Myofibroblastic Malignancies – a Continuing Controversy

THE MYOFIBROBLAST Myofibroblasts are modified fibroblasts which were first identified in granulation tissue, where they are probably derived from local fibroblasts, and which form the principal component of a number of reactive and benign soft tissue lesions. Under mechanical stress, the fibroblasts acquire cytoplasmic actin-containing microfilaments or stress fibres which express β−and γ-actins and impart contractility to the cell. The stress fibres are continuous at the cell surface with the fibronexus adhesion complex. With continuing mechanical tension, these ‘proto-myofibroblasts’, under the influence of transforming growth factor β1 and cellular fibronectin, become terminally differentiated myofibroblasts . These cells have better-developed fibronexus and cytoplasmic stress fibres (expressing αSMA, and sometimes desmin and smooth muscle myosin), enabling more effective contractility. In wound healing, as epithelialization is completed, the myofibroblasts are presumed to disappear by apoptosis 4, . In other situations myofibroblasts or myofibroblast-like cells might be derived from (vascular) smooth muscle cells or from pericytes, which seem to be related to smooth muscle cells, or by metaplasia from epithelial cells as seen in spindled carcinomas. Morphology Myofibroblasts are stellate or bipolar cells, with nuclei which are elongated and tapered or wavy like those of fibroblasts, or shorter, ovoid, and pale staining, with distinct, punctate small central nucleoli. Cell boundaries are indistinct, and the cytoplasm is sparse, lightly eosinophilic, or amphophilic. There is sometimes a paranuclear pale zone representing the Golgi complex. Ultrastructurally, the nuclei are indented, and the cytoplasm has abundant rough endoplasmic reticulum and peripheral bundles of thin cytoplasmic filaments (stress fibres) with dense areas. Other features include Golgi complex, collagen secretion granules in Golgi-derived vesicles, and a specific cell-stromal attachment, the fibronexus. This is a transmembrane complex of intracellular microfilaments in continuity with extracellular, longitudinally disposed fibronectin fibrils. It is absent in smooth muscle. Smooth muscle cells differ from myofibroblasts additionally by the presence throughout the cytoplasm of myofilament bundles with focal dense bodies, and by their surface features which include pinocytosis-like vesicles or caveolae, cell membrane thickenings and interrupted or continuous external lamina. These features are variably developed in leiomyosarcomas, in which the lesional cells can resemble myofibroblasts. In the latter, however, the cytoplasmic filaments form a peripheral band, there is more rough endoplasmic reticulum and the surface specialisations are absent. Fibroblasts are spindle shaped cells with tapered nuclei and variable amounts of rough endoplasmic reticulum which can be inactive or active (distended with secretory products), so that the cells can be slender (often with a wavy nucleus) or plump. They lack external lamina, pinocytosis and myofilaments. A number of fibroblastic lesions, however, have a component of myofibroblasts and it is possible that cells can modulate between the two morphological and functional states.