Breast Cancer

Vol. 12 No. 4 O c t o b e r 2005

Original Article
Pathophysialogy of Seroma in Breast Cancer
Katsumasa Kuroi * ~, Kojiro Shimozuma .2, Tetsuya Taguchi ,3, Hirohisa Imai .4, Hiroyasu Yamashiro .5,
Shozo Ohsumi .6, and Shinya Saito .7
9~Departmentof Surgery, Showa University Toyosu Hospital, *2Departmentof Healthcare and Social Services, University
of Marketing and Distribution Sciences, *SDepartment of Surgical Oncology, Osaka University Graduate School of
Medicine, *4Departmentof Health Science, School of Medicine, Asahikawa Medical College, *SDepartmentof Surgery,
Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, *~Department of Surgery, National
Hospital Organization Shikoku Cancer Center, *TDepartmentof Health Science, Kochi Women's University,Japan.

Purpose: Seroma is the most common complication of mastectomy. The aim of this systematic review
is to clarify the pathophysiology of seroma.
M a t e r i a l s a n d Methods: A computer-assisted MEDLINE search was conducted, and additional ref-
erences were found in the bibliographies of these articles. The reference terms "breast cancer", "mastec-
tomy", "seroma", "lymphocele" and "lymphocyst" were used as both keyword and subject terms. The
search was limited to studies published in English.
Results: The definition of seroma was highly variable across studies, but was most commonly a sero-
ma large enough to be noticed by the patient or medical staff and affecting the patient's satisfaction in the
immediate or acute postoperative period. So far, only limited data are available on the severity of seroma.
With respect to the pathophysiology of seroma, the data indicated that several anatomical factors, espe-
cially dead space, likely contribute to seroma formation. However, it was obscure whether seroma was
due to lymph-like fluid or exudate.
Conclusion: There is considerable variability in the way seroma is defined across studies, and its
pathophysiology remains uncertain.
Breast Cancer 12:288-293, 2005.
Key words: Seroma, PathophysioJogy, Mastectomy, Breast cancer

Seroma is the most common problem occur-
ring after mastectomy, and most surgeons view it
as necessary evil rather than a serious complica-
tion, as it usually resolves within a few weeks.
However, excessive fluid accumulation will stretch
the skin and cause it to sag, resulting in patient
discomfort and prolongation of the hospital stay 1).
In addition, patients may occasionally be troubled
by continuous collection of fluid requiring multi-
ple visits for aspiration. To prevent and manage
seroma formation, it is crucially important to
Reprint requests to Katsumasa Kuroi, Department of Surgery, Showa
University Toyosu Hospital, 4-1-18 Toyosu, Koutou-ku, Tokyo 135-
8577, Japan.
E-maik kurochan@dd.iij4u.or.jp
Abbreviations:
BCT, Breast conserving therapy; IR, Immediate reconstruction;
LDH, Lactate dehydrogenase; MRM, Modified radical mastectomy;
RCT, Randomized controlled trial, VEGF, Vascular endothelial
growth factor
Received January 31, 2005; accepted June 1, 2005
understand its pathophysiology. In this study,
we systematically reviewed the literature on this
topic.
Materials and M e t h o d s
To identify published articles on seroma, a
computer-assisted MEDLINE search was con-
ducted up to December 2004, and additional refer-
ences were found in the bibliographies of these
articles. The reference terms "breast cancer",
"mastectomy", "seroma", "lymphocele" and "lym-
phocyst" were used as both keyword and subject
terms. The search was limited to studies pub-
lished in English. Randomized controlled trials
(RCTs), prospective studies and retrospective
studies as well as smaller descriptive studies were
collected, and comprehensively reviewed for how
seroma was defined. With regard to the patho-
physiology of seroma, these studies were system-
atically reviewed, and the quality of evidence was

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B r e a s t C a n c e r Vol. 1 2 No. 4 O c t o b e r 2 0 0 5
categorized according to the "levels of evidence
and grades recommendation" of the Oxford Cen-
ter for Evidence-based Medicine 2). The strength of
evidence was categorized as grade A: consistent
level 1 studies, grade B: consistent level 2 or 3
studies or extrapolations from level 1 studies,
grade C" level 4 studies or extrapolations from lev-
el 2 or 3 studies, grade D: level 5 evidence or trou-
blingly inconsistent or inconclusive studies at any
level.
R e s u l t s and D i s c u s s i o n
Definition of Seroma and its Incidence
Seroma is an accumulation of serous fluid that
develops following the formation of skin flaps dur-
ing mastectomy or in the axillary dead space in
the immediate or acute postoperative period 3>.
There has been no consistent definition of seroma
in the literature, although it has been documented
most frequently when it is symptomatic, bother-
some to the patient, palpable, fluctuant or bal-
lotable, or tense, and requires at least one needle
aspiration .14). In contrast, in a study of Burak et
al. 15~,seroma was documented only when multiple
aspirations were required, or if insertion of a new
drain was necessary in persistent cases. Similarly,
other studies used the term seroma if a verified
volume of more than 5 to 20 ml of fluid was obt-
ained by puncture and aspiration 1~'17). On the other
hand, some studies have used ultrasonography to
verify seroma 1~~ and it is interesting to note that
in a study by Jeffrey et al. 1~ 92% of patients devel-
oped seroma that was detectable by axillary
sonography, and 42% required at least one aspira-
tion. In that study, irrespective of whether or not
aspiration was performed, all the seromas were
found to resolve within one month on physical
examination, and within 4 months on sonographic
examination. Thus, ultrasonography can detect
seroma at a much higher rate than is clinically
apparent, and axillary seroma takes longer to
resolve on sonographic examination compared
with physical examination. On the basis of this
review, the incidence of seroma varied from 10% to
over 85%2,2228~,depending not only on how it was
defined, but also on the detection methods emp-
loyed.
With respect to the severity of seroma, one
study of particular interest indicated that most
were minor and self-limiting when categorized as
minor if fluid collection required outpatient aspira-
tion, and as major if fluid collection required surgi-
cal drainage 29). In association with this, the "Com-
mon Terminology Criteria for Adverse Events
v3.0" grades seroma as grade 1 if asymptomatic,
grade 2 if symptomatic (medical intervention or
simple aspiration indicated), and grade 3 if symp-
tomatic (interventional radiology or operative
intervention indicated) 3~ According to this defini-
tion, the majority of seromas documented would
be categorized as grade 2, and as grade 3 in rare
cases; however, grade 1 seromas have so far been
underestimated.
In addition, it is interesting to note that a case
of seroma formation occurring 4 years after breast
reconstructive surgery has been documented in a
patient who was treated with docetaxel TM. Alth-
ough a definite causal relationship between sero-
ma formation and docetaxel is difficult to estab-
lish, this case serves as a reminder that seroma
can recur or appear several years after surgery.
Systematic Review of Seroma
Pathophysiology
Through a systematic review of the literature,
pooling of the available data was felt to be inappro-
priate, not only because of a paucity of high-quali-
ty evidence, but also considerable variability in the
approach and methodology used to determine the
etiology of seroma. Here, therefore, we provide a
s u m m a r y of the best evidence available on this
topic. This includes one RCT investigating the
effect of an antifibrinolytic agent on seroma for-
mation, six studies investigating the composition
of seroma aspirates or drainage fluid, one retro-
spective study investigating the risk factors for
seroma formation, and one representative review
(Table 1).
]) Anatomical Factors
In terms of healing and repair, if a mastectomy
wound is clean and without debris or infection, it
should heal by primary union, with m i n i m u m
granulation tissue 32). In the absence of a stable
apposing surface to which flaps can adhere, the
wound will heal by secondary union, which is a
slower process leaving a large amount of granula-
tion tissue covering the open surfaces. In this
respect, several anatomical factors make fluid
accumulation likely after breast surgery. For
example, the dissection is generally extensive and
results in a large potential dead space beneath the
flaps. Thus, irregularity of the chest wall, especial-
ly in the deep axillary fossa, makes it difficult for
289
Kuroi K, e t a l Pathophysiology o f Seroma in Breast Cancer

Table 1. Evidence Summary

Type of study No. of patients Evaluation items Results and conclusion

Author, year (Evidence level)

Aitken Narrative review - Complications associated with Several characteristics of breast

198322) (level 5) mastectomy, surgery such as large dead space,
irregularity of chest wall, consistent
chest wall movement appear to make
fluid accumulation likely.

Tadych Laboratory analysis 2 Protein, cell count in aspirated The aspirates had the characteristics
19871) (level 5) fluid from patients with pro- of lymph.
tracted seroma.

Watt-Boolsen Laboratory analysis 27 Number of leucocytes, granu- Seroma fluid appeared to be an exu-
1989 TM (level 5) locytes, lymphocytes, and IgG date.
in drainage fluid.

Oertli RCT 160 Use of tranexamic acid, an There was no significant effect of
199497) (level 2) antifibrinolytic agent. tranexamic acid against seroma for-
mation.

Bonnema Laboratory analysis 16 Electrolytes, total protein,
1999 ~6) (level 5) albumin, globulins, hemo-
globin, transferrin, IgG, fib-
rinogen, lipids, blood cells,
glucose, osmolality, creatine
phosphokinase in axillary dr-
ainage fluid on the first, fifth,
and tenth postoperative days.
Seroma fluid seems to be a peripher-
al lymph-like fluid. However, the cell
content is somewhat different from
that of lymph, and it contains no fib-
rinogen.

McCaul Laboratory analysis 18 Blood cells, total protein, albu- The fluid was composifionally differ-
2000~9) (level 5) min, globulin, lipids, calcium, ent from lymph, but similar to inflam-
gamma- glutamyl transferase, matory exudate.
and aspartate aminotrans-
ferase in drainage fluid, and
preoperative plasma sample.

Woodworth, Retrospective study 252 (MRM, 184; Incidence of seroma. Incidence of seroma: 2.5% in MRM +
20001') (level 3) BCT, 64; MRM + IR vs 19.6% in MRM (p = 0.009). The
IR, 40) overall incidence of seroma was
15.5%.

Wu Laboratory analysis 16 (Breast cancer, VEGF, endostatin levels in VEGF levels: wound fluid > plasma.
200340) (level 5) 8; Healthy female- plasma and drainage fluid VEGF levels in wound fluid: day 1 <
to-male transsexu- before, and at day 1 and 4 day 4.
als, 8) after mastectomy. Endostatin levels: wound fluid < plas-
ma.
Endostatin levels in wound fluid: day
1 > day 4.
VEGF and endostatin levels in plas-
ma: day 1 = day 4.
Local VEGF increase and endostatin
decrease appears to be a physiologi-
cal response to operative trauma.

Jain Laboratory analysis 37 (estimated from Protein and LDH in aspirates A high concentration of proteins and
200413) in RCT data) from the first aspiration of LDH in the fluid aspirates suggested
(level 5) seroma. that they are primarily exudate in
nature.

Abbreviations: BCT: breast conserving therapy, IPc immediate reconstruction, LDH: lactate dehydrogenase, MRM: modified radical
mastectomy, RCT: randomized controlled trial, VEGF: vascular endothelial growth factor.

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B r e a s t C a n c e r Vol. 12 No. 4 October 2 0 0 5
Table 2. The S t r e n g t h o f E v i d e n c e
Factors
Lymph or exudate
Contribution of fibrinolysis
Contribution of anigiogenesis regulators
Irregularity of chest wail, constant chest wall movement
Large dead space
flaps to adhere '~. At the same time, constant chest
wall movement due to respiration, together with
shoulder movement, creates shearing forces that
delay flap adhesion 3:~. In accordance with these
factors, immediate reconstruction using tissue
expander following mastectomy has reduced the
incidence of seroma formation, presumably by fill-
ing the dead space in the chest wall H~.
2) Nature of Seroma Fluid
The term "seroma" suggests that the fluid orig-
inates from ultrafiltration of blood. Traditionally,
however, lymph leakage from the upper extremity
through the transected axillary lymph trunks is
believed to be an important factor in fluid secre-
tion and seroma formation, and postoperative arm
use is thought to act as a pump that forces large
quantities of lymph into the empty axillary fossa ~).
Therefore, the term "lymphocele" or "lympho-
cyst" is also used. In support of this, a laboratory
analysis of fluid aspirated from two patients with
protracted seroma revealed characteristics of
lymph, with a low protein concentration compared
to serum and a cell content that was limited to
lymphocytes 1>. The occurrence of chylous leak-
age, although rare after mastectomy, may be con-
sistent with this assumption of lymph leakage ~4).
The occurrence of chylous leakage is thought to
be dependent on anatomical variations in the ter-
mination of the thoracic duct, which may render it
susceptible to injury during mastectomy ~.
On the other hand, Bonnema et al. ~ have
investigated the chemical and cellular compo-
nents of axillary drainage fluid. On the first post-
operative day, it contained blood components, but
one day after operation it changed to a peripheral
lymph-like fluid that contained cells different from
those of lymph, more protein and no fibrinogen,
making coagulation impossible. In association
with these findings, Oertli et al. ~7~ postulated that
fibrinolytic activity of the plasmin system in serum
and lymph may contribute to fluid accumulation,
and that fibrin complexes that have already formed
Evidence grade (remarks)
D (inconclusive)
D (inconclusive)
D (based on level 5 evidence)
D (based on level 5 evidence)
C (extrapolation from level 3 study)
within and around vessels may become degraded,
resulting in further leakage of fluid from vessels.
However, their RCT failed to show any signifi-
cant benefit of tranexamic acid, an antifibrinolytic
agent, against seroma formation.
In contrast, Watt-Boolsen et al. ~ have demon-
strated that seroma is not merely an accumulation
of serum, but exudate resulting from an acute
inflammatory reaction, and concluded that sero-
ma formation reflects an increased intensity and
prolongation of the first phase of wound repair.
McCaul et al. :~ have also demonstrated that drai-
nage fluid has a composition different from that of
lymph, but similar to that of inflammatory exu-
date. On the other hand, Wu et al. 4~ have reported
an increase of vascular endothelial growth factor
(VEGF) and a decrease of endostatin in drainage
fluid immediately after surgery. VEGF is a known
mediator of angiogenesis, vascular proliferation
and permeability, and endostatin is a potent
inhibitor of angiogenesis 414~. Therefore, these
changes may not only reflect induction of angio-
genesis as a physiological response to operative
trauma, but also enhanced accumulation of fluid.
On the basis of this systematic review, the
strength of evidence for each factor was graded
(Table 2). There was grade C evidence for a large
dead space causing seroma, although it was obs-
cure whether seroma is composed of lymph-like
fluid or exudate. If the former is the case, it is
important to prevent lymph leakage during and
after mastectomy, whereas in the latter case care
should be taken to minimize the intensity and dura-
tion of the first exudate phase of wound repair.
Conclusion
This study has highlighted the need for a con-
sistent definition of seroma in association with its
severity. Based on this systematic review, a large
dead space appears to contribute to seroma forma-
tion, although it is obscure whether seroma is
291
Kuroi K, e t a l
composed of lymph-like fluid or exudate. Further
study is needed to gain a better understanding of
the pathophysiology of seroma. In terms of sero-
ma prevention, the key factors appear to be oblit-
eration of the dead space and securing flaps to
underlying tissues. Additional factors would incl-
ude minimization of lymph spillage and s e r u m
ooze, and a rapid removal of accumulating fluid.
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