CONTROVERSIAL TUMORS OF FIBROBLASTIC DIFFERENTIATION
The ubiquitous flbroblast is capable of a wide variety of morphologic and functional adaptations in relation to its body site as well as local physiologic and pathologic changes. The active collagen synthesizing fibroblast is a spindle shaped or plump epithelioid cell with a prominent juxtanuclear Golgi apparatus and a well developed branching rough endoplasmic reticulum (RER) that is variably distended with a finely granular secretory product. In contrast, the resting flbrocyte generally is a smaller cell with less conspicuous organelles. In poorly cellular collagen sparse "myxoid" sites, the fibroblast is spindly or stellate with long thin cytoplasmic processes. In response to inflammation and injury (wounds), the fibroblast often transforms into a contractile myofibrob last with peripheral arrays of actin microfilaments and/or a fibrohistiocyte with prominent lysosomes that is often mistaken for a true histiocyte.
Because of the protean morphologic appearance of the fibroblast described above, fibroblastic tumors, both benign and malignant, are not uncommonly mistaken for other entities, notably smooth muscle and histiocytic neoplasms. The immunophenotypic variations of the vimentin expressing fibroblasts reflect its morphologic/functional states and also lead to diagnostic confusion. For example, smooth muscle actin (SMA) and desmin are variably coexpressed with vimentin in reactive and neoplastic myofibroblasts, while subsets of fibroblasts coexpress CD34 (solitary fibrous tumor and dermatofibrosarcoma protuberans). This presentation concerns two controversial entities, malignant fibrous histiocytoma (MFH) and myofibrosarcoma, that are not considered by many pathologists to be either fibroblastic tumors or distinct nosologic entities.
Malignant Fibrous Histiocytoma
- Pleomorphic Fibrosarcoma
The eminent Columbia University pathologist Arthur Purdy Stout
coined the term "malignant fibrous histiocytoma" on
the basis of tissue culture studies by Margaret Murray that purportedly
showed that these "pleomorphic fibroblastic tumors"
arose from tissue histiocytes capable of flbroblastic transformation,
i.e., "facultative fibroblasts." Enzinger and Weiss
subsequently defined five subtypes of MFH as follows: (1) storiform-pleomorphic,
(2) myxoid, (3) giant cell, (4) inflammatory, and (5) angiomatoid.
Until recently, MFH was the most common adult soft tissue sarcoma.
On the basis of more recent ultrastructural and inimunohistochemical (IIHIC) studies, virtually all of the "fibrohistiocytic tumors" do not show true histiocytic differentiation, e.g., the dermal fibrous histiocytoma is more correctly termed a dermatofibroma. Fletcher correctly reported that MPH is overdiagnosed, since these tumors often are pleomorphic forms of other sarcomas, e.g., pleomorphic leiomyosarcoma and dedifferentiated liposarcoma.
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| Fig. 1. High grade myxoid fibrosarcoma (left thigh). Pleomorphic nucleus and dilated RER, x3,000. | Fig. 2. Pleomorphic fibrosarcoma (MFH) (right thigh). Giant myofibroblast, x2,400. |
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| Fig. 3. Giant cell fibrosarcoma (MFH) (upper arm). Multinucleate fibroblast, x4,000. | Fig. 4. Pleomorphic fibrosarcoma (MFH) (left thigh). Histiofibroblast. Note the RER and lysosomes, x3,000. |
Detailed ultrastructural and IIHC studies of over 130 cases of MPH in our department as well as those of other laboratories have clearly shown that the storiform-pleomorphic, myxoid, and most likely some of the giant cell subtypes are fibrosarcomas in which most of the phenotypic forms of the fibroblasts are variably found as well as a complement of undifferentiated cells. While the classic flbrosarcoma is an. uncommon cytologically uniform spindle cell tumor with a herringbone pattern, most cases of MPH may be regarded as pleomorphic fibrosarcoma. Many of the cells composing the above three variants of MPH are large fibroblastic or myofibroblastic cells with a markedly pleomorphic nucleus or multiple nuclei. The cytoplasm occasionally is pervaded by numerous vimentin intermediate filaments ("rhabdoid fibroblasts"). Nonneoplastic inflammatory cells, notably lymphocytes and true histiocytes (macrophages) also are variably present in many of these tumors. The so-called inflammatory (xanthoma cells) and angiomatoid (a myofibroblastic tumor?) subtypes of MPH require further study. Sarcomas consisting only of undifferentiated cells should be designated undifferentiated sarcoma, NOS.
Myofibrosarcoma
It is aptly stated by Schurch and associates in a recent editorial
in the American Journal of Surgical Pathology that "neoplastic
transformation of the myofibroblast is an uncommon event."
Ultrastructurally, in addition to a well developed RER, the myofibroblast
contains parallel bundles of ectoplasmic actin microfilaments
with interspersed fusiform densities, plasmalemmal attachment
plaques, and associated extracellular microtendons (fibronexus
of Eyden). Other features include remnants of apparent external
lamina, variable numbers of pinocytotic vesicles, and intermediate
and gap junctions. Schurch et al. have recently reported five
myoflbroblast immunophenotypes as follows: (1) vimentin; (2) vimentin,
SMA, and desmin; (3)~ vimentin and SMA; (4) vimentin and desmin;
and (5) vimentin, SMA, and smooth muscle myosin heavy chain with
or without desmin. It is thus apparent that these cells are not
uncommonly erroneously designated smooth muscle cells by pathologists,
and myofibroblasts can only confidently be identified by electron
microscopy. In smooth muscle cells, the RER is poorly developed,
mitochondria often are prominent, and actin filaments pervade
the cytoplasm. A fibronexus also is absent.
True cases of ultrastructurally verified myofibroblastomas and myofibrosarcomas have been reported in the literature. The benign neoplasms, e.g., cases of mammary myofibroblastoma, are more common than the rare malignant tumors (we have only five cases in our files). Misdiagnoses commonly result from misinterpreting reactive myofibroblasts present in many sarcomas as neoplastic cells, and not requiring the overwhelming majority of tumor cells to be myofibroblasts.
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| Fig. 5. Myofibrosarcoma (upper back). Note the RER and actin filaments, x4,000. |
References