—  SHORT COURSE #46  —

Cutaneous Mesenchymal Tumors and Non-Mesenchymal Mimics:
An Update and Approach to Diagnosis

Case 5 - Dermatofibrosarcoma Protuberans with Fibrosarcomatous Change

Steven D. Billings, M.D.
Andrew L. Folpe, M.D.


Clinical History
A 32 year-old man presented with a firm nodule on the trunk. An excisional biopsy was obtained.

Morphology
The biopsy showed relatively normal epidermis overlying a circumscribed, moderate to markedly cellular dermal and subcutaneous tumor. The majority of the tumor had a distinctly fascicular growth pattern that in areas had a herringbone pattern. In this area the tumor showed increased cellularity, cytologic atypism, and numerous mitotic figures. At the periphery, the tumor had a more storiform pattern, was less cellular, and was composed of uniform, slender spindled tumor cells. Entrapment of individual fat cells was seen in the storiform area.

Diagnosis: Dermatofibrosarcoma protuberans with fibrosarcomatous change

Discussion

Clinical and Histopathological Features
Dermatofibrosarcoma protuberans (DFSP) most commonly presents in early to mid adult life. However, a wide age range may be affected, and cases in children and even infants are well documented. Typically DFSP arises in the trunk or proximal extremities. The initial presentation is as a plaque that may subsequently develop into a nodular or multinodular mass. The plaque stage may clinically cause confusion with sclerosing dermatoses such as morphea or scleroderma.

In its classic form, DFSP is a relatively stereotypical lesion, consisting of an exquisitely storiform proliferation of monotonous, slender spindled cells with dark nuclei and lightly staining cytoplasm, typically showing diffuse infiltration of the subcutaneous adipose tissue ("honeycomb pattern"). DFSP usually displays little heterogeneity within a given lesion, lacking the admixed cell populations of siderophages and foamy macrophages seen in its principal morphologic mimic, dermatofibroma/ benign fibrous histiocytoma. However, small subsets of DFSP may deviate morphologically from this classic appearance, and may show such features as GCFB-like areas, fibrosarcomatous change, myxoid change and myoid nodule formation. Prominent myxoid change may cause significant diagnostic difficulty, inasmuch as the accumulation of ground substance can efface the characteristic storiform pattern, cause the tumor cells to take on a more stellate appearance, and accentuate the usually inapparent, but surprising complex, underlying capillary vasculature, reminiscent of that seen in myxoid liposarcoma. Myoid nodules are characterized by a smooth muscle or myofibroblastic proliferation surrounding vessels within the tumor. This appears to be a reactive process.

The Bednar tumor, or pigmented DFSP is now recognized as a morphologic variant of DFSP. Pigmented DFSP closely resembles ordinary DFSP, but is remarkable for the presence of pigmented dendritic cells present in varying amounts within the tumor. Ultrastructurally, these dendritic cells contain mature melanosomes. The origin of the pigmented cells remains controversial. Whereas some have proposed that these tumors are colonized by melanin containing cell, others suggest that the tumor synthesizes melanosomes. Regardless of the origin of these melanosomes, pigmented DFSP is clearly closely related to DFSP, as evidenced by their similar clinical presentations, the presence of areas identical to ordinary DFSP within pigmented DFSP, the occurrence of lesions with composite features of pigmented DFSP and GCFB, and the presence in pigmented DFSP of the same genetic alterations as in ordinary DFSP.

A more controversial histologic finding is the presence of sarcomatous change in DFSP. Although these areas may resemble malignant fibrous histiocytoma or myxofibrosarcoma, they most commonly resemble ordinary fibrosarcoma. Such fibrosarcomatous areas have a fascicular herringbone pattern, and have more prominent nuclear atypia and a higher mitotic rate compared with conventional DFSP. Fibrosarcomatous transformation in DFSP appears to be related to mutations in the p53 pathway. Some authors have suggested that DFSP-FS may have a higher rate of local recurrence and distant metastasis. The true impact of fibrosarcomatous change on the biologic behavior of DFSP remains uncertain. Although fibrosarcomatous change may signify a potentially more aggressive course, patients treated with an adequately wide excision appear to have clinical outcomes similar or identical to those with conventional DFSP.

There have been recent advances in the therapy of DFSP, which traditionally has a local recurrence rate as high as 20% even with wide excision (3 cm margins). Mohs micrographic surgery appears to offer a better approach with local recurrence rates between 2-7%. Dermatofibrosarcoma protuberans may grow in a very asymmetric fashion and the Mohs technique can compensate for this phenomenon allowing complete excision where a traditional wide local excision would leave residual tumor.

Genetics
In 1990 the presence of a supernumerary ring chromosome in DFSP was first reported. Subsequently it was discovered that the this giant chromosome contained an occult translocation, t (17;22), resulting in a gene fusion whereby the platelet derived growth factor β (PDGFβ) gene is placed under the control of the collagen type 1 α1 (COL1A1) gene promoter. It has been proposed that this fusion gene product promotes autocrine stimulation of tumor growth in DFSP. It is now clear that almost all DFSP contain this specific cytogenetic abnormality. As is discussed below, an identical translocation has been identified in GCFB. Knowledge of the cytogenetic abnormality of DFSP has lead to potential chemotherapeutic treatment. Imatinib mesylate (STI-571) selectively inhibits specific tyrosine kinases including platelet-derived growth factor- β, and there is both in vitro and clinical evidence to support a role for this drug in the treatment of DFSP in selected cases.

Differential Diagnosis
The differential diagnosis of DFSP primarily centers on dermatofibroma (DF). In many respects, this differential diagnosis is less problematic than is traditionally thought provided an adequate biopsy. Often times these lesions can be differentiated at scanning magnification. DFSP has a very infiltrative pattern of growth that often permeates the subcutaneous fat while DF is a relatively circumscribed tumor that rarely and only superficially involves the subcutis. Another scanning magnification feature is the presence of hyperplasia and hyperpigmentation of the epidermis often seen overlying DF; this epidermal change is much less often seen in DFSP. In DF the tumor cells are arranged in haphazardly arranged short fascicles with a more heterogeneous population of cells that varies from plump spindle cells to histiocytic cells and often with secondary changes including siderophages and inflammatory cells. This is in contrast to the more uniform DFSP.

In superficial biopsies, it may still be difficult to distinguish DFSP from DF. In such cases, immunostains for CD34 and Factor XIIIa may be helpful. When interpreting CD34 and Factor XIIIa immunostains in this differential diagnosis, it is important to remember that both markers may be present in both DFSP and DF. However, DFSP and DF have different patterns of expression of CD34 and Factor XIIIa. DFSP shows uniform, strong expression of CD34 in essentially all of the lesional cells, occasionally with a reactive cuff of Factor XIIIa-positive cells, whereas DF typically shows a more mixed population of CD34 and Factor XIIIa-positive cells, admixed with S100 protein-positive Langerhans cells and CD68-positive histiocytes. Pigmented DFSP may on occasion be confused with a true melanocytic tumor, such as cellular blue nevus or melanoma. Unlike true melanocytic tumors, pigmented DFSP express CD34 and are negative for S100 protein and melanocytic markers (e.g., HMB45, Melan A). Apolipoprotein D (ApoD) has been relatively recently proposed as another useful positive marker of DFSP, in a single study. It is unclear what advantages, if any, this marker has over CD34, and caution is merited in its potential use in this differential diagnosis.

Giant Cell Fibroblastoma
It is now clear that GCFB (GCFB) is the juvenile form of DFSP. This was first proposed by Shmookler et al in 1989, who detailed cases of GCFB with both histologic and clinical overlap with DFSP. This relationship has been further supported by the description of tumors with composite features of DFSP and GCFB, by their identical immunophenotype, and by cases of GCFB that have recurred as DFSP and vice versa. Giant cell fibroblastoma also harbors the same cytogenetic abnormality as DFSP.

Clinical and Histopathological Features
GCFB usually occurs in a much younger patient population than does DFSP, with the majority of patients in the first decade of life. Cases in adults are uncommon, although it should be noted that GCFB may rarely be seen in older adults and that DFSP may occur in infants. Like DFSP, GCFB typically presents as dermal or subcutaneous mass, which most frequently involves the trunk, thigh or inguinal region. The clinical behavior of GCFB is essentially the same as DFSP, with frequent local recurrences, but only extremely rare metastases. Fibrosarcomatous change is, however, extraordinarily rare in classic GCFB. Histologically, GCFB shows varying cellularity and is composed of spindled to stellate cells with mild to moderate nuclear pleomorphism loosely arranged in an abundant myxoid to hyalinized stroma. Typically these spindled cells infiltrate around adnexal structures and though fat in an identical fashion to DFSP. Most characteristically, this stroma displays prominent cracking artifact, with the formation of pseudovascular spaces lined by a discontinuous layer of enlarged, multinucleated tumor giant cells. The presence of such cells may result in an incorrect diagnosis of a pleomorphic sarcoma, if one is unaware of the appearance of GCFB.

Differential Diagnosis
The differential diagnosis of GCFB usually centers on sarcomas such as myxofibrosarcoma (myxoid malignant fibrous histiocytoma). Unlike GCFB, myxofibrosarcoma typically presents as a more deeply seated mass in older adults, and is histologically characterized by multinodular growth, arborizing thick-walled blood vessels, and solid nodules of pleomorphic, mitotically active cells. Although an atypical DF (dermatofibroma with monster cells) might also be considered in the differential diagnosis of GCFB, the absence of the distinctive myxohyaline matrix with cracking artifact should allow this distinction without undue trouble. Probably the most difficult entity to distinguish from GCFB is the fibrous hamartoma of infancy, a tumor that occurs in a very similar age group, may contain both infiltrative monomorphic spindled cells as well as myxohyaline matrix, and may be CD34-positive. Unlike GCFB, however, fibrous hamartoma of infancy is does not contain multinucleated giant cells, and is a triphasic tumor, with nodules of primitive mesenchymal cells, fascicles of mature-appearing fibroblastic cells, and fat.

Selected references
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