Low Grade Sarcoma with CD34 Positive Fibroblasts, and Low Grade Myofibroblastic Sarcomas
Royal Marsden Hospital
LOW GRADE SARCOMAS WITH CD34-POSITIVE FIBROBLASTS
Most fibroblastic lesions lack specific immunohistochemical
markers and express only vimentin which is of no diagnostic value. A subset of benign and malignant
fibroblastic tumors, however, is composed of CD34-positive cells. The human hematopoietic progenitor
cell antigen (CD34) is a 110-kDa transmembrane cell surface glycoprotein encoded by a gene in the 1q32
region  . It reacts with several non-hematopoietic tissues including vascular endothelium,
endoneurial cells, and a subset of dermal dendritic interstitial fibroblastic cells in connective tissue,
around blood vessels, nerves, smooth muscle bundles and hair follicles, and their tumors  .
CD34 is also variably expressed in a variety of mesenchymal neoplasms including some tumors of
fibroblasts. These include dermatofibrosarcoma (DFS), fibrosarcoma arising in DFS, solitary fibrous
tumor  and hemangiopericytoma, and a minority of cases of myxofibrosarcoma and
myxoinflammatory fibroblastic sarcoma  and pleomorphic hyalinizing angiectatic tumor
(DFS) is a relatively common lesion, which
is more frequent in males with a peak age incidence of 25-45 years, and which occurs especially on the
trunk and upper limbs. It begins as a dermal plaque or nodule and grows slowly, sometimes becoming
multinodular. DFS recurs, especially if incompletely excised; metastasis occurs in fewer than 5% of
cases and follows multiple recurrences; exceptionally, there is fibrosarcomatous or MFH-like
transformation which is associated with a more aggressive course.
The lesion is composed of uniform elongated thin spindle cells with minimal cytoplasm and
indistinct margins, in a striking and monotonous "tight" storiform pattern. The tumor forms a nodule or
ill-defined plaque in the dermis which extends into subcutaneous fat with a characteristic honeycomb
pattern including trabeculae or layers of infiltrating tumor parallel to the skin surface.
Immunostaining shows strong diffuse CD34 expression, and focal reactivity for smooth muscle actin, but
usually no significant staining for S100 protein. Some cases are CD117-positive, which has led to the
suggested use of imatinib (Glivec) in locally advanced DFS or in metastatic disease
The cell type of DFS is not clearly characterized
ultrastructurally: histiocytic, perineural, pericytic and endothelial origin have all been suggested but
most agree that there are variably developed features of fibroblasts (notably rough endoplasmic
reticulum). The strong and diffuse CD34 expression supports the hypothesis that the tumor might be
derived from (or differentiating towards) any of the local populations of normal CD34-positive
fibroblasts - intradermal, periadnexal, or endoneurial. Occasionally, there are also focal peripheral
filament bundles suggesting myofibroblastic differentiation. In keeping with this, some DFS are
actin-positive, and focal areas of 'myoid' differentiation have been described in both DFS and, more
frequently, in DFS-FS
. In these, the cells have short, blunt-ended nuclei with
eosinophilic cytoplasm which is SMA positive but desmin and CD34 negative, and electron microscopy has
shown (mostly) myofibroblastic differentiation. It has been suggested
, however, that
this represents a change in the stroma rather than the lesional cells. The feature has no clinical
significance. Factor XIIIa (which stains dermal "dendrocytes") is generally not detectable in the
principal lesional cells of DFS
DFS has a reciprocal translocation, t(17;22)(q22;q13) (with a
supernumerary ring chromosome) resulting in fusion of the genes COL1A
(17q21-22) and PDGFB1(22q13)
. The same abnormalities have
also been shown in fibrosarcoma arising in DFS, in which COL1A1-PDGFB transcripts have been demonstrated
. Other rearrangements, including t(2;17) and t(9;22) have rarely been found in DFS
 . Gene expression profiling has shown high expression of a group of genes which included
PDGFB and osteonectin  .
Myxoid and pigmented variants of DFS are described. Rarer atrophic, palisading and
granular cell variants are also recognized but lack clinical significance. Myxoid
DFS can be diagnosed by the characteristic cytology as well as the (variable) CD34 positivity. It
must be distinguished from a range of benign myxoid lesions and from myxofibrosarcoma (by absence of
nuclear pleomorphism and the different vascular pattern). Pigmented DFS (Bednar
tumor)  has melanin-containing S100 protein-positive cells singly or in small
clusters. This variant is incidentally more common in individuals with pigmented skin. It is
cytogenetically identical to regular DFS  , and can also undergo fibrosarcomatous change
Fibrosarcoma can arise in DFS, both de novo and in recurrent lesions
. It is characterized by greater cellularity, fascicular architecture and increased
mitotic activity. CD34 can be positive or negative in the fibrosarcomatous area  . The
fibrosarcomatous component behaves relatively aggressively, with local recurrence in over 50% and
metastasis in 15% of cases  . However, adequate local control of DFS with fibrosarcomatous
changes, with clear surgical margins, can reduce both local recurrence and the incidence of metastasis
Giant cell fibroblastomais a rare childhood (and occasionally adult) lesion
of dermis/subcutis, predominantly arising in back of thigh, groin and chest wall (in a similar
distribution to DFS)
. GCF has recurrent potential. It is poorly circumscribed and
infiltrative in skin and subcutis, with spindle and bland multinucleate cells in a fibrous and myxoid
stroma, and focally forms cystic spaces lined by tumor (not endothelial) cells. Cellularity is variable,
and both hypercellular and hypocellular (fibrous) areas occur. The lesional cells are CD34 positive and
giant cell fibroblastoma has been recorded as recurring partially or completely as dermatofibrosarcoma
protuberans, of either classical or pigmented types. This tumor is therefore currently considered to be
a (juvenile) variant of DFS. The multinucleate cells are seen ultrastructurally to have a single nucleus
with marked indentation and convolution. The cytogenetic abnormalities and
molecular events in GCF are identical to those in DFS
Solitary fibrous tumor
This neoplasm (SFT) was originally described in
the pleura and has since been described in almost every site, including peritoneum, pericardium and
mediastinum, liver, upper respiratory tract including nasal cavity, salivary gland and breast
 . SFT is increasingly recognized in soft tissues
. The lesion is
circumscribed but rarely encapsulated, and is composed of plump or slender spindle or rounded cells in a
collagenous background. The cells are bland and have scanty cytoplasm; multinucleated cells are
sometimes present. Lesional cells are arranged in a "patternless" pattern, sometimes with alternating
hyper- and hypocellular regions. In the latter, there is variable collagenization, which is focally
dense although stroma is sometimes myxoid. The vessels are focally hemangiopericytomatous, and islands
of mature fat can occur (lipomatous hemangiopericytoma
). Mitotic activity varies from
0-50 per 10 HPF, and some cases have necrosis or hemorrhage. Immunohistochemically, strong and diffuse
CD34 and bcl-2 expression are a feature of this tumor type
. Indeed, a
CD34-negative tumor in an extra-pleural location should probably not be diagnosed as solitary fibrous
tumor unless the other evidence is compelling  . CD99 is also positive  and
sporadically there is focal positivity for actin, S100 protein and (exceptionally) cytokeratin.
Electron microscopy shows fibroblastic cells with very occasional myofibroblasts. In spite of the
original reports of pleural tumors, SFT does not show evidence of mesothelial differentiation. A variety
of genetic findings has been reported including loss of 13q, 4q and 21q; trisomy 21; and gains at
chromosome 8 and at 15q; t(4;15)(q13;q26)  , t(6;17)(p11.2;q23)  , and
t(9;22)(q31;p13)  , and also, once again, rearrangements involving 12q13-15  .
Predominantly myxoid SFT (myxoid change exceeding 50% of the tumor) is very uncommon,
perhaps representing <5% of SFT  . Cords of bland spindle cells lie in a vascular myxoid
stroma, with focal cellular aggregates, and most also have areas of typical solitary fibrous tumor with
variable collagenization and staghorn vessels. Nuclear atypia is absent. All cases are positive for
CD34 and CD99. None of the reported cases experienced recurrence or metastasis.
SFT displays a spectrum of behavior. Recurrence is more
likely with larger and histologically aggressive tumors, and atypical and malignant variants in soft
tissue have been identified
. Suggested criteria for malignant SFT  are
(1) presence in an otherwise typical SFT of at least two of: high cellularity with nuclear crowding and
overlapping, pleomorphism, and mitoses >4/10 hpf (and one could perhaps add necrosis); and (2)
development of sarcoma in the site of a previous SFT. CD34 expression can be lost in the malignant
Stout and Murray originally described
hemangiopericytoma (HPC) in 1942  with a further report of 25 cases in 1949 .
Examination of these series suggests a heterogeneous group of neoplasms, including probable myofibroma.
Stout himself stressed that the exact nature of the cells in these tumors had not been proved, and that
there was no scientific basis in support of the designation. HPC is in fact becoming a diagnosis of
exclusion as a wide variety of benign and malignant lesions show at least focally the non-specific but
characteristic branching and staghorn open vascular pattern . Many cases that would
previously have been termed hemangiopericytoma are now, on the basis of diffuse CD34 expression,
diagnosed as solitary fibrous tumors (SFT).
Some Tumors with Hemangiopericytomatous Pattern
|Cellular hemangioma |
Benign fibrous histiocytoma (deep)
Solitary fibrous tumor
Giant cell angiofibroma
|Congenital infantile fibrosarcoma |
Nerve sheath tumors
Liposarcoma (round cell)
Malignant fibrous histiocytoma
Pericytes are spindle cells surrounding small arterioles,
capillaries and pre- and post-capillary venules, usually in a single complete or incomplete layer.
Ultrastructurally, pericytes have overlapping processes and a continuous or interrupted external lamina
lies between them and the endothelium. Variable features include micropinocytosis, microfilaments with
dense bodies and junctions. Their immunophenotype varies with location: those around precapillary and
postcapillary vessels express smooth muscle actin (SMA), whereas pericytes around capillaries are SMA
negative . The latter perivascular cell has been considered to represent a persistent
primitive mesenchymal cell that can, according to circumstance and specific location, differentiate into
(vascular) smooth muscle cells, glomus cells, preadipocytes and osteoblasts . This cell
type has also been postulated as the precursor cell of MFH . The group of tumors termed
PEComas is supposedly derived from a SMA/HMB45 positive perivascular epithelioid cell but the normal
counterpart of this cell has not been demonstrated .
The pericyte lacks specific morphologic features, and it is not clear that
hemangiopericytoma, which is usually SMA negative, is composed of pericytes
Nevertheless, cases still remain which are diagnosed as HPC after extensive investigation. A current
definition might be: a tumor which has (a) spindled, plump, or rounded cells with small to moderate
amounts of cytoplasm and indistinct cell margins; (b) a consistent HPC-vascular pattern throughout the
entire tumor, with reticulin surrounding individual cells, and (c) the absence of specific
differentiation, both morphologically and immunohistochemically. Such tumors usually occur in the deep
soft tissue of extremities and retroperitoneum (here associated with hypoglycaemia and hypophosphatemia)
but cases are reported in the breast, orbit, nasal cavity, and CNS as well.
CD34 positivity has been reported in apparent HPC, but the majority of cases formerly
called HPC are now regarded as solitary fibrous tumors, especially when the
CD34 expression is strong and diffuse. However, in SFT the HPC pattern is usually only focal. There is
an occasional report of desmin or smooth muscle actin positivity, and FXIIIa and HLA-DR expression have
been reported in a constant subpopulation of HPC cells, as well as a few cells with FVIIIRAg
. This is not, however, specific, as FXIIIa is present in many spindle cell tumors.
Recently, scanty focal CD117 has been described in a small number of HPC .
Neoplastic cells in HPC are described ultrastructurally as having overlapping processes
with poorly developed junctions, focal myoid differentiation, and a fragmented external lamina between
tumor cells and between them and the endothelium
. In SFT, the cells are
fibroblast-like without external lamina, with rare myofibroblasts
myofilaments are seen in pericytes , and recently a group of tumors has been described with perivascular
myoid differentiation . This group included tumors with histologic features of
infantile-type myofibromatosis, tumors with composite features of "hemangiopericytoma" and glomus tumor,
and tumors with a distinctive concentric perivascular proliferation of spindle cells. Morphologic
overlap among the groups suggests they are part of a single spectrum, termed perivascular myomas or
myopericytomas, and some of these resemble and perhaps overlap with vascular leiomyoma. Strictly
speaking, since they show specific differentiation these should be excluded from the HPC category.
Cytogenetic studies can exclude or identify specific tumor types with a
hemangiopericytomatous pattern, such as synovial sarcoma with its t(X;18)(p11.2;q11.2)  and
round cell liposarcoma which predominantly shows t(12;16)(q13;p11). Changes described in HPC have
included t(1;3)(q22;q11) and t(7;12)(p22;q13)  ; t(12;19)(q13;q13.3)  and
t(13;22)(q22;q11)  . Thus, 12q13 is implicated  but this segment is rearranged
in several soft tissue sarcomas and the findings are not specific  .
The behavior of HPC cannot always be predicted from the histology. A benign HPC lacks
cellular pleomorphism, necrosis and hemorrhage and has a low mitotic rate (either < 4/10 hpf
 or < 1/20 hpf  ). With this definition, around 70% of HPC behave in a
benign fashion, but some histologically benign cases have metastasized. The existence of a borderline
grade (<4mitoses/10hpf, <5% necrosis) has been suggested  but the numbers are too
small to assess the validity of this study. Clear-cut malignant cases, with necrosis and mitotic rates
higher than above, have five- and ten-year survival rates of around 40% and 29% respectively.
In conclusion, most soft tissue tumors with a hemangiopericytomatous pattern can be given
a more specific diagnosis. Many are now classified as solitary fibrous tumors, especially if they show
varying cellularity and fibrosis and diffuse immunoreactivity for CD34 and bcl2 and often CD99. Some
remain which can be termed hemangiopericytoma although there is no conclusive evidence that the tumor
cells are derived from pericytes.
Soft tissue tumors in adults have been
described with HPC pattern and a component of mature fat
, mostly in males in deep soft
tissue, mediastinum or retroperitoneum. They are circumscribed and display an intricate mix of HPC areas
and adipose tissue. Perivascular or stromal hyalinization and focal myxoid change can be seen. Atypia
is rare and the reported lesions have been benign. Cases are generally CD99 positive but expression of
CD34 and bcl2 has been variable. Folpe et al found CD34 in 2 of 4 cases  , and in the
series of Guillou et al, 7 of 12 were bcl2 positive and 10 of 13 were CD34 positive (one case expressed
neither)  , so that at least some of these might represent variants of SFT  .
Sinonasal hemangiopericytoma is a CD34-negative lesion with smooth
muscle-like features that might represent differentiation towards a glomus or perivascular myoid cell
and appears to be unrelated to HPC or SFT elsewhere.
Myxoinflammatory fibroblastic sarcoma
This is a recently documented
low-grade fibrosarcoma, which occurs mainly in digits, wrist and ankle regions, and predominantly in the
subcutis. Montgomery et al  described 51 such cases as in flammatory myxohyaline tumor of
distal extremities with virocyte or Reed-Sternberg-like cells. They occurred over a wide age range (4 –
81 years) and affected the sexes equally. 35 were in fingers, hand, wrist or arm, and 13 in toe, foot or
lower leg. Many of the patients were treated aggressively but recurrences were noted in six of
twenty-seven patients with follow-up. Almost simultaneously, a series of 44 apparently similar tumors in
patients aged between 20 and 91 years was reported  as "acral myxoinflammatory fibroblastic
sarcoma". These authors also noted a relation to tendon sheaths and joints in some cases. There was
local recurrence in two thirds (67%) and several patients required amputation after repeated local
recurrences, and histologically documented metastasis to lymph node in one individual. 5 tumors of the
hand reported as "inflammatory myxoid tumor of the soft parts with bizarre giant cells"  ,
appear to be the same entity. It is now known that this tumor can occur more proximally 
and the term acral has been dropped in the 2002 WHO classification  .
Myxoinflammatory fibroblastic sarcomas form infiltrative multinodular masses characterized
by dense inflammation merging with myxoid to collagenous stroma. The myxoid zones contain
(multi)vacuolated lipoblast-like fibroblasts, as seen in other myxoid fibroblastic lesions and
representing stromal mucin within dilated RER. The inflammatory zones have scattered bizarre cells with
vesicular nuclei and large inclusion-like nucleoli with abundant focally vacuolated cytoplasm,
reminiscent of Reed-Sternberg cells or "virocytes", some of which contain phagocytosed neutrophils.
Ultrastructurally, these cells contain markedly dilated cisternae of rough endoplasmic reticulum, and
perinuclear whorls of intermediate filaments. Other components include eosinophils, neutrophils,
lymphocytes, plasma cells, Touton giant cells and siderophages, and fibrosis (including sclerosed and
hyalinized areas). Normal and atypical mitoses are seen among the bizarre cells, and some cases display
Immunostains are positive for vimentin and negative for CD30, CD15, and S100 protein; 4 of
13 cases were cytokeratin positive  . In the Swedish series, 7 of 25 were CD34 positive, 2
were SMA positive in occasional bizarre cells, and Ki67 labeling index was less than one per cent
 . Ultrastructural studies in this series demonstrated fibroblastic characteristics, and the
ganglion-like cells are interpreted as modified fibroblasts. Clonal chromosome changes have been
described in one case, which showed a complex karyotype with a reciprocal translocation t(1;10) (p22;q24)
in addition to the loss of chromosomes 3 and 13  .
LOW GRADE SARCOMAS OF MYOFIBROBLASTS
Myofibroblasts are modified fibroblasts
which were first described in granulation tissue  and have since been identified in normal
tissues and as the predominant cell in certain reactive lesions. In granulation tissue, in which they
have been most intensively investigated, they are probably derived from local fibroblasts
, in response to mechanical stress, and their functions, appearance and immunoprofile
vary in relation to the phase of activity  . This is reflected in the variable morphology
of reactive lesions such as nodular fasciitis, and contributes to the range of appearances seen in other
pathological conditions. Myofibroblast-like cells might sometimes be derived from vascular smooth muscle
cells or from pericytes  , or by metaplasia as in spindled carcinomas  . Some
fibroblastic lesions have a component of myofibroblasts, but myofibroblasts do not apparently
differentiate to smooth muscle cells. In wound healing, as epithelialization is completed, the
myofibroblasts are presumed to disappear by apoptosis
Myofibroblasts are short, bi- or tripolar spindle-shaped or stellate cells, with crenated
or ovoid pale-staining nuclei each of which has a single distinct, punctate nucleolus. There is sparse
cytoplasm with indistinct cell margins. In addition to synthesizing collagens and other stromal
components including fibronectin and laminin, myofibroblasts have contractile elements
} . Other ultrastructural features of myofibroblasts
include a prominent Golgi complex and collagen secretion granules in Golgi-derived vesicles. Fibroblasts have variable amounts of rough endoplasmic reticulum which can become
distended with secretory products, but they lack external lamina, pinocytosis and organized cytoplasmic
filaments. Fibroblasts express only vimentin, whereas myofibroblasts display various combinations of
vimentin, actin isoforms (especially a-smooth muscle actin), desmin, and myosin
Desmin is found less often in myofibroblastic neoplasms than in smooth muscle tumors  , but
both types of neoplasms can have detectable desmin, muscle specific actin (MSA) and smooth muscle actin
(SMA). Myofibroblasts express calponin but usually lack h-caldesmon, a marker of smooth muscle
differentiation  . Some myofibroblastic lesions can show cytoplasmic (but not usually
membranous) immunoreactivity for CD117 (c-kit); this varies with technical factors, including the
antibody and whether there is antigen retrieval  . In intra-abdominal lesions, this can
lead to confusion with gastrointestinal stromal tumor  .
Benign neoplasms of myofibroblasts occur in soft tissues, bone and visceral locations.
The term myofibrosarcoma, by analogy with the term fibrosarcoma, indicates a malignant tumor of
myofibroblasts  . Myofibrosarcomas display a range of appearances from fasciitis-like
neoplasms to high grade sarcomas. Low- and intermediate-grade myofibrosarcomas are distinct from
pleomorphic myofibrosarcomas, which are malignant fibrous histiocytoma-like tumors. Other low-grade
malignant tumors with myofibroblasts include inflammatory myofibroblastic tumor and infantile
fibrosarcoma, each of which has characteristic genetic abnormalities.
The myofibrosarcoma concept has been controversial. Many
fibroblastic lesions have myofibroblasts, and the proportion of neoplastic myofibroblasts required is not
defined. It is difficult to confirm myofibroblastic differentiation without electron microscopy, and
there is no universal agreement on the ultrastructural criteria of the neoplastic myofibroblast
} . Since
subcellular features can be incompletely or abnormally developed in malignant cells, the fibronexus has
not been an absolute requirement for most investigators. This structure has, however, been reported in
several myofibrosarcomas  , and has been illustrated more often in case reports than it has
been mentioned by their authors
. Identification of a cell type depends on several
features, and the fibronexus is only one of the features used to define myofibroblastic
It has also been held that sarcomas supposedly composed of myofibroblasts are actually
poorly developed smooth muscle tumors  . Low-grade leiomyosarcomas, however, usually have
well-developed smooth muscle differentiation. Furthermore, although the cytoplasmic filament patterns
can be somewhat similar in myofibroblasts and smooth muscle cells, the two cell types differ in other
respects - unlike myofibroblasts, smooth muscle cells have external lamina, and cell membrane plaques as
well as pinocytotic vesicles. Leiomyosarcoma and myofibrosarcoma can both display actins and desmin, but
the latter is less often seen in myofibroblastic neoplasms. Also, in myofibrosarcomas, the actin
staining is often manifested as a peripheral rim rather than throughout the cytoplasm  .
The paucity of h-caldesmon in myofibroblastic lesions additionally supports their separate identity
Thus, the ultrastructural features and immunohistochemistry, in conjunction with the
morphology, are sufficiently distinctive to identify myofibroblastic differentiation in sarcomas. The
two principal low grade lesions in this category are myofibrosarcoma and inflammatory myofibroblastic
Low-grade myofibrosarcoma is a distinctive neoplasm which occurs in soft
tissues and bone as a fasciitis- or fibrosarcoma-like spindle cell sarcoma which infiltrates locally but
rarely metastasizes. Myofibroblasts were observed in well-differentiated fibrosarcoma in 1975
 , and the first 'sarcoma of myofibroblasts' was reported 3 years later  .
About 50 cases have since appeared in the literature
Low- and intermediate-grade myofibrosarcomas occur at any age (range 7-85 years, mean 40) with a
slight male predominance and tumor size ranging between 1.5 and 17 cm. Tumors can arise in extremities,
trunk including breast, and retroperitoneum, but there is a predilection (up to one-third of cases) for
the head and neck region in both soft tissue (including oral cavity especially tongue, face and neck),
and bone, notably maxilla and mandible
Myofibrosarcomas can be found in subcutis or submucosa, but are mostly deep soft tissue or
intraosseous tumors. They can be circumscribed, but mostly infiltrate irregularly along connective
tissue septa or into skeletal muscle. The tumors are composed of mostly bland or focally pleomorphic
stellate or spindled cells with tapered or ovoid nuclei with small nucleoli, and scanty or moderate
amounts of eosinophilic cytoplasm. The patterns include fibrosarcoma-like fascicles, sheets or storiform
whorls, with variable collagenous or myxoid stroma and scanty inflammation. Nuclear atypia is always
present at least focally and usually mildly with scattered enlarged hyperchromatic nuclei, but larger
atypical cells are sometimes seen. Mitotic activity is observed but necrosis is unusual Recurrences
tend to be more pleomorphic
, but in one example a breast metastasis from a grade 2
fibrosarcoma-like tumor resembled nodular fasciitis  .
Electron microscopy shows myofibroblasts which have variable RER, cytoplasmic filament bundles, and in
some cases minimal external lamina. Fibronexus structures and collagen secretion granules are rarely
found. Low-grade myofibrosarcomas express actin (as a peripheral rim, beneath the cell membrane), and
about one-half express desmin, usually in fewer cells
. These antigens can be
expressed separately, with either a desmin positive/SMA negative or desmin negative/SMA positive
immunophenotype  . Calponin is diffusely positive, but h-caldesmon is only focally
expressed in an occasional case  . These findings are similar to those in nodular
fasciitis, and differ somewhat from leiomyosarcoma, which usually displays diffuse h-caldesmon as well as
calponin. Fibronectin  has been found in some myofibrosarcomas but not collagen IV or
laminin. Rare myofibrosarcomas focally display cytokeratins or CD34  , and one example had
focal S100 protein positivity  . ALK-1 expression has not been reported.
Immunohistochemistry of smooth muscle and fibro/myofibroblastic tumors
| Des || SMA || MSA || S100|| EMA ||CK ||CD34 || Calp || hCald|
|Leiomyosarcoma || + ||+ || + || + || + ||+ || ± || + || +|
|Myofibrosarcoma|| ± ||+ || ± || -*|| - ||-* || - || + || -*|
|Fibrosarcoma* || - ||-*|| - || - || - ||- || ± || - || -|
|+ = diagnostically useful |
+ = also sometimes found
± = inconsistently reported
- = absent
* = very occasionally positive
|des = desmin |
SMA = smooth muscle actin
MSA = muscle specific actin
EMA = epithelial membrane antigen
CK = cytokeratin
calp = calponin
hcald = heavy caldesmon
Low-grade myofibrosarcomas are indolent, but they can relapse and metastasize even after a
long period. In one series, there was local recurrence in two of 11 patients and metastasis in one
 . In the series of Montgomery et al  , 4 of 9 low-grade myofibrosarcomas,
and three of four intermediate grade tumors recurred (one twice), and one intermediate-grade tumor which
arose in the breast resulted in pulmonary metastasis after 12 months.
Myofibrosarcomas can resemble
benign myofibroblastic lesions such as nodular fasciitis and fibromatosis, and other sarcomas, notably
fibrosarcoma and leiomyosarcoma. Both clinical data and morphology are important for diagnosis since
immunohistochemistry does not discriminate between myofibroblastic lesions and the immunophenotype
overlaps with that of smooth muscle.
Nodular fasciitis is a mainly subcutaneous lesion which appears suddenly and grows rapidly
but does not usually exceed 5 cm in diameter. There are myxoid, cellular and fibrous areas, often in
different parts of the same lesion. Nuclear atypia and necrosis are absent. Myofibrosarcoma is more
cellular and uniform than nodular fasciitis, and infiltrates more widely. Fibromatosis has files of
slender spindle cells in dense collagen with slit-like blood vessels and mast cells, and lacks nuclear
atypia. Fibromatosis also infiltrates skeletal muscle, but muscle fibres show atrophy rather than
separation by tumor as in myofibrosarcoma.
Adult-type fibrosarcoma has a more herringbone-like fascicular architecture, and cells
with scanty cytoplasm and elongated tapered nuclei. There is variable intercellular collagen and myoid
markers are usually absent. Leiomyosarcoma typically has alternating fascicles of cells that are more
parallel-sided with square-ended nuclei scattered paranuclear vacuoles. Caldesmon expression is more
widespread. Other spindle cell sarcomas such as synovial sarcoma, malignant peripheral nerve sheath
tumor, some examples of angiosarcoma and spindle cell rhabdomyosarcoma can be recognized by their
morphology and by their specific immunophenotype. In head and neck and breast tumors, spindle cell
carcinoma has to be excluded by use of multiple cytokeratin antibodies.
Inflammatory myofibroblastic tumor (IMT) is most commonly seen in the lung
in childhood. Extrapulmonary tumors usually arise within the abdomen, (retroperitoneum or mesentery) as
a solitary or multicentric mass
with peak incidence in the first or second decades
with a slight female predominance. There are sometimes B-type systemic symptoms, anemia and
hypergammaglobulinemia. Similar cases have also been termed inflammatory fibrosarcoma  ,
but these conditions probably represent a single entity with a spectrum of morphology and behavior
 , i.e. a low-grade neoplasm of myofibroblasts.
IMT presents with multinodular and sometimes multiple firm white or yellow tumors up to 10
cm in diameter. Histologically (Fig 18) these are irregularly infiltrative lesions with three principal
patterns, usually found in combination (1) fasciitis-like, with bland stellate or short spindle cells in
a vascular, myxoid and inflamed stroma, including numerous plasma cells (2) fascicular and fibrosarcoma-
or leiomyosarcoma-like, again with marked inflammation (3) hypocellular areas with hyalinization and
calcification. The lesional cells are usually uniform, but atypical cells with prominent nucleoli
 , and ganglion-like or Reed-Sternberg-like cells can occasionally be seen 
Ultrastructurally, the cells are fibroblastic and myofibroblastic
. Most cases are positive for SMA and MSA, and a smaller number for desmin some (especially those
in a submesothelial location) express cytokeratins. ALK immunostaining is positive in 36% to 60%
of cases, with a granular pattern in cytoplasm or nucleus, and sometimes cell and
nuclear membranous accentuation the variant patterns possibly relating to different fusion genes. ALK
expression, found predominantly in abdominal and pulmonary IMT in childhood, might be associated with an
Genetically, many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion
of the anaplastic lymphoma kinase (ALK) gene, located on 2p23, which encodes a tyrosine kinase receptor,
with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset  . A
transcript involving ALK and CLTC (clathrin heavy chain gene, localized to 17q23) has additionally been
reported  .
A third of cases, especially among intra-abdominal tumors,
recur at least once. IMT can have increasing atypia with recurrence, and metastasizing sarcomatous
change, with metastasis has been reported  . However, no factors have been identified
which reliably predict behavior in these tumors. It has been suggested that the presence of atypia,
ganglion-like cells, p53 expression and aneuploidy might be useful to identify IMT that might undergo
pursue a more aggressive clinical course
. Surgical resection is the usual treatment
for both primary and recurrent tumors.
The differential diagnosis relates to the various
histological patterns. Retroperitoneal fibrosis has a distinctive clinical picture, is more inflammatory
with mixed cells, and lacks pleomorphism. Fibromatosis has a distinctive architecture (intra-abdominal
fibromatosis can have prominent keloidal collagen bundles) and is infiltrated by mast cells rather than
plasma cells. Low grade myxofibrosarcoma has a more monomorphous pattern and lacks the prominent
inflammatory component. Inflammatory MFH has atypical xanthomatous cells, while inflammatory
leiomyosarcoma is more myoid, although the distinction can sometimes be difficult. Solitary fibrous
tumor demonstrates CD34 expression, and sarcomatoid mesothelioma displays epithelial markers. Follicular
dendritic cell sarcoma can masquerade as inflammatory pseudotumor in liver or spleen (see above) but is
readily identified by expression of CD21, CD23, and CD35. When there is intestinal wall involvement or a
prominent fascicular architecture, the possibility of GI stromal tumor may be raised. This has shorter,
plumper cells and less inflammation, and immunostaining with CD117 is positive with a membranous
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