19.1 Introduction

Dermatofibrosarcoma protuberans (DFSP) is a rare but locally aggressive spindle cell neoplasm accounting for less than 2% of all soft tissue sarcomas and less than0.1%ofallmalignancies[1].Immunohistochemical and ultrastructural studies indicate that the tumor is of a fibroblastic origin [2]. This intermediate-grade cutaneous malignancy commonly occurs in the dermis and has the potential to invade through fascial planes into muscle and bone. It may occur on any part of the body with a predilection for the trunk. DFSP rarely exhibits metastases, but it has the propensity of subclinical involvement [3, 4].

Treatment generally focuses on surgical removal of the tumor to prevent local recurrence. Clinical exam alone cannot predict the extent of involvement. DFSP can be resected with either wide local excision (WLE) or Mohs micrographic surgery (MMS) [4–8]. Successful treatment outcome is dependent on achieving negative surgical margins while preventing functional deficits.

Summary: Epidemiology

•DFSP accounts for approximately 0.1% of all human cancers.

•Patients between the third and fifth decades have the highest age-specific annual incidence rates.

•Overall, African-Americans represent the highest annual incidence rate among all the races, followed by Caucasians.

19.2Epidemiology

According to the descriptive epidemiology study of cancer registries of the Surveillance, Epidemiology, and End Results (SEER) program from 1973 to 2002, the overall incidence of DFSP is 4.2 per million. DFSP accounts for approximately 0.1% of all cancers in the database. Standardized for race and gender, the data indicated that patients between the third and fifth decades have the highest age-specific annual incidence rates. Overall, African-Americans represent the highest annual incidence rate among all the races, followed by Caucasians. There is no gender predilection. However, beyond the sixth decade, men were found to have higher incidence rates than women [1].

Summary: Pathogenesis

•Dermatofibrosarcoma protuberans may be related to previous trauma, vaccination, burns, or insect bites.

•The p53 pathway and microsatellite instability causing DNA mismatch repair are implicated in tumor progression.

•Up to 95% of DFSPs are characterized by genetic abnormalities of t(17;22) causing fusion of collagen type 1 alpha 1 (COL1A1) gene on chromosome 17 with the plateletderived growth factor B (PDGFB) chain gene on chromosome 22.

•Constitutive activation of platelet-derived growth factor receptor (PDGFR) by PDGFB may lead to uninhibited growth of neoplastic cells.

19.3Pathogenesis

The exact etiology of DFSP is unknown, and its pathogenesis remains controversial. A history of previous local trauma is often elicited. There are reports of DFSP occurring in sites of previous vaccinations including immunizations for smallpox, yellow fever, tetanus, and tuberculosis [9, 10]. DFSP has been reported to arise in burn scar in two patients and from an infected insect bite in one case report [11–13]. The development of malignancy has been attributed to the persistent inflammation and/or wound healing associated with vaccine components, constant irritation, chronic ulceration, the release of local toxins following injury, poor lymphatic regeneration, repeated trauma, or exposure to noxious environmental agents [14, 15]. In addition, accelerated growth of DFSP has been reported during pregnancy. DFSPs appear to express low levels of hormone receptors, which may be one factor that accounts for their accelerated growth during pregnancy [16, 17].

Molecular studies of pathogenesis of DFSP are limited. It is hypothesized that the p53 pathway may be involved in DFSP tumorigenesis, and more specifically, in the fibrosarcomatous areas of DFSP. Point and missense mutations of p53 gene were found in metastatic DFSPs but not in non-fibrosarcomatous variants of DFSPs [18, 19]. In addition, microsatellite analyses of DFSPs have revealed defective DNA mismatch

repair in tumor replication via microsatellite polymorphisms. This microsatellite instability has been implicated in tumor progression of DFSP in both nonfibrosarcomatous and fibrosarcomatous variants [20].

Cytogenetic analyses have demonstrated that up to 95% of DFSPs are characterized by anomalies of chromosomes 17 and 22 consisting of a supernumerary ring chromosome deriving from t(17;22) or a reciprocal translocation t(17;22)(q22;q13) [21, 22]. The frequency of each of these cytogenetic abnormalities is unknown [22, 23]. These cytogenetic abnormalities fuse collagen type 1 alpha 1 (COL1A1) gene on chromosome 17 with the platelet-derived growth factor B (PDGFB) chain gene on chromosome 22 (Fig. 19.1).

COL1A1 PDGFB

PDGFR

ATP ATP

Fig. 19.1 Dermatofibrosarcoma protuberans, cytogenetics. Collagen type 1 alpha 1 (COL1A1) gene on chromosome 17 fuses with the platelet-derived growth factor B (PDGFB) chain gene on chromosome 22. The resultant COL1A1-PFGFB fusion protein undergoes posttranslational processing to form functional PDGFB, the ligand for the cell surface receptor, tyrosine kinase platelet-derived growth factor receptor (PDGFR). COL1A1 collagen type 1 alpha 1 gene, PDGFB platelet-derived growth factor B, PDGFR kinase platelet-derived growth factor receptor

Fig. 19.2 Dermatofibrosarcoma protuberans, fluorescence in situ hybridization. Multiple signals in the spindle cells of a DFSP specimen indicating fusion between chromosomes 17 and 22 (magniÞcation ×1000) (Reprinted from Najarian et al. [28], copyright 2010, with permission from John Wiley & Sons Ltd)

The reported breakpoint of PDGFB is constant at exon 2, whereas the breakpoint in COL1A1 is variable and may occur on exons 6–49 [23]. The resultant COL1A1- PFGFB fusion protein undergoes posttranslational processing to form functional PDGFB, the ligand for the cell surface receptor, tyrosine kinase plateletderived growth factor receptor (PDGFR). It is thought that deregulated expression of PDGFB, with concomitant autocrine stimulation of PDGFR, could be a critical molecular event in the pathogenesis of DFSP [24–26]. Constitutive activation of PDGFR may cause uninhibited growth of connective tissue cells and tumor proliferation [27].

These molecular changes in DFSP can be detected cytogenetically by polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH) techniques (Fig. 19.2) [28]. The combination of FISH and comparative genomic hybridization (CGH) techniques has been valuable in identifying the composition of the DFSP ring chromosomes [22, 29, 30]. Reverse transcription–polymerase chain reaction (RT-PCR) assays can be used to detect the COL1A1-PDGFB fusion transcripts in DFSP specimens either frozen or paraffin-embedded [31]. Takahira et al. have amplified and quantified PDGFB gene copies and PDGFB/ PDGFRB mRNA levels by a real-time PCR system for DFSP samples in which the fusion transcripts had been successfully detected. The authors found no correlation between the PDGFRB expression level and histologic subtype of DFSP [32]. Quantification of PDGF-B RNA by real-time polymerase chain reaction (RT-PCR) has shown higher expression of PDGF-B gene in DFSP than standard PCR, yielding less false-negative results in distinguishing DFSP from its benign counterpart, dermatofibroma [33].

Fig. 19.3 Dermatofibrosarcoma protuberans. (a) A multinodular plaque on groin/medial thigh area. (b) Erythematous, pigmented scar-like plaque arising in area of previous DFSP

excision. (c) Erythematous-brown atrophic plaque and nodule on back. (d) Telangiectatic and flesh-colored tumor mass on the scalp (Photo courtesy of Dr. Mark DeLacure)

Summary: Clinical Features

•Dermatofibrosarcoma protuberans typically presents as a ßesh-colored, blue-red plaque, nodule, or subcutaneous mass.

•Itmostcommonlyoccursonthetrunkandextremities followed by the head and neck region.

•Tumor invasion into underlying fascia, muscle, and bone can be observed.

•Pediatric DFSP accounts for 6% of all DFSP cases.

19.4Clinical Features

DFSP initially manifests itself as an asymptomatic flesh-colored, blue-red to hyperpigmented patch, patch, plaque, nodule, or subcutaneous mass (Fig. 19.3). Although DFSP may occur anywhere on the body, the most common location is the trunk (up to 72%), followed by the extremities (up to 30%). Head and neck involvement ranges from 5% to 15% [1, 34]. DFSP may not always present as the prototypical protuberant mass. Some cases exhibit overlying telangiectasias,

suggesting vascular lesions. Others have demonstrated atrophy in the form of atrophoderma or morphea [35, 36]. A less commonly described clinical variant is the multiple clustered dermatofibroma (MCDF) which should be distinguished from multiple eruptive dermatofibromas (MEDF). MCDF portends a benign course, whereas MEDF is associated with immunosuppression [37]. Exhibiting indolent behavior, DFSP may remain quiescent over an extended interval of months to years before becoming symptomatic [38]. By gradually infiltrating adjacent tissue, it can become multifocal, large, painful, and ulcerative. Tumor invasion and fixation to underlying fascia, muscle, and bone can be observed late in the course of disease [39, 40].

Pediatric DFSP, although rare, accounts for 6% of all DFSP cases in children younger than 16 years of age. Congenital DFSP is even rarer with approximately 61 cases reported in literature. Variable clinical presentations as flesh-colored, blue, or red nodules/plaques often lead to misdiagnoses as vascular malformations, nevi, or fibromatoses [35, 41]. There is a 5-year average delay between initial presentation and the final diagnosis. The frequency of pediatric DFSP cases may be underestimated due to subtle clinical findings. Some cases diagnosed during adulthood may have represented congenital or childhood DFSP [35, 42]. Giant cell fibroblastoma (GCF), a benign neoplasm rarely encountered in children, must be distinguished from DFSP [43, 44].

Summary: Pathology

•Dermatofibrosarcoma protuberans consists of cytologically bland spindle cells in a whorled or storiform pattern infiltrating into subcutaneous tissue.

•It stains positively for CD34 and nestin and negatively for factor XIIIa.

•The fibrosarcomatous variant is characterized by a herringbone pattern of hypercellular spindle cell proliferation and is associated with high a risk of metastasis.

19.5Pathology

Histologically, DFSP appears as a well-differentiated tumor with fascicular proliferation of cytologically bland spindle cells in a whorled or storiform pattern

(Fig. 19.4a). Patch lesions may demonstrate tumor-free epidermis, while nodular lesions have cells infiltrating deep into subcutaneous tissue, described as honeycomb architecture (Fig. 19.4b). Long-standing DFSP invades the neighboring dermis, subcutis and underlying fascia by pseudopod-like, irregular projections of monomorphous cells with low mitotic activity. These infiltrative and asymmetric characteristics on light microscopy make the tumor border ambiguous and partly account for the high rate of recurrences [4, 45]. The spindle cell proliferation of DFSP can be confused with other fibrohistiocytic neoplasms including, but not limited to, dermatofibroma, dermatomyofibroma, fibrosarcoma, and atypical fibroxanthoma [36].

Immunohistochemical studies can facilitate the diagnosis of DFSP, and more importantly to distinguish it from dermatofibroma (DF), the benign counterpart. DFSP typically stains positively for CD34 and negatively for factor XIIIa, whereas DF stains negatively for CD34 and positively for Factor XIIIa (Fig. 19.5). However, the diagnostic value is not absolute since 20% of DFSPs will stain negatively for CD34 and 20% will stain positively for Factor XIIIa [2, 46]. In addition, CD163, a hemoglobin scavenger receptor, is expressed by DF in 83–89% of cases and may differentiate cellular DF from DFSP [2, 47]. Nestin, a neuroepithelial stem cell marker, preferentially labels DFSP in contrast with DF, with the exception of intralesional blood vessels. Several authors have concluded that CD34, Factor XIIIa, CD163, and nestin can aid in histopathological differential diagnosis of the two disorders [48, 49].

Several histopathologic variants have been described including pigmented DFSP or Bednar tumor, myxoid DFSP, fibrosarcomatous DFSP (FS-DFSP), granular cell DFSP, DFSP/FS-DFSP with foci of myoid/myofibroblastic differentiation, DFSP with areas of giant cell fibroblastoma, palisading, and Verocay body prominent DFSP [50]. A rare variant of DFSP, Bednar tumor constitutes less than 5% of all cases of DFSP. Variable number of melanosome-containing dendritic cells are found in classic DFSP, which accounts for the black discoloration of the tumor on light microscopy [51, 52].

The fibrosarcomatous (FS) variant, a rare phenomenon, deserves special mention since it has a high rate of metastasis. FS change is characterized by a hypercellular spindle cell proliferation with a herringbone or fascicular architecture (Fig. 19.6). FS areas resembling pleomorphic sarcoma have also been identified [53, 54]. Unlike classic DFSP, FS-DFSP loses CD34

positivity and possesses a high MIB-1 labeling index, a feature that may be used an adjunctive tool to identify fibrosarcomatous areas in DFSP [55, 56]. The true incidence of FS change in DFSP is unknown but has been estimated to be 7–27%. There is no consensus on the risk of recurrence incurred by the FS variant. However, the local metastasis rate of FS-DFSP in the

literature is between 10% and 15% with lung being the most common site of metastases [54, 55, 57]. Abbott et al. report that metastases occurred in patients with less than 15% FS change in DFSP. They emphasize the importance of addressing even focal FS changes in DFSP with long-term clinical follow-up of the patient [55].