Soft Tissue Pathology
Moderators: Dr. John R. Goldblum and Dr. Cyril Fisher
Case 2 -
The Conceptual Evolution of Low Grade Fibromyxoid Sarcoma
Angelo Paolo Dei Tos MD
Department of Pathology
4-year-old female with a slow-growing 8-cm mass in the buttock.
Case 2 - Slide 1
Low grade fibromyxoid sarcoma (LGFMS) represent a distinct clinicopathologic entity, the first
description of which dates back to the years between 1987 and 1993, when Dr. Harry Evans published his
experience with this previously unrecognized soft tissue neoplasm
Since that, a conceptual
evolution in our understanding of this lesion has occurred, that involves morphology, immunophenotypic
characterization, molecular genetics and clinical behavior.
Classic forms of LGFMS tend to occur in the proximal extremities and on the trunk of young adults,
with a peak incidence in the third decade
However, approximately 20% of cases occur in patients
younger than 18 years of age
Both sexes result to be equally affected. Clinical presentation is
relatively non specific, characterized by the occurrence of slowly growing, deep seated, painless soft
issue mass, most often attaining a size ranging between 6 and 10 cm. Grossly, LGFMS ten to be relatively
well-circumscribed, with a firm, whitish cut surface. In its original description, LGFMS is
microscopically characterized by a cytologically bland spindle cell proliferation, set in stroma that
alternates collagenized hypocellular areas and more cellular myxoid foci (Fig 1A and B).
Fig. 1A - LGFMS Fig. 1B - LGFMS
The vascular network is composed of small, capillary size blood vessels, often exhibiting a
curvilinear or branching configuration, somewhat reminiscent of the vascular architecture exhibited by
low grade myxofibrosarcoma and myxoid liposarcoma respectively. Mitotic activity is minimal.
Interestingly, a minority of cases shows multiple foci of increased cellularity. This phenomenon appears
to be observed more frequently when dealing with local recurrences (Fig.2).
Fig.2 – Foci of increased cellularity
Transition to genuine high grade pleomorphic sarcoma is not observed, with the exception of one case
reported by Evans , that "dedifferentiated" 30 years after initial surgery.
From the morphological stand point, the most relevant conceptual evolution is represented by the
suggestion that those lesions reported under the descriptive term "hyalinizing spindle cell tumor with
giant collagen rosettes" 
actually represent part of the morphological spectrum of LGFMS . In fact
it has subsequently become evident that, approximately 30% of LGFMS sarcoma, in addition to the classic
morphology, may feature the presence of variably formed, large rosettes, composed of hyalinized collagen
demarcated by a palisade of more epithelioid lesional cells (Fig 3). As a further confirmation of the
existence of a morphologic continuum, also the clinical presentation overlaps with that of conventional
forms of LGFMS.
Fig. 3. LGFMS with giant rosettes
Immunohistochemically, in addition to vimentin, LGFMS, with or without giant rosettes, is
characterized by occasional expression of smooth muscle actin and/or muscle specific actin. The
detection of myogenic contractile proteins may favor the hypothesis of myofibroblastic differentiation.
Desmin, keratin and CD34 immunopositivity has been reported only exceptionally . In ours and others
experience, and in contrast with previous reports, it sound like approximately 30-40% of cases of LGMFS
may express epithelial membrane antigen (EMA), raising the important differential diagnosis with
perineurioma. (Fig 3).
Fig. 3 – EMA immunoreactivity in LGFMS
Diagnostically LGFMS sarcoma is generally regarded as a challenging lesion. Most diagnostic problems
are related to its bland cytomorphology, that partially justifies diagnostic confusion with benign soft
tissue neoplasm. The differential diagnosis of LGFMS includes in fact several benign and low grade
entities. Nodular fasciitis is ruled out on the basis of the absence of the typical cell culture growth
pattern, minimal or absent smooth muscle actin immunoreactivity and low mitotic count. EMA
immunopositivity is in part shared with perineurioma that most probably represent the most challenging
differential diagnosis However neoplastic cells in perineurioma exhibits long bipolar cytoplasmic
processes (highlighted by EMA immunostaining) and the vasculature is much less prominent than in LGFMS.
Desmoid fibromatosis is ruled out on the basis of the absence of the typical alternation of myxoid and
collagenized zones. Immunopositivity for beta-catenin also represents a valuable diagnostic clue in
favor of desmoid fibromatosis .
Dermatofibrosarcoma protuberans (DFSP) is a superficially located,
infiltrating, CD34 positive, spindle cell proliferation characterized by a distinctive "honeycomb"
pattern of infiltration of subcutaneous adipose tissue. Low grade myxofibrosarcoma is a multinodular,
superficially located, predominantly myxoid neoplasm featuring the presence of spindle cells,
pseudolipoblasts and characteristic capillary-size, archiform blood vessels.
The clinical behavior of LGFMS also represent a major conceptual shift when initial and current data
are compared. Early retrospective studies clearly indicated that LGFMS, in stark contrast with its
bland morphology, actually represented an aggressive neoplasm, showing a local recurrence rate of 68%, a
metastatic rate of 41% and a mortality of 18%
Data from prospective studies as well as from the
unpublished experience of referral centers now indicate a local recurrence rate of less than 10%, a
metastatic rate of 6% and a overall mortality of 2%. The explanation for such a significant change is
relatively easy to unveil. Most patients included in earlier studies had been most likely treated on
the basis of a diagnosis of benign tumor. This seems to be quite logical in consideration of the bland
looking appearance of LGFMS. Actually one of the great merit of Evans' papers, is to have drawn the
attention on a potentially misleading soft tissue sarcoma. Now that LGFMS is properly recognized and
treated with radical surgery, patient's outcome has improved dramatically, to the extent that LGFMS may
be considered the paradigm of the impact of accurate histopathological classification over patient's
chance of cure.
An additional point of recent interest is represented by the occurrence of LGFMS in the pediatric
population. A significant proportion of cases may occur in young children. At least in one series 
LGFMS in children tend to more superficial and smaller in size. As a consequence of easier surgical
removal, prognosis of LGFMS seems to be particularly favorable in this age group.
Mesenchymal neoplasm as whole exhibits tendency to carry distinctive karyotypic aberrations, most
often balanced chromosome translocations . LGFMS is a recent adjunct to the list of soft tissue neoplasm
showing tumor specific karyotypic anomalies. Cytogenetic analysis have demonstrated the presence of a
recurrent balanced translocation t(7;16)(q32-34;p11)
fusing the gene FUS and CRB3L2 . More rarely the
FUS gene fuses with the CREB3l1 gene . Both CREB3L1 and CREB3L2 encodes for proteins belonging to the
leucine-zipper family of transcription factors, and show high sequence homology in their DNA-binding
domains. As a consequence downstream action of the chimeric protein should produce similar molecular
events. As further demonstration of how genetics tends to further validate morphologic observations,
LGFMS with giant rosettes shows complete cytogenetic overlap with conventional LGFMS . From the
therapeutic standpoint, LGFMS is regarded as a low grade sarcoma in which radical surgery with free
margins represent a key step to minimize local recurrences and subsequent metastatic spread.
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