—  SPECIALTY CONFERENCE  —

Bone & Soft Tissue Pathology

Case 5 - Low-grade Fibromyxoid Sarcoma

Christopher D.M. Fletcher
Brigham and Women's Hospital
Boston, MA


Click on each slide thumbnail image for an enlarged view


Clinical History
A 19 year old man presented with a two-year history of a slowly enlarging lump in the arm. A 3 cm intramuscular mass was shelled out.


Case 5 - Figure 1 - Note the alternating fibrous and myxoid areas.
Case 5 - Figure 2 - The lesional cells are arranged in a swirling pattern or vague fascicles.
Case 5 - Figure 3 - Note the uniform cytomorphology and pale indistinct cytoplasm.



Case 5 - Figure 4 - Note the typically abrupt transition between fibrous and myxoid areas.
Case 5 - Figure 5 - In the myxoid areas, prominent thin-walled vessels are often evident.
Case 5 - Figure 6 - There is no significant nuclear atypia or hyperchromasia.



Case 5 - Figure 7 - SMA immunostaining highlights blood vessels, but the tumor cells are negative.
Case 5 - Figure 8 - The tumor cells in this case are also negative for CD34, S100 protein, desmin and EMA.


Pathologic Findings
Macroscopically, the tumor appeared relatively circumscribed and had a variably myxoid or more fibrous cut surface. Low power examination shows striking alternation between areas of tumor with myxoid or more collagenous matrix. In the myxoid areas, there are prominent thin-walled blood vessels, some of which are branching. In both the fibrous and myxoid areas, the tumor cells are arranged in a predominantly swirling or focally more fascicular pattern. The tumor cells have short tapering nuclei that show, at most, only mild atypia and the tumor cell cytoplasm is pale and indistinct. The mitotic rate is very low and no necrosis is evident. Since the lesion has been shelled out, it is difficult to fully examine the character of the lesional margin but, for the most part, this case appears to be relatively circumscribed. Immunostaining revealed that the spindle cells in this lesion are entirely negative for SMA, CD34, S-100 protein, EMA and desmin.

Diagnosis
Low-grade Fibromyxoid Sarcoma

The first two cases of low-grade fibromyxoid sarcoma were described by Evans in 19871 [1] and a further case report appeared in the literature in 1990. [2] The combination of remarkably bland morphology, a tendency to metastasize and the limited case numbers meant that general acceptance of this distinctive lesion was slow to come. However, this entity has since been further defined as a distinct clinicopathologic entity following the publication of two larger series, [3, 4] and a large series demonstrating the morphologic overlap of these lesions with so-called hyalinizing spindle cell tumor with giant rosettes was published more recently. [5] Low-grade fibromyxoid sarcoma typically arises in the deep soft tissues, principally around the proximal extremities or limb girdles, of young and middle-aged adults. Males appear to be affected slightly more frequently than females. Less frequent sites of involvement include the retroperitoneum and subcutis. [6] Most cases run a protracted course with eventual pulmonary metastasis (often after more than 10 or even 20 years) in a significant proportion of cases, perhaps as many as 20-30%.

Histologically, low-grade fibromyxoid sarcoma is a poorly to moderately cellular tumor composed of uniform spindle cells with ill-defined, palely eosinophilic cytoplasm and small, relatively hyperchromatic oval nuclei. Mitoses are infrequent. It is not the cytologic appearance of the individual tumor cells which allows reliable recognition of this entity, but rather their characteristic arrangement into alternating fibrous and myxoid areas. Cells in both areas frequently show a whorled or swirling pattern of growth and within the myxoid areas, in addition to spindle cells, stellate cells are also often present. A focally more fascicular pattern may also be evident. Most tumors display areas of infiltration into surrounding skeletal muscle and/or fat. Additional features include frequent arcades of thin-walled vessels and, in some cases, focal collections of cells showing mild nuclear pleomorphism, perivascular condensation of tumor cells, thick bands of keloidal collagen and amianthoid fibers. Recurrences may show increased cellularity but areas of dedifferentiation to an 'MFH-like' pattern have not been reported. It has also now been appreciated that the entity initially described as 'hyalinizing spindle cell tumor with giant rosettes' [7] is essentially the same tumor type with just the same metastatic potential; [5] the relative number, size or prominence of the rosette-like structures in these lesions represents a spectrum, which is also influenced by the extent of tissue sampling. These rosettes generally have a densely hyalinized collagenous core, surrounded by a rim of tumor cells having a relatively more rounded appearance.

Immunohistochemically [4] the tumor cells are positive for vimentin. Very occasional cells also may show immunopositivity with antibodies to smooth muscle actin, pan-muscle actin, desmin and pan-keratin, in keeping with focal myofibroblastic differentiation, but this is infrequent. For reasons which are unclear, at least 30% of cases show EMA positivity. [8] No staining is seen with antibodies to S-100 protein, although CD34 positivity may be seen. In cases studied electron microscopically, the tumor cells possess ultrastructural features of fibroblasts. In recent years it has been shown that these tumors, including so-called hyalinizing spindle cell tumor, have a characteristic t(7;16)(q33;p11) translocation, [9, 10] the gene fusion product of which has been cloned. [8, 10] Not only does this provide impressive validation of Dr. Harry Evans' original recognition of this tumor type, but it also provides a means by which the diagnosis can be proven (using FISH or RT-PCR) in difficult or questionable cases. As with translocations in most other sarcoma types, it turns out that the (7;16) translocation is both specific and also present in virtually all cases. The downstream signalling consequences of the resulting gene fusion(s) remain to be determined.

The differential diagnosis of low-grade fibromyxoid sarcoma includes both benign and malignant lesions such as myxoid neurofibroma, perineurioma, cellular myxoma, desmoid fibromatosis, dermatofibrosarcoma protuberans, malignant peripheral nerve sheath tumor and low-grade myxofibrosarcoma.

Neurofibromas often possess myxoid stroma but are distinguished by the presence of more slender and wavy nuclei, specific features of neural differentiation (e.g. Wagner-Meissner-like corpuscles), consistent S-100 protein positivity and the presence of intralesional nerve fibers. Soft tissue perineurioma characteristically has bipolar cytoplasmic processes, a more evenly myxoid or fibrous stroma, an often more whorled growth pattern and is more consistently EMA-positive. Cellular myxoma lacks both the swirling growth pattern and areas with a prominent collagenous stroma. Most such lesions, instead, have no distinct pattern and often show numerous stromal muciphages. Desmoid fibromatoses consist of spindle-shaped cells with an infiltrative growth pattern, and may also contain myxoid foci. Nuclei however tend often to be plump and vesicular and the predominant architecture is fascicular, a feature lacking in fibromyxoid sarcoma. Additionally a substantial proportion of tumor cells in desmoid fibromatoses typically are actin positive.

The myxoid variant of dermatofibrosarcoma protuberans may focally resemble low-grade fibromyxoid sarcoma but differs in its dermal or subcutaneous location, the presence of a typical storiform growth pattern and consistent CD34 immunopositivity. MPNST often contains foci with a myxoid stroma but the cells generally have hyperchromatic, elongated wavy nuclei and are arranged at least partly in a fascicular pattern; perivascular accentuation or whorling is common and around 50% of cases show S-100 protein immunoreactivity. In addition, ultrastructural examination of malignant peripheral nerve sheath tumors often shows production of an external lamina, complex interdigitation of cytoplasmic processes and desmosome-like structures.

Differentiation of low-grade fibromyxoid sarcoma from low-grade myxofibrosarcoma may present a greater challenge not least because of the confusingly similar nomenclature. However there are undoubted morphologic differences between these lesions. It is the low-grade myxofibrosarcomas which focally may resemble low-grade fibromyxoid sarcoma due to their myxoid stroma, rich vascular pattern and linear condensation of tumor cells around blood vessels. However, low-grade myxofibrosarcomas are more uniformly myxoid and generally lack areas with a fibrous stroma; they do not show a whorled arrangement of tumor cells, and, even in the most differentiated cases, they always show a greater degree of nuclear pleomorphism and hyperchromasia than is seen in low-grade fibromyxoid sarcoma. It is important to make the distinction between these two tumors since in our experience low-grade myxofibrosarcoma rarely, if ever, metastasizes, whereas low-grade fibromyxoid sarcoma frequently does if followed-up for long periods.

References

  1. Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987; 88:615-619.

  2. Devaney DM, Dervan P, O'Neill S, Carney D and Leader M. Low-grade fibromyxoid sarcoma. Histopathology 1990; 17:463-479.

  3. Evans HL. Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol 1993; 17:595-600.

  4. Goodlad JR, Mentzel T, Fletcher CDM. Low-grade fibromyxoid sarcoma: clinicopathological analysis of eleven new cases in support of a distinct entity. Histopathology 1995; 26:229-238.

  5. Folpe AL, Lane KL, Paull G, Weiss SW. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol 2000; 24:1353-1360.

  6. Billings SD, Giblen G, Fanburg-Smith JC. Superficial low-grade fibromyxoid sarcoma (Evans tumor): a clinicopathologic analysis on 19 cases with a unique observation in the pediatric population. Am J Surg Pathol 2005; 29:204-210.

  7. Lane KL, Shannon RJ, Weiss SW. Hyalinizing spindle cell tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma. Am J Surg Pathol 1997; 21:1481-1488.

  8. Mertens F, Fletcher CDM, Antonescu CR et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma and cloning of a novel FUS/CREB3L1 gene. Lab Invest 2005; 85:408-415.

  9. Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. Am J Surg Pathol 2003; 27:1229-1236.

  10. Panagopoulos I, Storlazzi CT, Fletcher CDM et al. The chimeric FUS/CREB3I2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromos Cancer 2004; 40:218-228.