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Myxoinflammatory Fibroblastic Sarcoma: Morphologic and Genetic Updates.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, malignant soft tissue neoplasm that was first described in 1997 by Montgomery, (1) with further nearsimultaneous descriptions the following year by Montgomery et al (2) (51 cases), Meis-Kindblom and Kindblo (m) 3 (44 cases), and Michal4 (5 cases). The entity was described by Montgomery et al as an "inflammatory myxohyaline tumor of the distal extremities with virocyte or Reed Sternberg-like cells," (2(p1)) by Michal as an "inflammatory myxoid tumor of the soft parts with bizarre giant cells," (4(p1)) and by Meis-Kindblom and Kindblom as an "acral myxoinflammatory fibroblastic sarcoma." (3(p1)) In these series, tumors occurred primarily in the distal extremities of adults with a mean age of 45 years. Because it is now established that the tumors can arise at nonacral sites, it is currently classified by the World Health Organization as MIFS. (5) Myxoinflammatory fibroblastic sarcoma is now recognized as a low-grade sarcoma of the soft tissues that has a tendency to recur locally and that rarely metastasizes.

CLINICAL FEATURES, PROGNOSIS, AND TREATMENT

Myxoinflammatory fibroblastic sarcoma is a rare neoplasm, with fewer than 200 cases reported. (6) Although it predominantly occurs in younger adults, with a peak incidence in the fourth and fifth decades, the age distribution is wide, with cases reported in the pediatric population (2,7) and up to the 10th decade. (3) There is generally equal sex distribution, with some small series showing a very slight male predilection (1.1:1). (2,3) Myxoinflammatory fibroblastic sarcoma presents as a poorly defined, usually painless, and slow-growing mass, with reported durations ranging from 6 weeks to 20 years. (3) Lesions are generally small, although they vary in size from 1 to 10 cm. Tumors predominantly arise in the soft tissues, grow in an infiltrative pattern, and can be superficial, involving the dermis and subcutis and rarely ulcerating epidermis (8) or can traverse the deep fascia and/or involve tendon sheaths. Myxoinflammatory fibroblastic sarcoma rarely infiltrates the adjacent skeletal muscle, and while bone invasion is documented radiologically, it is exceedingly rare. The radiologic features of MIFS vary because of the range of histologic components present, and MIFS can be misinterpreted as a spectrum of pathologic lesions, from inflammatory processes of the tenosynovium, to benign lesions such as giant cell tumor of tendon sheath, ganglion cyst, and proliferative fasciitis, to other sarcomas, particularly myxofibrosarcoma and myxoid liposarcoma.

Predominantly, MIFS occurs in acral sites, including the hands, feet, digits, web spaces, and popliteal fossae. The upper extremities are affected more commonly than the lower extremities, and the soft tissues of the fingers and hand are the most common sites. Increasing numbers of nonacral cases are described; these comprise the proximal upper and lower extremities, neck, scalp, and trunk, including the back, chest wall, and shoulder, which has led to the omission of the word acral from the World Health Organization nomenclature. (5) No definite predisposing factors are known, although occasionally a history of preceding trauma is described. In an immunocompromised renal transplant patient, MIFS has been reported to occur on the dorsum of the foot, behaving as a low-grade sarcoma without recurrence after 2 years. (9)

Most cases of MIFS behave as low-grade malignancies, with variable numbers of local recurrences. The regional recurrence rate has been estimated at 22% to 67%, (3,10) with first recurrences appearing between 3 months (6) and 5 years (11) after initial diagnosis. Metastatic potential is well documented but relatively rare, with reported incidences of less than 2%. (5) Metastases can occur to inguinal lymph nodes or distantly to lungs and liver and can rarely lead to death. (12) Rarer metastatic sites have included the neck and base of the skull but were not associated with death at 6 years after presentation. (12) As yet, there are no known reliable clinical or pathologic parameters helpful in predicting biologic behavior. (11,13) The current appropriate management is wide local excision, with follow-up observation and systemic oncologic reassessment for locally recurrent and metastatic disease, including imaging of the chest. (8) Some authors have suggested quarterly follow-up care for the first 2 years and then every 6 months for up to 5 years. (14) Preoperative radiation therapy, alone or in combination with a postoperative regimen, has been applied in a number of cases, (15) with one tumor showing complete tumor necrosis after neoadjuvant radiotherapy. Radiation therapy is usually indicated for multiple local recurrences, and chemotherapy is administered for metastatic disease. Amputation may be necessary when wide resection fails to preserve a functional extremity or in cases following multiple recurrences and failing grafts. One tumor, situated in the right popliteal fossa within the tibial nerve, was reported to have been treated by isolated limb perfusion with tumor necrosis factor [alpha] and melphalan, followed by radiation therapy and local excision. (16)

PATHOLOGIC FEATURES OF MIFS AND MORPHOLOGY

Grossly, MIFS is a multinodular and infiltrative lesion with a gray-white to yellow cut surface showing a firm to myxoid consistency. It is usually situated in the subcutis, with frequent dermal involvement, and is often attached to underlying fascia, tendons, or ligaments. Microscopically, tumors characteristically comprise moderately cellular nodules of basophilic myxoid material alternating with fibrohyaline and focally hemorrhagic stroma, as well as a prominent mixed acute and chronic inflammatory cell infiltrate rich in eosinophils, neutrophils, lymphocytes, and plasma cells (Figure 1, A), with 3 morphologically distinct types of neoplastic cells that are scattered as single cells or cluster in nodules (Figure 1, B). Among the 3 types of constituent neoplastic cells, first are spindle to epithelioid cells with moderate degrees of nuclear atypia (Figure 1, B). Second are large, atypical epithelioid ganglion-like cells, which are often described as resembling Reed-Sternberg cells or virocytes and which can be mononucleate, binucleate, or sometimes multinucleate, with prominent large eosinophilic nucleoli, vesicular nuclei, occasional perinucleolar halos, and abundant amphophilic cytoplasm (Figure 1, C and D). Third are "pseudolipoblast" cells, atypical cells with compressed nuclei and abundant vacuolated myxoid basophilic cytoplasm containing extracellular mucinous material (Figure 2, A). Hemosiderin deposition, Touton-type giant cells, and emperipolesis can be present, with the latter an occasionally dominant feature. (17) The mitotic index is usually low and can be less than 1 in 10 high-power fields, although atypical mitoses can be present, and there is occasional necrosis. (11) The overall morphology of MIFS can differ considerably: the amount of inflammatory component varies (Figure 2, B and C) and can predominate to such an extent as to obscure the neoplastic cell population, giving an appearance resembling lymph node (Figure 2, B). Similarly, tumor cellularity can also vary, and this can be sparse, resembling myxoma (Figure 2, D).

Hybrid lesions comprising morphologic variants with mixed features between classical MIFS and hemosiderotic fibrohistiocytic lipomatous tumor (HFLT) are described. (18,19) Hemosiderotic fibrohistiocytic lipomatous tumor is a benign, predominantly fatty lesion (20,21) that usually presents subcutaneously in the foot or ankle of middle-aged women, sometimes after trauma or in association with venous stasis, and which can recur locally but has not been reported to metastasize to our knowledge. Morphologically, HFLT consists of lobulated lesions comprising plump fibrohistiocytic-like cells, sometimes containing intranuclear inclusions present in septal and perivascular distributions, but without forming a mass lesion. Scattered enlarged hyperchromatic cells are found in most cases. There is focally myxoid stroma within mature fat, with cells infiltrating fatty lobules in a honeycomb pattern. In addition, there is abundant hemosiderin deposition, hemorrhage, and inflammatory cells, including lymphocytes, histiocytes and multinucleate giant cells, plasma cells, and mast cells. Immunohistochemically, lesional cells express CD34 and calponin and occasionally lysozyme or CD68, although they are negative for other markers. Hybrid cases of MIFS/HFLT demonstrate features of both neoplasms, and the 2 components can be discrete or show a gradual morphologic transition, (18,19) with cellular myxoid nodules containing atypical spindle and epithelioid cells with virocyte-like inclusions, as well as adipose tissue mixed with bland spindle cells in honeycomb patterns with prominent hemosiderin deposition and an inflammatory cell infiltrate with lymphocytes and plasma cells.

ANCILLARY STUDIES

Immunohistochemistry and Electron Microscopy

Myxoinflammatory fibroblastic sarcoma shows variable immunoreactivity to a range of antibodies. Tumors are consistently diffusely and strongly positive for vimentin and focally positive for CD68, but there is variable expression of CD34, cytokeratin, epithelial membrane antigen, smooth muscle actin, calponin, and factor XIIIa. Variable reactivity has also been reported for CD163, epidermal growth factor receptor, [[alpha].sub.1]-antitrypsin, and CD117, although CD117 expression does not imply the presence of a KIT mutation. (12,31) p53 staining has been reported in 0% to 80% of tumor cells. (3,11) Myxoinflammatory fibroblastic sarcoma is generally negative for most other markers, (4) including CD45, CD15, CD30, HMB-45, Melan-A, desmin, glial fibrillary acidic protein, muscle-specific actin, and CAM 5.2, as well as neuron-specific enolase. (2) S100 protein and anaplastic lymphoma kinase 1 are generally negative but can rarely show positivity. The Ki-67 proliferation index (with MIB1) is typically low, usually labeling less than 10% of cells.

While the presence of virocyte-like cells has raised the possibility of an infectious etiology, both histochemical and immunohistochemical stains for bacteria, mycobacteria, fungi, cytomegalovirus, and herpes simplex virus have been consistently shown to be negative. Epstein-Barr virus latent membrane protein immunostain is also negative, as is largely in situ hybridization for the virus, although EBER has been shown to be positive in one case. (12) Polymerase chain reaction showed that 4 of 10 patients in a series had Epstein-Barr virus, but with features compatible with latent rather than active infection. (2) Ultrastructurally, the "cell of origin" has been described as a modified fibroblast, and all 3 types of the neoplastic cells of MIFS show features of fibroblasts and are rich in intermediate filaments, rough endoplasmic reticulum, and mitochondria. (10)

Genetics

Lambert et al (22) first described a reciprocal translocation t(1; 10)(p22; q24) in MIFS, which had a complex karyotype and deletions of chromosomes 3 and 13. In 2008, Wettach et al (23) described a clonal reciprocal translocation between chromosomes 1 and 10 in one HFLT, along with a further rearrangement involving the derivative chromosome 1 and chromosome 3. In 2010, a neoplasm demonstrating hybrid morphologic features of MIFS and HFLT and showing a der(10)t(1; 10) and abnormalities of chromosome 3 was reported. (18) Hallor et al (24) studied a series of 8 cases previously diagnosed as MIFS or harboring either t(1; 10) and/or ring chromosomes, with possible involvement of chromosome 3, and were able to confirm the existence of 2 distinct genetic pathways in MIFS, namely, a t(1; 10) resulting in the increased expression of FGF8 and amplification in ring chromosomes of a small segment in proximal 3p associated with overexpression of VGLL3. Also, t(1; 10) was found in one lesion originally thought to represent either ganglion or dermatofibrosarcoma protuberans, but the diagnosis was later revised to HFLT. The group mapped the break points of t(1; 10) to TGFBR3 on chromosome 1p22 and in or near MGEA5 on 10q24, which led to the transcriptional up-regulation of the NPM3 and, particularly, FGF8 genes located close to MGEA5. Delineation of the commonly amplified region on chromosome 3 showed an amplified 1.44-Mb region at 3p11-12 associated with increased expression of the VGLL3 and CHMP2B genes.

The t(1; 10) rearrangement between TGFBR3 and MGEA5 has shown loss of the telomeric part of the MGEA5 gene and deletion of the centromeric part of the TGFBR3 gene. (19) No increase in expression level of either of the 2 genes has been detected by real-time quantitative reverse transcription-polymerase chain reaction or gene expression analysis, (24) and no fusion product has been detected because these 2 components are transcribed in opposite directions and are unable to form a fusion transcript, (24) in contrast to most sarcomas with translocations that result in functional gene fusions. (19) The FGF8 protein is a member of the fibroblast growth factor family whose members are involved in a variety of biologic processes, including cell growth, morphogenesis, and embryonic development, as well as tissue repair, tumor growth, and invasion. FGF8 is expressed during embryogenesis and has an important role in the development of the midbrain and limbs but is thought to be transcriptionally silent in most normal adult tissues, (25,26) although its expression has been shown to be increased in various carcinomas, including those of breast, prostate, and ovary, as well as in synovial sarcoma. (32,33) Because FGF8 overexpression was identified, it was postulated that t(1; 10) may alter gene transcription away from the break point. (19)

The second distinct genetic pathway in MIFS, in which there is amplification of a small segment of proximal 3p on ring chromosome 3, leads to overexpression of 2 genes, VGLL3 and CHMP2B, of which VGLL3 is more relevant, showing good correlation between amplification and expression levels. (27) The presence of ring or marker chromosomes with 3p11.1-12.1 amplification has been shown to occur in a variety of high-grade sarcomas. (27) VGLL3 is thought to have a regulatory role in transcription, encoding a protein that is a cofactor of the TEAD family of transcription factors. More recently, Antonescu et al (19) studied a series of 7 cases of MIFS, 14 HFLTs, and 3 neoplasms with mixed morphology, finding consistent t(1; 10) with rearrangements of TGFBR3 and MGEA5 in both MIFS and HFLT. Five of seven cases of MIFS harbored a t(1; 10) unbalanced translocation, resulting from deletions of the telomeric part of MGEA5 and of the centromeric part of TGFBR3. The 2 remaining cases lacked this translocation, although they did show typical morphology of MIFS. Twelve of fourteen HFLTs and all 3 mixed lesions also shared a similar unbalanced pattern of TGFBR3 and MGEA5 rearrangements. It was postulated that the negative results seen in the small numbers of cases could have been because of the high inflammatory cell (relative to tumor cell) population. Three cases of pleomorphic hyalinizing angiectatic tumor (PHAT) and 3 other cases of non-MIFS were tested, all of which were negative for t(1; 10).

While HFLT has been regarded as a variant of PHAT (28) with a morphologic continuum between (early) PHAT and HFLT, the findings by Antonescu et al (19) instead suggest that HFLT and PHAT have different pathogenetic pathways. In addition, amplification of the VGLL3 locus on 3p.12.1 was present in 2 of 4 cases of MIFS, 3 of 3 mixed cases, and 5 of 5 HFLTs but not in any of the PHATs. As described above, HFLT shares similar epidemiologic features with MIFS, presenting in middle-aged adults (albeit more commonly in women) and in acral sites, mostly the ankle, foot, and leg, with a tendency for recurrence (in about 50%) but no described metastases. (20,21) Pleomorphic hyalinizing angiectatic tumor also occurs at similar sites and age as HFLT, with a common biologic behavior. Early PHAT can resemble HFLT such that it was postulated that HFLT may represent the precursor lesion of classical PHAT, (28) and PHAT is again a circumscribed lesion with hemosiderin pigment within tumor cells and focal myxoid change, although mature PHAT looks distinct from HFLT, comprising clusters of angiectatic thin-walled vessels with hyaline and fibrinoid material within their walls, along with spindle cells with large hyperchromatic nuclei and prominent intranuclear inclusions. Not all cases of MIFS harbor t(1; 10) or ring chromosome 3, however. Other reported genetic abnormalities include supernumerary ring chromosomes and a derivative chromosome 13 segment, (13) translocation t(2; 6)(q31; p21.3) as the only cytogenetic abnormality, (29) and 2 cases with genetic variability but both with chromosome 7 gains. (16)

DIFFERENTIAL DIAGNOSIS

Myxoinflammatory fibroblastic sarcoma is a rare neoplasm, predominantly arising as a slow-growing painless mass in the distal extremities of young or middle-aged adults. Given this picture, it is often misdiagnosed clinically as a benign lesion such as ganglion cyst, giant cell tumor, or tenosynovitis, and both radiologic and histologic features can be elusive. The amount of each tumor component present influences the range of lesions in the differential diagnosis. When the inflammatory infiltrate predominates, particularly in a lesion of low cellularity, the features can mimic an inflammatory or infectious process. Clinically, infective processes often involve organs and lymph nodes, while histologically histochemical stains for microorganisms are negative, and microbial infection is not supported immunohistochemically or with molecular testing, as detailed above. Sparsely cellular variants of MIFS can be mistaken for benign entities occurring in the acral or extremity regions such as myxoma. The cells of myxoma are spindle to stellate, with long cytoplasmic processes and bland nuclei. Both lack cellular atypia, ganglion-like cells, and a significant inflammatory component. Pigmented villonodular synovitis (diffuse-type tenosynovial giant cell tumor), another histologic mimic, usually involves a single joint, particularly the knee, but can affect other joints such as the hip or finger. This contains a heterogeneous population of sheets of bland mononucleate ovoid cells that lack atypia, often with hemosiderin deposition and a prominent inflammatory cell component with lymphoplasmacytic cells and histiocytes, including foamy macrophages and osteoclast-type giant cells. In contrast to MIFS, pigmented villonodular synovitis lacks eosinophils and neutrophils, as well as the large, atypical neoplastic cells and the myxoid foci. Nodular fasciitis, which can have myxoid stroma and lobulated morphology, is fairly easily differentiated from MIFS. Clinically, nodular fasciitis has a typical history of rapid growth after trauma and histologically shows a characteristic tissue culture-like appearance, often with a zonation pattern. Hemosiderotic fibrohistiocytic lipomatous tumor and PHAT are both in the differential diagnosis of acral soft tissue spindle cell lesions, being especially pertinent because mixed cases with features of HFLT and MIFS can occur. The t(1; 10) translocation has been detected in both HFLT and MIFS, and their relationship is yet to be elucidated. Hemosiderotic fibrohistiocytic lipomatous tumor, which typically involves the feet, histologically lacks eosinophils and neutrophils and shows strong CD34 expression. The striking feature of PHAT is the presence of dilated vascular spaces with subintimal fibrinoid material and atypical cells with nuclear pseudoinclusions in the absence of mitoses.

The malignant mimics of MIFS are frequently those neoplasms with a significant myxoid component. Myxofibrosarcoma shares common histologic features with MIFS, including nodularity, myxoid stroma, and pseudolipoblasts. Myxofibrosarcoma can show a variable range of appearance, from low-grade features with prominent myxoid stroma and cells with mild to moderate atypia, to features approaching pleomorphic high-grade sarcoma. Clinically, myxofibrosarcoma tends to occur in the extremities of older patients, usually at superficial sites. There is a rich vascular network of coarse arcuate vessels, and the inflammatory component is minor. Moreover, it tends to have a more homogeneous cell population without virocyte-like cells but generally has a greater degree of cytologic atypia. The focal storiform pattern with high-grade pleomorphism that can be seen in higher grades of myxofibrosarcoma are absent in MIFS. Of interest, a case of MIFS has been reported at the scar of a previously excised tumor that had been diagnosed as myxofibrosarcoma. (30) Myxoid liposarcoma occurs in the proximal extremities and buttock rather than the distal extremity sites but arises in deep soft tissues and lacks cellular atypia, virocyte-like cells, and a significant inflammatory cell infiltrate but often contains true lipoblasts with indented hyperchromatic nuclei. It has a delicate plexiform capillary network and is associated with characteristic FUS-CHOP (DDIT3) and EWSR1-CHOP gene fusions. Extraskeletal myxoid chondrosarcoma can occur in the extremities but has a distinct morphologic appearance of cords of bland polygonal cells in abundant myxoid stroma, lacks inflammation, and demonstrates characteristic translocations involving the fusion of NR4A3 to various partner genes. While the presence of virocyte-like cells can mimic extranodal Hodgkin lymphoma, patients may have a history of nodal lymphoma; histologically, Hodgkin lymphoma lacks myxoid areas and usually lacks neutrophils, and Reed-Sternberg cells express CD15 and CD30, whereas the large fibroblastic cells of MIFS do not stain for CD15, CD30, or CD45. When emperipolesis is marked, Rosai-Dorfman disease may mimic MIFS. It is associated with a rich lymphoid infiltrate and is S100 positive and CD1a negative.

CONCLUSION

Myxoinflammatory fibroblastic sarcoma is a rare soft tissue sarcoma that was initially observed in acral sites and is characterized by distinctive large, Reed-Sternberg-like cells and is associated with an intense inflammatory cell infiltrate. Because MIFS tends to manifest as slow-growing, often superficial lesions, they can be mistaken clinically for more common soft tissue lesions at these sites, including benign tumors or degenerative, reactive, or inflammatory processes. They can also overlap histologically with a variety of lesions, including those that are benign or inflammatory, which may lead to inappropriate management such as enucleation or marginal excision. Their tendency to grow in multinodular and infiltrative patterns can result in incomplete excision, which may partly account for their tendency to repeated local recurrence. It is important that MIFS is adequately characterized, not just for its risk of local recurrence, but also because a proportion of lesions can metastasize to distant sites such as lungs. While the immunoprofile of MIFS is variable, it has been shown to have emerging characteristic genetic features, particularly a t(1; 10) rearrangement that is shared with HFLT, and the relationship between these neoplasms remains to be better characterized. Fluorescence in situ hybridization for TGFBR3 and MGEA5 rearrangements is likely to be a valuable adjunct in determining the correct diagnosis in the future.

Please Note: Illustration(s) are not available due to copyright restrictions.

We acknowledge support from the National Institute for Health Research to The Royal Marsden and The Institute of Cancer Research Biomedical Research Centre for Cancer.

References

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Eleni Ieremia, MBBS, FRCPath; Khin Thway, MBBS, BSc, FRCPath

Accepted for publication October 2, 2013.

From the Department of Histopathology, Royal Marsden Hospital, London, United Kingdom.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Khin Thway, MBBS, BSc, FRCPath, Department of Histopathology, Royal Marsden Hospital, 203 Fulham Rd, London SW3 6JJ, United Kingdom (e-mail: khin.thway@rmh.nhs.uk).

Caption: Figure 1. Myxoinflammatory fibroblastic sarcoma. A, Microscopically, tumors comprise moderately cellular nodules of basophilic myxoid material alternating with fibrohyaline and focally hemorrhagic stroma, as well as a prominent mixed acute and chronic inflammatory cell infiltrate rich in eosinophils, neutrophils, lymphocytes, and plasma cells. B, Tumors characteristically contain 3 morphologically distinct types of neoplastic cells, present as single cells or clusters. C and D, Tumors contain large, atypical epithelioid ganglion-like cells, which are often described as resembling Reed-Sternberg cells or virocytes. These can be mononucleate, binucleate, or even multinucleate, including vesicular nuclei, prominent large eosinophilic nucleoli, occasional perinucleolar halos, and abundant amphophilic cytoplasm (hematoxylin-eosin, original magnifications x100 [A], x200 [B and D], and x400 [C]).

Caption: Figure 2. Myxoinflammatory fibroblastic sarcoma. A, Large "pseudolipoblast" cells contain atypical compressed nuclei and abundant vacuolated myxoid basophilic cytoplasm containing extracellular mucinous material. B, C, and D, The overall morphology of myxoinflammatory fibroblastic sarcoma can vary considerably. The amount of inflammatory component can predominate to such an extent as to obscure the neoplastic cell population (B), and the myxoid component can be fairly minimal (C). Tumor cellularity can vary. This example (D) shows a very sparsely cellular tumor, resembling a benign lesion such as myxoma (hematoxylin-eosin, original magnifications x40 [D], x100 [B], x200 [C], and x400 [A]).
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