and
symptoms. J Clin Oncol. 2009;27:390–397.
68. Tubiana M. Can we reduce the incidence of second primary
malignancies occurring after radiotherapy? A critical review.
Radiother Oncol. 2009;91:4–15, discussion 1–3. Second primary
malignancies (SPMs) occurring after oncological treatment have become a
major concern during the past decade. Their incidence has long been
underestimated because most patients had a short life expectancy after
treatment or their follow-up was shorter than 15 years. With major
improvement of long-term survival, longer follow-up, cancer registries and
end-result programs, it was found that the cumulative incidence of SPM
could be as high as 20% of patients treated by radiotherapy. This
cumulative proportion varies with several factors, which ought to be
studied more accurately. The delay between irradiation and solid tumor
emergence is seldom shorter than 10 years and can be as long as half a
century. Thus, inclusion in a cohort of patients with a short follow-up
leads to an underestimation of the proportion of SPM caused by treatment,
unless actuarial cumulative incidence is computed. The incidence varies
with the tissue and organs, the age of the patient at treatment, hereditary
factors, but also, and probably mainly, with dose distribution, size of the
irradiated volume, dose, and dose-rate. An effort toward a reduction in
their incidence is mandatory. Preliminary data suggest that SPMs are
mainly observed in tissues having absorbed doses above 2 Gy (fractionated
irradiation) and that their incidence increases with the dose. However, in
children thyroid and breast cancers are observed following doses as low as
100 mGy, and in adults lung cancers have been reported for doses of 500
mGy, possibly due to interaction with tobacco. The dose distribution and
the dose per fraction have a major impact. However, the preliminary data
regarding these factors need confirmation. Dose-rates appear to be another
important factor. Some data suggest that certain patients, who could be
identified, have a high susceptibility to radiocancer induction. Efforts
should be made to base SPM reduction on solid data and not on
speculation or models built on debatable hypotheses regarding the
dose-carcinogenic effect relationship. In parallel, radiation therapy
philosophy must evolve, and the aim of treatment should be to deliver the
minimal effective radiation therapy rather than the maximal tolerable dose.
Access the complete reference list online at

514.e1
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54. Dickie CI, Parent AL, Griffin AM, et al. Bone fractures following
external beam radiotherapy and limb-preservation surgery for
lower extremity soft tissue sarcoma: relationship to irradiated bone
length, volume, tumor location and dose. Int J Radiat Oncol Biol
Phys. 2009;75:1119–1124.
55. Eifel PJ, Donaldson SS, Thomas PR. Response of growing bone to
irradiation: a proposed late effects scoring system. Int J Radiat Oncol
Biol Phys. 1995;31:1301–1307.
56. Gevorgyan A, La Scala GC, Neligan PC, et al. Radiation-induced
craniofacial bone growth disturbances. J Craniofac Surg.
2007;18:1001–1007.
57. Norman SA, Localio AR, Potashnik SL, et al. Lymphedema in breast
cancer survivors: incidence, degree, time course, treatment, and
symptoms. J Clin Oncol. 2009;27:390–397.
58. Tsai RJ, Dennis LK, Lynch CF, et al. The risk of developing arm
lymphedema among breast cancer survivors: a meta-analysis of
treatment factors. Ann Surg Oncol. 2009;16:1959–1972.
59. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of
differences in the extent of surgery for early breast cancer on local
recurrence and 15-year survival: an overview of the randomised
trials. Lancet. 2005;366:2087–2106.
60. Eldredge-Hindy HB, Duffy D, Yamoah K, et al. Modeled risk of
ischemic heart disease following left breast irradiation with deep
inspiration breath hold. Pract Radiat Oncol. 2015;5:162–168.
61. Ozaslan C, Kuru B. Lymphedema after treatment of breast cancer.
Am J Surg. 2004;187:69–72.
62. Coen JJ, Taghian AG, Kachnic LA, et al. Risk of lymphedema after
regional nodal irradiation with breast conservation therapy. Int J
Radiat Oncol Biol Phys. 2003;55:1209–1215.
63. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter
trial of sentinel node biopsy versus standard axillary treatment in
operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst.
2006;98:599–609.
64. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no
axillary dissection in women with invasive breast cancer and
sentinel node metastasis: a randomized clinical trial. JAMA.
2011;305:569–575.
65. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or
surgery of the axilla after a positive sentinel node in breast cancer
(EORTC 10981-22023 AMAROS): a randomised, multicentre,
open-label, phase 3 non-inferiority trial. Lancet Oncol.
2014;15:1303–1310.
66. Eubank WB, Mankoff D, Bhattacharya M, et al. Impact of FDG PET
on defining the extent of disease and on the treatment of patients
with recurrent or metastatic breast cancer. AJR Am J Roentgenol.
2004;183:479–486.
67. Pierce SM, Recht A, Lingos TI, et al. Long-term radiation
complications following conservative surgery (CS) and radiation
therapy (RT) in patients with early stage breast cancer. Int J Radiat
Oncol Biol Phys. 1992;23:915–923.
68. Tubiana M. Can we reduce the incidence of second primary
malignancies occurring after radiotherapy? A critical review.
Radiother Oncol. 2009;91:4–15, discussion 1–3. Second primary
malignancies (SPMs) occurring after oncological treatment have become a
major concern during the past decade. Their incidence has long been
underestimated because most patients had a short life expectancy after
treatment or their follow-up was shorter than 15 years. With major
improvement of long-term survival, longer follow-up, cancer registries
and end-result programs, it was found that the cumulative incidence of
SPM could be as high as 20% of patients treated by radiotherapy. This
cumulative proportion varies with several factors, which ought to be
studied more accurately. The delay between irradiation and solid tumor
emergence is seldom shorter than 10 years and can be as long as half a
century. Thus, inclusion in a cohort of patients with a short follow-up
leads to an underestimation of the proportion of SPM caused by treatment,
unless actuarial cumulative incidence is computed. The incidence varies
with the tissue and organs, the age of the patient at treatment, hereditary
factors, but also, and probably mainly, with dose distribution, size of the
irradiated volume, dose, and dose-rate. An effort toward a reduction in
their incidence is mandatory. Preliminary data suggest that SPMs are
mainly observed in tissues having absorbed doses above 2 Gy (fractionated
irradiation) and that their incidence increases with the dose. However, in
children thyroid and breast cancers are observed following doses as low
as 100 mGy, and in adults lung cancers have been reported for doses of
500 mGy, possibly due to interaction with tobacco. The dose distribution
and the dose per fraction have a major impact. However, the preliminary
data regarding these factors need confirmation. Dose-rates appear to be
another important factor. Some data suggest that certain patients, who
could be identified, have a high susceptibility to radiocancer induction.
Efforts should be made to base SPM reduction on solid data and not
on speculation or models built on debatable hypotheses regarding the
dose-carcinogenic effect relationship. In parallel, radiation therapy
philosophy must evolve, and the aim of treatment should be to deliver

514.e3
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the minimal effective radiation therapy rather than the maximal tolerable
dose.
69. Suit H, Goldberg S, Niemierko A, et al. Secondary carcinogenesis in
patients treated with radiation: a review of data on radiation-
induced cancers in human, non-human primate, canine and rodent
subjects. Radiat Res. 2007;167:12–42.
70. Robison LL, Green DM, Hudson M, et al. Long-term outcomes of
adult survivors of childhood cancer. Cancer. 2005;104:2557–2564.
71. Hall EJ. Intensity-modulated radiation therapy, protons, and the
risk of second cancers. Int J Radiat Oncol Biol Phys. 2006;65:1–7.
72. Neglia JP, Nesbit ME Jr. Care and treatment of long-term survivors
of childhood cancer. Cancer. 1993;71:3386–3391.
73. Brenner DJ. Extrapolating radiation-induced cancer risks from low
doses to very low doses. Health Phys. 2009;97:505–509.
74. Deniz K, O’Mahony S, Ross G, Purushotham A. Breast cancer in
women after treatment for Hodgkin’s disease. Lancet Oncol.
2003;4:207–214.
75. Preston DL, Ron E, Tokuoka S, et al. Solid cancer incidence in
atomic bomb survivors: 1958–1998. Radiat Res. 2007;168:1–64.

27 
Pathophysiology of lymphedema
Raghu P. Kataru, Daniel A. Cuzzone, and Babak J. Mehrara
SYNOPSIS
■ Lymphedema is a progressive disease that can occur as a result of
congenital defects, iatrogenic injury, or infection of the lymphatic
system.
■ The lymphatic system is comprised of capillary lymphatics that drain
into progressively larger collecting vessels.
■ The pathology of lymphedema is due to accumulation of lymphatic
fluid leading to chronic inflammation, fibrosis, and adipose deposition.
■ Obesity and radiation significantly increase the risk of lymphedema
after surgery.
Introduction
Lymphedema is a progressive disease of the lymphatic system
characterized by chronic inflammation, adipose deposition,
hyperkeratosis, and fibrosis. Although the precise mechanisms
regulating the development of lymphedema remain unknown,
a key inciting event is lymphatic dysfunction and impaired
clearance of interstitial fluids. As a result, lymphedema can
develop due to genetic/developmental abnormalities of
the lymphatic system (i.e. primary lymphedema) in which
lymphatic vessels are absent or poorly developed. Primary
lymphedema may also occur secondary to pathologic pro­
cesses that directly impair lymphatic function. More com­
monly, lymphedema develops after trauma or infection of the
lymphatic system (secondary lymphedema). These inciting
events set off a cascade of tissue changes that in some cases
ultimately results in massive accumulation of adipose tissue
and the classic findings of elephantiasis (Fig. 27.1).
Estimates of the incidence of lymphedema vary widely.
Some studies report as many as 200 million patients in devel­
oping countries who suffer from lymphedema secondary to
parasitic infections by Wuchereria bancrofti. This disease has a
variable course with smoldering disease in some and rapidly
progressive/disabling lymphedema in others. Case reports of
massive extremity or scrotal lymphedema in patients with
filariasis have been reported resulting in significant morbidity
and mortality.
In the United States and Europe, the most common cause
of lymphedema is cancer treatment. Breast cancer survivors
comprise the largest group of affected individuals due to the
high incidence of breast cancer in these regions. It is estimated
that as many as 30–60% of breast cancer patients treated with
axillary lymph node dissection go on to develop lymph­
edema.1,2 Recent advances in sentinel lymph node biopsy
have decreased the requirement for full axillary lymph node
dissection and have decreased the incidence of lymphedema.
However, lymphedema does develop even after sentinel
lymph node biopsy in 5–7% of patients.3,4 Lymphedema is not
exclusively a disease of breast cancer survivors and occurs as
a complication of treatment of most other solid tumors, most
commonly gynecological cancers, melanoma, pelvic tumors,
and sarcomas. In fact, a recent meta-analysis estimated that
nearly 1 in 6 patients treated for a variety of solid tumors go
on to develop lymphedema.5,6 The development of lymph­
edema in patients with sarcomas is an interesting phenomenon
since lymph nodes are rarely removed in these tumors, sug­
gesting that widespread injury to the superficial lymphatic
system (as would occur with a wide excision of a skin sarcoma
in combination with radiation therapy) can sufficiently disrupt
the lymphatic vasculature and lead to the development of
lymphedema even when the regional lymph nodes are not
injured.
Anatomy and physiology
Lymphatic circulation
The lymphatic system plays a key role in a number of
physiologic processes including interstitial fluid and immune
cell transport, regulation of inflammation, responses to host
or foreign antigens, and fat absorption, among others. The

516
CHAPTER 27 • Pathophysiology of lymphedema
other by overlapping or intercalating button-like junctions.
Minute changes in tissue fluid content causes adjacent LECs
to separate due to the physical connections of these cells with
the surrounding tissues by anchoring filaments, thus enabling
entrance of cells and interstitial fluid into the initial lymphat­
ics. Once the interstitial fluid has entered the lymphatic
system, the overlapping regions between LECs is re-
established maintaining the fluid within the lymphatic vessel.
Fluid is propelled passively to pre-collectors and collecting
lymphatics located in the deeper dermis and subcutaneous
tissues. The LECs in collecting vessels, in contrast to the capil­
lary lymphatics, have continuous endothelial cell junctions
that prevent fluid leak with physical changes in the microen­
vironment. In addition, collecting lymphatics have a basement
membrane and are covered by smooth muscle cells that
can contract to propel lymphatic fluid forward. Lymphatic
collectors also have bicuspid valves located every 1–2 mm
that ensure one-way flow of interstitial fluid blocking
backflow into the capillary lymphatic system. The functional
lymphatic unit is defined as a lymphangion and contains a
region of collecting lymphatic vessel between two valves
(Fig. 27.3).
Lymphatic flow is determined by two factors. Passive
compressive forces arise from external compressive forces
such as muscle contractions, respiration, regional arterial
pulsation, and gravity. These forces, as their name implies,
passively propel interstitial fluid centrally. In normal limbs
(i.e. without history of lymphatic injury), passive compressive
forces such as massage or muscular contractions do not sig­
nificantly increase lymphatic pressure in collecting lymphatics
and do not increase flow. Active compressive forces arise from
Fig. 27.1  Severe (grade III) lymphedema of the left leg after melanoma resection.
Fig. 27.2  Microscopic anatomy of the lymphatic
system. (A) Schematic of superficial and deep
lymphatics of the skin. (B) Fluorescent
immunohistological depiction of mouse ear skin
lymphatic tree. Mouse ear skin whole mount stained for
Prox1 (pan LEC marker) and Smooth muscle actin alpha
to identify the capillary, pre-collecting and collecting
lymphatic vessels in a single plane (upper panel). High
magnification images 1, 2, 3 and 4 from the upper
panel image showing spatial separation of capillaries at
the ear tips to collectors at ear base. Note the collecting
lymphatic vessels being tightly wrapped by SMA cells
enabling them to pump the lymph. (A, Adapted from
Suami H, Pan WR, Taylor GI. Changes in the lymph
structure of the upper limb after axillary dissection:
radiographic and anatomical study in a human cadaver.
Plast Reconstr Surg. 2007;120:982–991.)
Normal
Skin
Subcutaneous
tissue
Lymph capillaries
and pre-collectors
Lymph collecting
vessels
Deep tissue
A
Collectors
ra
e e
ht fo piT
e
s
a
B
Pre-collectors
Initial capillaries
PROX1
4
4
3
3
SMA α
2
2
1
1
B
transport of immune cells and interstitial fluid from the
periphery begins in capillary lymphatics located in the dermis
(Fig. 27.2). These vessels are comprised of a single layer of
lymphatic endothelial cells (LECs) that are physically tethered
to the surrounding tissues by anchoring filaments and to each

517
Etiology of lymphedema
Lymph nodes
Lymph nodes filter lymphatic fluid as it is transported
within the lymphatic system back to the venous circulation
(Fig. 27.4). Although the number of lymph nodes is somewhat
variable, a typical adult has 600–700 lymph nodes located
in various regions and clustered in areas where body
parts come together or in/around intra-abdominal organs.
Interstitial fluid is transported centrally by collecting lym­
phatics and enters the subcapsular sinus of the lymph node
via afferent lymphatics. From there, the interstitial fluid (and
the antigens, antigen-presenting cells, and inflammatory cells
it contains) drain through lymph sinuses that surround lymph
node follicles where B cells reside. Lymphatic sinuses are
lined by reticular endothelial cells and antigen-presenting
cells enabling presentation and response to self/foreign anti­
gens. Macrophages located in these regions can also phago­
cytose bacteria for processing and clearance. In addition, fluid
exchange occurs through regional high endothelial venules
that permeate the lymph node enabling hematogenous deliv­
ery of immune cells and cytokines to the lymph node. The
lymphatic fluid exits the lymph node via efferent lymphatics
located at the lymph node medulla progressing to the next
lymph node chain or centrally for return back to the venous
system.
Etiology of lymphedema
Primary lymphedema
Numerous genetic defects are associated with development
of primary lymphedema (Table 27.1). These disorders have a
highly variable natural history in terms of timing of presenta­
tion and severity of symptoms. In addition, primary lymph­
edema may be familial with known or suspected genetic
defects, may occur as a result of spontaneous mutations, or in
some cases develop without a known cause. Familial forms
of primary lymphedema, even within members of the same
family, can have different presentation due to the penetrance
of the genetic mutation or causative factors and interaction
with environmental regulators. Thus, in some cases primary
lymphedema may present shortly after birth (i.e. congenital
lymphedema) or, more commonly, become manifest years
later with progressive symptoms (lymphedema praecox or
lymphedema tarda).
In most cases of primary lymphedema, the lymphatic
system is poorly developed with decreased numbers of lym­
phatic vessels (most commonly collecting lymphatics). It is
unclear if patients with primary lymphedema have defects of
the lymphatic system at birth or if these changes develop
postnatally. The current evidence suggests that in most cases
some degree of lymphatic dysfunction is present at birth and
that these changes gradually worsen over time. The rate at
which these changes occur is variable and can be altered by
environmental factors leading to differential presentation of
the disease. Studying these changes has been a challenge due
to our inability to serially monitor the lymphatic system non-
invasively; however, recent advances with lymphatic imaging
have been helpful in this regard.
Congenital lymphedemas occur more commonly in females,
more commonly involve the lower extremities, and account
intrinsic contraction of smooth muscle cells surrounding the
collecting lymphatics. These muscle cells are unique in that
they have features of both smooth and striated muscles and
have basal myogenic activity. Myogenic forces in the lym­
phatic system, similar to the heart, are responsive to preload
and afterload pressure changes. In addition, the force and
frequency of lymphatic pump contraction can be modulated
by vasoactive substances such as histamine and substance P,
among others. In general, increases in preload and after load
lead to an increase in contraction frequency and strength up
to a point. Persistent increases beyond this point lead to
lymphatic pump failure and vessel dilatation.
Fig. 27.3  Anatomy of a lymphangion. (A) Schematic representation of a
lymphangion (segment of lymphatic collector between two valves). (B) Fluorescent
immunohistological representation of a lymphangion (segment of lymphatic
collector between two valves) in mouse ear skin (upper). Note the 2 valves
immunopositive for integrin alpha 9 (a valve marker). High magnification image of a
single valve showing SMA cells (green), valve leaflets (red) and PROX1 stained
LECs (blue).
A
PROX1
PROX1
Lymphangion
Valve
Valve
Int α 9
Int α 9
SMA α
SMA α
Valve
B

518
CHAPTER 27 • Pathophysiology of lymphedema
Fig. 27.4  Schematic figure of a lymph node. Lymph enters
the lymph node subcapsular sinus via afferent lymphatics
and drains through the node via lymph sinuses, eventually
exiting the node via the efferent lymphatics in the hilum.
Blood capillaries and high endothelial venules enable
leukocytes to enter the lymph node and are a site of fluid
exchange.
Afferent lymphatics
Subcapsular sinus
Lymphatic trabecula
Blood capillaries
High endothelial
venule
Hilum
Efferent lymphatic
vessel
Artery
Vein
B cell zone
T cell zone
Capsule
Table 27.1  Genetic mutations and lymphedema
Gene
Syndrome
Pathology
References
FLT4 (5q35)
(coding region for vascular endothelial
growth factor receptor 3)
Milroy disease
Primary lymphedema of the lower
extremities. Upslanting “ski jump”
toenails due to nail bed edema
64, 65, 81
FLT4 (4q34)
(coding region for vascular endothelial
growth factor C)
Milroy-like lymphedema
Congenital lower limb lymphedema
73
FOXC2
Lymphedema-distichiasis
syndrome
Lower-limb lymphedema most often
presents at puberty; double row of
eyelashes
72, 73, 82
SOX18
Lypotrichosis–
lymphedema–
telangiectasia syndrome
Lymphedema, hair loss, and small dilated
blood vessels near the surface of skin
74
GJC2
(coding for connexin 47 (CX47)
Meige’s disease
Impaired gap junction activity, increased
risk of breast cancer-related
lymphedema
7
CCBE1 (18q21)
(encodes for collagen & calcium
binding EGF domain 1)
Hennekam syndrome
Severe lymphedema in limbs, genitalia, and
face; facial anomalies; seizures, mental
retardation; and stunted growth.
Symptoms often present in utero
75
KIF11 (10q24)
MCLMR syndrome
Microcephaly, congenital lower limb LE,
ocular abnormalities, learning disabilities
76
GATA2 (3q21)
Emberger syndrome
Unilateral or bilateral lower limb
lymphedema; presents in childhood;
severe cutaneous warts; myelodysplasia
77
WILD syndrome
WILD syndrome (warts, immunodeficiency,
lymphedema, and dysplasia)
78
AKT1
Proteus syndrome
Lymphatic malformations, skeletal,
cutaneous, and CNS abnormalities
79,80

519
Etiology of lymphedema
Secondary lymphedema
Secondary lymphedemas develop after injury or obstruction
of the lymphatic system. For example, infections with para­
sites in filariasis results in chronic obstruction of lymphatic
channels and subsequent immune responses that impair
lymphatic function leading to progressive disease.12 Filariasis
is caused by roundworms (most commonly Wuchereria ban­
crofti, Brugia malayi, and Brugia timori) that are transmitted by
mosquitos. The adult worms grow in the tissues and release
larvae into the blood stream (microfilariae) that are diagnostic
for the disease. However, patients with clinical disease may
be free of microfilariae in the blood, in which case the diag­
nosis is made either clinically, or by tissue biopsies, or serum
antigen testing. Filariasis is a major cause of morbidity in
developing countries and treatment remains limited to anti­
parasitic medications that only kill the developing larvae
rather than the adult worm.
Iatrogenic lymphatic injury in the course of cancer treat­
ment is another major cause of secondary lymphedema. In
fact, lymphedema is the most common long-term complica­
tion of cancer treatment (even more common than radiation-
induced sarcomas, or chemotherapy-induced renal or cardiac
failure). Lymphedema can develop in the course of treatment
for virtually all solid tumors including breast, gynecological
tumors, melanoma, sarcoma, and pelvic tumors. Lymphedema
can even develop after extirpation of head and neck tumors
(4% incidence) resulting in cosmetic deformity and functional
compromise.
Secondary lymphedema in cancer survivors occurs most
frequently months and sometimes years after the initial
surgery (Fig. 27.5). This delayed presentation together with
the fact that lymphedema develops in only a subset of patients
who undergo lymphadenectomy is important since these
findings suggest that lymphatic injury is necessary but not
sufficient for the development of the disease. Thus, additional
pathological changes are needed for patients to develop
lymphedema after lymph node dissection.
for 10–25% of all primary lymphedemas.7 The degree of swell­
ing of the limbs can be variable and in some cases may result
in severe abnormalities in one limb and relatively mild or
absent disease in the contralateral limb. Milroy’s disease is a
familial, sex-linked disorder in which inactivating mutations
occur in the vascular growth factor receptor-3 (VEGF-R3).
These mutations account for a relatively small number of
patients with primary lymphedema (2–3%) and usually
present shortly after birth with limb swelling and/or chylo­
thorax. The pathophysiology of this disease arises from the
fact that VEGF-R3 is primarily expressed by lymphatic endo­
thelial cells and serves as a key signaling molecule for endo­
thelial growth factor C (VEGF-C) and its closely related
molecule VEGF-D. Activation of VEGF-R3 results in transmis­
sion of intracellular signals that regulate lymphatic endothelial
cell differentiation, proliferation, migration, and endothelial-
derived nitric oxide production. Not surprisingly, patients
with Milroy’s disease have hypoplastic lymphatic vessels
with variable severity of dermal and collecting lymphatic
vessel agenesis.
In contrast to congenital lymphedemas in which the
disease presents shorty after birth, patients diagnosed with
lymphedema praecox present with lymphedema at some point
before the age of 35. The vast majority of these patients
develop unilateral lower extremity lymphedema and the
disease has a 4 : 1 female to male ratio. Additional evidence
implicating a sex-hormone link with this disease is the fact
that most patients begin to become symptomatic at the time
of puberty.7 Histologic examination of patients with lymph­
edema praecox has shown variable pathologic findings;
however, these patients often exhibit fewer capillary lymphat­
ics and hypoplastic collecting vessels. Most patients present
with unilateral lower extremity lymphedema (~70%) at some
point between birth and age 35. These patients characteristi­
cally have decreased number and caliber of lymphatics and
most commonly present during puberty with a female to male
ratio of 4 : 1.
The diagnosis of lymphedema tarda refers to patients who
develop primary lymphedema after the age of 35. This disease
is a diagnosis of exclusion since secondary causes of lymph­
edema are much more common in this age group. In addition,
lymphedema tarda is an infrequent presentation of primary
lymphedema and occurs most commonly in the lower
extremities of women. Although the pathophysiology of this
disease remains largely unknown, recent studies have shown
an association with loss-of-function mutations in the FOXC2
gene.8–10
The validity of classification schemes that categorize
primary lymphedema based on the age at which symptoms
present has been recently debated. This debate centers on the
fact that presentation of these disorders is highly variable due
to genetic and environmental factors and that this variability
decreases the utility of these categories for diagnosis. As a
result, recent studies have attempted to develop new classifi­
cation schemes based on the presentation of disease and
known genetic mutations.11 This approach categorizes con­
genital lymphedemas into five main groups: syndromic, sys­
temic or visceral, disturbed growth, congenital onset, and late
onset. The developers of this system contend that this diag­
nosis algorithm is more precise and as a result can be useful
for developing and testing of diagnostic or therapeutic
interventions.
Fig. 27.5  Timing of lymphedema (linear prediction) presented as a scatterplot of
median follow-up times of various studies. Note that development of lymphedema
occurs in a delayed fashion after surgery. (From Cormier, et al. Lymphedema
beyond breast cancer: a systematic review and meta-analysis of cancer-related
secondary lymphedema. Cancer. 2010;116:5138–5149.)
Follow-up (months)
Incidence of Lymphedema (%)
80
0
20
40
60
0
25
50
75
100
125

520
CHAPTER 27 • Pathophysiology of lymphedema
with some schemes classifying patients based on measured
differences.19 The use of measurements alone can be problem­
atic in some cases due to the relative subjective nature of this
test (i.e. a 2 cm difference in a thin patient is likely much more
significant than a 2 cm difference in a morbidly obese indi­
vidual). Nevertheless, measurements are a cornerstone of
lymphedema diagnosis and treatment.
Circumference measurements are usually performed at
defined intervals (in many cases 5 cm below and 5 cm above
the olecranon); however, a wide range of measures have been
reported. In addition, the inter and intra-operator validity of
circumference measurements has been questioned although
several reports have provided evidence that with training
these measurements can be performed reproducibly. Limb
volume measurements can be performed with water displace­
ment; however, this approach can be difficult for practical
purposes (for example some hospitals require using sterile
fluid for each patient). The perometer is an infrared scanner
that measures the limb circumference (arm or leg) in multiple
areas and then uses the truncated cone formula to calculate
limb volume and volume differentials (Fig. 27.7).20,21 This
device is useful but is unfortunately expensive and not widely
available in the United States. Limb volumes can also be cal­
culated by measuring limb circumferences at 4 cm intervals
and using the truncated cone formula as described by
Brorson.22 This approach is simple to perform and is a good
compromise between water displacement/perometer and
limb circumference measurements.
Radiologic tests can be useful in the diagnosis of lymph­
edema. For example, lymphoscintigraphy is a procedure in
which a radiolabelled colloid is injected in the distal extremity
On average, secondary lymphedema in breast cancer sur­
vivors develops approximately 8 months after the initial
surgery.13 In addition, the majority of patients (75%) are diag­
nosed within the first 3 years.2 In one unusual case report, a
patient developed lymphedema after a seemingly innocuous
injury 50 years after the initial lymphatic injury. Thus, in most
cases the acute surgical swelling that develops after breast
surgery and lymphadenectomy resolves within the first few
weeks of surgery and, in most cases, never recurs. However,
in some patients it recurs in a progressive and permanent
manner 8–12 months later. This process appears to be acceler­
ated somewhat in the lower extremity (perhaps due to the
effect of gravity) with lymphedema developing on average
4–6 months after surgery.
Once lymphedema develops, it is usually progressive in
nature with disease worsening over time. Although the rate
of disease progression can be decreased with aggressive
physical therapy and early diagnosis of lymphedema, some
unfortunate patients progress rapidly even despite wrapping
and aggressive symptomatic treatment. In addition, the rate
of disease progression in patients with lymphedema in general
is highly variable with some patients experiencing relatively
indolent disease necessitating little to no compression while
others progress rapidly to disabling disease that has little
response to therapy.14 Although the efficacy of manual lym­
phatic massage has been debated, most studies suggest that
these treatments are helpful in most patients, resulting in
decreased symptomatology and diminished rate of progres­
sion. In addition, these interventions are most effective in
early stage disease, therefore careful follow-up of patients
who are at risk for disease has been advocated.
The rate of disease progression and severity of disease can
be modulated by exercise and weight-loss programs. These
interventions are effective in both prevention and treatment
of lymphedema and should be encouraged in all at-risk
individuals.15,16 Interestingly, for many years physicians and
therapists warned patients who had undergone lymph node
dissection to avoid strenuous exercise or weight lifting with
their affected limb based on an idea that these activities would
increase blood flow to the limb and in turn increase lymphatic
load.2 However, this myth was eventually disproven by a
number of prospective randomized control studies demon­
strating efficacy of weight loss and exercise in the treatment
of lymphedema.17,18
Diagnosis
The diagnosis of lymphedema is usually made by clinical
exam and, in some cases, radiologic tests. The differential
diagnosis of primary or secondary lymphedema includes
venous insufficiency, congestive heart failure, malignancy
(either recurrent or primary causing lymphatic obstruction),
and infections. Patients with lymphedema often present with
swelling, skin tightness, heaviness, and fatigue. More rarely,
the presenting symptom is cellulitis and rapid swelling of the
affected extremity. Limb circumference and volume measures
are useful means of analyzing the degree of swelling in uni­
lateral cases and these measures are commonly used as a
means of following disease progression (Fig. 27.6). Differences
of more than 2 cm or a volume differential of more than 200 cc
is considered by most sources diagnostic of lymphedema,
Fig. 27.6  Lymphedema measurements. (A) Circumference measurements for
upper extremity lymphedema. (B) Water displacement method for calculating limb
volume. (Adapted from Pitsch F. Benefit of daflon 500 mg in chronic venous disease
related edema. Phlebology. 2006;13:17–21.)
A
B

521
Diagnosis
electrical current transmission through tissues, is used to
estimate the fluid content of the lymphedematous limb as
compared with the normal limb (Fig. 27.9).29 Although
this test can have variable results due to skin temperature,
superficial skin dryness, and other factors, some studies
and the rate/amount of uptake is then analyzed in the drain­
ing lymph node basins.23,24 Lymphoscintigraphy can also be
used to estimate dermal backflow, a condition in which
lymphatic blockage proximally results in the redirection
of lymphatic fluid from deep channels into the superficial
lymphatics. However, recent reports have suggested that
the sensitivity of lymphoscintigraphy (0.61) for early stage
lymphedema is lower than other methods such as MRI and
indocyanine green (ICG) lymphangiography.25 The lymphatic
vessels and pathologic changes in lymphedema can also be
visualized using MRI (MRI lymphangiography) with a high
degree of sensitivity and specificity.25–27 However, this tech­
nique is user- and radiologist-dependent and requires optimi­
zation of techniques.
Recent studies have advocated the use of indocyanine
green (ICG) near-infrared (NIR) lymphangiography in the
diagnosis and staging of lymphedema. In this test, ICG dye
is injected in the dermis of the affected extremity and lym­
phatic vessels are visualized using a NIR camera. It is impor­
tant to note that the use of ICG is currently only FDA approved
for intravenous injection and that intradermal injections for
visualization of the lymphatic system are an off-label use. This
method enables visualization of the superficial collecting
lymphatics, dermal backflow, and abnormal lymphatic vascu­
lature and is a helpful adjunct to the diagnosis of lymphedema.
Recent reports have suggested that ICG lymphangiography
has a high degree of sensitivity and specificity for diagnosing
lymphedema and that pathologic changes such as splash/
stardust/diffuse patterns are present even in early-stage
disease (Fig. 27.8).25 In fact, some authors have developed
lymphedema staging systems based on ICG lymphangiogra­
phy (see below).28 Experimental reports have also shown that
lymphatic pumping capacity (the rate of change in fluores­
cence intensity in a given vessel over time) can be a useful
measure of lymphatic function; however, this analysis has not
been widely adopted.
A few non-invasive methods are available for the diagnosis
of lymphedema. For example, with bioimpedance, the rate of
Fig. 27.7  Lower limb (left) and upper limb (right) perometer measurements.
(Adapted from Pero-systems Inc.)
Fig. 27.8  ICG anatomy of normal and lymphedematous limbs. (A) Collecting
vessels are clearly identified in the normal dorsal hand (arrow points to injection
site). (B) Lymphedematous hand with extensive dermal reflux and lack of clearly
identifiable lymphatics.
A
B
Fig. 27.9  Bioimpedance measurement compares the rate of electrical transmission
between the lymphedematous and normal limbs.

522
CHAPTER 27 • Pathophysiology of lymphedema
have suggested that bioimpedance is helpful in the diagnosis
of early-stage lymphedema in which volumetric or circumfer­
ence differences are subtle or non-existent. Finally, the
degree of skin and soft tissue fibrosis can be estimated with a
tonometer and followed longitudinally to monitor disease
progression.30,31
Lymphedema classification
Common classification systems for lymphedema rely primar­
ily on the clinical features of the disease. The International
Society of Lymphology staging system is the most widely
used scheme and is based on measurable swelling and pres­
ence or absence of pitting (Fig. 27.10; Table 27.2).32 In this
scheme, patients who have a history of lymphatic injury and
present with symptoms of lymphedema (e.g. heaviness,
fatigue) without swelling or measurable volume changes are
classified as latent lymphedema (stage 0). Patients with stage
I lymphedema (also known as spontaneously reversible
lymphedema) have measurable swelling and pitting edema
that improves with elevation or use of compression garments.
Stage II lymphedema (spontaneously irreversible lymph­
edema) is characterized by accumulation of fibroadipose
tissues that prevents reversal of symptoms by elevation or
compression. Finally, patients with severe swelling, fibrosis,
hyperkeratosis, and end-stage lymphedema symptoms are
diagnosed with stage III or lymphostatic elephantiasis.33
Changes in limb circumference or volume as compared to
the contralateral limb or preoperative values have also been
used as a means of classifying the severity of lymphedema.19,34
Although there is variability in these studies, the majority of
reports classify patients with limb circumference excess of
2 cm or 100 cc volume differential as mild lymphedema. Dif­
ferences of 2–4 cm (or more than 200 cc volume) is considered
moderate lymphedema. Patients who have measured differ­
ences of 4 cm or more are classified as having severe lymph­
edema. The utility of this classification scheme, however,
Fig. 27.10  Patient with pitting edema of the upper extremity resulting from breast
cancer-related lymphedema.
Table 27.2  International Society of Lymphology staging system
Stage
Pathophysiology
Description
0
Latent
lymphedema
Lymphatic vessels are injured.
Capacity for fluid transport is
impaired, but still sufficient to
drain lymph as necessary.
Lymphedema has not yet
occurred or is not yet apparent.
I
Spontaneously
reversible
lymphedema
Pitting has started – the affected
area indents when pressure is
applied to it. Swelling can be
contained with the use of
compression garments.
II
Spontaneously
irreversible
lymphedema
Affected tissue is considered to
be non-pitting and has a
spongy consistency. Fibrosis
starts to occur as the limbs
harden and increase in size. At
this point, compression
garments are ineffective at
suppressing symptoms.
III
Lymphostatic
elephantiasis
Swelling is irreversible, and the
tissue is heavily fibrosed and
unresponsive to treatment. Skin
has become significantly
thickened.
is highlighted by the fact that it assumes that the limbs
had equal circumference or volume preoperatively (a false
assumption in many patients due to differences based on
hand/leg dominance). In addition, not taking into account a
patient’s body habitus is problematic since a 2 cm difference
is much more significant in a thin patient than in an obese
patient.
ICG lymphangiography has been proposed by some
researchers as a useful means of classifying patients with
lymphedema. These efforts are important since they attempt
to use physiologic changes in addition to clinical exam find­
ings. Koshima et al. have proposed a system based on their
experience with lymphovenous bypass procedures (Table
27.3). These authors classified the progression of secondary
lymphedema into 4 steps based on ICG findings and termed
this scheme the NECST system (Fig. 27.11).28 The initial step
in the disease process is normal lymphatic vessels distal to the
zone of lymphatic injury. This is followed by lymphatic ectasis
(dilated lymphatics with flattening of lymphatic endothelial
cells), followed by contraction (loss of intraluminal diameter
in collecting lymphatics and thickening of smooth muscle cell
covering), and finally sclerosis (obliteration of the lumen with
proliferative smooth muscle cells).
The M.D. Anderson classification scheme also classifies
lymphedema into four stages based on ICG findings and
quantification of dermal backflow (Fig. 27.12; Table 27.4).35 In
this scheme, stage 1 patients have numerous patent lymphat­
ics and minimal/no dermal backflow. Stage 2 patients have a
moderate number of lymphatics and segmental dermal back­
flow. Stage 3 patients have few patent lymphatics with signifi­
cant dermal backflow throughout the entire arm. Finally, stage
4 patients have no patent lymphatics and severe dermal

523
Pathophysiology of lymphedema
patients who undergo lymphadenectomy, and even in these
individuals does so in a delayed fashion usually months to
years after surgery. A better understanding of these pathologi­
cal events is necessary for improved diagnosis and develop­
ment of rational targeted treatment or prevention options.
Although a number of studies have analyzed lymphatic vas­
cular changes in primary lymphedema and have identified a
wide variety of defects, the remainder of this discussion will
be dedicated to pathophysiological changes that occur in
secondary lymphedema following cancer therapy.
Lymphatic vascular defects in secondary
lymphedema
Lymphangiographic studies performed acutely after axillary
lymph node biopsy (i.e. before onset of lymphedema) dem­
onstrate dilated collecting lymphatics and blockage of flow in
these vessels in the axilla. Patients at this stage have subclini­
cal interstitial fluid stasis that is either not clinically measur­
able (stage 0 or latent lymphedema) or resolves spontaneously
with compression/elevation (stage I). Persistent subclinical
interstitial fluid stasis results in further dilatation of the col­
lecting lymphatics, lymphatic valvular incompetence, and
retrograde flow to capillary lymphatics located in the super­
ficial dermis (i.e. dermal backflow). At this point, the collect­
ing lymphatics maintain the ability to actively contract,
however the pulsations become more irregular with loss of
correlation between lymphatic pulse amplitude and stroke
volume.36 Lymphatic stasis leads to activation of endogenous
danger signals by local cells (adipocytes, endothelial cells,
myocytes, and inflammatory cells) which in turn promote
activation of chronic inflammatory pathways, expression of
inflammatory cytokines, and further promotion of leukocyte
entry into the lymphedematous tissues.37
In the early stages of injury following lymph node dissec­
tion, chronic inflammation and subclinical lymphatic fluid
stasis promote proliferation and collateralization of capillary
lymphatics in the superficial dermis. These vessels effectively
bypass the zone of obstruction and prevent development of
overt lymphedema (Fig. 27.14).38 However, in the fraction of
patients (30–50%) who go on to develop clinically measurable
lymphedema, sustained interstitial fluid stasis and ongoing
chronic inflammation lead to extracellular matrix collagen
deposition with resultant obliteration of capillary lymphatics
and smooth muscle cell proliferation around collecting lym­
phatics.39 Thus, we and others hypothesize that development
of clinically evident lymphedema is dependent on the failure
of both superficial and deep lymphatic systems (i.e. capillary
and collecting lymphatics, respectively) (Fig. 27.15). Patients
have overt accumulation of interstitial fluid in the subcutane­
ous tissues (stage II) and changes in limb volume or circum­
ference become possible by conventional measures. Interstitial
fluid accumulates primarily (60–70% of the total excess
volume) in the subcutaneous tissues between adipose tissues
and around small veins.40 To a lesser degree, fluid also accu­
mulates above/below the muscular fascia and in the dermis.
Collecting lymphatic vessels at this stage continue to actively
contract; however, these contractions are ineffective and fail
to propel lymphatic fluid forward.
Progression of lymphedema occurs as a result of accumula­
tion of adipose tissues, hyperkeratosis, fibrosis, and progres­
sive destruction/dysfunction of the remaining lymphatic
Table 27.3  Koshima lymphedema staging system
Type
Description
Normal type (Step 0)
Lymphatic vessels are normal and
fully functional
Ectasis type (Step 1)
Endolymphatic pressure is noticeably
increased, causing lymphatic
endothelial cells to flatten.
Lymphangiectasia, the dilation of
lymphatic vessels, starts to occur
Contraction type (Step 2)
Smooth muscle cells are converted
into synthetic cells, promoting
collagenous fiber growth. The wall
of the lymphatic vessel starts to
thicken
Sclerosis type (Step 3)
Lumen of lymphatic vessels are
narrowed if not completely
obstructed. Most of the tissue is
fibrosed, and lymphatic vessels
have lost their ability to transport
and concentrate lymphatic fluid
(Data from Mihara M, Hara H, Hayashi Y, et al. Pathological steps of cancer-
related lymphedema: histological changes in the collecting lymphatic vessels
after lymphadenectomy. PLoS One. 2012;7:e41126.)
Table 27.4  M.D. Anderson ICG lymphedema classification
system.35
Stage
Description
1
Many patent lymphatic vessels present and minimal
dermal backflow can be observed in localized areas
2
Moderate number of lymphatic vessels can be seen with
segmental dermal backflow
3
Few patent lymphatic vessels can be seen and
significant dermal backflow can be observed
throughout the entire arm
4
No patent lymphatic vessels can be seen. Severe
dermal backflow throughout the entire arm and hand
is apparent
backflow of the entire arm and hand. Although this scheme
is somewhat subjective, the authors have found that it is
useful for classification and patient selection for lympho­
venous bypass procedures.
Pathophysiology of lymphedema
Although lymphedema is common and morbid, surprisingly
little is known about the pathophysiology of this disease. The
histological hallmarks of the disease are edema, fibroadipose
tissue deposition, chronic inflammation, and hyperkeratosis
and recent studies have begun to shed light on how lymphatic
injury leads to these protean symptoms (Fig. 27.13). A key
concept in understanding the pathology of lymphedema is
that lymphatic injury is only the initiating step and that
additional pathological events are necessary for the develop­
ment of lymphedema clinically. This concept is highlighted
by the fact that lymphedema only develops in a subset of

524
CHAPTER 27 • Pathophysiology of lymphedema
Fig. 27.11  (A) NECST classification of lymphedema. Upper panel shows representative figures of patients with various stages of lymphedema. Lower panel shows
collecting lymphatic vessels corresponding to these stages. Note progressive sclerosis of the collecting lymphatics. (B) Histological changes in collecting lymphatics in the
NECST classification scheme. Note increasing deposition of smooth muscle actin around the lymphatic vessels with increasing stage. (Adapted from Mihara M, Hara H,
Hayashi Y, et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One.
2012;7:e41126.)
A
B
vessels (i.e. late stage II to III disease) (Fig. 27.16). The propor­
tion of fluid versus fat accumulation is variable in different
individuals and can have widely different patterns of deposi­
tion in the limb although some regions tend to swell more
than others (i.e. medial elbow area). In addition, progressive
fibrofatty deposition makes lymphedema therapy more resis­
tant to compressive therapies. This problem is compounded
by the presence of absent pulsations or completely sclerosed
collecting lymphatics with loss of luminal diameter41 and
absence of spontaneous lymph flow.
Regulation of fibrosis
Based on the evidence cited above, it is clear that extracellular
matrix fibrosis and progressive sclerosis of collecting lym­
phatics play a key role in the pathology of lymphedema. This
idea also provides a rationale for the increased risk of lymph­
edema in patients who have undergone radiation therapy
and is supported by experimental studies demonstrating that
fibrosis independently decreases lymphatic vessel regenera­
tion and lymphatic function.42,43 Lymphedema may therefore

525
Pathophysiology of lymphedema
Fig. 27.12  M.D. Anderson ICG lymphedema
classification system. (A) Stage 1: many patent
lymphatic vessels and minimal dermal backflow.
(B) Stage 2: moderate number of patent lymphatic
vessels and presence of segmental dermal backflow.
(C) Stage 3: few patent lymphatics and extensive
dermal backflow in the entire arm. (D) Stage 4: no
patent lymphatics and severe dermal backflow.
(Adapted from Chang DW, Suami H, Skoracki R. A
prospective analysis of a 100 consecutive
lymphovenous bypass cases for the treatment of
extremity lymphedema. Plast Reconstr Surg.
2013;132:1305–1314.)
A
B
C
D
Fig. 27.13  Histology of lymphedema. (A) H&E stain
of forearm skin demonstrating characteristic
hyperkeratosis of lymphedematous skin (white
brackets). (B) Forearm skin sections stained for type I
collagen (brown stain). Note dermal accumulation of
type I collagen.
A
B

526
CHAPTER 27 • Pathophysiology of lymphedema
Fig. 27.14  Photograph of lymphangiography performed in a canine model of right
axillary lymph node dissection demonstrating hyperplastic superficial lymphatic
vessels (black arrow) bypassing the right axilla to lymph nodes in the
supraclavicular area bilaterally (white arrows). (Adapted from Suami H, Yamashita S,
Soto-Miranda MA, Chang DW. Lymphatic territories (lymphosomes) in a canine: an
animal model for investigation of postoperative lymphatic alterations. PLoS One.
2013;8:e69222.)
Fig. 27.15  Hypothetical model for development of lymphedema after failure of
both deep and superficial lymphatic function.
Surgery
Lymphedema
Asymptomatic
Deep system injury
Superficial lymphatic
fibrosis
Superficial system
intact
simply be a fibrotic disorder with loss of functional paren­
chyma (i.e. capillary and collecting lymphatics) due to pro­
gressive fibrosis.
Using a variety of mouse models as well as clinical biopsy
specimens, our lab has shown that lymphedema results in
progressive fibrosis and that inhibition of this fibrotic response
markedly increases lymphatic regeneration and function. In
addition, we have shown that fibrosis in lymphedema is
mediated by a proliferation of CD4+ cells that differentiate
into a particular type of T-helper cell (Th2 cell) which in turn
produces vast amounts of profibrotic cytokines such as inter­
leukin 4, interleukin 13, and transforming growth factor
beta-1.44–46 Treatment of lymphedema patients with lympho­
venous bypass procedures is not only associated with symp­
tomatic improvement, but also decreased accumulation of
Fig. 27.16  Cadaver dissection and lymphangiography in
a patient with a history of unilateral axillary lymph node
dissection. Note loss of capillary (superficial) lymphatics
stained green in the upper limb after lymph node
dissection. (Adapted from Suami H, Pan WR, Taylor GI.
Changes in the lymph structure of the upper limb after
axillary dissection: radiographic and anatomical study in a
human cadaver. Plast Reconstr Surg. 2007;120:982–991.)
Cephalic
vein
Cephalic
vein
Elbow
Basilic
vein
Thumb
Thumb
Pre-collector
Superficial lymph
collecting vessel
Deep lymph
collecting vessel
b
m
u
h
T
b
m
u
h
T

527
Risk factors for lymphedema
of lymphedema development. Further, randomized clinical
trials have shown that diet-induced weight loss over a 12-week
period resulted in a significant reduction in arm volumes as
compared to controls who did not lose weight.62 Finally,
exercise studies have shown monitored exercise programs in
lymphedema patients not only led to weight loss but also
markedly decreased lymphedema symptoms as compared to
a sedentary control group. Thus, although the cellular mecha­
nisms regulating the interaction between obesity and lym­
phatic function remains unknown, it is clear that a relationship
does exist and that patients who are scheduled for lymphad­
enectomy or lymphatic surgery should be counseled to first
lose weight prior to proceeding with invasive interventions.
Radiation
Radiation therapy in combination with surgery is also a well-
known risk factor for development of lymphedema, increas­
ing the risk of disease development by as much as fivefold.63–66
Interestingly, lymphedema is significantly more prevalent in
obese patients treated with surgery and radiation, suggesting
that risk factors for lymphedema can act in an additive
manner.67 Although some studies have failed to show a rela­
tionship between radiation and development of lymphedema
after breast cancer treatments, some of these results may be
confounded by the fact that radiation in some studies included
only the chest wall and not the regional lymph node basins
(e.g. supraclavicular or axilla). In addition, it appears that the
negative effects of radiation on lymphedema development are
largely additive to those of surgery since the development of
the disease following radiation alone is unusual, occurring in
less than 7% of patients.66
Infection
Postoperative infections and cellulitis have long been thought
to be a risk factor for development of lymphedema, however
the mechanisms that regulate this potential interaction remain
unknown. In addition, it is unknown if development of an
infection is a symptom of subclinical lymphedema that even­
tually blossoms into full scale disease or if infection damages
remaining lymphatics thus resulting in disease development.
Nevertheless, previous gynecological reports have shown that
early infections following vulvar cancer surgery significantly
increase the incidence of lower extremity lymphedema
development.68 These findings have led some investigators to
suggest that avoiding cellulitis is a major method to avoid
lymphatic injury and disease progression, particularly in
patients with a previous history of lymphedema.69
Genetics
Genetics have long been shown to cause primary lymphedema
and lymphatic abnormalities. However, more recent studies
have identified genetic factors that also predispose patients to
developing secondary lymphedema. For example, Finegold et al.
found that women with mutations in the gene encoding for
connexin 47 or hepatocyte growth factor have a significantly
increased risk of developing lymphedema after mastectomy
and axillary lymph node dissection as compared with normal
controls.70,71 Another studied 157 single-nucleotide polymor­
phisms (SNPs) in 17 candidate genes and demonstrated that
at least four genes and three haplotypes may contribute to
CD4+ cells and fibrotic tissue. This observation, together with
our previous animal studies demonstrating that depletion of
CD4+ cells or inhibition of Th2 profibrotic cytokines markedly
decreases the symptoms of lymphedema, may serve as a
useful clinical intervention. This approach is currently under
investigation in a clinical trial using monoclonal antibodies.
Thus, pharmacological interventions may be a viable means
of treating lymphedema or may serve as an important adjunct
to surgery.
Regulation of adipose deposition
The end stage of lymphedema is progressive fibroadipose
deposition. Thus, the initial pathology of lymphedema is
accumulation of interstitial fluid; however, over time this fluid
promotes adipose deposition rendering compressive treat­
ments for lymphedema obsolete. It is clear, therefore, that
lymphatic (interstitial) fluid accumulation and adipose depo­
sition are closely related.47,48 This idea is supported by previ­
ous studies demonstrating that interstitial fluid potentially
increases adipocyte proliferation and differentiation in vitro.49
In addition, our lab has previously shown that lymphedema
results in proliferation and hypertrophy of local adipocytes
and that even mild lymphatic injury promotes expression of
adipocyte differentiation markers.49–51
The relationship between adipocytes and lymphatic endo­
thelial cells appears to be bidirectional in nature. This hypoth­
esis is based on recent reports demonstrating that obesity
markedly impairs lymphatic function both clinically and in
animal models. In addition, recent studies have shown that
super obese individuals (i.e. BMI >59) spontaneously develop
lower extremity lymphedema and that this effect is permanent
with little improvement after gastric bypass and weight loss.
More recently our lab has shown that lymphatic function is
directly proportional to body weight in mice and that a
threshold exists beyond which abnormalities in the lymphatic
system are easily measureable. These findings provide a
rationale for the fact that obesity is a major risk factor for
lymphedema.
Risk factors for lymphedema
A variety of genetic and environmental factors have been
shown to increase the risk of developing lymphedema includ­
ing obesity, radiation, infection, and genetic factors.3,52–58
Obesity
Obesity is among the first recognized risk factors for lymph­
edema59 and has since been shown to increase the risk
of disease in patients treated for a variety of solid tumors.
Prospective studies have shown that patients with a body
mass index (BMI) of >30 have at least a threefold increased
risk of developing lymphedema as compared with patients
with a similar stage breast cancer but a BMI of <25.60 Other
studies have shown that this relationship is almost linear
with higher baseline weight being correlated with develop­
ment of lymphedema after axillary lymph node dissection for
breast cancer.3 Greene and colleagues have shown that mas­
sively obese patients (BMI >59) in some cases spontaneously
develop lower extremity lymphedema.61 Even postoperative
weight gain in previously lean patients increased the risk

528
CHAPTER 27 • Pathophysiology of lymphedema
development of secondary lymphedema.72 By providing evi­
dence for genetic mutations as an important risk factor in
secondary lymphedema, these new discoveries challenge the
traditional perspective of secondary lymphedema being
solely due to mechanical trauma.72
Summary
Lymphedema is a debilitating and common disease that
occurs most commonly as a complication of cancer care.
Recent studies have shown that the pathophysiology of
lymphedema is related to lymphatic vessel dilation, valvular
incompetence, chronic inflammation and fibrosis. Treatment
strategies aiming to decrease these changes (e.g. manual
lymphatic massage or compressive pumps) decrease the rate
of progression of disease and are helpful adjuncts to therapy.
In addition, a better understanding of the pathophysiology of
lymphedema may enable development of targeted preventa­
tive or therapeutic strategies.
2. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort
of breast carcinoma survivors 20 years after diagnosis. Cancer.
2001;92:1368–1377. This was an important study because they had a
20-year follow-up on patients demonstrating that the incidence of
lymphedema increases with time after surgery.
5. Cormier JN, Askew RL, Mungovan KS, et al. Lymphedema
beyond breast cancer: a systematic review and meta-analysis
of cancer-related secondary lymphedema. Cancer. 2010;116:5138–
5149. This was a study that reviewed the literature and showed that
lymphedema is not simply limited to breast cancer survivors.
11. Connell FC, Gordon K, Brice G, et al. The classification and
diagnostic algorithm for primary lymphatic dysplasia: an update
from 2010 to include molecular findings. Clin Genet. 2013;84:303–
314. An excellent classification system for primary lymphedema.
18. Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and
resistance exercise in breast cancer patients receiving adjuvant
chemotherapy: a multicenter randomized controlled trial. J Clin
Oncol. 2007;25:4396–4404. An important level 1 study demonstrating
that exercise independently improves lymphedema.
28. Mihara M, Hara H, Hayashi Y, et al. Pathological steps of
cancer-related lymphedema: histological changes in the collecting
lymphatic vessels after lymphadenectomy. PLoS ONE.
2012;7:e41126. An excellent study demonstrating histological changes in
lymphatic collectors in patients with lymphedema.
35. Chang DW, Suami H, Skoracki R. A prospective analysis of 100
consecutive lymphovenous bypass cases for treatment of extremity
lymphedema. Plast Reconstr Surg. 2013;132:1305–1314.
36. Olszewski WL. Contractility patterns of human leg lymphatics in
various stages of obstructive lymphedema. Ann N Y Acad Sci.
2008;1131:110–118.
43. Avraham T, Daluvoy S, Zampell J, et al. Blockade of transforming
growth factor-beta1 accelerates lymphatic regeneration during
wound repair. Am J Pathol. 2010;177:3202–3214.
62. Shaw C, Mortimer P, Judd PA. A randomized controlled trial of
weight reduction as a treatment for breast cancer-related
lymphedema. Cancer. 2007;110:1868–1874.
73. Gordon K, Schulte D, Brice G, et al. Mutation in vascular
endothelial growth factor-C, a ligand for vascular endothelial
growth factor receptor-3, is associated with autosomal
dominant milroy-like primary lymphedema. Circ Res.
2013;112:956–960.
Access the complete reference list online at

528.e1
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20-year follow-up on patients demonstrating that the incidence of
lymphedema increases with time after surgery.
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28 
Benign and malignant nonmelanocytic
tumors of the skin and soft tissue
Rei Ogawa
SYNOPSIS
■ All typical skin and skin-associated soft-tissue tumors, apart from
malignant melanocytic tumors (malignant melanoma), are described
from the point of view of a plastic surgeon.
■ Biopsies should only be performed for a clear purpose, such as for the
differential diagnosis of benign tumors or to analyze the stage and
grade of malignant tumors, which would allow the area to be resected
to be determined.
■ One current and useful model is the reconstructive matrix, which helps
plastic surgeons to determine the best reconstructive solutions for
their patients in the context of particular medical and socioeconomic
environments by considering aspects of surgical complexity,
technological sophistication, and patient surgical risk.
Introduction
The skin consists of the epidermis, which is derived during
ontogeny from the superficial ectoderm, and the dermis,
which is derived from the mesenchyme. Starting in the first
3–4 weeks of human ontogeny, cells derived from the neural
crest migrate into the epidermis (Fig. 28.1) where they become
melanocytes and Schwann cells; the latter associate with
peripheral nerves in the skin. Later, the cutaneous append­
ages develop. These include hair, which originates from
epidermal cells, and hair papillae, which are filled with mes­
enchyme; vessels and peripheral nerve endings also develop
in the papillae. Other cutaneous appendages are the sebaceous
glands, which are derived from the epithelial wall of the hair
papillae, and the eccrine and apocrine sweat glands, which
are also epidermal in origin. There are also soft tissues that
are associated with skin, namely fat, muscles, and blood
vessels (all of which have a mesenchymal lineage) and nerves
(derived from neural crest cells). Thus, skin and skin-associated
soft-tissue tumors can be classified simply into those that are
of epithelial, cutaneous appendage, neural crest, and mesen­
chymal origin (Fig. 28.2).
In this chapter, all typical skin and skin-associated soft-
tissue tumors apart from malignant melanocytic tumors
(malignant melanoma) are described from the point of view
of the plastic surgeon.
Diagnosis
Inspection and palpation
The diagnosis of skin tumors starts with inspection and
palpation. The following information should be recorded:
the number of lesions (solitary or multiple), the shape of the
lesion (e.g., round, oval, polygonal, geographic, linear,
annular), its size, its elevation status (e.g., narrow-pedicled,
wide-pedicled, dome-like, hemispherical, flat elevated,
umbilicated), its surface status (e.g., smooth, rough, papillary,
granular, transudatory, xerophily, ulcerative, erosive, atrophic,
lustrous, necrotic), its color (e.g., normal, yellow, pale yellow,
erythematous, blackish brown, black, blue, depigmented,
pigmented, hyperemic, livid), its hardness (e.g., soft, elastic
soft, elastic hard, hard, bone-like hard, fluctuating), its align­
ment (e.g., localized, disseminated, centrifugal, systematized,
singular, symmetric, asymmetric, bilateral), its site, whether
there are any subjective symptoms (e.g., pain, itch, contracture
sensation, numbness, burning sensation, cold sensation), and
the time course of the appearance of the lesion (e.g., acute,
subacute, chronic, temporary, recurrent). Color plays a par­
ticularly important role in the diagnosis of skin lesions (Box
28.1). The possibility of malignant tumors should be suspected
at all times. If the shape, size, elevation status, or color of a
lesion changes rapidly, a biopsy should be considered.
Dermoscopy
Dermoscopy is a specialized technique that employs a binocu­
lar microscope to observe the skin surface. It is useful for
diagnosing pigmented lesions and is necessary for differen­
tially diagnosing malignant melanoma and nevus. It is also
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