Case 2 -

The Conceptual Evolution of Low Grade Fibromyxoid Sarcoma Angelo Paolo Dei Tos MD Department of Pathology Treviso, ITALY

Case History: 4-year-old female with a slow-growing 8-cm mass in the buttock. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer 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 [1, 2]. 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 [2, 3]. However, approximately 20% of cases occur in patients younger than 18 years of age [4, 5]. 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 [2], 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" [6] actually represent part of the morphological spectrum of LGFMS [4]. 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 [3]. 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 [7]. 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% [2, 3]. 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 [5] 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 [8]. More rarely the FUS gene fuses with the CREB3l1 gene [9]. 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 [10]. 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. References: 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. Evans HL. Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol. 1993;17:595-600. Goodlad JR, Mentzel T, Fletcher CD. Low grade fibromyxoid sarcoma: clinicopathological analysis of eleven new cases in support of a distinct entity. Histopathology. 1995;26:229-237. 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. Billings SD, Giblen G, Fanburg-Smith JC. Low grade fibromyxoid sarcoma Superficial low-grade fibromyxoid sarcoma (Evans tumor): a clinicopathologic analysis of 19 cases with a unique observation in the pediatric population. Am J Surg Pathol. 2005;29:204-210. 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. Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, Ricci F, Weber K, Furlong MA, Fisher C, Montgomery E. Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol. 2005 ;29:653-659. Panagopoulos I, Storlazzi CT, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosjo O, Rydholm A, Isaksson M, Mandahl N, Mertens F. The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer. 2004;40:218-228. Mertens F, Fletcher CD, Antonescu CR, Coindre JM, Colecchia M, Domanski HA, Downs-Kelly E, Fisher C, Goldblum JR, Guillou L, Reid R, Rosai J, Sciot R, Mandahl N, Panagopoulos I. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. 2005;85:408-415. 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.