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Seminars in Diagnostic Pathology (2013) 30, 13-28

Dermatofibrosarcoma protuberans: a comprehensivereview and update on diagnosis and management

Beatriz Llombart, MD,a Carlos Serra-Guillén, MD,a Carlos Monteagudo, MD, PhD,b

José Antonio López Guerrero, PhD,c and Onofre Sanmartín, MDa

From the aDermatology Department, Instituto Valenciano de Oncología, Valencia, Spain;bPathology Department. Hospital Clínico Universitario de Valencia, Universidad de Valencia, Valencia, Spain; and the

cLaboratory of Molecular Biology, Instituto Valenciano de Oncología, Valencia, Spain.

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial tumor characterized by high rates of localrecurrence and low risk of metastasis. DFSP occurs most commonly on the trunk and proximalextremities, affects all races, and often develops between the second and fifth decade of life. The tumorgrows slowly, typically over years. Histologically, several variants of DFSP have been described andshould be well characterized to avoid misdiagnosis with other tumors. These include pigmented(Bednar tumor), myxoid, myoid, granular cell, sclerotic, atrophic DFSP, giant cell fibroblastoma, andDFSP with fibrosarcomatous areas. Of all these variants, only the DFSP with fibrosarcomatous areas ishigh grade, with a higher rate of local recurrence and distant metastasis. DFSP is geneticallycharacterized by the t(17;22)(q22;q13), resulting in the fusion of alpha chain type 1 of collagen geneand platelet-derived growth factor beta gene. This translocation is present in 90% of DFSP andrepresents a very useful tool in the differential diagnosis of DFSP with other tumors with similarhistology. The standard treatment is wide local excision with at least a 2-cm margin. However, localrecurrence after apparently adequate surgical excision is well recognized. Mohs micrographic surgerywould be the treatment of choice with a better cure rate and maximal conservation of tissue. Whensurgery is insufficient, clinical evidence has suggested that imatinib mesylate is a safe and effectivetreatment in DFSP, especially in cases of local advanced or metastatic disease. This article presents anoverview of the state of the art in the clinicopathological management of this disease.© 2013 Elsevier Inc. All rights reserved.

KEYWORDSDermatofibrosarcomaprotuberans;Fibrosarcomatous;Imatinib;Mohs micrographicsurgery;Review;Genetic

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Dermatofibrosarcoma protuberans (DFSP) is a relativelyunusual, locally aggressive cutaneous tumor, characterizedby high rates of local recurrence, but low risk of metasta-sis.1,2 The first descriptions of this entity were made inde-endently in 1890 by Sherwell3 and Taylor.4 In 1924, Dariernd Ferrand5 designated this tumor as a progressive and

recurrent dermatofibroma. One year later, based on the

Address reprint requests and correspondence: Beatriz Llombart,MD, Departamento de dermatología, Instituto Valenciano de Oncología,C/Profesor Beltrán Báguena N°8, 46009 Valencia, Spain.

E-mail address: beatriz.llombart@uv.es.

0740-2570/$ -see front matter © 2013 Elsevier Inc. All rights reserved.doi:10.1053/j.semdp.2012.01.002

tendency of the tumor to develop protruding nodules, Hoff-man6 coined the term DFSP. Most early reports of DFSPescribed the clinical characteristics and the tendency forecurrence after surgical excision.

In 1962, Taylor and Helwig,7 in a review of 115 cases,described the histologic characteristics of the neoplasia indetail and characterized a fibroblastic growth appearing as alow-grade sarcoma in which the tumor cells were organizedin fascicles with a spiral or cartwheel arrangement. Gener-ally, the neoplastic cells show little or no pleomorphism,and the mitotic rate is low. Histologically, several variants

have been described that include pigmented (Bednar tu-

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14 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

mor), myxoid, granular cell, atrophic DFSP, DFSP withfibrosarcomatous areas (DFSP-FS), DFSP with areas ofgiant cell fibroblastoma (GCF), DFSP/DFSP-FS with fociof myoid/myofibroblastic differentiation, and sclerosing/sclerotic DFSP.

In 1993, immunoreactivity for CD34 in DFSP was de-scribed for the first time,8-10 and continues to be the mainmmunohistochemical marker for diagnosis of the DFSP,articularly when associated with the absence of immuno-taining for factor XIIIa. Nevertheless, 10% of DFSP areegative for CD34, and 25% of DFSP can be positive foractor XIIIa.11,12

Cytogenetic analysis of DFSP dates back to 1990, withinitial descriptions showing the presence of a recurrentt(17;22)(q22;q13) translocation or of supernumerary ringchromosomes containing material from chromosomal re-gions 17q22 and 22q13 accompanied by simple chromo-some trisomies.13,14 The combination of fluorescent in situybridization (FISH), comparative genomic hybridization,nd molecular techniques has been valuable in further de-iphering the composition of the DFSP chromosomal rear-angements, showing that these result in the fusion of thelpha chain type 1 of collagen (COL1A1) gene with thelatelet-derived growth factor beta (PDGFB) gene, the tran-criptional upregulation of the PDGFB gene being the resultf this fusion gene.15-18

In recent years, a number of advances have been maderegarding the immunohistochemical, chromosomal, andmolecular features of this tumor. Furthermore, innovativesurgical approaches and emerging targeted pharmacologictreatments have piqued new research and clinical interest inDFSP. This article presents a review and update on theepidemiology, histology, immunohistochemistry, cytoge-netics, and management of this tumor. Special emphasiswill be placed on describing the histology, molecular biol-ogy, and the treatment options through Mohs micrographicsurgery (MMS) and the use of PDGF receptor inhibitors.

Epidemiology

DFSP is a rare tumor that constitutes �0.1% of all malig-nancies and 1% of all soft-tissue sarcomas.1,19 Its incidencein the United States has been calculated to be between 0.8and 4.5 cases per million individuals per year.20,21 Never-theless, DFSP is the most common sarcoma of cutaneousorigin.2

DFSP most commonly occurs between 20 and 50 yearsof age, although its can appear at any age. The age spectrumvaries from congenital cases to patients �90 years. Al-though the proportion of pediatric cases in published seriesof DFSP ranges between 6% and 20%,7,22 DFSP is anasymptomatic tumor with a slow growth, and we believe, asother authors,22-25 that many cases diagnosed in adultsbegin during childhood. In addition, it should be taken intoaccount that GCF is currently considered to be the juvenile

form of DFSP.

Although DFSP has been described in all races, it isdifficult to draw specific conclusions regarding the racialincidence of DFSP because race is not mentioned in manyof the larger series of patients. In a recent epidemiologicstudy of 2885 cases,21 the incidence of DFSP in blackindividuals was observed to be approximately twice that ofwhites.

The literature reveals an equal sex distribution, with aslight male predominance in some series21,26,27 and slightfemale predominance in others.21,28,29

DFSP is preferentially located on the trunk. In 40%-50%of cases, the tumor is located in this area, generally on thechest and shoulders; in 30%-40% of cases, the tumor islocated in the proximal portion of the limbs (more often onthe arms than the legs); and in 10%-15% of cases, DFSPaffects the head and neck, generally the scalp, cheek, andsupraclavicular area.1,2 It has been reported that childhood

FSP has a greater tendency toward acral location. Rabi-owitz et al30 reviewed 27 cases of childhood DFSP andound that 14.8% were located on the hands or feet. How-ver, in our review of the 150 pediatric cases of DFSPublished till 2006,23 acral location was reported in �9% ofases. In our experience, acral DFSP is infrequent. Weelieve that some CD34 positive acral lesions described inhe literature as DFSP were in fact other fibroblastic-likeesions, for example, superficial acral fibromyxoma.

A history of trauma as a possible etiologic factor inFSP has been debated. Such events might favor the de-elopment of the tumor, as a history of trauma is reported in0%-20% of cases.2, 7 Likewise, cases of DFSP have beenescribed in which tumors are located on the sites of sur-ical scars,31 burns,32 radiodermatitis,33 vaccination scars,34

and sites of central venous lines.35

Clinical features

The appearance of the tumor depends on the stage of dis-ease, as the tumor progresses slowly over a long periodbefore entering a rapid growth phase.36 DFSP initially ap-pears as an asymptomatic, indurate plaque that may have aviolaceous, red-blue, or brown appearance, with a hardconsistency and fixed to the skin but not the deep layers(Figure 1A).1,7 Over a period, which can vary from a few

onths to decades, the DFSP grows with the developmentf multiple nodules within the plaque, from which its namerotuberans is derived (Figure 1B and C). Less commonly,FSP presents initially as a unique firm cutaneous nodule

Figure 1D). In the initial stages of DFSP (Figure 1A),iagnostic errors are common, with the lesion being inter-reted as a scar, morphea,37 morpheaform basal cell carci-

noma, atrophoderma, or vascular malformations.24 Whenthe tumor progresses (Figure 1B and C) or starts as aprotruding mass (Figure 1D), DFSP may be confused withanother tumor type; however, in our experience, the morefrequent mistaken diagnoses are sebaceous cyst, lipoma, or

dermatofibroma.

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15Llombart et al Dermatofibrosarcoma Protuberans

DFSP typically ranges in size from 2 to 5 cm, althoughon some occasions, and if not remedied earlier, these lesionsmay grow as large as 20 cm in diameter (Figure 2) and havemultiple satellite nodules. The tumor is usually fixed tooverlying skin, but not to deeper structures. However, re-current or long-standing tumors may invade fascia, striatedmuscle, periosteum, and bone (Figure 2).38-40

Figure 1 Clinical appearance. (A) Dermatofibrosarcoma protunodules within plaque of DFSP in the supraclavicular area. (C)scalp.

Figure 2 Giant recurrent dermatofibrosarcoma protuberans(DFSP) on the upper back. The histology of this case contained

areas of fibrosarcomatous transformation.

Histology

DFSP appears as a poorly circumscribed tumor that infil-trates the whole dermis destroying the preexisting structuresand spreading into the cellular subcutaneous tissue (Figure3A–D). The tumor is composed predominantly of a dense,uniform array of cells with spindle-shaped nuclei embeddedin varying amounts of collagen. This fibroblast-like prolif-eration is typically arranged into irregular, interwoven fas-cicles, resulting in a storiform pattern, as is seen in manyother fibrous proliferations. In some areas, the tumor cellsappear to be arranged radially about a central “hub,” pro-ducing a pattern resembling the spokes of a wheel or whirl-igig (Figure 3D). This pattern is most readily observed inthe more cellular areas and was reported in 1962 by Taylorand Helwig7 as being of great diagnostic value. Tumor cellsave large nuclei with low pleomorphism, and mitotic fig-res are infrequent, even in cellular areas. Inflammatorynfiltrates, hemosiderin deposits, multinucleated giant cells,nd foamy histiocytes are uncommon.41 DFSP may contain

small amounts of stromal mucin, which is often seen justbelow the epidermis.1 Cystic changes, dilated vascularpaces, and hemorrhage are sometimes present, but necrosisnd lymphovascular invasion are rare.7 The epidermis over

the tumors is usually thin, with flattened rete ridges. Lessoften, there is a slight-to-moderate acanthosis, although notto the extent that can be seen in dermatofibromas.7

The main histologic characteristic of DFSP is its capacity

(DFSP) as an asymptomatic, indurated plaque. (B) Protuberantnodular DFSP in the back. (D) DFSP as a unique nodule in the

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16 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

from the central focus of the tumor. The cellularity is greaterin the central zone than in the peripheral part of the tumor,where the edges invade the surrounding dermis and subcu-tis. The tumor cells invade the subcutaneous tissue in theform of tentacle-like projections through the septa and fatlobules. These tumor extensions contain few cells and, atfirst sight, can appear similar to normal fibrous tracts. Thismakes it difficult to determine the true extent of the lesionand may be why recurrences appear after excision withapparently wide margins. DFSP invades the fat with aparticular “honeycomb” pattern (Figure 3D) or, more fre-quently, with a multilayered pattern or “sandwich” involv-ing spindle cell layers oriented parallel to the skin sur-face.42,43 Involvement of the fascia, underlying muscles,periosteum, and bone is a late event.

Histologic subtypes

Pigmented DFSP (Bednar tumor)In 1957, Bednar44 originally described a specific tumor

hat showed a characteristic storiform pattern in the dermisnder the name “storiform neurofibroma.” He also dividedhis neoplasm into pigmented and nonpigmented types, ac-ording to the presence of melanin-containing cells. Later,mmunohistochemical studies performed in the cases, origi-ally reported by Bednar, observed that the tumor cells ex-

Figure 3 Histologic appearance of classic dermatofibrosarcomreplacing the dermis (H&E stain, 4�). (B) Dermal locationatrophic epidermis (H&E stain, 40�). (C) Deep aspect of that surrounded by infiltrating tumor cells (H&E stain, 40�H&E stain, 100�).

ressed CD34, but not protein S-100, rejecting their Schwan-

ian origin, and concluded that this neoplasm should beegarded as pigmented DFSP or Bednar tumor.45,46

Pigmented DFSP occurs predominantly in black personsand accounts for approximately only 1%-5% of all cases ofDFSP.45,47 Histologically, however, this unusual tumor isharacterized by spindle cells arranged in a storiform pat-ern admixed with a variable population of melanin-bearingendritic cells (Figure 4A and B). The presence of largeumbers of melanin-containing cells may cause some tu-ors to appear clinically blue or black. In other lesions,elanin is so scant that it can only be appreciated micro-

copically.1

The biological behavior of Bednar tumor is compara-ble with cases of conventional DFSP with very unusualmetastases.48 The fact that conventional DFSP may recurs pigmented DFSP,49 as well as the description of hybrid

pigmented DFSP with either fibroblastoma of giantcells50 or with fibrosarcoma,48,51,52 support the idea thatall these subtypes are different morphologic expressionsof the same neoplasm.

The histogenesis of Bednar tumor remains controver-sial. The presence of dendritic melanocytes and cellssuggestive of Schwannian differentiation has led someauthors to regard these tumors as being of neuroectoder-mal origin.46,53 Others have found no solid evidence ofneuroectodermal differentiation because the pigment

uberans. (A) Low-power view of tumor cells almost completelymatofibrosarcoma protuberans with uninvolved zone beneathor exhibits a honeycomb pattern of entrapped subcutaneous) Interwoven fascicles of cells forming storiform pattern

a protof dere tum). (D

cells are S-100 protein negative, and postulated that

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17Llombart et al Dermatofibrosarcoma Protuberans

pigmentation may simply reflect secondary melanocytecolonization from the epidermis and not constitute a realtumor component.47,54

GCFShmookler and Enzinger55 presented the original series of

CF as an abstract at the International Academy of Pathologyn Boston in 1982. In this study of 20 cases, 85% were �10ears old. The tumor was moderately cellular, involved theermis and subcutis, and consisted of ovoid fibroblastic cells,ultinucleated giant cells, and pseudovascular spaces. In 1989,

he same authors published a study of 28 cases including theriginal cases.56 The authors suggested a relationship betweenhis childhood tumor and DFSP because they observed cases ofFSP with GCF-likes areas (Hybrid cases) and proposed GCF

s the juvenile variant of DFSP.Histologically, GCF may demonstrate a unique combina-

ion of spindle cell patterns (including the storiform pattern),yxoid areas, pleomorphic and multinucleated giant cells,

istinctive sinusoid-like spaces, and tentacular infiltration ofdjacent subcutaneous tissue (Figure 4C and D).57 The sinu-

soidal spaces of vascular appearance do not constitute authen-tic vascular structures, as these sinusoidal spaces are not cov-ered by endothelial cells but by the neoplastic cells.55,56,58

Ultrastructural studies have demonstrated that the apparentmultinucleated giant cells under light microscope are reallycells with a polysegmented unique nucleus.59,60

The relationship between GCF and DFSP has been sus-

Figure 4 (A) The Bednar tumor is a pigmented variant of DFmelanin-bearing dendritic cells (H&E stain, 40�). (B) This view100�). (C) Giant cell fibroblastoma (GCF) is often myxoid and putissue spaces lined by multinucleated giant cells (H&E stain, 100

pected since the description of numerous cases of hybrid le-

sions,61,62 recurrent cases of GCF as DFSP,56,63 and viceersa,64 as well as recurrent GCF as Bednar tumor.65 Addi-

tional support for this relationship includes the same clinicalappearance, immunohistochemical and molecular features.57

Atrophic DFSPAtrophic DFSP is a depressed plaque, of soft or hard

consistency, which can be clinically confused with mor-phea, anetoderma, morpheaform basal cell carcinoma, andscar.22 The thickness of the dermis is reduced by �50% inomparison with the surrounding dermis, placing the sub-utis close to the epidermis, and, as in other subtypes ofFSP, a spindle cell proliferation replaces the dermis and

lmost invariably extends into the subcutis.22,66-73 The epi-dermis is usually normal or mildly atrophic, although slightand/or focal epidermal hyperplasia may be present. Atro-phic DFSP is usually confused with non-nodular (plaque)DFSP. In fact, all atrophic DFSP are clinically in plaque, butnot all of DFSP in plaque are atrophic at histologic level.74

This variant usually occurs in the third decade of life,affecting both men and women equally. Most cases presentin the trunk, with no differences with conventional DFSPregarding prognosis.75

Sclerosing DFSPSclerosing or sclerotic DFSP is characterized by the

existence of paucicellular or even acellular areas with a

aracterized by spindle cells mixed with a variable population ofs spindled character of cells and abundant pigment (H&E stain,d by giant cells (H&E stain, 40�). (D) GCF with pseudovascular

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18 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

that represent at least 50% of the tumor mass.76-79 However,arge areas of the neoplasm showing typical features ofFSP are always present, and a transition between typicalFSP and sclerotic areas is also observed. In addition, in

ome sclerosing DFSP, prominent nuclear palisade anderocay body formation has been described.80

The cause of sclerosis is unclear. No external injury,radiotherapy, or any other known cause can explain thishistology, suggesting a spontaneous phenomenon, althoughsome authors believe that these sclerosing DFSP are theresult of a long-term evolution of the tumor and the pro-duction of great amounts of collagen by neoplastic cells.77

Granular cell variant of DFSPThere are only 2 reports of 3 cases each describing this

variant,81,82 which is characterized by an intimate mixturef spindle cells with a significant population of cells havingbundant lysosomal granules, round eccentric nuclei, androminent nucleoli. Granular cells are strongly positive forK inhibitory factor (NK1C3) but negative for S-100.

FSP-FSFS change is defined by its characteristic fascicular, often

erringbone architecture, hypercellularity, abundant atypi-al cells, increased mitotic rate, and focal or complete lossf CD34 expression (Figure 5A–C).83-85 The incidence of

Figure 5 Histologic appearance of fibrosarcomatous dermatoells almost completely replacing the dermis and (H&E stain, 4esembling the herringbone pattern (H&E stain, 40�). (C) In Dtain, 100�). (D) Myxoid DFSP characterized by moderately ctain, 100�).

S changes in DFSP has been reported to be between 10%

nd 20% of all DFSP,86-89 the proportion of FS areasranging from 5% to �75% of the tumor.

This histologic variant is characterized by a more aggres-sive behavior, with a higher rate of local recurrence aftersurgery and an increased risk of distant metastasis.83,85,86,90

However, there is no full consensus on the clinical behaviorof DFSP-FS compared with classic DFSP.90,91

DFSP always has infiltrative borders, and a typical dif-fuse honeycomb infiltration into underlying fatty tissue isseen. However, in our experience,89 and also described byothers,88,92 the DFSP-FS often exhibits an expansive pat-ern, which can also be CD34 negative, in some parts of theumor. We believe that recognition of these features isandatory to avoid misdiagnosis.There are no differences in age, gender, location, clinical

ppearance, previous trauma, or presentation status betweenatients with DFSP-FS and DFSP. Clinically, DFSP-FS is aotentially more aggressive tumor than low-grade DFSPecause of the larger tumor size (Figure 2) and frequentnfiltration of the neighboring fascia and muscle.89

TP53 mutations and p53 overexpression have been re-lated to tumor progression in the FS change of DFSP. Infact, p53 expression in the FS areas ranges from 60% to92% compared with the practically null expression of thisprotein in the conventional areas of DFSP.90,93,94 Interest-ingly, at least 50% of cases with p53 expression are asso-

rcoma protuberans (DFSP-FS). (A) Low-power view of tumor) In DFSP-FS, the proliferation of spindled arrange in fasciclesFS, cells show mild-to-moderate nuclear pleomorphism (H&E

areas with abundant interstitial accumulation of mucin (H&E

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19Llombart et al Dermatofibrosarcoma Protuberans

Myxoid DFSP. Conventional Dfsp Often Contains Small Ar-eas of Myxoid Degeneration. However, on occasions, thepredominant histologic pattern throughout the tumor can bemyxoid (�50%). This variant is characterized by the pres-ence of moderately cellular areas made up of stellate orfusiform cells with abundant accumulation of hyaluroni-dase-sensitive mucin in the intercellular space (Figure5D).96 The tumor tends to be well vascularized, and areas oflassic DFSP with dense cellularity and a storiform patternan be found. Some cases show focal areas of FS andCF-like differentiation.97-99

Myxoid DFSP does not differ from conventional DFSPin terms of clinical characteristics or prognosis, and itsrecognition is only of use in the differential diagnosis withother myxoid tumors such as myxoid neurofibroma, super-ficial acral fibromyxoma, superficial angiomyxoma, low-grade myxofibrosarcoma, and myxoid liposarcoma. Almostall cases are positive for CD34, typically in a diffuse pat-tern, and negative for the neural marker S-100 protein.99,100

Myoid DFSP. Myoid Differentiation in Dfsp and Dfsp-fsSeems to Be a Rare Phenomenon. Calonje and Fletcher101

reported 5 DFSP with myoid areas distributed throughoutthe tumor and having no consistent relation to hair folliclesor blood vessel walls; the authors interpreted this as myoiddifferentiation of neoplastic cells of DFSP. Histologically,these tumors are typical DFSP-FS or ordinary DFSP exceptfor the presence of scattered to confluent nodules and bun-dles of eosinophilic spindle cells associated with well-de-fined cytoplasmic margins and vesicular nuclei associatedwith focal stromal hyalinization. However, Díaz-Cascajo102

Figure 6 (A, B) Strong CD34 expression in tumor cells of dermaDFSP area (bottom) stains strongly for CD34, whereas the fibrosa

Complete absence of CD34 staining in fibrosarcomatous DFSP (H&E st

briefly introduced 2 independent cases containing myoidareas and commented that in several sections, tumors revealeda close relationship between myoid areas and the wall ofintraneoplastic blood vessels. In fact, Sanz-Trelles et al92 statedthat the origin of the myomatous component areas could be ahyperplasia of the vascular muscle cells or proliferation ofpericytes with differentiation toward smooth muscle cells.However, other authors83 agreed that myoid differentiation is aariant of DFSP and DFSP-FS. Immunohistochemically, theyoid areas are typically negative for CD34 and desmin and

re positive for smooth muscle actin.

Immunohistochemical profile

The definitive diagnosis of DFSP is usually estab-lished on the basis of routine histopathological and im-munohistochemical features. Immunohistochemical ex-pression of CD34 has been considered characteristic forthe diagnosis of DFSP. Approximately 80%-100% ofDFSP express this marker (Figure 6A and B), althoughbetween 10% and 20% are negative, most commonly, thefibrosarcomatous variant (Figure 6C and D).10-12,84 Nonethe-less, CD34 expression has been increasingly reported in othersarcomas,103,104 such as inflammatory myofibroblastic tumor,myofibrosarcoma, epithelioid sarcoma, or angiosarcoma, andeven in some benign fibrohistiocytic lesions, such as soli-tary fibrous tumor, sclerotic fibroma,105 cellular digital fi-romas,106 nuchal-type fibroma,107 superficial acral fibro-yxomas,104,108 and dermatofibromas.12,109 Consequently,

this marker should now be considered less specific for DFSP.

sarcoma protuberans (DFSP) (H&E stain, 4� and100�). (C) Thetous area (top) is negative for this antigen (H&E stain, 4�). (D)

tofibrorcoma

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20 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

Factor XIIIa is very useful in the differential diagnosisbetween DFSP and cellular fibrous histiocytomas, as it isusually negative in DFSP. However, a fraction of between10% and 15% of cutaneous fibrous histiocytomas are neg-ative for this marker, and, approximately, the same propor-tion of DFSP shows some level of expression.12,109 As aonsequence, in recent years, new immunohistochemicalarkers have been described for the differential diagnosis

etween these 2 entities, including stromelysin III, apolipo-rotein D, nestin, and CD163, although most of these aretill under discussion. In summary, we could say that DFSPells usually express CD34 antigen, apolipoprotein D,110

and nestin,111 whereas they are negative for factor XIIIa,stromelysin III,112,113 HMGA1, HMGA2,109 tenascin,12

D2-40,114 and CD163.115

Cytogenetic and molecular biology of DFSP

Genetically, DFSP is characterized by a reciprocal trans-location t(17;22)(q22;q13) or more often as a supernumer-ary ring chromosome involving also chromosomes 17 and22.15,17,116,117 These chromosomal rearrangements lead to ausion of the COL1A1 gene in chromosome band 17q21 and3 and the PDGFB gene in chromosome 22q13.1.118 The

main consequence of the t(17;22)(q22;q13) is the overpro-duction of PDGFB by the tumor cells, which leads to theconstitutive activation of the PDGFB receptor, a type IIItyrosine kinase receptor.119,120 The recognition of this au-tocrine and paracrine action mechanism has given rise to thesuggestion that the tyrosine kinase inhibitors (TKI) such asimatinib mesylate could be therapeutic options for DFSPpatients as neoadjuvant treatment to reduce tumor size inlocally advanced tumors or in cases presenting metastaticdisease.121,122

The t(17;22)(q22;q13) can be detected either by FISH oninterphase nuclei and/or by multiplex reverse transcription

Figure 7 Representative illustration of the molecular diagnosis oshowing a specific COL1A1-PDGFB fusion gene between exon 46ual-fusion noncommercial probes showing 2 COL1A1-PDGFB fus

Color version of figure is available online at www.semdiagpath.com.)

polymerase chain reaction (RT-PCR) for detecting theCOL1A1/PDGFB fusion transcripts. RT-PCR has been themost extensively reported procedure. In all the cases de-scribed to date using RT-PCR, the break point of PDGFB isconstant (exon 2), whereas in COL1A1, the break point mayoccur in any of the exons codifying the alpha-helical region(exons 6-49). Till date, 34 different COL1A1/PDGFB fu-sion variants have been shown to be involved in the patho-genesis of DFSP.123,124 There is a tendency for the breakpoint to occur in exons located in the second half of theCOL1A1,89 exons 25, 29, 32, 43, and 46 being the mostrequently involved. It is important to emphasize the ab-ence of association between the different variants of theOL1A1/PDGFB fusion gene and the histopathological

ubtypes of DFSP or their clinical characteristics.125

Two strategies can be used for detecting the presence ofthe COL1A1/PDGFB rearrangement by FISH, using eitherPDGFB break-apart probes or noncommercial COL1A1/PDGFB dual-color dual-fusion probe strategies.90,124,126-128

Nevertheless, it is well recognized that dual-fusion FISHprobes are more specific than break-apart probes becausetheir false-positive rate is virtually nonexistent in normaltissue; this is because a positive result using dual-colordual-fusion probes requires 2 fusion signals, an event that isunlikely to occur by chance.

Using both RT-PCR (Figure 7A) and FISH (Figure 7B)strategies, some authors have identified the COL1A1/PDGFB rearrangements in up to 96% of cases.124 Weecently reported a large series of DFSP (103 cases) andound that 93% of cases presented the COL1A1/PDGFBranslocation.129 As other authors,127 we have demonstrated

that FISH is more sensitive than RT-PCR.129 This can beexplained by the nature of the nucleic acids analyzed andthe source of the material, which in most cases is fixed andparaffin embedded. For FISH studies, DNA in interphasenuclei is required, whereas for RT-PCR, more labile RNA

using both RT-PCR and FISH. (A) Sequencing electropherogram1A1 and exon 2 of PDGFB. (B) FISH carried out with dual-color

nals (yellow) and extra copies of COL1A1 (red) and PDGFB (red).

f DFSPof COLion sig

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21Llombart et al Dermatofibrosarcoma Protuberans

molecules are necessary, especially keeping in mind thatRNA is more affected by fixation processes than DNA. Inaddition, it has been demonstrated that the use of frozentissue for the RT-PCR could improve the success rate of thistechnique,125 although this material is not always availablein a routine pathology laboratory.

For a rapid molecular result, the method of choice isusually FISH. Although RT-PCR analysis is useful forretrospective studies or to confirm a doubtful FISH result,in daily practice, it is both laborious and time consuming.

In our opinion, although molecular studies are not nec-essary for routine pathologic diagnosis, the identification ofthe COL1A1/PDGFB rearrangements is mandatory in casesin which the differential diagnosis is inconclusive, such asunusual or rare histopathological subtypes, poorly informa-tive immunohistochemical features (CD34 negative), or be-fore starting treatment with imatinib mesylate in metastaticor locally advanced cases.

The COL1A1/PDGFB is present in all histologic DFSPubtypes, indicating a common pathogenic mechanism.owever, not all DFSP express the translocation,125 and

n a small percentage of DFSP (�10%), the COL1A1/DGFB fusion gene is absent. Bianchini et al130 reported

a case of DFSP in which they used FISH, RT-PCR, andkaryotyping to demonstrate that the COL1A1/PDGFBrearrangement was not present, but identified a newtranslocation between chromosomes 5 and 8 involvingthe CSPG2 and PTK2B genes at 5q14.3 and 8p21.2,respectively. Thus, the report confirmed the hypothesisthat a small percentage of DFSP can display differentgenetic abnormalities.

Diagnostic evaluation

After a diagnosis of DFSP, a complete history, reviewof systems, and physical examination of the patientsshould be performed. DFSP rarely exhibits lymphatic orhematogenous dissemination.1,2 Before surgery, mag-

etic resonance imaging is useful, which is more sensi-ive than palpation for ascertaining depth of tumor inva-ion. Magnetic resonance imaging seems to be useful inrimary DFSP in locations other than the head, neck, andpper part of the thorax.29 Computed tomography (CT) isnly indicated in rare cases in which underlying bonenvolvement is suspected.

Treatment

Surgery

Complete surgical resection is accepted as the optimaltreatment for local DFSP. However, the minimum resectionmargin needed to achieve local control remains undefined.Achieving local control of the tumor is difficult evidenced

by the fact that after conventional surgery, DFSP recurs in

a mean of 20% of cases, whereas with Mohs surgery,recurrence rates are reduced to �1%.

The high recurrence rate for conventional surgery can beexplained by the eccentric growth of the tumor when itinvades the subcutaneous cellular tissue. At this level, thetumor invades in the form of tentacle-like projections at adistance from the initial focus. These projections can passclinically unnoticed and can remain undetected if an ex-haustive histologic study of the surgical margins is notperformed.1,2,131 Studies in which DFSP had been excisedwith undefined or conservative surgical margins found localrecurrences rates ranging from 26% to 60%.27,132 In con-trast, after wide local excision (2-3 cm), the reported totallocal recurrence rate is much lower and varies from 0% to30%.27,86,89,132-135 Series in which margins of 5 cm weresed reported rates of recurrence of �5%.132,136 Therefore,

increasingly wider margins have resulted in lower recur-rence rates. Nevertheless, obtaining generous margins is notalways possible in patients when the tumors involve the faceor neck or in pediatric cases. In addition, as the surgicalmargins are extended, the risk of complications after sur-gery increases (infection, or bleeding), the closing of theresultant wound is more complex and may leave an impor-tant cosmetic defect.89

MMS uses the microscope to trace out the tentacle-likeprojections and a map to guide residual tumor excision. Incontrast to wide local excision, which uses representativevertical sectioning, the Mohs technique requires continuingsequential horizontal sectioning during resection (Figure 8).The efficacy of MMS in the treatment of DFSP has beendocumented in several studies, with a median recurrencerate of �1% and a range of 0% to 8.3%.89,131-133,135,137-139

A modified MMS technique is usually used in DFSP, withthe tissue fixed in formalin and embedded in paraffin. Thismodification slows the procedure but allows improved di-agnosis of fat invasion by the tumor, which can pass unrec-ognized in frozen sections. At our institution, modifiedMMS is routinely performed for the treatment of DFSP.89

First, the tumor is debulked by excision (Figure 8). Thisexcision margin is made just beyond the visible tumormargin and beneath the tumor mass. The Mohs layer istaken as a 0.5- to 1-cm margin of tissue excision around andunder the debulked excision wound positioning the scalpelat an angle of 45°. The Mohs specimen is oriented using silksuture thread and photographed. The tissue is divided intomultiple specimens, mapped for precise anatomic orienta-tion, and sent to the Mohs histotechnician for formalinfixation and paraffin embedding before taking horizontalsections. The sections are stained with hematoxylin andeosin and confirmed by CD34 immunostaining. In patientswith a positive margin(s), the residual tumor is excised withadditional 0.5-cm margins. The cyclic process of excision,mapping, and microscopic examination is repeated till notumor is microscopically detected. The skin defects aretemporarily covered with synthetic wound dressings till

complete excision is proven.89

ln

22 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

We agree with other authors89,131-133,135,137-139 that themodified Mohs surgery is the treatment of choice forDFSP. Mohs surgery offers the advantage of accurate andcomplete evaluation of the entire peripheral and deepmargins, resulting in extremely low reported rates oflocal recurrence.

Molecular target therapy

The COL1A1-PDGFB fusion protein is processed extra-cellularly to produce fully mature and functional PDGFB.This growth factor acts as a potent mitogen through theactivation of its PDGFB receptor,119 which has tyrosinekinase activity, and activates intracellular signaling path-ways, especially those mediated by PI3 kinase and Ras-MAP kinases. In turn, this activity controls vital cell

Figure 8 Mohs micrographic surgery. (A) DFSP located on sup(C) The tumor is debulked by excision. This excision margin is m(D) Defect after debulking. (E) The Mohs layer is taken as a 1-cm m(F) The Mohs specimen is oriented using silk suture thread and phofor precise anatomic orientation. (H) Wound after the first stage oavailable online at www.semdiagpath.com.)

functions, such as proliferation, cell adhesion, and apo- w

ptosis.119,140 The recognition of this action mechanism ofthe COL1A1-PDGFB fusion protein in DFSP has led tothe suggestion that TKI such as imatinib mesylate can beused as therapy in DFSP.121,122 Imatinib mesylate(STI571, Gleevec, Novartis Pharmaceuticals, Basel,Switzerland), a TKI, whose targets include ABL, BCR-ABL, KIT, and PDGFR has been postulated to be usefulin cases of DFSP that are not amenable to radical surgicaltreatment, thus offering a previously unavailable thera-peutic alternative for use in metastatic or locally ad-vanced DFSP.121,122

The first studies with imatinib mesylate involved pal-liative use of the drug in 4 patients with metastaticDFSP.121,141,142 In 2 cases, the effect was temporary andung metastases were reduced in size and number, but didot disappear, and in the remaining 2 cases, the treatment

cular area before surgery. (B) Drawing and measuring the tumor.st beyond the visible tumor margin and beneath the tumor mass.of tissue excision around and under the debulked excision wound.

hed. (G) The tissue is divided into multiple specimens and mappeds. (I) The defect is closed with a graft. (Color version of figure is

raclaviade juargin

tograpf Moh

as successful. These results led to larger clinical trials.

tvasc

vtfm(mtkpmaaddiDdgrsw

ldand

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23Llombart et al Dermatofibrosarcoma Protuberans

In 2005, McArthur et al122 assessed the clinical responseo imatinib mesylate in 10 patients— 8 with locally ad-anced DFSP and 2 with metastasis. Of these, 5 showed

partial response (50% reduction in tumor size), 4howed complete response, and only 1 showed nohange.

To our knowledge, around 100 patients with local ad-anced DFSP have been reported to be treated with ima-inib,122,143-157 with doses between 400 and 800 mg dailyor a period ranging from 2 to 24 months (median, 4onths), producing an average tumor reduction of 50%

range, 19%-100%) after a median follow-up time of 24onths (range, 88 days to 72 months). The toxicity of this

herapy is minimal, and the most common side effectsnown include dyspepsia, nausea, vomiting, and myelosup-ression. After treatment with imatinib, the surgical speci-en showed hypocellular fibrovascular tissue and even

cellular areas as a scar (Figure 9), whereas other tumorreas remained intact. Some authors have suggested that thisrug causes apoptosis of the tumor cells and completeestruction of the tumor,158,159 whereas others believe thatmatinib mesylate causes a change in the phenotype ofFSP involving reduced proliferation and, as a result, re-uced tumor size,141,160 thus facilitating more optimal sur-ery. It is not clear whether imatinib therapy before surgeryeduces the need for wide excision margins or for Mohsurgery.122 In our experience, imatinib therapy almost al-

Figure 9 Histologic images before and after surgery of residermatofibrosarcoma protuberans (DFSP) before treatment with iaucicellular histologic appearance with an abundant collagen dww.semdiagpath.com.)

ays reduces the clinical appearance and histologic cellu-

arity of tumor, but we cannot confirm that this treatmentecreases the overall breadth of tissue involvement. Hence,s other authors,146 we believe that the clinical use ofeoadjuvant therapy before complete excision remains to beetermined.

Several questions remain regarding the action mecha-ism of imatinib and possible resistance to this targetherapy in DFSP. However, imatinib is currently the goldtandard in the treatment of local advanced or metastaticFSP.Another consideration to remember is the fact that tu-

ors lacking the t(17;22) translocation may not respond tomatinib;122 thus, molecular analysis of the tumor usingT-PCR or FISH may be useful before the administration ofn imatinib-based therapy.

Radiotherapy

DFSP is considered to be radiosensitive, although therole of radiotherapy in treating this neoplasm remains un-certain. Radiation has been used as an adjuvant therapy aftersurgery, and can be considered in cases where there is aconcern about the adequacy of surgical margins, when pos-itive surgical margins are found after resection and furthersurgery is not feasible, or for negative surgical margins forlarge lesions. Radiation has occasionally been used as a

sease and after partial response to therapy with imatinib. (A). (B–D) DFSP after treatment with imatinib. The tumor shows a

on in the stroma. (Color version of figure is available online at

ual dimatinibepositi

primary treatment.161-166

dtcCp

lhatccma

24 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013

Follow-up recommendations andprognostic factors

After surgery, patients should be examined every 6 monthsfor the first 3 years and annually for the rest of the life.Physical examination should pay particular attention tocareful inspection and palpation of the scar because DFSP ischaracterized by its capacity for local recurrence. In thiscontext, most local recurrences appear within 3 years ofsurgery, although later recurrences can also occur.31,167

As DFSP metastasizes in only 2%-5% of cases, extensiveevaluations with CT scans, blood cell counts, and liverfunction tests are not indicated.1,2 DFSP most commonlyisseminates hematogenously to the lungs, particularly ifhe lesion is advanced, recurrent, or DFSP-FS; therefore, ahest x-ray should be performed for all patients, and chestT should be performed only for patients with suspicion ofulmonary metastases.

As stated earlier, metastases preferentially localize to theung, but have also been reported in the brain, bone, andeart. Although, it is difficult to determine which cases aret risk of metastasis, they generally involve recurrent lesionshat have progressed for many years and when a fibrosar-omatous component is seen by histology.86,90 The in-reased age, tumor size �5 cm, head or neck location, highitotic index, p53 mutations, and increased cellularity are

lso predictors of poor clinical outcome.86,91,95,168

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