Section 4 -

"Borderline" and Low-grade Malignant Myofibroblastic Neoplasms of Skin and Soft Tissues Thomas Mentzel Friedrichshafen, Germany

Myofibroblasts represent a functional stage of fibroblasts, occuring in the stroma in some normal tissues, in granulation tissue and in a variable amount of some reactive, pseudosarcomatous as well as benign and malignant mesenchymal neoplasms. The history of myofibroblasts is related with the question how fibrous tissues, that are not contractile, shorten, and these cells have been identified and characterized in the early 1970s as the pivotal cellular element of granuation tissues as fibroblasts acquiring smooth muscle cells features during granulation tissue evolution [1, 2, 3, 4]. Nonneoplastic myofibroblasts have been defined ultrastructurally as differentiated cells having features in common with fibroblasts and smooth muscle cells. Myofibroblasts contain a fibrillar system of bundles of actin filaments arranged parallel to the axis of the cells with scattered electron dense areas often located beneath the cell membrane. These intracellular microfilaments are in continuity with extracellular fibronectin fibrils forming the so-called fibronexus adhesion complex. The nuclei of myofibroblasts are often not smooth as in typical fibroblasts but indented by one or more transverse folds or contrictions. Myofibroblasts contain abundant rough endoplasmic reticulum, Golgi apparatus, pinocytic vesicles, are partly invested by basal lamina, and are surrounded by abundant extracellular matrix. Histologically, myofibroblasts are spindled or stellated cells with pale eosinophilic or amphophilic cytolasm and nuclei that are either elongated and tapered or ovoid with small nucleoli. Immunohistochemically, a variable expression of actins, desmin, myosin, calponin and fibronectin has been reported, whereas h-caldesmon, a marker of smooth muscle differentiation, is usually negative [5, 6]. In general, mesenchymal neoplasms are classified according to the nonneoplastic cells they most closely resemble, however, cellular and subcellular features in neoplastic cells can be incompletely or abnormally developed. Given that, it seems realistic, that neoplastic myofibroblastic cells may not show all features of nonneoplastic myofibroblasts and that i.e. ultrastructural features as fibronexus or stress fibres are not a conditio sine qua non for the definition of myofibroblastic neoplasms. In addition to reactive and benign myofibroblastic lesions, a number of atypical and low-grade malignant mesenchymal neoplasms have been described during the last years including desmoid fibromatosis, infantile fibrosarcoma, inflammatory myofibroblastic tumour and low-grade myofibroblastic sarcoma. Desmoid fibromatoses represent clonal fibro/myofibroblastic proliferations characterized by an infiltrative and desctructive growth and a high rate of often repeated recurrences, whereas metastases do not occur. The ill-defined neoplasms are composed of relatively bland, elongated, spindle-shaped tumour cells set in a collagenous stroma with a variable number of vessels, sometimes with perivascular edema. Tumour cells lack atypia and usually only few mitoses are found. Immunohistochemically, neoplastic cells stain focally positive for muscle specific actin and for alpha-smooth muscle actin, whereas desmin and S-100 protein are detected only rarely. In addition, a focal nuclear staining for β-catenin has been reported in distinction to comparable fibro/myofibroblastic neoplasms, however, this staining does not seem to be a reliable diagnostic marker. Some tumour cells in desmoid fibromatoses may show trisomies for chromosomes 8 and/or 20, and an inactivation of the APC tumour suppressor gene on chromosome 5q as well as β-catenin activating mutations have been found [7, 8, 9]. Infantile fibrosarcoma represents a rare neoplasm of early childhood arising in subcutaneous and deep soft tissues of the extremities, whereas it is seen more rarely on the trunk and in the head and neck region. Clinically, the neoplasms may reach a large size, grow locally aggressive and may recur, but metastases are very rare. Cases of infantile fibrosarcoma are poorly circumscribed, lobular masses composed of cellular bands and fascicles of spindled, only rarely round tumour cells with enlarged but relatively uniform nuclei. The proliferative activity is increased and areas of zonal tumour necrosis and haemorrhage are frequent. Often numerous vessels sometimes given a haemangiopericytoma-like appearance are present. Immunohistochemically, tumour cells stain positively for alpha-smooth muscle actin and desmin in a number of cases, and recently a specific translocation t(12;15)(p13;q25) resulting in the fusion of ETV6 and NTRK3 genes with oncogenic activation of the NTRK3 receptor tyrosine kinase gene has been identified [10, 11, 12]. Inflammatory myofibroblastic tumour forming with inflammatory fibrosarcoma a morphological spectrum of a single clinicopathological entity arises most commonly in the lung, the retroperitoneum, the mesentery or other visceral organs but may be seen in skin and deep soft tissues as well. Clinically, children and adults may be affected by solitary or multicentric neoplasms, and the rate of (sometimes repeated) local recurrences is increased (up to 40%) whereas systemic metastases or a tumour progression to a franc sarcoma are seen only rarely. Histologically, the infiltrating neoplasms are composed of relatively bland stellated or short spindled cells associated with numerous inflammtory cells, especially plasma cells, lymphocytes, and eosinophils arranged in a fasciitis-like, fascicular or sclerosing fashion. Occasionally, large atypical cells with enlarged vesicular nuclei containing prominent nucleoli with an increased number of also atypical mitoses are seen, and it seems that the presence of these cells in combination with increased p53 expression and aneuploidy is associated with a worse clinical outcome. Tumour cells in most cases express alpha-smooth muscle actin, whereas desmin is expressed only rarely; a focal expression of pancytokeratin is seen in about one-third of neoplasms. In addition ALK is positive especially in cases arising in childhood. Most recently it has been suggested, that the neoplastic spindled cells in inflammatory myofibroblastic tumour are closely related to fibroblastic reticulum cells, but this has to be substantiated. Cytogenetically, a subset of cases is characterized by the fusion of the ALK gene, located on 2p23 and encoding a receptor tyrosine kinase, with tropomyosin 3 or tropomyosin 4, and recently a transcript involving the ALK and the clathrin heavy-chain gene, located on 17q23 has been described. However, these clonal cytogentic rearrangements are seen most frequently ín cases arising in children and young adults, whereas they are only rarely found in adults beyond 40 years old [13, 14, 15, 16]. Low-grade myofibroblastic sarcoma represents a distinct atypical myofibroblastic neoplasm occurring predominantly in adult patients, whereas children are only rarely affected. Although low-grade myofibroblastic sarcomas show a wide anatomic distribution with cases arising in the skin, the gastrointestinal tract, the salivary gland and the nasal cavity/paranasal sinuses, the extremities and the head and neck region, especially the tongue and the oral cavity, seem to be preferred locations. Histologically, most cases of low-grade myofibroblastic sarcoma are characterized by a diffusely infiltrative growth, and are composed of cellular fascicles of spindle-shaped tumour cells, whereas hypocellular neoplasms with a prominent collagenous matrix are seen more rarely. Importantly, neoplastic cells show at least focally moderate nuclear atypia with enlarged and hyperchromatic nuclei, and mitoses are easily found. Neoplastic cells in low-grade myofibroblastic sarcoma have a variable immunophenotype with actin positive/desmin negative, actin negative/desmin positive and actin positive/desmin positive cases. In addition, tumour cells may stain positively for fibronectin, CD 34 and CD 99 (cytoplasmic), whereas h-caldesmon, β-catenin, S-100 protein and epithelial markers are usually negative. The presence of increased proliferative activity and tumour necrosis is associated with a more aggressive clinical behaviour [17, 18, 19, 20]. References Gabbiani G, Ryan GB, Majno G Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971; 27: 549-550 Gabbiani G Some historical and philosophical reflections on the myofibroblastic concept. Curr Topic Pathol 1999; 93: 1-5 Majno G, Gabbiani G, Hirschel BJ et al. Contraction of granulation tissue in vitro: similarities to smooth muscle. Science 1971; 173: 548-550 Majno G The story of the myofibroblasts. Am J Surg Pathol 1979; 3: 535-541 Eyden B Electron microscopy in the study of myofibroblastic lesions. 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