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Adventitial Cellular Myxofibroblastoma (another lesion rich in dendritic histiocytes)

chapter 2, tier 2, textual level

(vintage 1992-3)

The concept of a histiocyte facultatively functioning as a fibroblast is commonly cited as the basis for a category of fibrous histiocytoma. Cell culture studies often are cited as evidence supporting such a concept. In this approach, cells of a culture of “histiocytes” undergo a transformation to fibroblasts. In some of these studies, even malignant “histiocytes” (i.e., lymphoma cells) were described as undergoing such a transformation (Fig. C1t3D1 & 2). The results seem to be more in the nature of a demonstration of a basic limitation in the ability to culture cells. In the face of this limitation, which has impacted upon our concepts of neoplasia, a basic, ubiquitous cell line, the fibroblast, is an accessible phenotypic option for a different ubiquitous cell line, the histiocyte. The nature of the fibrous histiocytoma of the dermis, the dermatofibroma, was somewhat modified when immunoperioxidase stains became readily available. For a time, dermatofibroma was promoted as a dermal dendrocytoma (i.e., all cells of the tumor were characterized as being immunoreactive for factor XIIIa). More recently, the dendrocytes and fibroblasts of a dermatofibroma have been characterized as functionally related cells of mesenchyme.

The category of "histiocytic disorders" is inconstant; additions, as well as deletions, are common. "Epithelioid cell histiocytoma," a recent addition (g), has been characterized as a lesion with a high component of factor XIIIa (+) dendritic histiocytes. Wilson-Jones, et al, identified immunoreactive dendritic histiocytes as the native cells (g)." Having assigned the lesion to the histiocytic category, they then drew upon a recent characterization of dermatofibroma (b,f) to reinforce their interpretation (g).

Dermal dendritic histiocytes, those that are immunoreactive for factor XIIIa, have been characterized as "dermal dendrocytes" (f,tt). For some observers, the common dermatofibroma is a tumor of dermal dendrocytes: it is a dermal "dendrocytoma" (b). For others, histiocytes, that are immunoreactive for factor XIIIa, are residents in, but are not the native cells of, dermatofibromas. The role of these functionally distinctive histiocytes in the evolution of dermatofibroma, and some other fibrous lesions of the skin is controversial (b,i,f ).

We are reporting a group of distinctive cutaneous lesions with a predilection for acral locations; with “histiocytoid” or “epithelioid” cytologic features; and with a rich component of factor XIIIa (+), dendritic histiocytes. Most of the lesions are comparable to so-called "epithelioid cell histiocytoma," but our interpretation of the histologic patterns, and of the nature of the tumor cells differ from those of Wilson-Jones, et al, (g). The emphasis, which has been placed in the literature on the nature of the tumor cells in dermatofibromas, impacts on the conceptualization of a variety of fibrous, and myxomatous lesions of the skin. For Wilson- Jones, et al (g), their interpretation of the role of "dendrocytes" in the histogenesis of dermatofibroma had broad implications, identifying several tumors as representatives of neoplasms of the dendritic histiocytic system. Immunoreactivity for factor XIIIa, as it relates to the cellular populations in a group of dermatofibromas, is a relevant issue, and is an additional aspect of this study.

Materials and Methods

Prospectively for ten or more years (i.e., prior to 1992), one of us had coded examples of a distinctive lesion of the skin as "histoid myxoma".  Fifteen such cases from the respective files were reviewed. Following review, three of the cases were rejected, leaving a total of 12 cases showing basically uniform patterns.

The tentative designation, histoid myxoma, as utilized in the prospective stage of this study, entitled both histiocytoid and myxoid qualities, as manifested on routine sections with light microscopy. In some of these lesions, the cells were closely clustered in "epithelioid" patterns, a feature commonly equated with “histiocytoid” qualities. Other examples, focally or uniformly, were myxoid. Of the lesions, which had been examined for the presence of acid mucopolysaccharides during the provisional phase of this study, all had a background of acid mucopolysaccharides; even those which were uniformly cellular were histochemically myxoid. They were also rich in reticular fibers. They were fibromyxoid (or even myxofibroid).

The controversy inherent in the designation "myxoma" was appreciated during the provisional phase of the study. The original, assigned designation, histoid myxoma, merely acknowledged a mucinous matrix without addressing the problematic nature of myxomas.

A close association between tumor cells, and a plexus of vessels was a prominent feature of most of these lesions. The histologic patterns deviated from those of the usual hemangiopericytoma of soft tissue. In our search for an appropriate designation, "histiocytoid pericytoma" was one consideration.

As the final compromise, the designation, "adventitial cellular myxofibroblastoma," gives recognition to histologic patterns, immunohistochemical reactions, and electron microscopic findings. By some criteria, only in tissue culture are fibrogenic cells to be characterized as fibroblasts. In routine pathology, a fibrogenic cell with no other qualifying features, such as myoid qualities, is usually characterized as a fibrocyte.

Conceptually, a fibrocyte is a fibrogenic, mesenchymal cell in both a steady metabolic state, and a physiologically limited external milieu (e.g., a cell engaged in homeostatic functions). In the reticular dermis, fibrocytes are the terminal mediator for the maintenance of type I collagen, and the respective fluid matrix. In the adventitial dermis, they are the final mediator for the maintenance of type III collagen, and the respective matrix. The papillary dermis - a component of the adventitial dermis - generally is histochemically myxoid (mucinous).

Herein, fibroblasts are metabolically active cells with abundant cytoplasmic organelles; they produce extracellular collagen and matrix, in excess of quantities required either for the maintenance of homeostasis, or in the act of repair (an old approach to cells engaged in the production of proteinaceous products was the examination of a section of tissue stained by the methyl-green pyronine technique [Fig.c9t3P45]).

An alteration of the dermis in response to a metabolic dysfunction, that results in an increased prominence of mucinous matrix, qualifies as a mucinosis. The entitlement of a tumoral lesion as a fibroma or myxoma is found in the character of the stroma with little attention to the character of the component cells. Although the fibrocyte is the most ubiquitous of cells, fibromas (by definition) are rare. Fibrocytomas are non-existent. A few fibroblastomas have been defined. The only provision for the classification of myxomas is found in the character of the matrix; myxomas are not classified on the basis of cell type; the identification of a specific cell showing signs of differentiation, such as rhabdomyoblastic or lipoblastic differentiation, interdicts a diagnosis of myxoma.

Herein, a tumor of mesenchymal, fibrogenic cells, actively engaged in fibrogenesis, is a fibroblastoma. Such a lesion may be myxoid, myxofibroid, or fibrous, and may be associated with abundant or scanty stroma. It may be sparsely or richly cellular. In the general category of fibroblastomas, distinctions are provided by an evaluation of degree of cellularity, by the fibrous or myxoid quality of the matrix, and by the anatomic compartments from which the tumor cells are derived. In this context, all myxomas are also variants of fibroblastomas. The richness and character of any related vascular plexus is of questionable significance. The designation, adventitial cellular myxofibroblastoma, gives recognition to a presumed preferential site of origin (i.e., the adventitial dermis); to a range of matrical expressions; and to a basic cell type.

For selected cases, requests for the loan of paraffin embedded material were made. From this additional material, alcian blue or colloidal iron stains for acid mucopolysaccharides, and stains for reticular fibers were prepared. In addition, immunoreactions for the demonstration of S-100 protein, smooth muscle actin, epithelial membrane antigen, factor XIIIa, desmin, vimentin, lysozyme, Leu M-1, keratin, alpha-1 anti-chymotrypsin, and KP-1 were prepared.

A correlation of immunoreactivity for factor XIIIa with specific types of cells in dermatofibromas was deemed pertinent to the interpretation of patterns in adventitial cellular myxofibroblastoma. Two problems were appreciated in our approach to the nature of "dermal" dendrocytes. If the cells of dermatofibroma are truly, and purely, hematopoietically derived, dendritic histiocytes, then dermal fibrocytes are nothing more than a facultative adaptation by histiocytes. If, on the other hand, hematopoietically derived histiocytes are prominent among, but are not the sole cells of dermatofibromas, the resident dendrocytes possibly influence the differentiation and function of the native mesenchymal cells (i.e., dendrocytes and fibroblasts are interactive). Either horn of the dilemma bears upon the interpretation of the index cases (Fig.c2t3D3-6).

Fifteen dermatofibromas of both the fibrous and the fibro-histiocytic types were selected from daily dermatopathologic material and examined for immunoreactivity to Factor XIIIa with attention to the types, and immunoreactivity of the component cells.

Clinical Data

The clinical data is limited, and is not uniform for all the cases. For each category, the available data is summarized. Of 7 cases, there was one case in the first decade, one case in the third decade, 3 cases in the fourth decade, one case in the sixth decade, and one case in the seventh decade. Of 10 cases, 4 were males. Of 9 cases, 5 were acral on an extremity (foot, finger, heel, hand, and leg). The other listed sites included one each of the following: ear, right side, shoulder, and scalp. For one case, a duration of one year was recorded.

The clinical differential diagnoses included leiomyoma, wart, and Heberden's node.

The impressions of the contributing pathologists included sclerosing hemangioma, atypical pyogenic granuloma, Spitz nevus, epithelioid lesion, nerve sheath myxoma, and Kaposi's sarcoma.


Adventitial cellular myxofibroblastoma: In the most characteristic pattern, lesions were polypoid at the surface of the skin (Fig. c4t3P1 & 2). In most examples, a collarette of epidermis projected into the dermis at the base of the polypoid portions. A grenz zone usually separated the lesion from the epidermis but, focally in some examples, lesions extended close to the dermal-epidermal interface. The overlying epidermis showed effacement of the rete ridges. In the common presentation, the lesion was disc-shaped and circumscribed. A thin condensation of cellular fibrous tissue often outlined the interface with the reticular dermis. The lesions usually were confined to a widened papillary dermis. In rare examples, a column from the disc-shaped component in the papillary dermis extended into, or through, the reticular dermis in a pushing fashion (Fig. c4t3P3); in only one example, were collagen bundles of the reticular dermis entrapped. One lesion was expansile in the lower portion of the dermis and bulged into the subcutis. In this example, involving the dermis below the level of the papillary dermis, a predilection for the adventitia of skin appendages apparently was manifested. These lesions with deeper components also differed somewhat from the classical lesions of the papillary dermis; plump, rounded epithelioid cells were not as characteristic; some reservations regarding the identity of the superficial lesions with those which have deeper components are indicated.

The tumor cells were rounded ("epithelioid"), stellate (angulated), or spindled in outline (Fig.c2t3D7-9, Fig.c3t3D10, & Fig. c4t3P4-9); they were attached to neighboring cells by rigid cell processes. The nuclei were plump, and rounded or oval in outline. Some of the nuclei contained prominent central nucleoli; some contained clear vacuoles (Fig. c5t3P13); some were deeply and longitudinally grooved (the cells with grooved nuclei appeared to be representatives of the population of dendritic histiocytes that reside in the lesions). Chromatin was marginated. There were occasional mitotic figures. There were rare intranuclear inclusions of cytoplasm.  For most examples, the cytoplasm of the tumor cells was intensely chromatic, and somewhat basophilic (lavender) (Fig. c4t3P4-6). Hemosiderin deposits were scattered and inconspicuous.

A prominent plexus of small, dilated vessels with symmetrically rounded lumens, and delicately fibrous walls was a prominent feature of most examples. Tumor cells infiltrated the walls of some of the vessels (Fig.c3t3D13) and, additionally, were arranged radially around some of the vessels (Fig. c7t3P30 & 31). They also tended to form small whorls which were not clearly vascular in orientation (Fig. c4t3P6). In areas, neighboring whorls were separated by ill-defined, lytic clefts (Fig. c3t3D15, & Fig. c4t3P7). Small, morphologically common histiocytes were loosely clustered in these clefts. Rare mast cells were present in some of the clefts.

Cellularity was variable (c3t3D11-12). Some lesions were uniformly cellular with inconspicuous, intercellular matrix. In these examples, tumor cells were rounded, stellate, and spindled in outline. Focally, in some examples, cells were loosely, but regularly, spaced in a prominent mucinous matrix (Fig. c4t3P8, Fig. c5t3P37 & 38). In the mucinous regions, stellate tumor cells were attached to their neighbors by rigid cell processes. Some were arranged in loose whorls in the mucinous matrix. Some of the lesions were uniformly myxomatous and cellular. For these lesions, the pattern generally was pandermal in contrast to the more common pattern of a superficial plaque at the surface of the skin (perhaps, these are cellular myxomas rather than adventitial myxofibroblastomas). For those lesions with extensions of broad columns into the reticular dermis, the columns often were sharply outlined at their margins with the reticular dermis by a condensation of fibrous tissue. In one example, in an area adjacent to one such column, tumor cells formed ill-defined nests and fascicles in the reticular dermis. One of these nests was in continuity with, and partly surrounded, a peripheral nerve. This lesion was uniformly cellular with the cells individually isolated in a myxomatous matrix. In small foci in these myxomatous variants with deep components, the cells were compactly aggregated and rounded in outline.

A few lesions were mostly fibrotic. In the fibrous areas, the cells were spindle and stellate in outline (Fig. c8t3P26-29). In the fibrous components, some of the nuclei of the tumor cells were small and rounded. The tumor cells were individually compressed in a delicately laminated fibrous matrix. In an occasional example, some of the tumor cells formed ill-defined interlacing fascicles with poorly developed star-burst patterns at the loci of intersection. Some of the lesions were rather uniformly fibrous but, even in these lesions, occasional areas were cellular and rich in vessels, and some areas were myxomatous with more widely spaced cells. These mixed patterns linked the fibrous, myxomatous, and the cellular variants.

In some examples, distinctive round cells with vacuolated, mucinous cytoplasm were individually isolated, and clustered among the more characteristic cells (Fig. c5t3P12 &13Fig. c7t3P17-25, Fig. c5t3P32-36, Fig. c9t3P42, Fig. c10t3P51). These cells had pale basophilic, stringy cytoplasm. Nuclei were central, and chromatin was dense. Some of these cells were multinucleated. The cytoplasm was mucicarminophilic, and strongly reactive with alcian blue. With alcian blue or other stains, such as colloidal iron or Morvat’s, the background matrix, even in cellular zones, had a mucinous quality, and tumor cells were individually outlined (Fig. c9t3P43 & 44). In occasional angulated defects among the tumor cells, mucinous matrix was pooled. With a reticulum stain, coarse, individual reticular fibers, and condensed collagenous matrix outlined individual, and small groups of tumor cells (Fig. c10t3P55). On the reticulum stains, some of the collagenous condensations provided a chondroid quality. This quality may correlate with occasional zones on the H&E stained sections in which the matrix was delicate and hyalinized.

Rare giant cells with two or several nuclei were represented in some lesions. In one example with a component in the subcutis, giant cells were prominent.

Immunoreactions for S-100 protein showed scattered immunoreactive dendritic cells among the tumor cells (Fig. c9t3P50). The reactive dendritic cells were most numerous in the dermis between the tumor and the epidermis, and in the subjacent portion of the lesion. In addition, in some of the lesions, clusters of generally rounded tumor cells were faintly immunoreactive. Spindle cell components mostly were not immunoreactive, with the exception of one lesion in which clusters of tumor cells near the epidermis were reactive. In one example, only scattered cells were immunoreactive, preponderantly in nuclear patterns.

Immunoreactions for factor XIIIa showed a high component of positive dendritic cells in the neighboring dermis, and within the lesions (Fig. c9t3P47-49). In some examples, the matrix surrounding some of the reactive dendritic histiocytes was immunoreactive. Some of the tumor cells were faintly outlined at the cell membrane level. In a few examples, the cytoplasms of the tumor cells were lightly, and diffusely, stained (Fig. c9t3P49). Dendritic histiocytes embraced, and their cell processes were entwined about, many of the tumor cells (Fig. c9t3P48).

The tumor cells were immunoreactive for vimentin. An immunoreaction for Leu M1 in one case, and for KP-1 in three cases demonstrated positive, small cells in the neighboring dermis, and occasional positive, small, rounded cells among the tumor cells (Fig. c10t3P53). Many of the dendritic histiocytes were immunoreactive for lysozyme. In the reactions for lysozyme, background staining was a troublesome feature and, in one of the lesions, some of the nuclei of tumor cells were faintly immunoreactive. For two examples, scattered and clustered tumor cells were faintly immunoreactive for alpha-1 anti-chymotrypsin. In the same two lesions, dendritic cells were strongly immunoreactive for alpha-1anti-chymotrypsin (Fig. c10t3P54).

Immunoreactions for smooth muscle actin accentuated the vascular plexus. The tumor cells were not immunoreactive. Immunoreactions for CEA, desmin, keratin and epithelial membrane antigen were negative.

Dermatofibromas: Immunoreactivity for factor XIIIa in fifteen dermatofibromas was manifested in dendritic cells in both the adjacent dermis and in the dermatofibromas among the larger native cells. In occasional examples, the cytoplasms of the native cells were lightly stained. In contrast, the resident dendritic histiocytes in all examples were intensely immunoreactive. The native cells in fibrotic variants of dermatofibromas were dendritic or stellate in outline but differed in size, and in nuclear characteristics, from the resident, positive dendritic histiocytes.


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