Copyright © 2009 John Wiley & Sons A/S

J Cutan Pathol 2009: 36: 1293–1298
doi: 10.1111/j.1600-0560.2009.01256.x
John Wiley & Sons. Printed in Singapore

Journal of

Cutaneous Pathology

Adipose tissue remodeling in
lipedema: adipocyte death andconcurrent regeneration
Lipedema is a disease with unknown etiology presenting as bilateraland symmetric enlargement of the lower extremities due tosubcutaneous deposition of the adipose tissue. Here we describe thehistopathological features of the lipedema tissue and nonaffectedadipose tissue obtained from a typical patient with severe lipedema.
Immunohistochemical analyses indicated degenerative andregenerative changes of the lipedema tissue, characterized bycrown-like structures (necrotizing adipocytes surrounded by
infiltrating CD68+ macrophages; a feature commonly seen in obese
adipose tissue) and proliferation of adipose-derived
stem/progenitor/stromal cells (Ki67+CD34+ cells), respectively.
These findings suggested increased adipogenesis in the lipedema
tissue, which may further lead to hypoxia similar to that seen inobesity, resulting in adipocyte necrosis and macrophage recruitment.
The confinement to the lower extremities and the difference fromsystemic obesity warrants further elucidation in future studies.
Suga H, Araki J, Aoi N, Kato H, Higashino T, Yoshimura K.
Adipose tissue remodeling in lipedema: adipocyte death andconcurrent regeneration.
J Cutan Pathol 2009; 36: 1293–1298. © 2009 John Wiley & Sons
A/S.
Lipedema is a disease of unknown etiology characterized by bilateral and symmetric enlargement of
the buttocks and lower extremities due to subcutaneous deposition of the adipose tissue.1 Although it is
not a rare condition, lipedema is often misdiagnosed
as lymphedema presumably because most clinicians
are unaware of this disease.2,3 Several authors havereported differences in features between lipedema
and lymphedema, such as absence of skin thickening,
minimal improvement with elevation or compression
therapy, no swelling in the foot, and an uncommon
history of cellulitis in lipedema.1 – 5 Lipedema also differs from simple severe obesity in some aspects. First,
lipedema predominately affects women.1,5 Although
the majority of lipedema patients are overweight, asignificant number of them are of normal weight andhave disproportionately enlarged lower extremities.
In addition, those who were overweight reported noHirotaka Suga, Jun Araki, Noriyuki
Aoi, Harunosuke Kato, Takuya
Higashino and Kotaro Yoshimura
Department of Plastic Surgery, University ofTokyo Graduate School of Medicine, Tokyo, Japan

Kotaro Yoshimura, MD, Department of Plastic Surgery,
University of Tokyo Graduate School of Medicine
7-3-1, Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan
Tel: +81 3 5800 8948
Fax: +81 3 5800 8947
e-mail: yoshimura-pla@h.u-tokyo.ac.jp
Accepted for publication January 5, 2009change in lower extremity size with dieting or weightloss.5
Histological analysis of the adipose tissue in
lipedema shows edema with moderate hyperplasia,
and most commonly reveals a lack of the fibrotic
elements frequently seen in lymphedema.1 Some
reports describe abnormal histological findingsin lipedema, such as microangiopathy as an
early histological feature1 and a high prevalenceof microlymphatic aneurysms in affected limbs.6
Another article describes abnormal elastic fibers withan increased number of mast cells in lipedema tissue.7
Although these reports hint that aberrant cellular
activity actively occurs in lipedema, detailed analysesof adipose tissue from lipedemic individuals at thecellular level have not been performed. Furthermore,
there have been no reports that describe proliferativechanges accounting for the enlargement of adipose
tissue.

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Here we describe a case of severe lipedema showing
typical clinical features. Immunohistochemical comparative analyses of the affected and normal adipose
tissues from the same patient revealed histopathological findings of cellular remodeling in the affectedadipose tissue.
Case report
A 74-year-old Pakistani woman presented withbilateral enlargement of the lower extremities andbuttocks that had gradually developed over 30 years.
Although the patient suffered from no pain andhad no history of cellulitis, she had gait difficulties
due to the enlarged lower extremities (Fig.1).
She had no other remarkable medical conditions
or family history. Physical examination revealedmassive bilateral enlargement of the lower extremities
involving the buttocks without palpable subcutaneous
indurations or dermal thickening. No abnormality
was identified in the feet, and Stemmer’s sign wasnegative: a skin fold at the base of the second toe lifted
normally when pinched. Magnetic resonance imaging(MRI) revealed massive circumferential enlargementof the subcutaneous tissue. Together with theseclinical findings, the patient was diagnosed withlipedema. Biopsy samples from the medial patellar
fat pad (lipedema tissue) and inguinal subcutaneous
tissue (nonaffected adipose tissue) were examinedhistologically. No prior trauma had occurred at thebiopsy sites in the recent or remote past.

Methods
Harvested adipose tissues were zinc-fixed (ZincFixative; BD Biosciences, San Diego, CA) andparaffin-embedded. We prepared 6 − μm-thicksections and performed immunostaining using thefollowing primary anti-bodies: mouse anti-humanCD34 (clone QBEnd 10, dilution 1:500, Dako,Glostrup, Denmark), rabbit anti-human Ki67 (cloneSP6, dilution 1:200, Thermo Fisher Scientific,Fremont, CA), and mouse anti-human CD68 (cloneKP1, dilution 1:100, Dako). Isotypic anti-body
was used to serve as a negative control for eachstaining. For visualization with diaminobenzidine(DAB), peroxidase-conjugated secondary anti-bodies
appropriate for each primary anti-body (Nichirei
Biosciences, Tokyo, Japan) were used. Nuclei werecounterstained with hematoxylin. For a double
fluorescence staining, the following secondary antibodies were used: Alexa Fluor 488-conjugated goatanti-mouse IgG and Alexa Fluor 568-conjugatedgoat anti-rabbit IgG (both dilution 1:200, Molecular
Probes, Eugene, OR). Nuclei were stained with 4 ,6-diamidino-2-phenylindole (DAPI).

Fig. 1. Preoperative views of the patient. She presented with bilateral enlargement of the lower extremities involving the buttocks.

1294Adipose remodeling in lipedema
Observations
Hematoxylin and eosin staining of the excisional specimens showed edematous change in lipedema tissuecompared with the normal adipose tissue (Fig. 2).
Adipocytes in the lipedema tissue varied in size; large
adipocytes with a diameter of more than 150 μm
were frequently observed; in contrast, adipocytes
in the normal adipose tissue were more uniform
in size with an average diameter of approximately
100 μm. Though no apparent abnormality was seenin the vasculature, cellular infiltration and crown-likestructures (adipocytes surrounded by macrophages;
a typical finding in necrotic-like adipocyte death8 )were observed in the lipedema tissue (Fig. 2).
Immunohistochemistry for CD68 revealed that mostof the adipocyte-surrounding cells in the crownlike structure were CD68+, suggesting that they
were macrophages scavenging adipocyte debris that
could ultimately form multinucleated giant cells8(Fig. 3). Furthermore, immunohistochemical staining for Ki67 showed that there were a large numberof Ki67+ proliferating cells in lipedema tissue, while
they were rarely seen in the nonaffected adipose tissue(Fig. 4). The Ki67+ proliferating cells were spindleshaped (easily distinguished from macrophages bycellular shape and localization) and CD68–. Double
immunostaining for Ki67 and CD34 revealed thatmost Ki67+ cells were also CD34+. In nonaffectedadipose tissue, CD34 positivity, a marker for adipose
stem/progenitor cells (ASCs), was observed between
adipocytes or in the interstitial space, but the CD34+
cells were Ki67–(Fig. 5). These results suggest thatdegenerative changes of adipocytes are ongoing inlipedema tissue, while CD34+ ASCs are simultaneously proliferating and repairing the degenerative
adipose tissue.
Discussion
This case presented with typical clinical features
and MRI findings2 of lipedema, allowing fora relatively straightforward diagnosis. Treatment
options for lipedema are limited and controversial.
Conservative therapies such as dieting, leg elevation,and compression seem to have minimal effect.5 One
report described that suction lipectomy with limited
skin excision improved the contour and size of thetissue in some cases,3 while another report does notrecommend surgical treatments such as lipectomy orliposuction because of the possible risk of secondary
lymphedema.1
Detailed histological analyses of the affected tissue
revealed degenerative changes of adipose tissue
characterized by accumulation of macrophages andthe formation of crown-like structure. Interestingly,
these changes are similar to the findings observed inobese mice and humans.8 – 10 In obesity, increased
adipocyte size correlates with the frequency ofFig. 2. Hematoxylin and eosin. Edematous adipose tissue, large adipocytes, and crown-like structures were observed in lipedema.
Scalebar = 400 μm (top panels) and 100 μm (bottom panels).

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Fig. 3. a) Immunohistochemistry for CD68. CD68+ cells surrounded a necrotic adipocyte in the crown-like structures frequently seen inlipedema tissue. Scale bar = 100 μm. b) Number of crown-like structures per field. Crown-like structures were counted using three randomly
selected fields (×100).

adipocyte necrosis which results in the recruitmentof macrophages;8 these infiltrative macrophages
play a crucial role in the development of obesityrelated insulin resistance.10 In lipedema tissue,
it was suggested that some adipocytes undergo
necrosis and are subsequently scavenged by recruitedmacrophages, similar to what is seen in obesity.
Although the cause of adipocyte death in bothobesity and lipedema remains unclear, recent studies
have identified adipose hypoxia and dysregulationof adipose function in obesity.11,12 Hypoxia ismost likely induced by excessive hypertrophy andmay be a key factor responsible for degenerativechanges such as adipocyte death and subsequent
macrophage accumulation in lipedema as well. Some
previously reported histological findings such as
microangiopathy,1 microlymphatic aneurysms,6 andabnormal elastic fibers with an increased numberof mast cells7 may all be associated with thesedegenerative changes secondary to hypoxia.
Another interesting finding is an increase of cells
positive for both Ki67 and CD34; such proliferative change in lipedema has not been previously reported in the literature. ASCs have been1296

reported as CD34+ cells in the adipose tissueof mice and humans.13 – 17 ASCs not only function as tissue-specific progenitors16 – 18 but are also
multipotent13,14 and secrete angiogenic growth factors such as hepatocyte growth factor (HGF) undercertain circumstances.15 It was recently revealed that
adipose tissue has a very slow rate of turnover18 and its
perivascular progenitor cells (namely ASCs) differentiate into replacement adipocytes.14,17 Thus, ASCs
play important roles in physiological turnover,18
hyperplasia (obesity), and atrophy of adipose tissue, as well as in incidental remodeling, such as
post-injury repair.15 Increased proliferation of ASCsin lipedema suggests increased adipogenesis in theaffected adipose tissue, which accounts for the massive enlargement of adipose tissue in lipedema. The
rapid increase in adipogenesis could lead to hypoxia
as seen in obesity, resulting in adipocyte necrosis andmacrophage recruitment as described above. The
mechanisms underlying confinement to the lower
extremities and the difference of lipedema from systemic obesity should be elucidated in future studies.

Adipose remodeling in lipedema

Fig. 4. a): Immunohistochemistry for Ki67. There were a higher number of Ki67+ cells in lipedema. Scale bar = 100 μm. b) Percentage of
Ki67+ cells. Ki67+ cell number and total cell number were counted using three randomly selected fields (×100).

Fig. 5. Double staining for Ki67 (red) and CD34 (green). Ki67+ cells in lipedema tissue were also positive for CD34. Nuclei were stained with
4 , 6-diamidino-2-phenylindole (DAPI) (blue). Scale bar = 10 μm.

Conclusions
Comparative immunohistochemical analyses of
lipedema and intact adipose tissue indicated concurrent degenerative and regenerative changes ofthe lipedema tissue, characterized by necrotizing adipocytes and proliferation of adipose-derived
stem/progenitor/stromal cells, respectively. Thesefindings suggested increased adipogenesis in lipedema
tissue, which may further lead to hypoxia similar tothat seen in obesity, resulting in adipocyte necrosis
and macrophage recruitment.

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