Dermatofibrosarcoma Protuberans: Our Experience of 59 Cases

ONCOLOGY LETTERS 4: 1047-1055, 2012

Dermatofibrosarcoma protuberans: Our experience of 59 cases

ALESSIO STIVALA1, GIUSEPPE A.G. LOMBARDO1, GIANLUCA POMPILI1, MARIA STELLA TARICO1, FILIPPO FRAGGETTA2 and ROSARIO EMANUELE PERROTTA1

1Department of Medical and Surgery Specialties, Section of Plastic Surgery; 2Department of Pathological Anatomy, University of Catania, Cannizzaro Hospital, I-95126 Catania, Italy

Received March 3, 2012; Accepted May 11, 2012

DOI: 10.3892/ol.2012.887

Abstract. Dermatofibrosarcoma protuberans (DFSP) is a rare condition dermatofibrosarcoma protuberans (DFSP). In 1962, soft tissue tumor with intermediate malignancy. It is initially Taylor and Helwig (3) analyzed the histological characteristics located on the skin from where it is able to infiltrate the of DFSP and in 1992 it was discovered that immunoposi- deep structures and has a tendency to recur locally following tivity for CD34 correlated with negative immunostaining for inadequate excision. A t(17;22)(q22;q13) chromosome trans- factor XIIIa (4,5). Then, in 1997, Simon et al (6) identified location is the main cytogenetic alteration responsible for the that a translocation between chromosome 17 and 22 was the onset of DFSP. Treatment options include complete surgical distinguishing cytogenetic alteration in neoplastic tissues excision by performing conventional surgery with wide responsible for the development of DFSP. margins (>3 cm) or Mohs micrographic surgery. A retrospec- DFSP is classified as a rare tumor, however, it may be tive study was conducted in our Department of Plastic and considered as the most common stromal tumor of cutaneous Reconstructive Surgery and all data were collected from origin (7). Numerous epidemiological studies in the USA medical records of 59 DFSP patients within this department have reported a mean annual incidence rate between 0.8 and from 1999 to 2011. A total of 13 of 59 (22%) cases were 4.5 cases per million individuals (8-10). Rutgers et al (11) treated with conventional excision; 3 (5%) cases resulted in reviewed 902 DFSP cases and identified a 3:2 incidence ratio tumor-free margins, 8 (14%) cases required surgical revision of males to females. However, Criscione and Weinstock (12) and 2 (3%) cases lead to recurrence. A total of 46 of 59 (78%) studied 9 population-based cancer registries with a total of cases were treated with wide excision; 43 (73%) cases resulted 2,885 DFSP cases and reported a higher incidence in females. in tumor-free margins, 3 (5%) cases required surgical revi- It has also been found that DFSP has a higher incidence sion and 0 (0%) cases lead to recurrence. In conclusion, the rate among individuals aged between 20 and 50 years (13); data collected reveal the controversy surrounding the adop- however, several studies have reported more than 160 pedi- tion of general guidelines regarding safe margins. Further atric cases of acquired DFSP and more than 35 congenital studies are required to investigate the possibility of obtaining cases (7,14-19). In addition, it has been demonstrated that genotypically altered margins from margins that may appear giant cell fibroblastoma is the juvenile form of dermatofibro- phenotypically healthy. blastoma arising in childhood (20).

Introduction Materials and methods

In 1924, Darier and Ferrand (1) first reported a case of Patient data. A retrospective study was conducted in our progressive and recurrent dermatofibroma. One year later, Department of Plastic and Reconstructive Surgery and all Hoffman (2) described the tendency of the dermatofibroma data were collected from medical records of 59 DFSP patients tumor to develop into protruding nodules and termed the within this department from 1999 to 2011 (Table I). The histopathological diagnosis and immunohistochemical studies were conducted by the Department of Anatomical Pathology within the same hospital. Each medical record included the age, gender, tumor location and presentation, clinical features, treatment Correspondence to: Dr Alessio Stivala, Department of Medical modality, histopathological report, closure type and prognosis of and Surgery Specialties, Section of Plastic Surgery, University of each patient. Informed consent was obtained from each patient. Catania, Cannizzaro Hospital, 829 Via Messina, I-95126 Catania, Italy E-mail: [email protected] Methods. Surgical treatment was achieved by performing conventional and wide excision. Conventional surgery was Key words: dermatofibrosarcoma protuberans, Mohs surgery, adopted in areas where wide excision would have been diffi- conventional excision, wide excision, imatinib cult to perform, including the root of the nose, vulva, cheek and palpebral commissure. The mean margin used in this type of treatment was 1.07 cm. The majority of cases treated 1048 STI VA LA et al: FIFTY-NINE CASES OF DERMATOFIBROSARCOMA PROTUBERANS were subjected to wide excision with a mean margin of 3.4 cm. Clinically, DFSP behaves as a slow-growing asymptomatic Both surgical options were performed by removing the skin, plaque and consequently, the majority of patients consult their subcutaneous tissue and superficial fascia. doctors at a late stage (13). Initially, the neoplasm presents All specimens excised were subjected to formalin fixa- as a violaceous reddish-brown or pink indolent plaque with tion and sectioning to confirm the tumor-free margins and a hard consistency; at this stage the lesion may be misinter- histopathological positivity. The immunohistochemical stain- preted as a hypertrophic scar. Over time, the tumor diffusely ings adopted in this study included: CD34 antigen (clone, infiltrates the deep layers of the skin and the dermis, which QBEnd/10, NCL; Novacastra), Vimentin (clone, V9; Thermo leads to the development of several multiple nodules, which Scientific), ACTML, Van Gieson, hematoxylin and eosin, are indurated to palpation and adherent to the surrounding Protein S100 (clone, 4C4.9; Thermo), CD68 (clone, KP1; NCL) tissues, including the subcutaneous fat, fascia, muscle, peri- and Perl's iron staining. osteum and bone. Martin et al (28) distinguished three clinical forms of Follow up. Patient follow-up for recurrences ranged from non-protruding DFSP: morphea-like, atrophoderma-like and 3 to 120 months with a mean follow-up time of 62 months. angioma-like (Table IV). However, the most frequent presenta- A variety of surgical techniques were adopted for the most tion described in adults is a large plaque presenting multiple suitable wound closure, including primary intention, local nodules on its surface. flaps or grafting. DFSP is characterized by a low rate of metastasis and an No patient within this study had been treated with chemo- eccentric growth rate, which may determine a high level of therapy or radiation prior to treatment at our institution, and no local invasion. It was found that conventional surgery leads to additional adjuvant treatments were performed. local recurrence in up to 30% of cases (13). Kim (29) described seven histological DFSP subtypes Results of which 90% of cases are represented by ‘classic’ DFSP (Table V). Histologically, the ‘classic’ subtype of DFSP appears Clinical and surgical data are presented in Tables I‑III. As as a well‑differentiated fibrosarcoma initially located on the demonstrated in Table II, the mean patient age at time of dermis. The neoplasm is composed of a poor stroma with a diagnosis was 37 years (71% of cases were <50‑years-old dense growth of monomorphous fusiform cells and a large and 29% of cases were >50-years-old), and the majority of elongated nucleus characterized by little pleomorphism and cases presented were female (61%). The tumor was located a low mitotic index. In addition, spindle cells are irregularly on the trunk, upper extremities, lower extremities and head organized in linked fascicles with a storiform arrangement. and neck region in 49, 20, 15 and 16% of cases, respectively. Taylor and Helwig (3) reported a typical diagnostic pattern The protruding form of DFSP was the most frequent clinical of DFSP, which is represented by a cartwheel arrangement variety presented, occurring in 66% of all cases. Notably, 17% where cells are arranged radially around a central acellular of patients reported a prior alteration of the cutis, including collagenous area. previous wounds, surgical scars, actinic keratosis, blue nevus DFSP has the tendency to expand from the central and lentigo simplex. Additionally, no cases presented were focus and invade the surrounding tissues. The tentacle- recurrent at the time of their initial diagnosis. like projections invade the septa and fat lobules and adopt A total of 13 of 59 (22%) cases were t reated with conventional a honeycomb (30%) or multilayered (70%) subcutaneous excision due to the difficult location of the tumor (Table III). pattern (30,31). In both patterns, tentacle-like projections can Following surgery, 3 (5%) cases had tumor‑free margins, be inadvertently omitted during wide excision, determining a 8 (14%) cases required surgical revision and 2 (3%)cases possible cause of tumor recurrence followed by fascia, muscle lead to recurrence. Although conventional excision may lead and bone invasion. to a higher recurrence rate (as demonstrated by this study), The first immunohistochemical marker identified for in certain cases prognosis may be positively affected by this DFSP was the CD34 antigen. It is expressed in up to 90% treatment option. The remaining 46 (78%) cases were treated of cases, differentiating DFSP from other fibrohistiocytic with wide excision. No patient developed recurrences and only tumors (32,33) (Table VI). Previous studies have revealed 3 (5%) cases required surgical revision. Additionally, no patient that CD34 is also expressed by other sarcomas and benign referred to in Tables I-III presented metastatic disease. fibrohistiocytic lesions, including solitary fibrous tumor (34), sclerotic fibroma (35), superficial acral fibromyxoma (36), Discussion cellular digital fibromas (37), dermatofibromas (38) and nuchal-type fibroma (39). Consequently, CD34 may be The main etiological factor in the development of DFSP is considered as a non-specific marker for DFSP. Other immuno- the presentation of several prior traumas, including surgical histochemical markers, including factor XIIIa, stromelysin III, scars (21), trauma scars (22), burns (23), radiodermatitis (24), apolipoprotein D and CD163, have been found to be posi- vaccination sites (25), sites of central venous lines (26) and tive in dermatofibromas and negative in DFSP (13,39-41). insect bites (27). Bandarchi et al (42) also reported that D2-40 may be used The most common anatomical site affected by DFSP is the as a marker for the differential diagnosis between DFSP and trunk (42-72%), with the majority of cases found on the chest dermatofibroma (Table VI). and trunk. A total of 16 to 30% of DFSP cases are located on Molecular biology techniques, including reverse‑tran- the proximal extremities (particularly on the legs) and up to scriptase polymerase chain reaction and fluorescent in situ 16% of cases affect the head and neck areas (7,13). hybridization, have revealed that DFSP is characterized by ONCOLOGY LETTERS 4: 1047-1055, 2012 1049 Surgical Recurrence No revision No No Recurrence No No No No No revision revision No No No Surgical No Surgical Recurrence or surgical revision surgical type Closure Local flap 1 closure Local flap

1 closure 1 closure Local flap 1 closure Local flap 1 closure 1 closure 1 closure

Graft 1 closure Local flap 1 closure 1 closure 1 closure +

- +

- + + + + + +

- + - + EMA -

+ Vimentin Actin 1A4 Vimentin Vimentin Vimentin CD68 S-100 Actin 1A4 CD68 Vimentin Vimentin VIII Factor Bcl-2

+ + + + + + + + + + - + + + + + + + + + - CD34 Vimentin CD34 CD34 CD34 S100 CD34 CD68 CD34 CD34 CD34 CD34 CD34 CD34 CD34 CD34 CD34 Actin 1A4 CD31 CD99 CD34 CD34 CD34 and cytogenetic results Immunohistochemistry

CE CE CE CE CE WE WE WE WE WE WE WE WE WE WE WE WE Surgical modality

Clinical features Morphea-like Protruding DFSP Protruding DFSP Morphea-like, protruding DFSP fibrosarcoma Protruding DFSP Protruding DFSP Morphea-like Morphea-like Atrophoderma-like Protruding DFSP Protruding DFSP Morphea-like Protruding Protruding DFSP Atrophoderma-like Protruding DFSP Protruding DFSP

Presentation On apparently normal cutis normal cutis On prior scar surgical On apparently normal cutis On prior fronto- temporal On prior scar surgical On apparently normal cutis On apparently normal cutis normal cutis On apparently normal cutis On apparently normal cutis On prior scar surgical actinic keratosis On apparently normal cutis normal cutis normal cutis On prior scars On apparently On apparently On prior On apparently On apparently

Location Left arm Left ankle Left shoulder Forehead and root of the nose Right inguinal region Right supraclavicular region Right flank Left leg Left shoulder Back Right supraclavicular region Back Abdomen Left thigh Scalp Right cheek Nape F F F F F F F F F F F M M M M M M Gender 20 30 30 9 68 54 60 57 36 34 14 27 32 66 34 24 57 Age (years)

Date of diagnosis 03/11/2000 06/11/2000 21/04/1999 19/05/2000 23/09/2000 03/10/2000 03/10/2000 27/01/2001 26/06/2001 04/07/2001 29/10/2001 09/05/2002 30/09/2002 10/12/2002 28/12/2002 10/01/2003 03/02/2003 Table I. Summary of 59 cases dermatofibrosarcoma protuberans between 1999 and 2011. Table Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1050 STI VA LA et al: FIFTY-NINE CASES OF DERMATOFIBROSARCOMA PROTUBERANS No No No No revision revision revision No No No No No No No No Surgical No No Surgical Surgical No Recurrence or surgical revision surgical type Closure 1 closure 1 closure Local flap 1 closure

Local flap 1 closure 1 closure 1 closure Graft 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure Local flap

+ + -

+ +

CD34 - + - Bcl-2 + Actin 1A4 S-100 Vimentin Actin 1A4 Actin 1A4

- + + - + + + + + + + + + + + + - + + + S-100 S-100 CD34 CD34 CD34 CD34 CD34 CD34 Desmin, CK CD34 CD34 Actin 1A4 CD34 S-100 CD34 CD34 CD34 CD34 CD34 CD34 Hemosiderin CD34 CD34 and cytogenetic results Immunohistochemistry

CE WE WE WE WE WE WE WE WE WE WE WE WE WE WE WE WE WE Surgical modality

Clinical features Pigmented DFSP Pigmented DFSP Protruding DFSP Protruding DFSP Protruding DFSP Pigmented DFSP Protruding DFSP Protruding DFSP Protruding DFSP protruding DFSP Ulcerated protruding DFSP Protruding DFSP Protruding DFSP Protruding DFSP Morphea-like Protruding DFSP Protruding DFSP Morphea-like Ulcerated

Presentation On prior blue nevus and lentigo simplex normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis normal cutis normal cutis On apparently normal cutis On apparently normal cutis normal cutis normal cutis On prior scar surgical On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently On apparently On apparently On apparently On apparently

Location Right leg Left breast Left breast Left shoulder Left arm Right thigh Left shoulder Abdomen Right arm Scalp Left shoulder Chest Left laterocervical region Right foot Right forearm Right arm Chest Left leg F F F F F F F F F F F F F M M M M M Gender 64 67 28 54 14 26 21 26 18 24 39 19 28 25 19 19 23 52 Age (years)

Date of diagnosis 11/08/2003 21/03/2003 07/04/2003 28/04/2003 06/05/2003 16/06/2003 23/06/2003 03/07/2003 21/07/2003 17/09/2003 27/10/2003 24/03/2004 05/08/2004 18/09/2004 21/10/2004 12/05/2004 05/01/2005 08/04/2005 Table I. Continued. Table Patient no. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 ONCOLOGY LETTERS 4: 1047-1055, 2012 1051 Surgical No revision revision revision revision No Surgical Surgical No No No No No No No No No No Surgical No No Recurrence or surgical revision surgical type Closure Local flap 1 closure

Local flap 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure 1 closure Graft Graft 1 closure Local flap 1 closure 1 closure 1 closure -

- - - -

- - Actin 1A4 - - Vimentin S-100 S-100 CD31 CD117 CD68 + + + + + + + + + + + + + + + + - + + CD34 CD34 CD34 CD34 CD34 CD163 CD34 CD34 CD34 CD34 CD34 CD34 Actin 1A4 CD34 CD34 Desmin CD34 CD31 CD163 CD34 CD34 CD34 CD34 and cytogenetic results Immunohistochemistry

CE CE CE CE CE CE WE WE WE WE WE WE WE WE WE WE WE WE Surgical modality

Clinical features Protruding DFSP Morphea-like Morphea-like Morphea-like Protruding DFSP Protruding DFSP Pigmented DFSP Morphea-like Protruding DFSP Morphea-like Atrophoderma-like Pigmented DFSP Protruding DFSP Protruding DFSP Protruding DFSP Protruding DFSP Protruding DFSP Protruding DFSP

Presentation On prior scar surgical On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On pigmented cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis On apparently normal cutis

Location Left inguinal region Left shoulder Right inguinal region Abdomen Right arm Abdomen Left arm Left scapular region Left arm Abdomen Left arm Right arm Right shoulder Right thigh Scalp Left cheek Vulva Palpebral commissure F F F F F F F F F M M M M M M M M M Gender 43 37 31 56 32 29 28 52 63 37 37 37 69 53 57 29 35 33 Age (years)

Date of diagnosis 11/02/2006 16/11/2007 12/04/2005 10/05/2005 14/10/2005 01/04/2006 20/12/2006 06/02/2007 12/03/2007 26/06/2007 09/01/2008 29/02/2008 19/03/2008 30/03/2009 28/07/2009 04/12/2009 23/12/2009 29/04/2010 Table I. Continued. Table Patient no. 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 1052 STI VA LA et al: FIFTY-NINE CASES OF DERMATOFIBROSARCOMA PROTUBERANS

Table II. Clinical features of 59 DFSP patients.

No. of Total cases Clinical features cases (%) No revision No No Surgical No No Recurrence or

surgical revision surgical Gender Male 23 39 Female 36 61

type Age at diagnosis Closure Graft

1 closure Local flap 1 closure Local flap 1 closure Mean age (years) 37 - <50-years-old 42 71 >50-years-old 17 29 Clinical presentation

+ Morphea-like 11 19 Atrophoderma-like 3 5 CD68 + + + + + + Angioma-like 0 0 Protruding DFSP 39 66 CD34 CD34 CD34 CD34 CD34 CD34 and cytogenetic results Immunohistochemistry Pigmented DFSP 6 10 Location Trunk 29 49

WE WE WE WE WE WE Upper extremities 11 20 Surgical modality Lower extremities 9 15 Head and neck region 10 16

Presentation On apparently normal cutis 49 83 On pigmented/prior altered cutis 10 17

Clinical features DFSP, dermatofibrosarcoma protuberans. Protruding DFSP Pigmented DFSP Protruding DFSP Protruding DFSP Protruding DFSP Protruding DFSP

Table III. Correlation between excision modality and prognosis.

No. of cases treated ------Presentation On apparently normal cutis On apparently normal cutis normal cutis normal cutis normal cutis normal cutis On apparently On apparently On apparently On apparently Conventional Wide Total Prognosis excision (%) excision (%) (%)

Tumor free 3 (5) 43 (73) 46 (78) Surgical revision 8 (14) 3 (5) 11 (19)

Tumor recurrence 2 (3) 0 (0) 2 (3)

Location Total 13 (22) 46 (78) 59 (100) Left thigh Left arm Gluteus Left flank Temporal region Temporal Left shoulder F F F CE, conventional excision; WE, wide excision. CE, conventional excision; M M M supernumerary ring chromosomes or a reciprocal transloca-

Gender tion between chromosome 17 and chromosome 22 t(17;22) (q22;q13) (6,43). This translocation involves the collagen type 1 α 1 (COL1α1) gene located on chromosome 17 and the 43 42 32 1 47 64 Age PDGFβ gene located on chromosome 22. In DFSP, COL1α1 (years) is highly expressed and acts as an inducer of gene transcription (44). COL1α1-PDGFβ fusion leads to the transcription of a fully active PDGFβ protein, which triggers mitosis through

the activation of the PDGFβ receptor (PDGFβR) via auto- Date of diagnosis

15/03/2011 20/05/2011 04/08/2011 04/10/2011 crine and paracrine stimulation of its functional ligand (45). 20/07/2010 24/12/2010 The PDGFβR is composed of three structural domains: an dermatofibrosarcoma protuberans; protuberans; dermatofibrosarcoma extracellular binding, a transmembrane and a cytoplasmic domain with tyrosine kinase activity. The tyrosine kinase Table I. Continued. Table Patient no. 54 55 56 57 58 59 DFSP, ONCOLOGY LETTERS 4: 1047-1055, 2012 1053

Table IV. Clinical variants of the preprotuberant stage of DFSP as described by Martin et al (25).

Variant Clinical features Onset

Morphea-like White or brown indurated plaque appearing as a scar, morphea, Childhood morpheaform basal cell carcinoma or dermatofibroma plaque Atrophoderma-like Soft depressed white or brown plaque similar to atrophoderma Congenital or anetoderma Angioma-like Indurated red or violaceous plaques with clinical appearance Uncommon similar to vascular malformations or angiomas

DFSP, dermatofibrosarcoma protuberans.

Table V. Histological subtypes of DFSP as described by Kim (29).

Subtype Histological characteristics Clinical features

‘Classic’ DFSP Monomorphous fusiform cells (spindle cells) with Most common subtype (90%) large elongated nucleus and poor cytoplasm, low Rare metastasis (≤0.5%) mitotic index Giant cell fibroblastoma Giant multinucleated cells, sinusoidal vessels, Frequently observed in myxoid stroma childhood Bednar tumor Melanocytes and deposits of melanin Observed in African and American patients Sclerotic DFSP Abundant stroma with several layers of collagen Rare subtype and areas of denser cellularity Myxoid DFSP Spindle cells grouped in nodules with eosinophilic Rare subtype cytoplasm Atrophic DFSP Atrophic mid-dermis with subcutaneous tissue Frequently observed in close to the epidermis childhood Fibrosarcomatous DFSP High mitotic index with high cellularity and Subtype with the highest recurrence marked nuclear pleomorphism rate and metastatic potential, most aggressive variant

DFSP, dermatofibrosarcoma protuberans.

Table VI. Immunohistochemical markers used for differential diagnosis of DFSP.

Marker Expressed Not expressed

CD34 DFSP, inflammatory fibrosarcoma,myofibrosarcoma, Dermatofibroma, malignant fibrous histiocytoma, angiosarcoma, epithelioid sarcoma pediatric myofibromatosis, fibrosarcoma, hypertrophic scars or keloids Factor XIIIa Dermatofibroma DFSP Stromelysin III Dermatofibroma DFSP Apolipoprotein D Dermatofibroma DFSP CD163 Dermatofibroma DFSP D2-40 Dermatofibroma DFSP

DFSP, dermatofibrosarcoma protuberans.

activates an intracellular signaling cascade that affects physio Primary treatment of DFSP consisted of complete surgical logical cell processes, including chemotaxis, proliferation and excision of the lesion. It has been reported (46) that standard apoptosis (13). surgical resection leads to a local recurrence rate of up to 60%, 1054 STI VA LA et al: FIFTY-NINE CASES OF DERMATOFIBROSARCOMA PROTUBERANS

Table VII. Correlation between surgical margins and local margins, since margins that are phenotypically recognized to recurrence rate in DFSP wide local excision. be tumor-free, may hide the genetical translocation t(17;22) (q22;q13). Further studies should investigate the possibility Surgical margin Recurrence of obtaining genotypically altered margins from margins Author (Refs.) (cm) rate (%) that may appear phenotypically healthy. This may improve the accuracy of tumor excision and the predictability of Chang et al (46) 5 <5 further possible recurrences. Fiore et al (47) 3 20 Gloster et al (48) <2 40 References

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