Soft Tissue Tumors of Borderline Malignancy
Moderators: Dr. Cyril Fisher and Dr. John R. Goldblum
Section 3 -
CD34-Positive Soft Tissue Tumors of Borderline Malignancy
University of Occupational and Environmental Health
CD34 (hematopoietic progenitor cell antigen) is a 110-kDa
transmembrane glycoprotein of an unknown function, and expressed in hematopoietic stem cells, and several
nonhematopoietic tissues, including endothelium, the interstitial cells of Cajal, and a subset of
dendritic interstitial fibroblastic cells present in the dermis, especially periadnexally and
perivascularly, and in the endoneurium
CD34 also variably reacts with a variety of mesenchymal
tumors, including boderline soft tissue tumors. These tumors include dermatofibrosarcoma protuberans
(DFSP) and its variants, extrapleural solitary fibrous tumor (SFT), hemangiopericytoma (HPC),
hemangioendothelioma, Kaposi sarcoma, extragastrointestinal stromal tumor, and some cases of atypical
lipomatous tumor/well differentiated liposarcoma and myxoinflammtory fibroblastic sarcoma. This
presentation will be focused on DFSP, SFT and HPC, and also briefly refer to the other borderline soft
Dermatofibrosarcoma Protuberans (DFSP)
DFSP typically presents during early or mid-adult life in the trunk and proximal
extremities, although it rarely occurs in children. The majority of original tumors presented as a
solitary, nodular or protuberant mass involving the subcutis and the dermis, but recurrent lesions often
form multiple discrete subcutaneous nodules. Rarely DFSP appears as an atrophic plaque. The tumor
diffusely infiltrates the dermis and subcutis, spreading along connective tissue septa or intricately
interdigitating with subcutaneous adipose tissue with a honeycomb or lacelike appearance. The tumor is
composed of a monotonous proliferation of small to medium-sized spindle cells arranged in a distinct
storiform or cartwheel pattern. The mitotic activity is low or moderate. Occasional tumors containing
myxoid areas, where the storiform pattern becomes less distinct, simulating
myxoid liposarcoma . Very rarely, DFSP with granular cell change was
In 5% to 20% of DFSP, fibrosarcomatous (FS) change occurs
either in the initial lesion or in the recurrent one
FS areas consist of a cellular proliferation
of plump atypical spindle cells with hyperchromatic nuclei arranged in variably interlacing fascicles,
often displaying a herringbone appearance. The FS areas show a significantly highly mitotic rate.
Exceptionally, DFSP cases transformed into MFH-like sarcoma were also reported. Myoid areas are occasionally recognized as randomly distributed, scattered bundles
or small nodules of spindle cells with deeply eosinophilic cytoplasm, more often in FS areas than in DFSP
Immunohistochemically, tumor cells in DFSP areas are diffusely positive for CD34
whereas FS areas in most DFSP-FS cases had no CD34-positive tumor cells or show only focal and weak
staining . Both components are negative for actin and desmin, although scattered myoid nodules show
an actin-positive, desmin-negative immunoreactivity
P75 (low-affinity nerve growth factor
has been reported positive in the tumor cells . S-100 protein and EMA are usually
negative, although exceptional cases expressing those antigens have been reported
histogenesis of DFSP is undetermined, the tumor cell differentiation resembles that of CD34-positive
dermal fibroblasts. Most ultrastructural studies on DFSP revealed that the fibroblastic cells were the
chief component ,
whereas others proposed neural differentiation .
Cytogenetic studies in DFSP have shown two consistent features: a reciprocal
translocation, t(17;22)(q22;q13), and a supernumerary ring chromosome derived from the translocation,
. This rearrangement creates a chimeric COL1A1-PDGFB gene which seems to play an important
role in the tumorigenesis of DFSP
Recently, imatinib mesylate (Glivec) has been considered a
novel treatment for locally advanced or uncontrollable DFSPs .
DFSP is a locally aggressive tumor and has been reported to recur in up to over half of
patients. Because the risk of local recurrence correlates with the extent of the local excision,
treatment of this type of tumor ideally is wide local excision. It seems that conventional DFSP without
FS areas probably does not metastasize. The metastatic rate of DFSP-FS ranges from 0% to 20%, probably
depending upon the extent of the wide excision .
Bednar tumor (pigmented DFSP) is an uncommon variant of DFSP, and accounts
for approximately 1 to 5% of all cases of DFSP. The clinical manifestations of patients and the anatomic
locations of the tumors are similar to ordinary DFSP. The histologic pattern of Bednar tumor is
indistinguishable from ordinary DFSP except for scattered melanin-containing cells. The pigmented cells
do not appear to be neoplastic, and may simply reflect secondary melanocyte colonization from the
The t(17;22) and the COL1A1-PDGFB fusion transcripts have been also detected in Bednar
tumors by FISH 
and RT-PCR , respectively.
Giant cell fibroblastoma (GCF) (juvenile DFSP) is an uncommon soft tissue
tumor occurring predominantly in the first decade of life and exceptionally in adults. It is
preferentially located in the trunk, presents a slowly growing, infiltrative subcutaneous mass, and may
recur locally in up to 50% of cases; however, there are no documented examples of metastatic GCF .
The tumor is composed of a proliferation of parallel fibroblastic spindle cells scattered with
multinucleated giant cells with a peripheral overlapping arrangement of nuclei displaying a floret-like
appearance, being closely associated with dense collagen fibers. Sinusoidal-like spaces rimmed by either
a continuous or discontinuous layer of the giant cells are another characteristic finding of GCF.
Immunohistochemically, most of the tumor cells are positive for vimentin and CD34. Shmookler, Enzinger
and Weiss suggested that GCF might represent a juvenile form of DFSP on the base of the extensive
homology of both clinical and morphologic variables . Others have confirmed the close relationship
of these two tumors in reports . Cytogenetic and molecular genetic studies have identified the
reciprocal translocation t(17;22)
 and consequent COL1A1-PDGFB fusion
in GCF tumor
samples, respectively, confirming that GCF is a juvenile analogue of DFSP.
Solitary Fibrous Tumor (SFT)
SFT originally described in the pleura is now known to be quite ubiquitous , and
well-documented examples have been increasingly recognized in soft tissues
Most SFTs are
observed in adults over age 30 years, but rare occurrences in children have been reported. Most tumors
in the peripheral soft tissue are found in the subcutis, and others are located in the deep soft tissues
of extremities. Microscopically, the alternation of hypercellular and hypocellular areas, the deposition
of dense bundles of collagen, and occurrence of a hemangiopericytoma (HPC)-like vascular pattern at least
focally in most cases are the most characteristic features. Most with a HPC-like pattern were termed HPC
in the past. Occasionally the stroma is very myxoid . The tumor cells in
most cases are bland, and have relatively uniform spindle to oval or rounded nuclei, scanty cytoplasm
with indistinct borders, arranged in a so-called "patternless pattern". Mitotic activity is low in most
cases. Some SFTs may contain giant multinucleated stromal cells, overlapping morphologically with giant cell angiofibroma, that was originally reported in the orbit, and has been
considered to belong to the spectrum of SFT with a benign behavior . Features correlating with risk
of malignant behavior are high cellularity, moderate to marked cytologic atypia, mitotic rate over 4/10
HPF, and tumor necrosis
There are rare cases with abrupt transition from conventional
benign-appearing SFT to overtly high grade sarcoma.
Immunohistochemically, tumor cells in SFT are typically uniformly positive for CD34 .
Many cases are also variably positive for bcl-2 
and CD99 . Focal positivity for smooth muscle
actin, S-100 protein, and cytokeratins has been reported . Ultrastructural studies showed that the
tumor cells were fibroblastic with very occasionally myofibroblastic differentiation
Cytogenetically, SFTs are heterogeneous, and no specific cytogenetic abberrations has been founded.
Although most SFTs behave in a benign fashion, some recur locally, and rarely metastasize,
indicating this tumor has a clinical spectrum from benign to malignant
There is no strict
correlation between morphology and behavior, but most histologically benign-appearing SFTs are
non-recurring and non-metastasizing, and histologically malignant tumors tend to behave aggressively.
Lesions showing convincingly pericytic differentiation undoubtedly exist, and can be
designated as discrete entities . These include myopericytoma, glomus tumor, glomangiopericytoma,
myofibroma, and sinonasal HPC. Many cases that would previously have been termed HPC have no convincing
evidence of true pericytic differentiation both immunohistochemically and ultrastructurally, and are now
diagnosed as SFT. The tumors still currently named HPC other than sinonasal
HPC closely resemble cellular areas of SFT and appear fibroblastic not pericytic in nature, and the
border between the two neoplastic entities has become increasingly blurred, and the separation is often
The discrete subset of lesions remaining as HPC (so-called HPC) occur most often in
middle-aged adults, and arise most often in deep soft tissues, especially in the retroperitoneum and
pelvic cavity, and the meninges. Histologically, so-called HPCs are closely similar to cellular areas of
SFT with a consistent HPC-vascular pattern having a staghorn configuration throughout the entire tumor.
The tumor cells are usually closely packed, and typically have uniform, oval to spindle bland nuclei and
scanty pale or eosinophilic cytoplasm with indistinct borders. Mitotic activity is fairly variable. In
contrast to SFT, stromal collagenization and an alternating hypercellular and hypocellular growth pattern
are usually absent. Rare tumors termed lipomatous HPC have both an HPC
pattern and adipocytic component. Most of the lipomatous HPCs show varying cellularity and are
considered as a variant of SFT rather than of HPC .
Immunohistochemically, comparable to SFT, the tumor cells are typically positive for CD34
and CD99, whereas with rare exceptions, smooth muscle actin is negative, indicating no phenotypic
features of mature pericytes. Ultrastructurally, most of so-called HPCs are composed of fibroblastic
cells or undifferentiated spindle cells with subtle pericyte-like features, without convincing evidence
of true pericytic differentiation. Cytogenetical changes reported in HPCs are not specific.
There have been no recent prognostic studies on so-called HPC. According to the older
data of the large series, that probably included cases of SFT, by Enzinger and Smith in 1976, prominent
mitotic activity (4 or more mitotic figures per 10 HPF), necrosis, hemorrhage, and increased cellularity
constituted ominous signs usually observed in tumors that later recurred or metastasized . With this
definition, around 70% of their cases behaved in a benign fashion. They described that the prognosis was
also related to the size of the tumor (larger than 6.5 cm), location (the trunk and the retroperitoneum),
and recurrence of the tumor.
Other CD34-Positive Soft Tissue Tumors of Boderline Malignancy
These include borderline vascular tumors, and gastrointestinal stromal tumor occurring in
the omentum, mesentery, and retroperitoneum (extragastrointestinal stromal tumor)
. Spindle cells in
some cases of atypical lipomatous tumor/well differentiated liposarcoma  and myxoinflammatory
fibroblastic sarcoma  are also variably positive for CD34.
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