DFSP was considered a tumor exclusive to adult patients until 1957, when it was reported in a 5-year-old boy. Since then, more than 30 cases of congenital DFSP have been reported in addition to many more cases in children.33–35

Congenital DFSP has the same immunohistochemical characteristics and the same molecular abnormalities as conventional DFSP, although the clinical and histologic differences are usually evident. Congenital DFSP usually presents as a macule or atrophic plaque rather than as a tumor and is very often confused with vascular malformations or tumors, morphea, atrophoderma, atrophic scarring, or cutis aplasia congenita.33,35

From the histologic point of view, early-stage tumors may lack some of the characteristic findings of DFSP such as the storiform pattern or infiltration of the subcutaneous cell tissue. In these cases, diagnosis is often delayed.

In 1982, Shmookler and Enzinger36 reported a series of 20 cases of a rare fibroblastic tumor. It mainly appeared in patients aged less than 10 years and was characterized histologically by fibroblast cell proliferation along with multinucleated giant-cell proliferation in a fibromyxoid stroma. The authors named the entity giant-cell fibroblastoma. Seven years later, the same authors proposed that giant-cell fibroblastoma be considered an infantile variant of DFSP.37 The close relationship between giant-cell fibroblastoma and DFSP was shown through the presence of the same clinical, histologic, and immunohistochemical characteristics and the same molecular abnormalities.38 However, it differs from conventional DFSP in that the age of onset is more often younger than 10 years, giant multinucleated cells are present, and there is a myxoid stroma in histology.

In 1957, Bednar39 described a tumor, supposedly of neural origin, that showed a storiform pattern along with pigmented spindle cells. The author named this entity pigmented storiform neurofibroma. Subsequently, it was noted that Bednar tumor shared clinical and histologic characteristics with DFSP, and so the tumor is currently considered a pigmented variant.27 Bednar tumor accounts for 1% to 5% of cases of DFSP and appears more often in black patients, unlike conventional DFSP.27,40 Clinically, it is usually indistinguishable from conventional DFSP although it may appear pigmented if there is sufficient melanin in the tumor. Pigmentation is, however, usually a histologic finding. Indeed, histologically, the essential characteristic of Bednar tumor is the presence of a population of dendritic cells with melanin in a greater or lesser proportion. From the immunohistochemical point of view, as with conventional DFSP, the tumor is positive for CD34 and negative for S100.27,41

Cases of DFSP that recurred in the form of Bednar tumor42 and also the presence of fibrosarcomatous areas in metastatic Bednar tumor have been reported. In addition, Bednar tumor has specific chromosomal abnormalities that distinguish it from conventional DFSP.43 This all illustrates the common prognosis and nature of the 2 types of tumor.

In 1985, Lambert et al.44 reported 5 cases of DFSP with clinical characteristics resembling a plaque morphea or a morpheaform basal cell carcinoma, given that the surface appeared depressed. The term dermatofibrosarcoma nonprotruberans was proposed because, histologically, the lesions were clearly cases of DFSP. Cases similar to those of Lambert and coworkers were later published, and the term atrophic DFSP came to be used to refer to DFSP with the clinical appearance of morphea.

Clinically, the entity consists of an irregular plaque, occasionally depressed, with an atrophic appearance, sometimes with superficial telangiectasias, and a flesh, erythematous, or brownish coloration.45

Atrophic DFSP is defined histologically by a decrease of more than 50% in the thickness of the dermis compared to healthy peritumoral dermis.46 Cases of atrophic DFSP with the characteristic DFSP translocation have been reported.47

Sclerosis within the tumor is rare. When it does occur, it appears to be a spontaneous process, with no trigger or history of inflammatory processes or radiotherapy. Of the 72 cases of DFSP reported by Díaz-Cascajo et al.48 only 2 (5%) had sclerotic changes in more than 50% of the tumor mass, thereby confirming that sclerosis is uncommon in DFSP.

From the histologic point of view, in the sclerotic areas, the neoplastic cells are gradually replaced by sclerotic tissue without a notable decrease in the tumor thickness, as is the case with atrophic DFSP. The amount of collagen in these areas correlates with the loss of tumor cellularity.49 Cases have also been reported in which the sclerotic areas correspond to tumor nodules.50 The sclerotic areas are partially positive for CD34, and positivity correlates with a decrease in tumor cells, which remain embedded in the sclerotic stroma.

For Díaz-Cascajo et al,48 excessive production of collagen by tumor cells, without concurrent inflammation, and the presence of transition between typical areas of DFSP and sclerotic areas may be a sign of involution. The 3 cases described by Hattori50 correspond to long-standing DFSP, and could provide support for the theory of Díaz-Cascajo and coworkers.

The presence of areas of myoid differentiation in DFSP is a rare occurrence that was first described in 1996 by Calonje and Fletcher.51 These authors reported 5 cases of common DFSP or DFSP with a fibrosarcomatous component. Disperse bundles and nodules were present with confluent eosinophilic spindle cells, a well-defined cytoplasm, and vesicular nuclei very similar to those of smooth muscle cells or myofibroblasts. These myoid areas were negative for CD34 but did stain for actin. The areas appear both on the surface and in the deep layers of the tumor. They do not tend to be located close to the muscle, arrector pili, or vascular walls, but seem to be randomly distributed, indicating that they formed their own areas of the tumor. However, many authors think that these myoid areas do not reflect true differentiation of DFSP but rather a reactive phenomenon that presents in the form of hyperplastic stromal myofibroblasts.52,53

Regardless of the exact significance of this finding, the presence of areas of myoid differentiation in DFSP is rare and usually occurs in cases of DFSP with a fibrosarcomatous component.51

The myxoid variant of DFSP was first described in 1983 by Frierson and Cooper.54 Subsequently, several case reports have been published as well as an extensive series of 23 cases by Reimann et al.55 in 2007. All cases coincide in highlighting that myxoid DFSP is very uncommon.

From the clinical and prognostic point of view, the tumor is similar to conventional DFSP, with the exception that it appears to present more frequently on the limbs than on the trunk.55 Histologically, the tumor is composed of spindle cells or stellate cells with a palely eosinophilic cytoplasm in a lobulated arrangement. In the stroma, the abundant presence of myxoid material, which by definition has to be present in more than 50% of the tumor,55 means that the storiform pattern is less noticeable. Mitosis is limited and there is usually little pleomorphism. Characteristically, there are numerous branched vessels with thin walls. CD34+ cells can be detected in most cases. This finding and the honeycomb infiltration pattern are usually the strongest diagnostic criteria given that in most cases histologic diagnosis is complex.

In 1951, Penner reported a case of metastatic DFSP which contained areas of fibrosarcoma.56 In the following years, many cases and series of DFSP with a fibrosarcomatous component (DFSP-FS) have been published. Wang et al.57 performed a study in which they separately analyzed the DFSP area and the fibrosarcomatous area in 6 patients with DFSP-FS. They found the same molecular abnormalities in all 6 samples of DFSP and in 5 samples of fibrosarcomatous tissue, providing support for the common histogenesis of these 2 components. The presence of fibrosarcomatous areas in the DFSP is observed in 7% to 17% of cases according to the series.40,58,59 From the clinical and epidemiological point of view, DFSP-FS is no different from conventional DFSP. Histologically, there are areas indistinguishable from a fibrosarcoma within the DFSP lesion. These areas are characterized by a dense proliferation of spindle cells, arranged in long bundles that cross to form a herringbone pattern.58 The fibrosarcomatous areas can occupy from 5% to 90% of the tumor, but according to Weiss and Goldblum,5 DFSP is considered to have a fibrosarcomatous component when the occupation is at least 5% to 10% of the tumor (Fig. 3B). Immunohistochemical staining with CD34 in the fibrosarcomatous areas is usually less intense or absent compared to contiguous areas of DFSP. In contrast, it has been shown that there is overexpression of p5359 and a high mitotic index in areas of fibrosarcoma.

Vimentin is expressed in all mesenchymal cells; thus almost all sarcomas, including DFSP, are positive for this protein.60

Nestin is an intermediate filament that was first described as a marker of neuroectodermal stem cells and subsequently identified in mesenchymal stem cells in bone marrow, lung, muscle, and the pancreas.11 Recently, the usefulness of this protein has been demonstrated in DFSP, particularly to differentiate it from dermatofibroma (DF). Mori et al.,15 compared staining with nestin and other immunohistochemical markers in 16 cases of DFSP and in 30 cases of DF. Positive results were obtained for nestin in 94% of DFSP samples and in only 13% of DF samples. In other more recent studies, even more robust results were obtained, with intense staining being reported in all cases of DFSP.13,14

In normal skin, CD34 is expressed in endothelial cells, in perifollicular spindle cells, in perivascular and periadnexal spindle cells, and in interstitial dendritic cells of the reticular dermis.61,62

CD34 is considered a relatively specific marker for vascular neoplasms, but in 1992 Aiba et al.62 studied CD34 expression in a series of fibrohistiocytic tumors such as DF, DFSP, hypertrophic and keloid scarring, and found that the only tumor that expressed it was DFSP. Similar findings were later reported by Kutzner.63 In 1994, Cohen et al.64 reviewed all studies published until then (9 series involving 96 cases) and calculated that 88% of DFSP are CD34 positive. Since then, several studies have reported results of immunostaining with CD34, with positive results in 92% to 100% of cases65–67; it therefore seems to be a very useful marker for differentiating between DFSP and other fibrohistiocytic tumors, especially DF (Fig. 3C).

Even though most cases of DFSP express CD34, positive staining for CD34 has been reported in many benign and malignant tumors, such as inflammatory myofibroblastic tumor, solitary fibrous tumor, sclerotic fibroma, superficial acral fibromyxoma, Kaposi sarcoma, neurofibroma, perineurioma, and melanoma.61

Factor XIIIa is a tetrameric protein that is expressed in normal skin and in dermal dendrocytes of the papillary dermis, especially around superficial vessels.67 In 1989, Cerio et al.68 reported positive staining for factor XIIIa in 30 cases of DF, whereas in 16 cases of DFSP, staining was absent or limited, suggesting that this marker could be useful for differentiating between these 2 tumors. Most studies report positivity in between 90% and 95% of DF and, in addition, expression occurs in most cells and is very intense, unlike in DFSP, where staining is positive only in 10% to 15% of cases.64,67,69

Differential diagnosis of DFSP is often established with DF and so, CD34 (positive in most cases of DFSP and in up to 25% of DF69) and factor XIIIa (negative in most cases of DFSP and positive in almost all cases of DF) are the most widely used markers; however other markers have also been reported to be useful.

In 2004, West et al.70 studied the expression of apolipoprotein D (ApoD) in 421 soft tissue tumors and found that the tumor with most extensive expression of this marker was DFSP, unlike common DF, which were all negative. Subsequently, other studies confirmed that ApoD may be interesting for differentiating between DFSP and DF.

Another immunohistochemical marker that has been studied in DFSP is stromelysin 3. In the studies of this marker, the results show more extensive expression in DF than in DFSP, with the differences being more or less striking depending on the study.71

Most studies are in agreement that DFSP has a low proliferative index as determined both with Ki-67 and MIB-1.59,72

Immunohistochemical expression of p53 is usually negative or weakly positive in DFSP and most frequently associated with DFSP-FS.59 However, p53 may be useful for distinguishing between DFSP and DF given that this protein is not usually expressed in DF.

There are many studies in the literature of DFSP treated with conventional surgery. However, the approach to tumor excision varies greatly and so it is difficult to draw specific conclusions about the use of conventional surgery in DFSP. Table 1 shows the series of at least 10 cases of DFSP treated with conventional surgery. From 1951 to 2011, there were 38 such series, which included a total of 1782 patients.16,17,20,24,25,30,79–110 On analyzing the resection margin, most series used the term wide margin, without specifying exactly how much healthy skin was excised; moreover, in many cases, the tumors were excised several times until histologically negative margins were achieved.102,105,109 Other series used a safety margin ranging from 1 to 5cm. There is a trend towards a lower number of relapses in cases excised with larger safety margins.88,101 Many of the studies do not report whether or not underlying muscular fascia were spared during the excision of DFSP. Nevertheless, it can be calculated that DFSP recurs in up to 60% of cases of excision with wide margins, without specifying either the margin used or whether or not muscular fascia were included in the excision. Only 9 of the 38 series did not report any recurrences and in more than half of these series, recurrences were reported in more than 20% of cases.

The first author to report use the use of MMS was Dr Mohs himself in 1978.111 Since then, many individual case reports and series have reflected the usefulness of this technique in the treatment of DFSP and propose it as the treatment of choice.112 Twenty-six series with 10 cases or more of DFSP treated with MMS have been published (Table 2).29,30,78,96,105,109,113–133 The recurrence rates reported with MMS in the 27 series of DFSP range from 0% to 8.3%, that is, much lower than the rates reported with conventional surgery with wide margins. In addition, 22 of the 27 series did not report any recurrence with follow-up in excess of 2 years. In addition, MMS provides the true, narrow margin of healthy tissue in each case, unlike conventional surgery with wide margins, which may be incomplete or include a large quantity of healthy, uninvolved tissue.

The most widely used technique is the variant known as the slow Mohs procedure.125 This is performed as follows (Fig. 4A–D). First, there is a debulking or excision of the tumor or scar tissue itself in the case of recently excised tumors with involved margins. Then, the first stage of 0.5 to 1cm of clinically healthy skin is taken, using a scalpel angle of 45° and cutting down through the entire subcutaneous tissue and the most superficial layers of the muscular fascia. Before removing this first stage, the specimen is mapped with silk sutures and a photograph taken. The debulked material is processed conventionally, fixed in formol, and embedded in paraffin. Parallel cuts are then stained with hematoxylin and eosin. The first Mohs stage is pinned to a plaque of polyurethane foam to ensure that it retains its shape and to prevent retraction. The sample is sent in a recipient containing formol. The photograph of the specimen before removal from the patient is also sent to the pathologist. The pathologist first separates the lateral margins with cuts from the epidermis to the bottom of the specimen. The base is then detached with horizontal cuts. All pieces obtained are assigned a number and the whole process is reproduced from the photograph. The cuts are stained with hematoxylin and eosin and studied under the microscope, looking for evidence of DFSP. In the event that doubtful areas or those difficult to interpret are found, immunohistochemical staining of the same section is undertaken with CD34. If, after studying all the margins, no evidence of DFSP is found, the surgical defect is closed. If, however, a margin with evidence of disease is found, excision continues, with referrence to the photograph to determine exactly the involved margin. This procedure is repeated until all margins are negative. Once this has occurred, the defect is closed definitively. The advantage of the slow Mohs technique is that the cuts are of much greater quality and it is much easier to find evidence of DFSP, unlike conventional Mohs techniques which, because the specimen analyzed is frozen, provide a histologic section that is much harder to interpret. The slow Mohs technique, however, takes much longer than the conventional Mohs technique.

Figure 4.

Slow Mohs surgery for dermatofibrosarcoma protuberans. A, Debulking or narrow-margin excision of the tumor. B, First stage of the Mohs procedure. Mapped ring of clinically healthy skin. C, Surgical defect after first stage. Exposure of the muscle plane. D, Division of the specimen by the pathologist.

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Identification of unregulated expression of the PDGDB receptor as a result of translocation t(17;22) led to the hypothesis that inhibitors such as imatinib of the protein tyrosine kinase present in the receptor could be active in DFSP. Imatinib binds competitively to the PDGF receptor and blocks its tyrosine kinase activity. After encouraging results in preclinical studies, several clinical studies have reported good response to imatinib in metastatic and locally advanced DFSP.108,134–153 The agent has been used as neoadjuvant, prior to excision, with responses ranging from reductions in tumor size of 19% to complete clinical response (Table 3).108,134–153 However, the studies in which complete response have been obtained should be reviewed critically before more widespread use of imatinib in DFSP. With regard to the 4 cases with complete response published by McArther et al.,138 in addition to the short follow-up period, histologic study was only performed in 2 patients. After treatment with imatinib, the histologic findings characteristically show a tumor with low cellularity and abundant hyalinized collagen, which can be falsely interpreted as disease-free tissue.138,141 Therefore, the COL1A1-PDGFB translocation should be studied to demonstrate or rule out tumor persistence after treatment with imatinib in DFSP that has apparently regressed in conventional histology. Nevertheless, according to all studies published, imatinib appears to be beneficial as neoadjuvant treatment in cases of locally advanced disease or as palliative treatment in cases of metastatic disease.138,141

The role of radiotherapy in the management of DFSP has not been extensively studied and has generated some debate. Given that surgical treatment can guarantee cure in most cases, radiotherapy does not seem appropriate as there is insufficient experience of its use in DFSP.

Most published cases and series correspond to DFSP excised with narrow or positive margins, with the subsequent use of radiotherapy.92,154 Thus, radiotherapy is reserved for truly inoperable disease, when imatinib treatment is not possible, or as palliative treatment.