Tenosynovial Giant Cell Tumor
Case Report and Review
David R. Lucas, MD
 Tenosynovial giant cell tumors are a group of generally
benign intra-articular and soft tissue tumors with common
histologic features. They can be roughly divided into
localized and diffuse types. Localized types include giant
cell tumors of tendon sheath and localized pigmented
villonodular synovitis, whereas diffuse types encompass
conventional pigmented villonodular synovitis and diffuse-
type giant cell tumor. Localized tumors are generally
indolent, whereas diffuse tumors are locally aggressive.
Recent developments indicate that tenosynovial giant cell
tumors are clonal neoplastic tumors driven by overexpres-
sion of CSF1. Herein, I report a case of intra-articular,
localized tenosynovial giant cell tumor (or localized
pigmented villonodular synovitis) and review the classifi-
cation, histopathology, and recent developments regarding
its pathogenesis.
(Arch Pathol Lab Med. 2012;136:901–906; doi:
10.5858/arpa.2012-0165-CR)
REPORT OF A CASE
A 24-year-old man presented with right knee pain with
‘‘popping and catching.’’ The pain began 4 years earlier
following a twisting injury while playing basketball. Magnetic
resonance imaging disclosed a torn medial meniscus and a 2.5-cm
mass in the anterior joint space with low signal lines, likely
representing hemosiderin (Figure 1). He underwent arthroscopic
surgery with partial synovectomy. A nodular, encapsulated mass
(Figure 2, A and B) was easily dissected and removed. Microscop-
ically, it showed classic features of tenosynovial giant cell tumor
(TSGCT) (Figure 3). Based upon these results a diagnosis of intra-
articular localized TSGCT was rendered. The patient had not
returned to visit his orthopedic surgeon in two years.
PATHOLOGIC FINDINGS
In this case, the tumor was well circumscribed and easily
removed by simple excision. Aside from its intra-articular
Accepted for publication March 30, 2012.
From the Department of Pathology, University of Michigan, Ann
Arbor.
The author has no relevant financial interest in the products or
companies described in this article.
Presented at the New Frontiers in Pathology: An Update for
Practicing Pathologists meeting; University of Michigan; October 13,
2011; Ann Arbor, Michigan.
Reprints: David R. Lucas, MD, Department of Pathology, Univer-
sity of Michigan, 1500 E Medical Center Dr, Room 2G332, Ann
Arbor, MI 48109 (e-mail: drlucas@umich.edu).
Arch Pathol Lab Med—Vol 136, August 2012
location, it otherwise had the morphologic attributes of a
giant cell tumor of tendon sheath GCTTS. In particular, it
was well circumscribed, multinodular, and encapsulated.
However, unlike GCTTS, it involved the synovial surface of
a large joint. This is an example of intra-articular, localized
TSGCT, also known as localized pigmented villonodular
synovitis (PVNS).1 Unlike conventional PVNS, this type is
indolent. Therefore, understanding this distinction has
important clinical implications. Tenosynovial giant cell
tumor consists of 4 clinicopathologic subtypes (Table).
CLASSIFICATION AND CLINICOPATHOLOGY
OF TSGCT
Giant Cell Tumors of the Tendon Sheath
(Localized TSGCT)
Giant cell tumor of tendon sheath is the most common
form of TSGCT. As the name implies, it arises from
synovial-lined tendon sheaths. Giant cell tumor of tendon
sheath occurs at any age, with peak incidence in the third to
fourth decades. It usually presents as a painless, slowly
growing mass. Three-fourths of these tumors occur in the
digits, especially the fingers, usually on volar surfaces. It is
the second most common soft tissue tumor of the hand,
second only to ganglion. Grossly, it is well circumscribed
and encapsulated and often has a bosselated or clefted outer
surface (Figure 4). On cut section, it is lobulated and
variegated with tan, red-brown, golden, and bright yellow
areas. Its lobular architecture is defined by fibrous bands
(Figure 5). The cell population is polymorphous (Figure 6)
comprising large histiocytoid cells with abundant eosino-
philic cytoplasm and eccentric vesicular nuclei, smaller
mononuclear stromal cells with oval or reniform nuclei,
osteoclast-like giant cells, and xanthoma cells. Mitotic
figures can sometimes be very abundant. Large hemosiderin
deposits, zones of fibrosis including areas resembling
osteoid (Figure 7), sheets of xanthoma cells (Figure 8), and
dyshesive cellular areas forming a pseudoalveolar pattern
(Figure 9) are common findings. Some tumors are
composed of a monotonous population of stromal cells
with only rare giant cells (Figure 10). Giant cell tumor of
tendon sheath is generally indolent and is successfully
treated by simple excision. However, it recurs approximately
25% of the time.2
Localized PVNS (Intra-Articular, Localized TSGCT)
Localized PVNS is morphologically identical to GCTTS. It
presents as a circumscribed, sometimes pedunculated, intra-
articular mass. The knee is the most common location. On
Tenosynovial Giant Cell Tumor––Lucas 901
 Figure 1. Magnetic resonance image of localized, pigmented villo-
nodular synovitis demonstrates a well-circumscribed, 2.5-cm nodule
within the anterior joint space (arrow).
Figure 2. A, Grossly, localized pigmented villonodular synovitis forms
a well-circumscribed, encapsulated mass, which on cut surface (B) has
a multinodular architecture variegated with brown, tan, golden, and
bright-yellow areas.

imaging, it appears as a well-circumscribed tumor, and

intraoperatively, it presents as a sessile, polypoid mass
arising from the synovium. Simple excision is usually
curative.1
Conventional PVNS (Intra-Articular, Diffuse-Type
Giant Cell Tumor)
Pigmented villonodular synovitis is the prototypic form of
diffuse TSGCT. The nomenclature has become complicated
by introduction of the terms localized PVNS and diffuse-type
giant cell tumor (GCT). The latter term encompasses both
intra-articular and extra-articular tumors (see below). The
term PVNS, however, is universally recognized across
disciplines. Pigmented villonodular synovitis is rare, with
an estimated annual incidence of 1.8 patients per million. It
usually affects young adults (average age, 35 years) but has a
wide age range and is slightly more common in women. It
usually affects large joints, especially the knee,3 which
accounts for 75% to 80% of cases. The hip is the second
most common site (15%). Other less frequent sites include
the ankle, elbow, temporal mandibular joint, and spine. It
typically presents as a longstanding, painful mass with
hemarthrosis, and it limits range of motion.
Imaging studies demonstrate an ill-defined, periarticular
mass, often with associated cortical erosions and subchon-
dral cysts (Figure 11). Magnetic resonance imaging shows
low T1 and T2 signals, contrast enhancement, and signal
voids secondary to hemosiderin, sometimes referred to as

!
Figure 3. Localized pigmented villonodular synovitis is histologically
identical to all other forms of tenosynovial giant cell tumor in its cellular
composition, consisting of a polymorphous population of epithelioid
histiocytes with eccentric, pale nuclei; small, mononuclear stromal
cells; and multinucleated osteoclast-like giant cells (hematoxylin-eosin,
original magnification 3200).
Figure 4. Giant cell tumor of tendon sheath often has a bosselated or
clefted outer surface.
Figure 5. The architecture of giant cell tumor of tendon sheath often
shows a highly lobular pattern defined by thick, fibrous bands
(hematoxylin-eosin, original magnification 320).
Figure 6. This high-power micrograph highlights the cytologic features
of the mixed-cell types in a giant cell tumor of tendon sheath
(hematoxylin-eosin, original magnification 3400).
Figure 7. Giant cell tumor of tendon sheath can sometimes have
extensive stromal fibrosis, including a hyalinized collagen matrix
forming osteoid-like structures (hematoxylin-eosin, original magnifica-
tion 3400).
Figure 8. Sheets of xanthomas cell (top), which, grossly, appear bright
yellow, and hemosiderin-laden macrophages (bottom) are common in
all forms of tenosynovial giant cell tumor (hematoxylin-eosin, original
magnification 3400).
902 Arch Pathol Lab Med—Vol 136, August 2012 Tenosynovial Giant Cell Tumor––Lucas
blooming. Grossly, most tumors exceed 5 cm, are red-brown
or tan, and have a prominent villonodular growth pattern
(Figure 12). The villi vary from thick to fine and delicate.
Pigmented villonodular synovitis usually affects large areas
of the synovial surface. Erosions into underlying cortex
(Figure 13, A) and articular cartilage (Figure 13, B) are often
present. Microscopically, PVNS comprises the same poly-
Arch Pathol Lab Med—Vol 136, August 2012
morphous cell population as other TSGCTs do; however, it
is unencapsulated, has pronounced villonodular architecture
(Figure 14), and often contains elongated synovial-line
spaces (Figure 15). Pigmented villonodular synovitis is
treated with wide, local excision and total synovectomy or
arthroplasty; it has a high local recurrence rate, up to 50%,
often with multiple recurrences.4
Tenosynovial Giant Cell Tumor––Lucas 903
 Figure 12. Grossly, pigmented villonodular synovitis forms long,
broad to delicate villous structures. It varies from golden to red-brown
and usually covers a large area of the synovial surface.
Figure 13. These 2 intraoperative, postsynovectomy photographs
depict numerous cortical erosions on the (A) proximal femur and (B) a
deep erosion of the articular surface secondary to pigmented
villonodular synovitis.

Figure 9. Some tumors have large, discohesive areas that form a

pseudoalveolar pattern (hematoxylin-eosin, original magnification
3100).
Figure 10. Monotonous sheets of stromal cells, with uniform, oval to
reniform nuclei, are common in tenosynovial giant cell tumor. Mitotic
figures can be very abundant as shown (hematoxylin-eosin, original
magnification 3400).
Figure 11. Magnetic resonance image of conventional pigmented
villonodular synovitis depicts a very large mass involving both anterior
and posterior synovium (arrow heads) with erosions into the proximal
tibial plateau and posterior distal femur.
904 Arch Pathol Lab Med—Vol 136, August 2012 Tenosynovial Giant Cell Tumor––Lucas
Figure 14. This low-power micrograph illustrates the characteristic villonodular architecture of pigmented villonodular synovitis consisting of thick
and thin villi arising above a solid nodular area (hematoxylin-eosin, original magnification 340).
Figure 15. Synovial-lined, clefted areas are common in pigmented villonodular synovitis (hematoxylin-eosin, original magnification 3200).
Figure 16. Magnetic resonance image of a case of diffuse-type giant cell tumor of the foot highlights the invasive nature of this disease, which forms
a massive tumor infiltrating between metatarsal bones to involve both the plantar and dorsal compartment (arrows).
Figure 17. Diffuse-type giant cell tumor characteristically infiltrates adjacent soft tissue structures depicted by diffuse invasion and entrapment of
adipose tissue in this example (hematoxylin-eosin, original magnification 3200).

Diffuse-Type GCT (Extra-Articular, Diffuse TSGCT) Malignant TSGCT (Malignant PVNS)

Diffuse-type GCT is defined by invasive, extra-articular
disease (Figure 16), regardless of whether the GCT arose
from a joint or soft tissue. In fact, most cases are believed to
represent extra-articular extensions of primary intra-articu-
lar disease.5,6 Because of its diffusely invasive growth,
however, it is often impossible to define the origin.
Diffuse-type GCT has a similar age distribution, location,
and symptoms as PVNS does. The most common sites are
the knee, ankle, wrist, and foot. Diffuse-type GCTs form
large, firm to spongelike, often clefted masses. Microscop-
ically, they are identical to other forms of TSGCT in its cell
population. However, unlike localized TSGCT, diffuse type
GCT widely infiltrates and entraps adjacent soft tissue
(Figure 17) and frequently erodes bone. Pseudoalveolar
spaces and cellular areas devoid of giant cells are often
present. Diffuse-type GCT is locally aggressive and recurs in
33% to 50% of cases, often with multiple recurrences.5,6
Very rarely, a histologically benign, diffuse-type GCT
metastasizes, usually following multiple recurrences.5,6
Arch Pathol Lab Med—Vol 136, August 2012
Malignant TSGCT is very rare. The standard definitional
criteria are the presence of a frankly malignant tumor
coexisting with benign TSGCT or recurrence of a previously
treated TSGCT in the form of a malignant neoplasm.6 Many
malignant TSGCTs are radiation-associated tumors, which
occur many years after radiotherapy for uncontrolled PVNS.
They often comprise large, polygonal cells with granular,
eosinophilic cytoplasm. Trisomies 7 and 5 have been
detected.7
PATHOGENESIS
The pathology of TSGCT was first described by Henry Jaffe
in 1941 as pigmented villonodular synovitis, bursitis, and
tenosynovitis.8 As this nomenclature indicates, TSGCT was
believed to be a reactive, nonneoplastic condition. This
conclusion was supported by failure to detect clonality
utilizing a polymerase chain reaction based assay for
methylation of the X-linked human androgen receptor gene.9
Cytogenetic studies, however, suggested otherwise. For
Tenosynovial Giant Cell Tumor––Lucas 905
 Classification and Nomenclature of Tenosynovial
Giant Cell Tumors (TSGCTs)
Site of Origin Localized TSGCT Diffuse TSGCT
Tendon sheath/bursa GCTTS Diffuse-type GCT
Intra-articular Localized PVNS Conventional PVNS
Abbreviations: GCT, giant cell tumor; GCTTS, giant cell tumor of the
tendon sheath; PVNS, pigmented villonodular synovitis.
example, simple structural and numeric aberrations, as well
as a variety of balanced chromosomal aberrations, have been
discovered. In particular, clonal structural aberrations affect-
ing the 1p11 to 1p13 region,10 and trisomies11 of chromo-
somes 5 and 7 were commonly found. Using fluorescent in
situ hybridization probes, Nilsson et al10 detected recurrent
breakpoints localized to 1p13, often partnered with 2q35.
Based on these results, they suggested activation of a growth
promoting gene through balanced translocation as the
pathogenic mechanism. However, because similar transloca-
tions had been found in hemorrhagic and rheumatoid
synovitis, there were still doubts about a neoplastic origin,
especially in the face of the lack of clonality detected by the
X-linked human androgen receptor gene assay.9
Macrophage colony stimulating factor (CSF1) is a secreted
cytokine/hematopoietic growth factor that plays an essential
role in the proliferation, differentiation, and survival of
monocytes, macrophages, and related cells. It is localized to
the 1p13 breakpoint and appears to have a major oncogenic
role in TSGCT.12 Using a variety of molecular techniques,
investigators from Stanford University12 detected high levels
of receptor (CSFR1) expression in most of the cells in TSGCT.
By contrast, high ligand (CSF1) expression was limited to a
small population of mononuclear stromal cells, which also
harbored CSF1 translocations. In some cases, CSF1 was fused
to COL6A3 (2q35). From these results, they concluded that
TSGCT was indeed a neoplasm. However, the neoplastic cells
constitute a minor component within the tumor, accounting
for only 2% to 16% of the cells. Most cells are nonneoplastic,
inflammatory cells recruited and activated by CSF1 produced
by the neoplastic cells, a phenomenon they called tumor
landscaping. In addition, because the neoplastic cells also had
strong CSF1 expression, they postulated that the neoplastic
cells are driven by an autocrine mechanism. Finally, because
the neoplastic cells are so sparse, they probably eluded
detection in the X-linked human androgen receptor gene
clonality assay. These same researchers13 subsequently
identified a subset of tumors with high CSF1 expression
but the absence of the 1p13 translocation, suggesting an
alternate mechanism in some tumors.
906 Arch Pathol Lab Med—Vol 136, August 2012
In summary, TSGCT can be roughly divided into localized
and diffuse types, with diffuse types being much more
aggressive. Based on cytogenetic and molecular findings,
most tumors appear to be clonal, neoplastic proliferations
driven by CSF1 production of the neoplastic cells, which
account for only a small percentage of the cell population in
TSGCT. Finally, CSFR1, which is highly expressed in
TSGCT, is a group III receptor tyrosine kinase that shows
structural homology with KIT. Thus, in theory, TSGCT could
be inhibited by a tyrosine kinase receptor inhibitor, such as
imatinib (Gleevec, Novartis, Basel, Switzerland). In fact,
imatinib therapy has indeed shown early success in the
treatment of relapsing PVNS.14
References
1. Dines JS, DeBerardino TM, Wells JL, et al. Long-term follow-up of
surgically treated localized pigmented villonodular synovitis of the knee.
Arthroscopy. 2007;23(9):930–937.
2. Reilly KE, Stern PJ, Dale JA. Recurrent giant cell tumors of the tendon
sheath. J Hand Surg Am. 1999;24(6):1298–1302.
3. Murphey MD, Rhee JH, Lewis RB, Fanburg-Smith JC, Flemming DJ, Walker
EA. Pigmented villonodular synovitis: radiologic-pathologic correlation. Radio-
graphics. 2008;28(5):1493–1518.
4. Granowitz SP, D’Antonio J, Mankin HL. The pathogenesis and long-term
end results of pigmented villonodular synovitis. Clin Orthop Relat Res.
1976;(114):335–351.
5. Somerhausen NS, Fletcher CD. Diffuse-type giant cell tumor: clinicopath-
ologic and immunohistochemical analysis of 50 cases with extraarticular disease.
Am J Surg Pathol. 2000;24(4):479–492.
6. Weiss SW, Goldblum JR, eds. Enzinger and Weiss’s Soft Tissue Tumors. 5th
ed. Philadelphia, PA: Mosby Elsevier; 2008.
7. Layfield LJ, Meloni-Ehrig A, Liu K, Shepard R, Harrelson JM. Malignant
giant cell tumor of synovium (malignant pigmented villonodular synovitis). Arch
Pathol Lab Med. 2000;124(11):1636–1641.
8. Jaffe HL, Lichtenstein L, Sutro CJ. Pigmented villonodular synovitis, bursitis
and tenosynovitis: a discussion of the synovial and bursal equivalents of the
tenosynovial lesions commonly denoted as xanthoma, xanthogranuloma, giant
cell tumor, or myeloma of the tendon sheath, with some consideration of the
tendon sheath lesion itself. Arch Pathol. 1941;31:731–765.
9. Vogrincic GS, O’Connell JX, Gilks CB. Giant cell tumor of tendon sheath is
a polyclonal cellular proliferation. Hum Pathol. 1997;28(7):815–819.
10. Nilsson M, Höglund M, Panagopoulos I, et al. Molecular cytogenetic
mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors.
Virchows Arch. 2002;441(5):475–480.
11. Fletcher JA, Henkle C, Atkins L, Rosenberg AE, Morton CC. Trisomy 5 and
trisomy 7 are nonrandom aberrations in pigmented villonodular synovitis:
confirmation of trisomy 7 in uncultured cells. Genes Chromosomes Cancer.
1992;4(3):264–266.
12. West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial
giant-cell tumor from activation of CSF1 expression by a translocation in a
minority of tumor cells. Proc Natl Acad Sci U S A. 2006;103(3):690–695.
13. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression
of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor,
rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol.
2007;31(6):970–976.
14. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib
mesylate for the treatment of locally advanced and/or metastatic tenosynovial
giant cell tumor/pigmented villonodular synovitis. Cancer. 2012;118(6):1649–
1655.
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