Diff Dx (S1C6t5)

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chapter 5, tier 2, textual level

In adventitial cellular myxofibroblastomas, the spectrum of histologic patterns is divisible into three general categories: 1)  predominantly myxomatous lesions, 2) predominantly cellular lesions, and 3) predominantly fibrous lesions. Myxomatous lesions are likely to be relegated to the category of cutaneous myxoma. Lesions that are rather uniformly cellular are likely to be confused with lesions in the fibrohistiocytic category (including dermatofibroma). Uniformly, and delicately, fibrous lesions might be confused with lesions in the fibrohistiocytic category. In all these variants, cellular patterns with a prominent vascular component might suggest a peculiar hemangiopericytoma or glomus tumor; some of the lesions of myopericytoma resemble lesions that herein are classified as adventitial myxofibroblastoma.

Myxomatous tumors of the skin are rare; most examples are sparsely cellular. Lesions which appear to qualify as true myxomas (lesions that are myxoid and variably cellular) include subungual myxomas, and a group of small myxomas, including the adventitial variants. Cutaneous myxomas of the cardiac myxoma (Carney's) syndrome (ddd,o) are representative of the adventitial group. Allen, et al, (a) have proposed that most, if not all, of the myxomas and myxomatous lesions of the skin, including focal cutaneous mucinosis, are best characterized as variants of angiomyxomas. In part, the designation, angiomyxoma, is an accommodation which skirts the controversial nature of the true myxoma. In many cutaneous myxoid lesions, a vascular component is just not that prominent. The appropriateness of angiomyxoma as a generic designation, embracing all the myxomas of the skin, is questionable. Aggressive myxomas of the genitalia and the soft tissue have been characterized as "aggressive angiomyxomas" (aaa).

Some small cutaneous myxomas, including some of the lesions of Carney's syndrome, are perifollicular in orientation, and some are additionally associated with patterns of hamartomatous follicular epithelial hyperplasias or dysplasias ("trichogenic adnexal myxomas") (ddd). In these relationships, the mesenchymal component might be characterized as an alteration of the adventitial dermis, and the respective lesion as adventitial in type. Trichodiscomas are included in the adventitial category. Trichodiscoma, as characterized by Pinkus (n), was a dome-shaped, sessile and myxomatous papule or plaque. Some examples seem to be fibromyxomatous variants of perifollicular fibromas (ccc): they have myxomatous qualities and are associated with distorted patterns of follicular differentiation; they are fibrofollicular hamartomas. Myxomas, associated with distortions of follicular components, have "kininic" qualities. Subungual myxoma is a true neoplasm of soft tissue with a propensity for local recurrence (h). The cells are stellate in outline with long rigid processes. They are regularly spaced in the myxoid matrix, and are uniform in distribution. Nuclei tend to be plump and hyperchromatic. The periarticular myxoma of soft tissue is histologically similar (l). Other true myxomas of the skin, other than the subungual and adventitial variants, are poorly defined and tend to be assigned to a general category.

The myxomatous matrix of adventitial cellular myxofibroblastoma only rarely is as prominent as that of the common lesions which are classified as myxomas. Some of the largest examples of adventitial cellular myxofibroblastoma focally are richly myxomatous. In myxomas, nuclear chromatin is usually dense. Although the nuclear chromatin of cells in adventitial cellular myxofibroblastoma tends to be stippled, in richly myxomatous components of some examples, the nuclear chromatin of the tumor cells is dense and uniformly distributed. The reticulum of adventitial cellular myxofibroblastoma usually is more abundant than that of the common small myxomas.

Focally, in some examples of adventitial cellular myxofibroblastoma, tumor cells form loose whorls in a myxomatous matrix. In some examples, the cells of some of the whorls are rounded in outline; they are faintly, and irregularly, positive for S-100 protein. For such examples, nerve sheath myxoma (mm) might be considered in the differential diagnosis. The plexiform, or multinodular quality of nerve sheath myxoma is not a feature of adventitial cellular myxofibroblastoma. Nerve sheath myxoma has no preference for adventitial domains. Extensions of tumor along a small nerve into the neighboring dermis was noted in only one example of adventitial cellular myxofibroblastoma. This pattern is also rare in nerve sheath myxoma, and is not an aid in the differential diagnosis of these two lesions.

Some examples of adventitial cellular myxofibroblastoma extend into the deeper portion of the dermis, and even into the subcutis. They are uniformly cellular, richly myxomatous, and at least partly subcutaneous. If the criteria for the diagnosis of soft tissue tumors are applied to these cellular variants, myxoid liposarcoma becomes a consideration. In the current conceptualizations of soft tissue tumors, there is little provision for cellular variants of myxoma. Cellular myxoid lesions, involving adipose tissue, are likely to be assigned to the category of myxoid liposarcoma, even in the absence of demonstrable lipoblasts. This is particularly true of examples with a prominent plexus of small vessels. Low grade myxoid liposarcomas are not primary lesions of the dermis; most adventitial cellular myxofibroblastomas are confined to the dermis.

Giant cell tumor of tendon sheath (benign synviocytoma) occasionally presents as a solitary nodule of the skin of the hand (d), and characteristically is partitioned by fibrous septa. Some examples are polypoid at the surface of the skin (q). Patterns are variable, but clusters of rounded histiocytes with occasional giant cells are a characteristic feature. In the clusters, the loosely spaced histiocytes outline angulated clefts. Xanthoma cells and hemosiderin deposits, a relatively common feature of giant cell tumors, are not a prominent feature of adventitial cellular myxofibroblastoma, but rounded, vacuolated, mucicarminophilic cells occasionally are. The mucicarminophilic cells, when represented, tend to be locally distributed among the tumor cells, and some are multinucleated.

The vascular components of some adventitial cellular myxofibroblastoma, with a tendency for tumor cells to be arranged concentrically in organoid patterns around vessels, constitute peritheliomatous or glomoid qualities. Reticulum stains and vessel-related immunoreactions such as smooth muscle actin, or factor XIIIa accentuate the prominent vascular components of adventitial cellular myxofibroblastoma. Factor XIIIa (+), dendritic histiocytes in hemangiopericytomas of the soft tissue have been interpreted as undifferentiated cells of “pericytic” nature, and characterized as markers of differentiation (t). By certain criteria, a pericyte is a contractile cell, and a deviant smooth muscle cell. By other criteria, a pericyte is a perivascular cell with no distinguishing characteristics (e). For some observers, the pericyte is a resting mesenchymal cell with the potential for divergent differentiation (m,u). It recently has been proposed that dendritic pericytes and myoid pericytes are related in an evolutionary sequence (e). Beyond these speculations, a sequential relationship between the undifferentiated pericyte, and the contractile pericyte has not been conclusively established.

Adventitial cellular myxofibroblastoma, hemangiopericytoma, and dermatofibroma all share the feature of a high component of factor XIIIa (+) dendritic histiocytes. A histogenetic identity for lesions in these three categories is not established by the communality. The communality probably is evidence of a functional interdependence of dendritic histiocytes, and a variety of mesenchymal cells, including fibroblasts. Perhaps, the relationships bear upon angiogenesis. In our experience, dendritic histiocytes, that are immunoreactive for factor XIIIa, are common in a variety of benign, vessel-rich lesions of the skin. They have been described in lesions of Kaposi's disease (i).

Purportedly, the cells of glomus tumor are reactive for smooth muscle actin; whereas, the cells of hemangiopericytoma are not (e). The tumor cells of adventitial cellular myxofibroblastoma are not immunoreactive for smooth muscle actin. Some of its vessels have thick, fibrous walls in which tumor cells are loosely spaced:  the tumor cells have "pericytic" qualities. These distinctive vessels are not associated with a component of smooth muscle cells. Thin walled vessels with spindle cells, which are immunoreactive for smooth muscle actin, also are represented in adventitial cellular myxofibroblastomas.

The designation, fibroblastoma, has found little utility in the characterization of soft tissue tumors. Giant cell fibroblastoma (eee) clearly is not an adventitial myxofibroblastic disorder; it does not have adventitial qualities. Many lesions, which might qualify as variants of fibroblastomas, are more appropriately characterized as myofibroblastomas. The lesions in the fibromatosis category and nodular fasciitis are examples. Perhaps, myofibroblasts are prototypic of fibroblasts of the reticular dermis, and the retinacula (including the fascia). Sclerosing myofibroblastomas, solitary myofibroblastoma (uu), and infantile "myofibromatosis" are primarily disorders of the reticular dermis. Contractility may be a useful function for cells of the reticular dermis, but may not be for fibroblasts in the adventitial dermis.

In lesions of histiocytosis X, the infiltrating cells are plump and rounded. They fill the papillary dermis and, often, some migrate into the epidermis. Some of the nuclei are elongated and deeply grooved. Some of the nuclei of tumor cells in adventitial cellular myxofibroblastoma are also elongated and deeply grooved.  The immunoreactivity of cells in the infiltrates of histiocytosis X easily provide a distinction from the native cells of adventitial cellular myxofibroblastoma. Cutaneous lesions of histiocytosis X usually have an adventitial quality. The infiltrates of histiocytosis X generally do not have a well-defined tumoral quality (at least the lesions selected for biopsy). The cutaneous lesions of histiocytosis X usually are multiple. Some congenital forms of histiocytosis X (benign regressing reticulohistiocytoma) are nodular, and do not have an adventitial quality. The clinical setting, the admixture of eosinophils, the common areas of necrosis, and the rapid clinical evolution of lesions are diagnostic features of congenital regressing reticulohistiocytoma (jjj).

Dermatofibromas occasionally press upon the epidermis. A superficial biopsy of such a lesion, which is also rich in rounded histiocytes, might be misinterpreted as adventitial cellular myxofibroblastoms.

Peculiar lesions of the nose ("lacunar cell tumors of the nose"), with widely spaced, round, clear, or pale cells in lacunar patterns in a hyaline matrix, had been included in the prospective phase of this study but, on review, in preparation for this study, were deleted.

The Designations, Histiocyte, Histiocytoid, and Epithelioid:

A Critique

The designation, histiocyte, was coined by Aschoff and Kiyona to describe mononuclear phagocytes in tissue (z). It denotes a functional state in a specific line of cells. Similar functions of a limited nature are accessible to many, if not all, cell lines, if autophagy and cytophagy are equated with the functions of histiocytes. A hematopoietic stem cell has been identified as the source of blood monocytes, and is ascribed to be the source of a variety of tissue histiocytes. With routine techniques at the light microscopic level, a histiocyte is any mononuclear cell with a reniform nucleus, delicate chromatin, a cell diameter of 10-25 um, and acidophilic cytoplasm. It is most characteristic when identified in a community with other inflammatory cells. A macrophage is a histiocyte but, as broadly defined at the light microscopic level, not all "histiocytes" are macrophages.

In practice, a variety of histiocytes, and a corresponding variety of histiocytic lesions have been characterized. In addition, histiocytes have been characterized as "facultative" fibrocytes, and as progenitors of an array of "fibrohistiocytic" tumors (p,kk). In these accommodations, fascicles of spindle and round cells in starburst patterns often are cited as features of fibrohistiocytic differentiation. To characterize a lesion as fibrohistiocytic on the basis of the above criteria is a morphologic accommodation. It does not resolve the problem of cell lineage (if such a problem is even relevant to the classification of neoplasms). Often, in the past in assigning a tumor to a category, a demonstration of the functional nature of the tumor cells has not been a requisite.

The category of histiocytic and fibrohistiocytic disorders is morphologically, immunologically, and enzymatically heterogeneous (aa-hh). It mostly antedates the characterization of histiocytes with cell markers. Some fibrohistiocytic disorders may represent functional adaptations in cell lines that are not related to the hematopoietic histiocyte (kk, p). Some alleged "histiocytic" disorders have been deleted from the general category; histiocytic medullary reticulosis is an example (ii,jj).

Currently, the demonstration of a specific cell marker often is equated with the identification of a distinctive line of cells. In the characterization of histiocytes, some of the immunoreactions include KP-1, LeuM-1, Leu-6, CD1, CD11b, CD14, CD15, lysozyme, S-100 protein, factor XIIIa, and alpha-1 anti-chymotrypsin. They are not of equal value or specificity. Some immunoreactions, that are commonly utilized to characterize a line of cells as to type, are, at best, only markers for cell functions. Some may provide indices for the rate of replication or activation of cells.

In peripheral tissue, the functions of histiocytes are diverse (Rosai, hh, ll). Two broad functional categories include the phagocytic system, and the dendritic system. The importance of phagocytosis as a distinguishing characteristic is relative. Phagocytic functions are accessible to a variety of cell lines, but the capacity of dedicated phagocytic histiocytes (cells of hematopoietic lineage in a phagocytic role), and their ability to phagocytose relatively large particles are unique attributes. The variable functions of peripheral histiocytes (those beyond the confines of the hematopoietic marrow and the vascular system) are accommodated in the concept of the M-PIRE system (v). Dendritic histiocytes (“dendritic reticulum cells”) have been identified in normal mesenchyme and epithelium. Subgroups of dendritic histiocytes have been defined on the basis of specific immunoreactions. In one subgroup, dendritic histiocytes are immunoreactive for S-100 protein. Langerhans cells (immunoreactive, S-100 (+), epidermal dendritic histiocytes) are prototypic. Dendritic Langerhans' cells of the epidermis function as sentinels in the initiation of certain cell mediated immune reactions (hh,ll).

If S-100 protein is a marker of function (a specific expression by phenotypically pluripotent, dendritic histiocytes), and also is a characteristic marker of specific epidermal, dendritic Langerhans' cells, then S-100 (+), extraepidermal, dendritic histiocytes might have a role in cell mediated immunity; they may function as "sentinel" cells. This function has not been confirmed. In the dermis, some dendritic cells have been characterized as dermal Langerhans cells but, in these characterizations, the requisite immunoreactions, and cellular organelles have not been demonstrated in all examples. Commonly, as a convenience, a positive reaction for S-100 protein, and a dendritic configuration have sufficed in the characterization of extraepidermal "Langerhans cells".

S-100 protein (+), dendritic histiocytes are common in the stroma, or among the neoplastic cells of a variety of neoplasms (x,y,j,oo). Atypical fibrous xanthoma (j) and papillary carcinoma of the thyroid are examples (oo). Conceptually, a histiocyte, which is dermal in location and immunoreactive for S-100 protein, would also qualify as a dermal dendrocyte. Such cells share some immunologic, and ultrastructural markers with the cells of histiocytosis X (ww,xx,yy). Neither the demonstration of Birbeck granules nor specific immunologic cell markers are sufficient to distinguish infiltrates of S-100 (+) dendritic histiocytes in the stroma of a neoplasm from the infiltrate of histiocytosis X. The diagnosis of histiocytosis X remains a privilege of the light microscopist, and is based upon tumoral qualities and distinctive cytologic features. Additional findings such as cell markers, and distinctive organelles are ancillary.

Histiocytosis X currently is characterized as Langerhans cell histiocytosis (qq,rr, wghist). Historically, it would have been more appropriate to characterize histiocytosis X (pp) as Lichtenstein's histiocytosis. Lichtenstein defined histiocytosis X as a clinicopathologic entity (pp): he had a clear understanding of the disorder. On the other hand, Langerhans was not concerned with the manifestations of disease: the diseased cells of histiocytosis X were not the object of his studies, and are not cytologic, functional, or biologic homologues of Langerhans cells.


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