Case 4 -

Cellular Fibrous Histiocytoma Steven D. Billings, M.D. Andrew L. Folpe, M.D.

Clinical History A 25-year-old man presented with a non-pigmented, small nodule on the posterior neck. A punch biopsy was obtained. Morphology The biopsy demonstrated a circumscribed, non-encapsulated lesion centered in the reticular dermis. At the periphery, the tumor cells interdigitated around collagen fibers of the reticular dermis. The tumor was composed of fascicles of relatively uniform, lightly eosinophilic, spindled cells with oval to tapered normochromatic nuclei. Scattered mitotic figures were present but atypical mitotic figures were not seen. A relatively large area of necrosis was present. Diagnosis: Cellular fibrous histiocytoma Discussion Clinical and Histopathological Features Cellular fibrous histiocytoma (CFH) is an important variant of benign fibrous histiocytoma (dermatofibroma, DF). CFH has some clinical similarities as well as some importance differences with conventional DF. In contrast to conventional DF, CFH occurs more frequently on the proximal rather than distal extremities and presents as a lesion in the head and neck area in approximately 30% of cases. In contrast, less than 1% of DF occur in the head and neck. CFH present as asymptomatic nodules ranging in size from < 1-2.5 cm, and may be clinically mistaken for a variety of entities including epidermoid cyst, pyogenic granuloma, and basal cell carcinoma. Histologically, CFH have a number of low-power architectural similarities to ordinary DF, including overall circumscription (but not encapsulation), epidermal hyperplasia, and peripheral collagen trapping. A small percentage may be polypoid with a surrounding collarette of epidermis. It should be emphasized that CFH may show focal extension into the subcutis in up to a third of cases, either in a lacelike pattern involving the edge of the fat lobules or a fascicular pattern following the subcutaneous septae. Trapping of individual fat cells, as seen in dermatofibrosarcoma protuberans (see below) is not seen, however. CFH arising in areas with relatively little subcutaneous fat, such as the face, may rarely show infiltration of deeper structures, such as skeletal muscle and even parotid gland. As befits its name, CFH tend to be more cellular than ordinary DF, and often grow in a predominantly fascicular, or occasionally storiform, pattern. In contrast to ordinary DF, which are usually heterogenous lesions containing an admixture of spindled to oval tumor cells, siderophages, multinucleated giant cells and inflammatory cells, CFH tend to be composed almost exclusively of spindled tumor cells. Mitotic figures are usually easily identified in CFH, and the mitotic rate may rarely be as high as 10 mitotic figures/10 high powered fields (HPF). Atypical mitotic figures, however, are not seen. Another potentially worrisome feature is the presence of central necrosis, which is present in approximately 10% of otherwise unremarkable CFH. As might be expected, the presence of necrosis in a cellular, somewhat monomorphic and mitotically active spindle cell tumor may easily result in the mistaken diagnosis of a sarcoma, if one is not aware of this potential pitfall. Unlike most sarcomas, however, the cells of CFH do not display significant nuclear membrane abnormalities or hyperchromatism. Although immunohistochemistry can be useful in the recognition of CFH, it is often more useful in the exclusion of other tumors, rather than the positive identification of CFH. Whereas most conventional DF will show some immunoreactivity with antibodies to Factor XIIIa, this marker is often negative in CFH (in fact, none of the 74 cases in the original description of CFH were Factor XIIIa-positive!). In our practices, we have observed variable Factor XIIIa expression in CFH. CFH may show some smooth muscle actin expression in a "tram-track" pattern, reflective of myofibroblastic differentiation, but do not express desmin. Most importantly, the lesional cells of CFH are negative for CD34 and S-100 protein. It is important to recognize that CFH, as well as ordinary DF, may contain entrapped CD34 and/or S-100 protein-positive cells, and may also on occasion show a peripheral or deeply located cuff of CD34-positive reactive cells. These reactive cell populations should be rigorously distinguished from the CD34 or S100-negative tumor cells. Differential Diagnosis The differential diagnosis of CFH includes principally dermatofibrosarcoma protuberans (DFSP) and leiomyosarcoma (LMS) (Tables 1 and 2), as well as spindled variants of epithelioid sarcoma. CFH with a pronounced storiform growth pattern can easily be mistaken for DFSP, especially on small biopsies. However, DFSP are typically arranged in a more uniform storiform pattern, have more uniform, slender spindle cells, and show extensive infiltration into the subcutaneous fat, with entrapment of individual adipocytes in a "honeycomb" pattern. As noted above, this is in contrast to the less extensive involvement of the subcutis that may be seen in CFH. Unlike CFH, DFSP do not show peripheral collagen trapping. Additionally, DFSP tend to be much more monomorphic than CFH, lacking secondary cell types, lipidization or aneurysmal change. Immunohistochemistry for CD34, strongly positive in almost all DFSP, is also valuable in this differential diagnosis. DFSP do not express Factor XIIIa, although occasional cases may show entrapped or peripheral Factor XIIIa-positive cells, analogous to CD34-positive cells in CFH. Although other markers such as HMGA1 and HMGA2, stromelysin 3, and S100 A6, have been suggested as potentially useful in this differential diagnosis, it is likely that they will not ultimately be superior to careful examination of the routine histologic slide and appropriate use of CD34 and Factor XIIIa. CFH with a more principally fascicular growth may be confused with cutaneous (pilar) LMS. LMS differs from CFH by virtue of its more orderly fascicular arrangement, with intersection of fascicles at right angles, and by its more prominent cytoplasmic eosinophilia, with perinuclear vacuoles, and elongated, straight sided nuclei ("cigar shaped"). LMS also lacks peripheral collagen trapping and secondary elements. By immunohistochemistry, LMS shows uniform expression of smooth muscle actin, with filling of the entire cell cytoplasm, and is much more often desmin-positive, as compared with CFH. In the distal extremities, CFH may closely simulate a predominantly spindled epithelioid sarcoma (ES), and vice versa. Exclusively or largely spindled ES are often deceptively bland appearing and may contain hyalinized collagen, reminiscent of CFH. ES do not contain secondary elements such as foamy macrophages and siderophages, and generally show at least focal hyperchromatism (but this may be very subtle). For this reason, we are in the practice of routinely immunostaining all suspected CFH on the extremities with pan-cytokeratin antibodies, particularly in younger patients. It has recently been suggested that CD10, which is expressed in dermal dendrocytes but not epithelioid sarcomas, may be helpful in this differential diagnosis. It should be noted that ES may be Factor XIIIa-positive. Clinical Behavior In contrast to ordinary DF, which recur in <5% of cases, CFH has a high rate of local recurrence (approximately 20 - 30%). Extraordinarily rare bona fide CFH have been reported to metastasize to regional lymph nodes or the lungs. These rare tumors had no histologic features that would have predicted this unusual behavior, although they did frequently recur locally prior to metastasizing. Such tumors appear to pursue a relatively indolent course; two reported patients with documented pulmonary metastasis were either disease free after lymph node dissection and lung segmentectomies or had stable pulmonary metastatic disease for many years. The implication of these rare cases is not entirely clear. Given that CFH are in almost all cases relatively small and non-destructive, and metastasize extraordinarily infrequently, they should be considered as a group benign rather than tumors of intermediate malignancy or sarcomas. We routinely recommend excision with microscopically negative margins for cases of CFH, in particular with recurrent tumors. In cosmetically sensitive areas, Mohs micrographic surgery may be of value. There is no evidence to suggest a role for adjuvant therapy or wide excisions. Other Important Histologic Variants of Benign Fibrous Histiocytoma Aneurysmal Benign Fibrous Histiocytoma Aneurysmal benign fibrous histiocytoma (ABFH) is characterized by large cystic blood filled spaces, often associated with numerous siderophages, within a tumor that otherwise is quite similar to conventional DF. Like conventional DF, ABFH usually contain a polymorphous population of cells, with lipidized cells, siderophages and multinucleated giant cells. Features of ABFH may be seen within CFH and vice versa. As in CFH, ABFH often contain mitotic figures. ABFH is also clinically similar to CFH, with a local recurrence rate of approximately 20% and extremely rare reported metastasizing cases. In our experience, ABFH are most often mistaken for melanoma, vascular tumors, and angiomatoid (malignant) fibrous histiocytoma. The dark pigmentation of ABFH clinically, and its intense pigment deposition and sometimes high cellularity may mimic melanoma. Important clues to this distinction include the absence of an overlying junctional melanocytic proliferation, the presence of pigment primarily in macrophages rather than neoplastic cells, the "chunky" and refractile nature of the hemosiderin pigment, and the peripheral presence of typical BFH. In difficult cases, immunohistochemistry for melanocytic markers (e.g., S100 protein, HMB45, Melan-A) may be helpful. Additionally, storiform growth is quite unusual in vascular tumors. Perhaps the most important entity in the differential diagnosis is angiomatoid (malignant) fibrous histiocytoma, a fibrohistiocytic tumor of intermediate malignancy. Histologically, angiomatoid (malignant) fibrous histiocytoma is quite distinctive and is characterized by the presence of a dense fibrous capsule and a surrounding lymphocytic infiltrate that may closely mimic metastatic disease involving a lymph node. This chronic inflammatory infiltrate is generally most prominent around the periphery of the tumor, and in some cases there is germinal center formation. The blood-filled cystic spaces for which this tumor is named are present in most but not all cases, and are lined by flattened tumor cells rather than true endothelium. The cells of angiomatoid (malignant) fibrous histiocytoma may be either distinctly histiocytoid in appearance or may be spindled and are arranged in a variety of growth patterns, including sheets, meningioma-like whorls, and short-fascicles. Although the cells of angiomatoid (malignant) fibrous histiocytoma are typically cytologically bland, occasional cases may show striking pleomorphism, which does not appear to have clinical significance. The mitotic rate is typically low. Cases without the large cystic spaces show at least some evidence of hemorrhage, such as intracellular hemosiderin or focal hemorrhage. In some cases this hemorrhage may be extensive and elicit a striking desmoplastic reaction, obscuring the underlying neoplasm. Angiomatoid (malignant) fibrous histiocytoma have a unique immunophenotype, with expression of desmin, epithelial membrane antigen and CD68 in over 60% of cases. At the genetic level, AMFH are characterized by t(2;22) (EWS-CREB1), t(12;22) (FUS-ATF1) or t(11;22) (EWS-ATF1). The t(2;22) appears to be the most common translocation. It should be noted that the first two the same t(2;22) and t(12;22) fusion is identical to that seen in clear cell sarcoma of tendons and aponeuroses, emphasizing the need to integrate molecular findings with morphology and immunohistochemistry. Epithelioid Fibrous Histiocytoma Epithelioid fibrous histiocytoma (epithelioid cell histiocytoma, EFH) frequently occurs on the lower extremities, and often shows a well-formed epithelial collarette. EFH are well-circumscribed and are principally composed of cytologically bland, polygonal to epithelioid tumor cells arranged around numerous small blood vessels (so-called "sclerosing hemangioma" pattern). Peripheral collagen trapping is usually inapparent in the most epithelioid areas, although at least focal areas resembling ordinary DF are often present. EFH may be confused with a Spitz nevus, an epithelial tumor, or a benign vascular tumor, such as a pyogenic granuloma. Recognition of a component of conventional benign fibrous histiocytoma with a storiform growth pattern and peripheral collagen trapping should allow recognition of EFH in most cases. EFH are usually positive for Factor XIIIa but negative for S-100 protein, cytokeratins and vascular markers. Atypical Fibrous Histiocytoma "Atypical fibrous histiocytoma" is defined as a lesion that shows the overall low-power cyto-architectural features of an ordinary DF or one of its recognized variants (e.g., CFH, AFH), but which has on higher power examination striking cytologic atypia, often in combination with mitotic activity. The atypical cells can be focal or comprise the majority of the tumor. Such cases have also been referred to as "dermatofibroma with monster cells" and "pseudosarcomatous dermatofibromas", among other terms. If correctly diagnosed (see below), the behavior of atypical fibrous histiocytoma is essentially identical to that of CFH and AFH, with relatively frequent local recurrences and extraordinarily rare metastases. As a result of their prominent cytologic atypia, atypical fibrous histiocytoma is often confused with atypical fibroxanthoma (AFX)/ malignant fibrous histiocytoma. Unlike AFX, which occurs in sun-damaged skin of the head and neck in elderly patients, atypical fibrous histiocytomas occur in younger patients, most frequently on the extremities or trunk. Malignant fibrous histiocytomas are larger tumors of deep soft tissue that only secondarily involve the dermis. It cannot be overemphasized that the diagnosis of "atypical fibrous histiocytoma" should be reserved for cases that have the overall low-power appearance of a DF/BFH, as well as other characteristic features such as peripheral collagen trapping. Other Fibrous Histiocytoma Variants A variety of other histologic subtypes of fibrous histiocytoma have been described. These include keloidal dermatofibroma, granular cell dermatofibroma, clear cell dermatofibroma, myxoid dermatofibroma, palisading fibrous histiocytoma, and lipidized fibrous histiocytoma. The reader is referred to the provided references for a more complete discussion of these entities. Table 1 - Cellular Fibrous Histiocytoma vs Dermatofibrosarcoma Protuberans CFH DFSP Circumscription Relatively circumscribed Infiltrative Epidermal hyperplasia Often present Absent Involvement of subcutis Limited Extensive Collagen trapping Present Absent Growth pattern Fascicular to storiform Storiform Immunophenotype Factor XIIIa -/+; CD34 - Factor XIIIa -; CD34 + Table 2 - Cellular Fibrous Histiocytoma vs. Cutaneous Leiomyosarcoma CFM LMS Epidermal hyperplasia Often present Absent Collagen trapping Present Absent Growth pattern Fascicular to storiform Fascicular with perpendicular pattern Nuclear features Oval to tapered spindled cells Blunt ended, cigar-shaped Immunophenotype Actin focally positive; desmin negative Actin and desmin positive References Calonje E, Mentzel T, Fletcher CD. Cellular benign fibrous histiocytoma. Clinicopathologic analysis of 74 cases of a distinctive variant of cutaneous fibrous histiocytoma with frequent recurrence. Am J Surg Pathol. 1994;18:668-76. 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