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Lipid microspherules in synovial fluid of patients with pigmented villonodular synovitis.

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We describe 2 patients with pigmented villonodular synovitis. In both patients, synovial fluids (SF) were
characterized by the presence of abundant, strongly
birefringent lipid microspherules, which appeared as
Maltese crosses and were found both inside foam cells
and free in the SF. Histologically, the synovial membranes showed pigmented villonodular synovitis, with
aggregation of foam cells containing abundant lipid
microspherules in their cytoplasm. Observation of numerous birefringent lipid microspherules and foam cells
in SF may be a clue to the diagnosis of pigmented
villonoddlar synovitis.
Lipid bodies in synovial fluid (SF) have been
seen in a variety of disorders. Rhomboid cholesterol
crystals may be found in the chronic joint effusions of
patients with rheumatoid arthritis (RA) and osteoarthritis (1). Extracellular fat droplets are present in
effusions of traumatic arthritis (2) and, rarely, in
aseptic necrosis (3) and RA (4).
Recently, intra- and extracellular lipid microspherules have been found in SF from patients with
both acute and chronic forms of undiagnosed arthritis
(5-8). These crystals were not seen under ordinary
light microscopy, but were easily visualized under
From the Department of Orthopedic Surgery, Kobe University School of Medicine, Kobe, Japan.
Kazuhiro Ugai, MD: Assistant Professor of Orthopedic
Surgery; Masahiro Kurosaka, MD: Instructor of Orthopedic Surgery; Kazushi Hirohata, MD: Professor of Orthopedic Surgery.
Address reprint requests to Kazuhiro Ugai, MD, Department of Orthopedic Surgery. Kobe University School of Medicine,
7-Chome, Kusunoki-cho, Chuo-ku, Kobe, Japan.
Submitted for publication January 12, 1988; accepted in
revised form April 14, 1988.
Arthritis and Rheumatism, Vol. 31, No. 11 (November 1988)
polarized light microscopy, where the birefringent
spherules appeared as Maltese crosses.
We describe 2 patients with pigmented villonodular synovitis (PVS), in whom the SF were characterized by the presence of abundant lipid microspherules.
The possibility that these crystals were shed from
foam cells of the synovial lesions is discussed.
Patient 1. Patient 1, a 36-year-old Japanese
man, had a 10-year history of right knee joint swelling.
On admission, the right knee was tensely swollen, and
the range of motion was limited slightly. Results of
radiography of the knee were negative. Bloody, dark
brown fluid (50 ml) was aspirated from the affected
joint. The SF had reduced viscosity and a leukocyte
count of 4,500 cells/mm3, with 3% polymorphonuclear
neutrophils (PMN), 50% lymphocytes, 16% macrophages, and 31% foam cells (Figure 1A).
A fresh drop of SF examined under polarized
light microscopy showed abundant, strongly birefringent microspherules both inside and outside the foam
cells (Figure 1B). No other crystals were seen. The
foam cells with the birefringent spherules were sudanophilic with Sudan black stain. Serum lipid values
were in the normal range (cholesterol 179 mg/dl,
triglycerides 85 mg/dl, P-lipoprotein 459 mg/dl, and
free fatty acid 293 pEq/liter), as were other laboratory
Synovectomy was performed because of the
recurrent joint swelling. Diffusely thickened, chocolate-brown synovium containing numerous solid yellow nodules was found at surgery. Histologically, the
synovium showed plump hyperplastic villus forma-
Figure 1. Photomicrographs of synovial fluid from patient 1. A, May-Giemsa-stained sample viewed under
ordinary light, showing lipid-laden foam cells. Note also lymphocytes and degenerated red blood cells. B, Wet
preparation viewed under polarized light, showing intracellular and extracellular crystals that appear as Maltese
crosses. Spaces in the cell are nuclei. Inset, The same cell under ordinary light. (Original magnification X 400.)
Figure 2. Photomicrographs of a nodular lesion in the synovial membrane from patient 1. A, Hematoxylin and
eosin-stained sample viewed under ordinary light, showing pale-staining foam cells and hemosiderin-containing
macrophages (original magnification X 200). B, Wet preparation viewed under polarized light, showing abundant
extracellular and intracellular Maltese crosses (original magnification x 400).
tion, hemosiderin-containing superficial lining cells,
and hemosiderin-laden macrophages deeper in the
synovium. Multinucleated giant cells were scattered in
all sections. Abundant foam cells with clear, lipidcontaining cytoplasm were present in clusters and as
sheets that formed the palpable yellow nodules (Figure
2A). On wet smear examination of the nodules, abundant intracellular lipid microspherules with the Maltese cross appearance were seen in the foam cells and
free in the surrounding media (Figure 2B). The diagnosis was PVS, based on these histologic findings.
Patient 2. Patient 2, a 30-year-old Japanese
woman, had undergone synovectomy of the right knee
joint because of repeated hemarthrosis. The histologic
diagnosis was PVS. Three years later, the right knee
joint swelled again, and she was admitted to the
hospital. On admission, 20 ml of bloody SF was
removed from the affected joint. The SF showed a
leukocyte count of 7,600 cells/mm3, with 2% PMN,
70% lymphocytes, 23% macrophages, and 5% Sudan
black-positive foam cells. Under polarized light, a
fresh drop of S F showed abundant intra- and extracelMar Maltese cross crystals similar to those observed
in patient 1.
Serum lipid values were cholesterol 172 mg/dl,
triglycerides 80 mgldl , plipoprotein 4 12 mgldl , and
free fatty acid 184 pEq/liter. Other laboratory findings
were normal. A repeat synovectomy was performed.
At surgery, the synovium was thickened, nodular, and
reddish-brown or yellow. The histologic appearance
was characteristic of PVS, with foam cell-rich nodules
in deeper zones and scattered throughout the lining.
Macrophages and giant cells had also infiltrated
throughout the synovium.
Birefringent lipid microspherules with the appearance of Maltese crosses have been described as
liposomes, smectic mesophases, or lipid liquid crystals
(9). Their significance as phlogistic factors is unclear.
Some investigators recently reported the presence of
lipid liquid crystals in inflammatory effusions of patients with unexplained acute monarthritis (5-7) and
chronic polyarthritis (8). Experimental arthritis may
be induced in the rabbit by intraarticular injection of
liposomes prepared sterile, in vitro, and free of endotoxin (10). In the reported cases of idiopathic acute
monarthritis, a significant PMN-rich leukocytosis was
observed in the SF (10,00040,500 cells/mm3, 7497%
PMN); these PMN contained lipid crystals.
In contrast, our patients had a mild leukocytosis with a low percentage of PMN: 3% in patient 1, and
2% in patient 2. Lipid bodies in the foam cells were
clearly demonstrated by May-Giemsa staining and
Sudan black staining, and these cells contained the
Maltese cross lipid crystals; none were found in PMN.
Thus, at the time our patients were assessed, it did not
appear that the lipid crystals contributed to an acute
inflammatory reaction. Schlesinger et a1 (8) described
a patient with an unexplained chronic polyarthritis
whose S F revealed birefringent lipid-containing macrophages. The synovium of this patient contained
scattered lipid-laden macrophages in the sublining
layer. Those authors suggested that the lipid crystals
might induce a nonspecific synovitis.
The origin of these crystals in joint fluid is
uncertain. One postulate is that lipid crystals result
from the breakdown of cell membranes, particularly
erythrocytes (1 1). This is a possible source of the lipid
crystals in PVS, because the effusions are usually
bloody. The consistent finding of foam cells, however,
both in the synovial membrane and fluid, loaded with
lipophilic material that produces lipid liquid crystals
on wet smear preparation, strongly suggests that these
chronic phagocytic cell infiltrates are the usual source
of the crystals in PVS.
PVS, first described by Jaffe et a1 (12) in 1941, is
a monarticular proliferative process that involves the
synovial tissues and is most commonly observed in the
knee joint. The pathogenesis is unknown; however,
neoplasm, inflammation, trauma, and disturbance of
fat metabolism have been proposed as causes (13). The
synovium thickens, forming clusters of villi, which are
sometimes spread diffusely, but sometimes are entirely localized or nodular. Histologically, the lesions
consist of hyperplastic synovial cells, hemosiderinbearing cells, foam cells, and multinucleated giant
cells. An abundance of foam cells, often forming solid
nodules, typifies the lesion of PVS (14). While occasionally seen in the inflammatory response of other
arthritic disorders, including RA, foam cell infiltrates
are usually scant. We did not detect birefringent lipid
microspherules in S F collected from 14 patients with
RA or 18 patients with osteoarthritis (unpublished
Previously, we reported that the foam cells in
PVS exhibit Fc receptors and phagocytic capacity,
both of which are characteristics of macrophages (15).
Further, on enzymologic analysis, the lipid in the foam
cells revealed cholesterol ester. We consider foam
cells to be infiltrating cells of monocyte origin, and we
think that the accumulation of cholesterol ester in the
macrophage may be related to an insufficiency of acid
cholesterol esterase in their lysosomes (15).
Reports on the laboratory analysis of SF in PVS
are rare. None indicate the presence of lipid crystals in
the fluid, and few detail any observations of foam
cells (16).
From the results presented here, the finding of
birefringent lipid microspherules and foam cells in the
SF suggests the possibility of PVS. Synovial biopsy
with a wet smear preparation and Sudan black staining
is likely to be of use in confirming the diagnosis of
Acknowledgments. We thank Drs. Morris Ziff and T.
Derek Cooke for help in preparing the manuscript and
Toshiko Konuma for secretarial help.
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synovitis, patients, villonodular, pigmented, synovial, lipid, fluid, microspherules
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