Verification, Histologic Classification, and Histogenesis of MFH (1970's & 1980's)
During the 1970's and 1980's a number of large series of cases of MFH were published reaffirming the concept of MFH as a pathologic entity [6, 7, 8, 9] . Since neoplasms designated as MFH exhibit a wide range of histological appearances, Enzinger and Weiss subdivided them into five subtypes: 1. Storiform-pleomorphic; 2. myxoid (myxofibrosarcoma); 3. giant cell (malignant giant cell tumor of soft parts}; 4. inflammatory (xanthosarcoma and malignant xanthogranuloma}; and 5. angiomatoid [10, 11] . The most common and prototypical histologic subtype is a cellular tumor consisting of a variable mixture of storiform and pleomorphic areas aptly designated storiform-pleomorphic MFH. This classic subtype consists of plump spindly fibroblastic cells arranged in short fascicles in a storiform or cartwheel pattern around slit-like blood vessels. Occasional plump histiocytic cells also are evident. In the pleomorphic areas, the fibroblastic cells are plumper and greater numbers of histiocytes are seen. A characteristic feature of the pleomorphic areas is the presence of numerous giant tumor cells with hyperchromatic irregular nuclei and an abundant cytoplasm. Mitotic figures, normal and abnormal, also are prominent. Nonneoplastic elements include xanthoma cells and chronic inflammatory cells. Delicate collagen fibers surround individual cells. In the myxoid subtype at least half of the tumor should be myxoid. Highly myxoid neoplasms that contain well-differentiated bipolar fibroblastic cells have been designated myxofibrosarcoma [12, 13] . Approximately one forth of cases of MFH are myxoid [11]. The last three variants of MFH are uncommon and more controversial. The giant cell subtype is a multinodular neoplasm consisting of a mixture of fibroblasts, histiocytes and osteoclast-type giant cells. Bands of collagen fibers and areas of hemorrhage and necrosis are notable. This variant is also termed malignant giant cell tumor of soft parts [11]. The inflammatory (prominent xanthoma cells and secondary inflammatory cells) and angiomatoid (histiocytes, blood-filled spaces, intense inflammation, and extensive necrosis) subtypes probably are not variants of MFH and require further study. They will not be discussed in this presentation. Malignant fibrous histiocytoma thus became the commonest type of soft tissue sarcoma in elderly adults until the 1990's.

Ultrastructural studies of many cases of MFH, notably the common storiform-pleomorphic subtype, were published in these two decades in order to identify the cell types composing the sarcomas and establish their histogenesis [11, 13, 14, 15] . The following cell types were identified: spindly fibroblastic cells with a prominent rough endoplasmic reticulum (RER); histiocytic (histiocyte-like) plump cells containing lysosomes, lipid droplets, hyaline globules (some cells), and surface pseudopodia; intermediate-type cells with features of both fibroblasts and histiocytes; undifferentiated (primitive mesenchymal) tumor cells with a scanty cytoplasm containing few organelles; histiocyte-like multinucleate tumor giant cells with short RER cisternae, lysosomes, lipid and filopodia; myofibroblasts with RER cisternae and peripheral arrays of actin myofilaments; and xanthomatous cells that have numerous membrane bound lipid droplets. The most common cell types were fibroblastic, histiocyte-like, intermediate, and undifferentiated. The myxoid variant (myxofibrosarcoma) consisted of fibroblastic cells with dilated RER cisternae containing a flocculent substance similar to that of the myxoid matrix. The stroma also contained variable numbers of collagen fibers [13, 14, 15, 16] . Histochemical and immunohistochemical studies demonstrated the presence of a number of lysosomal enzymes primarily in the histiocytic cells, notably acid phosphatase [17], naphthyl thiol acetate esterase [14], alpha-1-antitrypsin and antichymotrypsin [18, 19] , lysozyme [19], and monocyte/macrophage differentiation antigens [20]. These findings were inconclusive since some of the investigators claimed that the presence of lysosomal enzymes in the tumor cells indicated histiocytic origin [18, 20] , while most of the reports (particularly in the late 1980's) stated that they do not express the characteristic histiocyte immunoprofile [19, 21, 22, 23] .

Three theories of histogenesis (cell of origin) emerged from the above studies. The overwhelming majority of investigators favored origin from a primitive (undifferentiated) multipotential mesenchymal cell that differentiates into both fibroblastic and histiocytic neoplastic cells [11, 14, 15, 16, 17, 21, 24, 25, 26, 27, 28, 29] . Only a minority of reports favored histiocytic [2, 3, 20, 30] or fibroblastic [31] origin.

Concept of Malignant Fibrous Histiocytoma Challenged (1990's to Present)
Even before the last decade of the 20^th century some distinguished pathologists questioned the concept of MFH. In 1986, Enzinger stated that MFH has become a diagnosis of exclusion [28], while Dehner in 1988 raised the question as to whether MFH is a morphologic pattern or a true pathologic entity [32]. Perhaps the most provocative report concerning the overdiagnosis of MFH was that by Fletcher in 1992 [33]. A critical review of 159 neoplasms diagnosed as pleomorphic sarcoma/MFH revealed that only 13% could possibly be diagnosed as MFH. The majority of these tumors were pleomorphic subtypes of other sarcomas, e.g., liposarcoma. Meister also raised the question as to whether MFH is a histomorphologic pattern or a distinct tumor type [34]. Fletcher, in his Soft Tissue Tumors chapter of a Diagnostic Histopathology of Tumors book, stated that it is accepted that virtually none of the so-called "fibrohistiocytic tumors" show true histiocytic differentiation and noted that the term "fibrohistiocytic" is a misnomer [35]. Fletcher also noted that in tumors designated pleomorphic MFH a specific line of differentiation can be demonstrated in most cases. Precise classification of "pleomorphic sarcoma/MFH" requires thorough sampling of the tumor and the judicious use of immunohistochemistry and/or electron microscopy [33, 35, 36] .

More critical histochemical, immunohistochemical, and ultrastructural studies of cases of so-called MFH, notably the storiform-pleomorphic classic subtype, also found that neoplastic histiocytes or "facultative fibroblasts" are not present in these tumors [36, 37, 38, 39, 40, 41, 42, 43] . McHugh and Miettinen reported that the so-called histiocyte-specific marker KP1 (CD68) is found in a variety of soft tissue tumors as well as melanomas and carcinomas [41]. Iwasaki and associates suggested that MFH is a tumor of "facultative histiocytes," or fibroblasts that show partial histiocytic differentiation, the opposite of the "facultative fibroblast" [38]. A critical evaluation of 130 cases of MFH, all of which were ultrastructurally examined in our laboratory at Memorial Sloan-Kettering Cancer Center, found that the classic storiform-pleomorphic subtype, and most likely the myxoid and giant cell variants are fibrosarcomas variably consisting of fibroblasts with a well developed RER which often is dilated, myofibroblasts with additional peripheral actin myofilaments, large rounded fibroblastic cells with an abundant cytoplasm containing a prominent Golgi apparatus and variable numbers of primary and secondary lysosomes, and undifferentiated mesenchymal cells cells with a scanty cytoplasm and few organelles [36]. In the myxoid tumors, the dilated cisternae of the fibroblasts contained a flocculent substance similar to that found in the myxocollagenous stroma. In addition to various types of fibroblastic cells, osteoclast-like multinucleate cells characterized the giant cell neoplasms. Excluding likely nonmalignant osteoclasts, the giant fibroblastic tumor cells had primarily multisegmented nuclei with clumped chromatin and large nucleoli. The abundant cytoplasm often contained accumulations of vimentin filaments, which when prominent, appears rhabdoid by light microscopy and corresponds to the hyaline/eosinophilia of the cytoplasm. The only true histiocytic cells identified in the tumors were obviously nonneoplastic (reactive). The largest series of ultrastructurally studied cases of MFH was published in 2000 by Suh, Ordonez, and Mackay from the M.D. Anderson Cancer Center in Houston, Texas [42]. They examined 157 cases representing the four main subtypes of MFH with immunohistochemical stains performed on 77 neoplasms. Their findings were similar to ours. No true histiocytic differentiation was evident and it was concluded that "malignant fibrous histiocytoma forms part of the histologic spectrum of tumors of fibroblasts." However, the concept of MFH being a "pleomorphic fibrosarcoma" is still not accepted by many surgical pathologists with an interest in soft tissue neoplasms, since fibrosarcomas are regarded to consist of a relatively uniform population of spindle cells devoid of multinucleated or pleomorphic giant cells – the classic definition [43, 44] .

The Remarkable Differentiation Capabilities of the Fibroblast
In 1990, Sappini, Schurch and Gabbiani published an important paper concerning the differentiation capabilities of fibroblastic cells, including the expression of cytoskeletal proteins as markers of these phenotypic modulations [45]. Schmitt-Graf and associates subsequently reported myofibroblastic phenotypic heterogeneity as another example of fibroblastic cell plasticity [46]. Benign and malignant neoplasms composed primarily of myofibroblasts – myofibroblastomas and myofibrosarcomas – also were widely reported [36, 47, 48, 49, 50, 51] . The current status of myofibroblasts in nonneoplastic conditions and neoplasms is reviewed by Schurch et al. [52]. Montgomery and Fisher recently reported cases of MFH in which myofibroblastic differentiation of the neoplastic cells was prominent [53]. They proposed the designation "pleomorphic myofibrosarcoma" for these neoplasms.

In addition to smooth muscle and histiocytic differentiation, fibroblasts also are capable of cytokeratin protein expression indicative of epithelial differentiation, notably in cases of MFH [45, 54, 55, 56, 57, 58, 59, 60] . In the cases of MFH expressing cytokeratin proteins, the number of immunoreactive cells varies from only 1% to a high of 32%. We recently reported four cases of fibrosarcoma that morphologically resembled plasmacytoma or carcinoma [61]. Interestingly, cytokeratin markers were negative, two cases expressed epithelial membrane antigen, and all the tumors were strongly positive for vimentin. In addition to the classic ultrastructural features of fibroblasts, rudimentary cell junctions, lumen-like structures, microvilli, and neurosecretory-type granules were variously seen in the four neoplasms.

Considering that "myofibroblast" is accepted terminology for fibroblasts exhibiting smooth muscle features, in order to be consistent, we propose the designation "histiofibroblast" for the so-called fibrohistiocytic cells, and "epithelialfibroblast" for the uncommon fibroblasts with cytokeratin immunoreactivity and/or ultrastructural epithelial cell structures. The former designations "facultative fibroblast," "facultative histiocyte," and "fibrohistioblast" [62] are archaic, confusing, and inaccurate. Likewise, the commonly used term "fibrohistiocyte" is a misnomer since these cells are most likely fibroblasts showing some histiocytic features [35].

Pleomorphic Fibrosarcoma
and a Proposed New Classification for Tumors Formerly Designated Malignant Fibrous Histiocytoma
It is intriguing why many pathologists do not accept the designation pleomorphic fibrosarcoma while pleomorphic liposarcoma [63], leiomyosarcoma [64], and rhabdomyosarcoma [65] are recognized as distinct histologic entities? It is noteworthy that Stout in his classic 1948 paper on fibrosarcoma classified these tumors as congenital, fibroblastic, juvenile, myxoid, and pleomorphic variants `66,67}. Figure 9 of Hajdu's historic commentary on fibrosarcomas illustrates a "high grade pleomorphic fibrosarcoma with pleomorphic fibroblasts in abundant collagenous matrix" [67]. Ultrastructural examination of the large pleomorphic tumor cells found in most cases of MFH have clearly shown that these cells are fibroblasts (see above} [36, 40, 42] . Hajdu also stated that "undifferentiated malignant fibrous Neoplasms" were originally described by Stout in the 1950's.

On the basis of the above findings, we propose the following new classification for tumors that were formerly designated "MFH", excluding Enzinger's controversial inflammatory and angiomatoid subtypes:

Storiform-pleomorphic MFH	Storiform-pleomorphic or pleomorphic Fibrosarcoma Pleomorphic sarcoma, NOS
Myxoid MFH	Pleomorphic Myxofibrosarcoma
Giant cell MFH	Giant cell fibrosarcoma with osteoclasts Malignant giant cell tumor of soft parts

When another entity such as pleomorphic liposarcoma [63], dedifferentiated liposarcoma (primarily retroperitoneal tumors] [68], and pleomorhic malignant nerve sheath tumor [69] are ruled out, the neoplasm should be designated pleomorphic fibrosarcoma. Rare cases that demonstrate no line of differentiation by immunohistochemistry and electron microscopy should be classified as pleomorphic sarcoma, not otherwise specified (NOS). The overwhelming majority of tumors designated the myxoid subtype of MFH are pleomorphic myxofibrosarcomas [16, 36, 42, 70] . The majority of the uncommon giant cell variants of MFH are most likely giant cell fibrosarcomas with nonneoplastic osteoclasts [36, 42] . However, cases containing large numbers of histiocyte-like and xanthoma cells questionably show fibroblastic differentiation and are more appropriately designated "malignant giant cell tumor of soft parts" [11]. Since the diagnostic term "malignant fibrous histiocytoma" is familiar to surgeons and clinicians, when the new classification is used the term MFH should be placed in parenthesis after the diagnosis, e.g., pleomorphic fibrosarcoma (MFH). Consider that hematologists and hematopathologists no longer use the old term "malignant lymphoma, histiocytic type, diffuse" in the current non-Hodgkin's lymphoma classifications!

It is interesting to speculate whether the MFH-like areas in other specific types of soft tissue sarcoma exhibit fibroblastic differentiation. It has been reported that the most common pattern of dedifferentiated areas of dedifferentiated liposarcomas consist of "high-grade pleomorphic MFH" or "storiform fibroblastic MFH" [68, 71, 72] . As expected from the cellular complexity of "MFH", cases that have had cytogenetic analysis show a wide range of abnormal karyotypes [49].

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