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ANNPLA-1000; No. of Pages 7 Annales de chirurgie plastique esthétique (2014) xxx, xxx—xxx
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ORIGINAL ARTICLE
Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients§ ´ duction des marges Dermatofibrosarcome de Darier-Ferrand : re ´ rience de 35 patients avec la technique « Slow-Mohs ». Expe B. Chaput a,b,*,c, T. Filleron b, S. Le Guellec b, T. Meresse a,b, M. Courtade-Saïdi c, J.-L. Grolleau a, C. Chevreau b, I. Garrido a,b, D. Gangloff a,b a
` s, 31059 Toulouse, France Service de chirurgie plastique et reconstructrice, 1, avenue Jean-Poulhe Institut Claudius-Regaud, 20, rue de Pont-St-Pierre, 31000 Toulouse, France c ˆ pital de Rangueil, Service d’anatomie pathologique et d’histologie-cytologie, UF d’histologie-cytologie, ho ` s, TSA 50032, 31059 Toulouse cedex 9, France 1, avenue Jean-Poulhe b
Received 19 August 2013; accepted 17 November 2013
KEYWORDS Dermatofibrosarcoma protuberans; Margins reduction; Slow-Mohs micrographic surgery; Paraffin-embedded sections
Summary Introduction. — Dermatofibrosarcoma protuberans (DFSP) is a potentially malignant dermal mesenchymal tumour with a high risk of local recurrence. DFSP presents a sprawling appearance whose complete excision requires important margins. DFSP was initially resected with a 5 cm excision margins, and more recently 3 cm then 2 cm margins were recommended. Mohs micrographic surgery (MMS) helps reduce these margins thanks to a 3-dimensional excision around the tumour, which is analysed in its entirety. We used the modified MMS called slow-MMS and tried every time it was possible to perform direct closure. Methods. — Thirty-five patients presenting a DFSP between 2004 and 2013 within the Plastic Surgery unit at Claudius Regaud Institute were included in this retrospective study. The patients were treated with slow-MMS using paraffin-embedded sections. Results. — One surgery was necessary for 72% of patients. For 17%, we had to perform a second surgery, and for 11% a third one. Our median clinical excision margins was 17 mm (range 9.0:30.0). After a median follow-up of 46 months (range 35.2:60.2), we didn’t observe any
§
Presented at French Plastic Surgery meeting in 2012, November. * Corresponding author. Service de chirurgie plastique et reconstructrice, 1, avenue Jean-Poulhès, 31059 Toulouse, France. E-mail address: [email protected] (B. Chaput).
0294-1260/$ — see front matter # 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.anplas.2013.11.001
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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B. Chaput et al. recurrence. Only one case required a local flap; for the others, the loss of substance was resolved with a direct closure. Conclusion. — Slow-MMS enabled a local control of the margins without recurrence at 46 months in our series. Besides, it helps performing smaller margins than wide excision and thus preserving the tissues. In our opinion, this is the treatment of choice regarding DFSP for which tissue sparing is essential. It seems particularly appropriate near functional areas or on the face. # 2013 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Dermatofibrosarcome ; Chirurgie micrographique slow-Mohs ; coupes en paraffine
Re ´sume ´ Introduction. — Le dermatofibrosarcome (DFS) de Darier-Ferrand est une tumeur dermique mésenchymateuse de malignité intermédiaire avec un risque important de récidive locale. En effet, le DFS présente un aspect tentaculaire qui va s’infiltrer le long des septa conjonctifs sous la forme de pseudopodes et dont l’exérèse complète va nécessiter des marges conséquentes. Le DFS était initialement traité par excision large avec des marges de 5 cm, puis plus récemment des marges de 3 puis 2 cm ont été recommandées. La chirurgie micrographique de Mohs (CMM) propose de réduire ces marges en réalisant une cupule en périphérie de la tumeur qui est analysée dans sa totalité en anatomopathologie. Me ´thodes. — Trente-cinq cas de DFS pris en charge entre 2004 et 2013 dans l’unité de chirurgie plastique de l’institut Claudius-Regaud à Toulouse ont été étudiés rétrospectivement. Les patients ont bénéficié d’une chirurgie de Slow-Mohs avec analyse horizontale des coupes après inclusion en paraffine. Re ´sultats. — L’âge médian de découverte du DFS était de 42 ans (range 18—81). Une seule intervention a été nécessaire pour 72 % des patients. Pour 17 % nous avons dû réaliser une deuxième procédure et pour 11 % une troisième procédure. Nos marges d’exérèse clinique médiane étaient de 17 mm (marge d’exérèse + épaisseur de la cupule) (9,0 : 30,0). Après un suivi médian de 46 mois (35,2 : 60,2), nous n’avons pas observé de récurrence. Un seul cas a nécessité une reconstruction par un lambeau locorégional, dans tous les autres cas la perte de substance a pu être refermée par une suture directe. Conclusion. — La chirurgie micrographique de Mohs autorise un contrôle local des marges sans récurrence à 46 mois dans notre série de 35 patients en mode slow-mohs. De surcroît, elle permet de réaliser des marges plus faibles que l’excision large et ainsi d’être conservateur sur les tissus. C’est pourquoi, il s’agit pour nous de la technique de choix dans le DFS où l’économie tissulaire est fondamentale. Elle trouve particulièrement sa place dans les zones fonctionnelles ou sur la face. # 2013 Elsevier Masson SAS. Tous droits réservés.
Introduction DFSP is a rare dermal mesenchymal tumour (0.1% of cutaneous tumours / 2% of sarcomas) whose incidence varies from 0.8 to 4.2 cases per million of inhabitants per year [1]. It is the most frequent cutaneous sarcoma. It usually affects patients between 20 and 40, preferentially men [2]. As it infiltrates along the conjunctive septa, a complete excision based on the visible or palpable lesion is difficult to perform. Potentially malignant, DFSP metastasizes very seldom [3], but the main challenge regarding its management remains the high risk of local recurrence. The purpose of this study was to use the experience of our centre to highlight the benefit to practice MMS in DFSP in order to limit surgical margins and to reduce local recurrences. Besides, we emphasized our operating mode as ‘‘slow’’, which was not a problem for patients’ management.
Material and methods This is a retrospective study conducted at Claudius Regaud Institute in Toulouse, France, from 2004 to 2013 on 35 patients presenting a DFSP. The diagnosis of DFSP was histologically
confirmed by an initial biopsy then by the definitive excision specimen. The tissues were embedded in paraffin, stained with hemalun-eosin, and finally the definitive diagnosis of DFSP was confirmed on positive CD34 immunostaining. The thickness of the sections was from 3 to 5 mm. The patients were followed in consultation every 2 months. Clinical data collected included age, gender, discovery and site of the tumour, follow-up, and all the surgical and anatomopathological procedures. Mohs modified technique or slow-Mohs was performed by two surgeons (D.G and I.G), either under general or local anaesthesia with 1% lidocaine with epinephrine (AstraZeneca1). Tumour excision was performed as a 908 dissection with margins between 1 and 2 cm from the visible and palpable tumour. Our management always aimed at having total margins below 2 cm (tumour excision margins + thickness of the 3-dimensional excision) and allowing whenever possible an immediate closure. In depth, the excision of a healthy anatomical barrier was systematic. Around and under the tumour area, a 3-dimensional excision was performed with a thickness as close as possible to 5 mm to be easily put into a cassette by the pathologist. The surgical specimens were mapped and colour coded by the pathologist for precise anatomical orientation. The tissues were fixed in
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Surgical data.
General anaesthesia (n = 30) 86% / Local anaesthesia (n = 5) 14% Number of procedures 1 (n = 25) 72% 2 (n = 6) 17% 3 (n = 4) 11% Median excision: 37.11 cm2 (range 12.37: 109.95) Skin closure Immediate (n = 29) 83% Controlled wound healing (n = 4) 11% Split skin graft (n = 1) 3% Local flap (n = 1) 3% Postoperative complications (n = 4) 11% Delay of wound healing Diastasis recti Haematoma Scar dehiscence Median clinical excision margins: 17 mm (tumour excision margins + thickness of the 3-dimensional excision) (range 11.0: 30.0)
formalin. Then, the tumour biopsies were put into cassettes to be paraffin-embedded, and then stained with hemaluneosin for the horizontal analysis of the margins. The slides were analysed by pathologists who were specialized in DFSP. The pathologists were informed of the procedure and they were asked to provide the results as soon as possible. When the biopsy was positive, we performed the same procedure within the following days.
Results We managed 35 patients for DFSP between 2004 and 2013 in our department using slow MMS. No patient was lost to follow-up (Table 1). The median patient age was 42 years
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(range 18-81). Sixty percent were men (n = 21) and 40% were women (n = 14). The DFSP discovery was made by a dermatologist in 43.5% of cases (n = 10), by a general practitioner in 30.4% of cases (n = 7), or by the patients themselves in 26.1% of cases (n = 6). The sites of involvement were the face and neck (5.7%), upper limbs (14.3%), lower limbs (17.1%), anterior trunk (31.4%), and posterior trunk (31.4%) (Fig. 1). For all the patients, it was a primary management and not a recurrence. The patients presented no local trauma before the DFSP appeared (wound, burn, local infection, or scar). No patient benefited from an additional imaging examination to assess tumour infiltration. None of our patients presented a surgically unresectable DFSP. We did not use any neoadjuvant treatment before surgery. On the surgical plan (Fig. 2), 85% (n = 30) of patients benefited from general anaesthesia and 15% (n = 5) from a local anaesthesia. The median size of the excision was 37.11 cm2 (range 12.37: 109.95). A direct closure after excision was possible in 83% of cases (n = 29), a controlled wound healing was necessary in 11% of cases (n = 4), and a skin graft or a local flap was performed in 6% of cases (n = 2). In this last case, the DFSP excision had a diameter of 12 cm and closure with a local flap was the optimal solution. The mean size of the excision when we could not directly suture was 95 mm long (65-120) and 70 mm large (50—100), i.e. 66.5 cm2 in average (32.5—108). Minor postoperative complications were reported in 11% of cases (n = 4) (a delay of wound healing, a diastasis recti, a haematoma, and one scar dehiscence). The median time to get the anatomopathological results was 5 days (range 0: 13). Apart from the initial biopsy, the mean number of surgeries was 1.4 (median 1, range 1: 3). In 17% of cases, two surgeries were necessary because the first biopsy was positive, and in 11% of cases a third surgery was performed because the second biopsy was still positive. Our median clinical excision margins were 17 mm (tumour excision margins + thickness of the 3-dimensional excision) (range 11.0: 30.0). No local or distant recurrence was highlighted nor metastasis. No patient was displeased by the management duration. The median duration of follow-up was 46 months (range 35.2: 60.2).
Figure 1 Lateral thoracic DFS (left). Surgical view: the lesion is delimited. Excision of 1 cm that we practice compared to 5 cm margins that could be used. Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Figure 2 The procedure: we first perform the excision of the lesion. We remove the visible tumor with a layer of surrounding tissue (A). A 3-dimensional exeresis is performed with a thickness as close as possible to 3 mm to be easily put into a histocassette by the pathologist (B). The surgical specimens are oriented and inked to realize a precise mapping by the pathologist (C). Immediate closure of the wound (D).
Discussion DFSP is a rare dermal tumour presenting a high risk of local recurrence, which remains the main difficulty regarding its management. The risk factors for DFSP are still unknown. Taylor reported 16.5% of local traumas [4] but we did not highlight pre-existing traumas to the DFSP appearance in our series. The development of DFSP is not concentric compared to other tumours, which is why wide excision does not seem to be the best technique to manage these tumours, as it would obviously sacrifice too much healthy tissue. It is
Table 2
accepted that the risks of recurrence decrease when the margins increase [5—8] (Table 2). However, no correlation was made between the size of the tumour and the required excision margins [9]. MMS is currently the main alternative to a wide excision (Table 3). The aim of MMS is to reduce as much as possible the surgical excision margins while limiting local tumour recurrences. The modified MMS or slow-Mohs using paraffin-embedded sections was first described by Breuninger et al. in 1988 [10]. It consists like Mohs technique of a histological 3D analysis of
Mohs micrographic surgery.
Study/Authors
Recurrence rate (%)
Follow-up (months)
7
0
60
Breuninger et al. (1994) [32]
23
0
60
Parker et al. (1995) [20]
20
0
40.8
Dawes et al. (1996) [33]
24
8.3
61.2
Ratner et al. (1997) [34]
58
1.7
57.6
Huether et al. (2001) [35]
33
3
45.6
Ah-Weng et al. (2002) [9]
21
0
47
Dubay et al. (2003) [21]
11
0
48.4
Snow et al. (2004) [13]
29
0
60
Meguerditchian et al. (2010) [36]
20
0
40.4
Tan et al. (2011) ‘‘Slow mohs’’ [17]
35
0
29.5
1.2
55
Mohs (1978) [31]
Total
Number of patients
281
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Wide local excision.
Study/Authors
Number of Patients
Margins (cm)
Recurrence rate (%)
Follow-up (months) 105
Smola et al. (1991) [37]
20
1—5
30
Rutgers et al. (1992) [27]
19
2—3
0
158.4
Arnaud et al. (1997) [38]
107
5
2.1
61
Bowne et al. (2000) [26]
159
NC
Joucdar et al. (2001) [39]
65
5
Chang et al. (2004) [40]
60
Dubay et al. (2004) [21] Behbahani et al. (2005) [41]
21
57
7.6
60
>3
16.7
59
43
NC
0
48.4
34
3
0
60
NC
3.7
NC
Fiore et al. (2005) [42]
218
Popov et al. (2007) [43]
40
3
0
40
Heuvel et al. (2009) [44]
38
2-3
7
89
Meguerditchian et al. (2010) [36]
28
2
3.6
49.9
Farma et al. (2010) [45]
206
2
1
64
Total
865
N/A
7.5
73
the margins thanks to a peripheral surgical incision. Conventional histological analysis techniques do not examine 100% of the margins whereas 3-dimensional excision is analysed in its entirety (Fig. 3). Compared to MMS, slow-Mohs technique embeds the sections from the 3-dimensional excision in paraffin and does not analyse frozen sections. Unlike of the United States, where the surgeons analyze the tumour themselves, in Europe we need pathologists. They consider, however, slow-Mohs as a time-consuming procedure and on this specific point the cancer centers such as Claudius Regaud institute seem more favorable. Moreover, the valorisation by the health insurance remains insufficient [11,12]. In our unit, wide excision with margins of 5 cm was the standard technique, but the arrival of a plastic surgeons team at the institute has given a new impetus to the management of DFS. We decided to use slow-Mohs technique as for us it was easy to perform in daily practice. The pathologists were told of the procedure the day before to be in optimal conditions. Although, this is a more expensive and timeconsuming procedure, it seems to be more reliable in terms of histological analysis. Many authors have reported a higher
Figure 3
difficulty to differentiate healthy tissue from tumour tissue on frozen sections [13—16]. In fact, Tan et al. reported a higher recurrence of DFSP in MMS using a frozen section analysis than in those using paraffin embedded sections [17]. This might be due to very small residues, which are more difficult to differentiate from healthy dermal tissue after being frozen, which can alter the tissue architecture [18]. Situations where paraffin-embedded sections clearly showed the presence of tumour were also reported, although frozen sections coming from the same sections were healthy [17]. The fusiform organisation of DFSP cells associated to the tumour infiltrates scattered in the healthy dermis as well as the common presence of scar tissue or of granulation secondary to biopsies or to the initial surgery are many negative factors which make reading frozen sections more difficult. The input of CD34 immunostaining helped increase the frozen sections’ screening sensitivity, but many false positives remained [17,19]. Our study conducted on 35 patients with DFSP highlighted a noticeable reduction compared to the margins recommended in the literature with wide excision. We never performed total margins above 2 cm at first (tumour clinical
Histologic procedure. The tissues are cut and put into cassette before paraffin embedding.
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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margins + thickness of the 3-dimensional excision) in order to spare tissue. A smaller excision also means less postsurgical complications. The aim was to perform a direct closure in every case and to wait for the results. Our median clinical excision margins were 17 mm with a 0% recurrence rate at 46 months. We noticed the thickness of the 3dimensional excision is quite variable as it is a complex procedure where it is sometimes difficult to stay perfectly regular. Parker et al. reported their experience of MMS with 15 mm margins for DFSP below 2 cm, and performed a complete excision in 80% of cases [20]. Nouri et al. reported a 0% recurrence rate on 20 patients with a median follow-up of 56.4 months [16] and Dubay et al. reported a 0% recurrence rate on 11 patients with a median follow-up of 52.8 months [21]. We noticed that many authors described very low recurrence rates (0-8.3%) with MMS. The articles about slow-Mohs are less numerous, but recently Tan et al. reported their experience on 35 patients over a median follow-up of 29.5 months with a 0% recurrence rate [17]. In the literature on wide excision, the teams who practised margins below 3 cm reported important recurrence rates [19]. We understand that wide excision seems interesting for many surgical teams as it is fast, cheaper, and easier to perform than MMS. Monnier et al. showed a significant difference of recurrence depending on margins in 66 patients over 9.6 years. They found 47% of recurrences with margins lower than 3 cm and 7% between 3 and 5 cm [22]. To maintain the patients’ comfort, we frequently chose general anaesthesia (85%). In 83% of cases, we could perform a direct closure and the patients did not come back home with an open wound. It is sometimes reproached to the slowMohs technique to be uncomfortable for patients, but in our study the procedure was well tolerated, and for us the advantages of this technique remain more important than this inconvenience [23]. Recurrences of DFSP would be more frequent on the face [21,24,25], maybe because the surgeons hesitate to perform wide excisions on these areas. Metastases are exceptional but described: 1% for Browne et al. in 159 patients [26], up to 4% of metastases reported by Rutgers et al. in a series of 913 patients [27]. In our series, no lesion was unresectable. Here, we must underline the importance of a multidisciplinary management with the oncologist, the radiotherapist, and the pathologist, who in addition to the surgeon can give their opinion concerning management planning. For large tumours on the face or very deep tumours, there is a hope with neoadjuvant treatments, which are being developed. Imatinib mesylate (GLIVEC1) and Pazopanib (VOTRIENT1) are targeted treatments, which are efficient on tumour reduction [28]. The translocation t(17:22) resulting from the fusion of the COL1A1-PDGFB gene is present in 95% of patients and plays a role in the targeted treatments’ efficiency [3]. For Kerob et al. in a multicentre phase II study conducted on 25 patients, imatinib mesylate targeting the breceptor of the platelet-derived growth factor would reduce by 20% the size of the tumour in more than a third of the DFSP cases receiving a neoadjuvant treatment [3]. The radiotherapy alone or associated to surgery showed moderate efficiency in the treatment of DFSP [29]. This tumour remains however radiosensitive. It can be used to manage an unresectable or incompletely resected tumour to limit local recurrences [2]. Sun et al. even recommended radiotherapy
as a systematic adjuvant treatment to decrease the risk of local recurrence [30]. The role of radiotherapy and of targeted treatments (Imatinib mesylate, Pazopanib) still needs to be assessed before being systematically suggested. To conclude, our management with slow-Mohs enabled us within reasonable periods of time to suggest a DFSP excision to our patients with median clinical excision margins of 17 mm. This management was confirmed on a series of 35 patients presenting a DFSP with a median follow-up of 46 months without recurrence. We suggest a systematic management of DFSP using the slow-Mohs technique, a procedure which proved to be efficient to spare tissue and to limit recurrences. The functional areas (periorificial, periarticular, or genital) as well as the face and nose are special candidate sites for this type of procedure. If MMS is unavailable, surgery with 3-cm lateral margins have to be recommended [19].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs [13] Snow SN, Gordon EM, Larson PO, Bagheri MM, Bentz ML, Sable DB. Dermatofibrosarcoma protuberans: a report on 29 patients treated by Mohs micrographic surgery with long-term follow-up and review of the literature. Cancer 2004;101:28—38. [14] Tom WD, Hybarger CP, Rasgon BM. Dermatofibrosarcoma protuberans of the head and neck: treatment with Mohs surgery using inverted horizontal paraffin sections. Laryngoscope 2003;113:1289—93. [15] Loss L, Zeitouni NC. Management of scalp dermatofibrosarcoma protuberans. Dermatol Surg 2005;31:1428—33. [16] Nouri K, Lodha R, Jimenez G, Robins P. Mohs micrographic surgery for dermatofibrosarcoma protuberans: University of Miami and NYU experience. Dermatol Surg 2002;28:1060—4. [17] Tan WP, Barlow RJ, Robson A, Kurwa HA, McKenna J, Mallipeddi R. Dermatofibrosarcoma protuberans: 35 patients treated with Mohs micrographic surgery using paraffin sections. Br J Dermatol 2011;164:363—6. [18] Massey RA, Tok J, Strippoli BA, Szabolcs MJ, Silvers DN, Eliezri YD. A comparison of frozen and paraffin sections in dermatofibrosarcoma protuberans. Dermatol Surg 1998;24:995—8. [19] Pallure V, Dupin N, Guillot B, Association for Recommendations in Dermatology. Surgical treatment of darier-ferrand dermatofibrosarcoma: a systematic review. Dermatol Surg 2013;39: 1417—33. [20] Parker TL, Zitelli JA. Surgical margins for excision of dermatofibrosarcoma protuberans. J Am Acad Dermatol 1995;32: 233—6. [21] DuBay D, Cimmino V, Lowe L, Johnson TM, Sondak VK. Low recurrence rate after surgery for dermatofibrosarcoma protuberans: a multidisciplinary approach from a single institution. Cancer 2004;100:1008—16. [22] Monnier D, Vidal C, Martin L, Danzon A, Pelletier F, Puzenat E, et al. Dermatofibrosarcoma protuberans: a population-based cancer registry descriptive study of 66 consecutive cases diagnosed between 1982 and 2002. J Eur Acad Dermatol Venereol 2006;20:1237—42. [23] Shumaker PR, Kelley B, Swann MH, Greenway Jr HT. Modified Mohs micrographic surgery for periocular melanoma and melanoma in situ: long-term experience at Scripps Clinic. Dermatol Surg 2009;35:1263—70. [24] Gayner SM, Lewis JE, McCaffrey TV. Effect of resection margins on dermatofibrosarcoma protuberans of the head and neck. Arch Otolaryngol Head Neck Surg 1997;123:430—3. [25] Angouridakis N, Kafas P, Jerjes W, Triaridis S, Upile T, Karkavelas G, et al. Dermatofibrosarcoma protuberans with fibrosarcomatous transformation of the head and neck. Head Neck Oncol 2011;3:5 [Review]. [26] Bowne WB, Antonescu CR, Leung DH, Katz SC, Hawkins WG, Woodruff JM, et al. Dermatofibrosarcoma protuberans: a clinicopathologic analysis of patients treated and followed at a single institution. Cancer 2000;88:2711—20. [27] Rutgers EJ, Kroon BB, Albus-Lutter CE, Gortzak E. Dermatofibrosarcoma protuberans: treatment and prognosis. Eur J Surg Oncol 1992;18:241—8. [28] Han A, Chen EH, Niedt G, Sherman W, Ratner D. Neoadjuvant imatinib therapy for dermatofibrosarcoma protuberans. Arch Dermatol 2009;145:792—6.
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[29] Suit H, Spiro I, Mankin HJ, Efird J, Rosenberg AE. Radiation in management of patients with dermatofibrosarcoma protuberans. J Clin Oncol 1996;14:2365—9. [30] Sun LM, Wang CJ, Huang CC, Leung SW, Chen HC, Fang FM, et al. Dermatofibrosarcoma protuberans: treatment results of 35 cases. Radiother Oncol 2000;57:175—81. [31] Mohs FE, Chemosurgery:. microscopically controlled surgery for skin cancer˘past, present and future. J Dermatol Surg Oncol 1978;4:41—54. [32] Breuninger H, Thaller A, Schippert W. Subclinical spread of dermatofibrosarcoma protuberans and resulting treatment modalities. Hautarzt 1994;45:541—5. [33] Dawes KW, Hanke CW. Dermatofibrosarcoma protuberans treated with Mohs micrographic surgery: cure rates and surgical margins. Dermatol Surg 1996;22:530—4. [34] Ratner D, Thomas CO, Johnson TM, Sondak VK, Hamilton TA, Nelson BR, et al. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multiinstitutional series with an analysis of the extent of microscopic spread. J Am Acad Dermatol 1997;37:600—13. [35] Huether MJ, Zitelli JA, Brodland DG. Mohs micrographic surgery for the treatment of spindle cell tumors of the skin. J Am Acad Dermatol 2001;44:656—9. [36] Meguerditchian AN, Wang J, Lema B, Kraybill WG, Zeitouni NC, Kane 3rd JM. Wide excision or Mohs micrographic surgery for the treatment of primary dermatofibrosarcoma protuberans. Am J Clin Oncol 2010;33:300—3. [37] Smola MG, Soyer HP, Scharnagl E. Surgical treatment of dermatofibrosarcoma protuberans. A retrospective study of 20 cases with review of literature. Eur J Surg Oncol 1991;17:447—53 [Review]. [38] Arnaud EJ, Perrault M, Revol M, Servant JM, Banzet P. Surgical treatment of dermatofibrosarcoma protuberans. Plast Reconstr Surg 1997;100:884—95. [39] Joucdar S, Kismoune H, Boudjemia F, Bacha D, Abed L. Les dermatofibrosarcomes de Darier et Ferrand — analyse rétrospective de 81 cas sur dix ans (1983—1994). Ann Chir Plast Esthet 2001;46:134—40. [40] Chang CK, Jacobs IA, Salti GI. Outcomes of surgery for dermatofibrosarcoma protuberans. Eur J Surg Oncol 2004;30:341—5. [41] Behbahani R, Patenotre P, Capon N, Martinot-Duquennoy V, Kulik JF, Piette F, et al. To a margin reduction in the dermatofibrosarcoma protuberans? Retrospective study of 34 cases. Ann Chir Plast Esthet 2005;50:179—85 [discussion 186-8]. [42] Fiore M, Miceli R, Mussi C, Lo Vullo S, Mariani L, Lozza L, et al. Dermatofibrosarcoma protuberans treated at a single institution: a surgical disease with a high cure rate. J Clin Oncol 2005;23:7669—75 [Review]. [43] Popov P, Böhling T, Asko-Seljavaara S, Tukiainen E. Microscopic margins and results of surgery for dermatofibrosarcoma protuberans. Plast Reconstr Surg 2007;119:1779—84. [44] Heuvel ST, Suurmeijer A, Pras E, Van Ginkel RJ, Hoekstra HJ. Dermatofibrosarcoma protuberans: recurrence is related to the adequacy of surgical margins. Eur J Surg Oncol 2010;36:89—94. [45] Farma JM, Ammori JB, Zager JS, Marzban SS, Bui MM, Bichakjian CK, et al. Dermatofibrosarcoma protuberans: how wide should we resect? Ann Surg Oncol 2010;17:2112—8.
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ANNPLA-1000; No. of Pages 7 Annales de chirurgie plastique esthétique (2014) xxx, xxx—xxx
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ORIGINAL ARTICLE
Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients§ ´ duction des marges Dermatofibrosarcome de Darier-Ferrand : re ´ rience de 35 patients avec la technique « Slow-Mohs ». Expe B. Chaput a,b,*,c, T. Filleron b, S. Le Guellec b, T. Meresse a,b, M. Courtade-Saïdi c, J.-L. Grolleau a, C. Chevreau b, I. Garrido a,b, D. Gangloff a,b a
` s, 31059 Toulouse, France Service de chirurgie plastique et reconstructrice, 1, avenue Jean-Poulhe Institut Claudius-Regaud, 20, rue de Pont-St-Pierre, 31000 Toulouse, France c ˆ pital de Rangueil, Service d’anatomie pathologique et d’histologie-cytologie, UF d’histologie-cytologie, ho ` s, TSA 50032, 31059 Toulouse cedex 9, France 1, avenue Jean-Poulhe b
Received 19 August 2013; accepted 17 November 2013
KEYWORDS Dermatofibrosarcoma protuberans; Margins reduction; Slow-Mohs micrographic surgery; Paraffin-embedded sections
Summary Introduction. — Dermatofibrosarcoma protuberans (DFSP) is a potentially malignant dermal mesenchymal tumour with a high risk of local recurrence. DFSP presents a sprawling appearance whose complete excision requires important margins. DFSP was initially resected with a 5 cm excision margins, and more recently 3 cm then 2 cm margins were recommended. Mohs micrographic surgery (MMS) helps reduce these margins thanks to a 3-dimensional excision around the tumour, which is analysed in its entirety. We used the modified MMS called slow-MMS and tried every time it was possible to perform direct closure. Methods. — Thirty-five patients presenting a DFSP between 2004 and 2013 within the Plastic Surgery unit at Claudius Regaud Institute were included in this retrospective study. The patients were treated with slow-MMS using paraffin-embedded sections. Results. — One surgery was necessary for 72% of patients. For 17%, we had to perform a second surgery, and for 11% a third one. Our median clinical excision margins was 17 mm (range 9.0:30.0). After a median follow-up of 46 months (range 35.2:60.2), we didn’t observe any
§
Presented at French Plastic Surgery meeting in 2012, November. * Corresponding author. Service de chirurgie plastique et reconstructrice, 1, avenue Jean-Poulhès, 31059 Toulouse, France. E-mail address: [email protected] (B. Chaput).
0294-1260/$ — see front matter # 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.anplas.2013.11.001
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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B. Chaput et al. recurrence. Only one case required a local flap; for the others, the loss of substance was resolved with a direct closure. Conclusion. — Slow-MMS enabled a local control of the margins without recurrence at 46 months in our series. Besides, it helps performing smaller margins than wide excision and thus preserving the tissues. In our opinion, this is the treatment of choice regarding DFSP for which tissue sparing is essential. It seems particularly appropriate near functional areas or on the face. # 2013 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Dermatofibrosarcome ; Chirurgie micrographique slow-Mohs ; coupes en paraffine
Re ´sume ´ Introduction. — Le dermatofibrosarcome (DFS) de Darier-Ferrand est une tumeur dermique mésenchymateuse de malignité intermédiaire avec un risque important de récidive locale. En effet, le DFS présente un aspect tentaculaire qui va s’infiltrer le long des septa conjonctifs sous la forme de pseudopodes et dont l’exérèse complète va nécessiter des marges conséquentes. Le DFS était initialement traité par excision large avec des marges de 5 cm, puis plus récemment des marges de 3 puis 2 cm ont été recommandées. La chirurgie micrographique de Mohs (CMM) propose de réduire ces marges en réalisant une cupule en périphérie de la tumeur qui est analysée dans sa totalité en anatomopathologie. Me ´thodes. — Trente-cinq cas de DFS pris en charge entre 2004 et 2013 dans l’unité de chirurgie plastique de l’institut Claudius-Regaud à Toulouse ont été étudiés rétrospectivement. Les patients ont bénéficié d’une chirurgie de Slow-Mohs avec analyse horizontale des coupes après inclusion en paraffine. Re ´sultats. — L’âge médian de découverte du DFS était de 42 ans (range 18—81). Une seule intervention a été nécessaire pour 72 % des patients. Pour 17 % nous avons dû réaliser une deuxième procédure et pour 11 % une troisième procédure. Nos marges d’exérèse clinique médiane étaient de 17 mm (marge d’exérèse + épaisseur de la cupule) (9,0 : 30,0). Après un suivi médian de 46 mois (35,2 : 60,2), nous n’avons pas observé de récurrence. Un seul cas a nécessité une reconstruction par un lambeau locorégional, dans tous les autres cas la perte de substance a pu être refermée par une suture directe. Conclusion. — La chirurgie micrographique de Mohs autorise un contrôle local des marges sans récurrence à 46 mois dans notre série de 35 patients en mode slow-mohs. De surcroît, elle permet de réaliser des marges plus faibles que l’excision large et ainsi d’être conservateur sur les tissus. C’est pourquoi, il s’agit pour nous de la technique de choix dans le DFS où l’économie tissulaire est fondamentale. Elle trouve particulièrement sa place dans les zones fonctionnelles ou sur la face. # 2013 Elsevier Masson SAS. Tous droits réservés.
Introduction DFSP is a rare dermal mesenchymal tumour (0.1% of cutaneous tumours / 2% of sarcomas) whose incidence varies from 0.8 to 4.2 cases per million of inhabitants per year [1]. It is the most frequent cutaneous sarcoma. It usually affects patients between 20 and 40, preferentially men [2]. As it infiltrates along the conjunctive septa, a complete excision based on the visible or palpable lesion is difficult to perform. Potentially malignant, DFSP metastasizes very seldom [3], but the main challenge regarding its management remains the high risk of local recurrence. The purpose of this study was to use the experience of our centre to highlight the benefit to practice MMS in DFSP in order to limit surgical margins and to reduce local recurrences. Besides, we emphasized our operating mode as ‘‘slow’’, which was not a problem for patients’ management.
Material and methods This is a retrospective study conducted at Claudius Regaud Institute in Toulouse, France, from 2004 to 2013 on 35 patients presenting a DFSP. The diagnosis of DFSP was histologically
confirmed by an initial biopsy then by the definitive excision specimen. The tissues were embedded in paraffin, stained with hemalun-eosin, and finally the definitive diagnosis of DFSP was confirmed on positive CD34 immunostaining. The thickness of the sections was from 3 to 5 mm. The patients were followed in consultation every 2 months. Clinical data collected included age, gender, discovery and site of the tumour, follow-up, and all the surgical and anatomopathological procedures. Mohs modified technique or slow-Mohs was performed by two surgeons (D.G and I.G), either under general or local anaesthesia with 1% lidocaine with epinephrine (AstraZeneca1). Tumour excision was performed as a 908 dissection with margins between 1 and 2 cm from the visible and palpable tumour. Our management always aimed at having total margins below 2 cm (tumour excision margins + thickness of the 3-dimensional excision) and allowing whenever possible an immediate closure. In depth, the excision of a healthy anatomical barrier was systematic. Around and under the tumour area, a 3-dimensional excision was performed with a thickness as close as possible to 5 mm to be easily put into a cassette by the pathologist. The surgical specimens were mapped and colour coded by the pathologist for precise anatomical orientation. The tissues were fixed in
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Surgical data.
General anaesthesia (n = 30) 86% / Local anaesthesia (n = 5) 14% Number of procedures 1 (n = 25) 72% 2 (n = 6) 17% 3 (n = 4) 11% Median excision: 37.11 cm2 (range 12.37: 109.95) Skin closure Immediate (n = 29) 83% Controlled wound healing (n = 4) 11% Split skin graft (n = 1) 3% Local flap (n = 1) 3% Postoperative complications (n = 4) 11% Delay of wound healing Diastasis recti Haematoma Scar dehiscence Median clinical excision margins: 17 mm (tumour excision margins + thickness of the 3-dimensional excision) (range 11.0: 30.0)
formalin. Then, the tumour biopsies were put into cassettes to be paraffin-embedded, and then stained with hemaluneosin for the horizontal analysis of the margins. The slides were analysed by pathologists who were specialized in DFSP. The pathologists were informed of the procedure and they were asked to provide the results as soon as possible. When the biopsy was positive, we performed the same procedure within the following days.
Results We managed 35 patients for DFSP between 2004 and 2013 in our department using slow MMS. No patient was lost to follow-up (Table 1). The median patient age was 42 years
3
(range 18-81). Sixty percent were men (n = 21) and 40% were women (n = 14). The DFSP discovery was made by a dermatologist in 43.5% of cases (n = 10), by a general practitioner in 30.4% of cases (n = 7), or by the patients themselves in 26.1% of cases (n = 6). The sites of involvement were the face and neck (5.7%), upper limbs (14.3%), lower limbs (17.1%), anterior trunk (31.4%), and posterior trunk (31.4%) (Fig. 1). For all the patients, it was a primary management and not a recurrence. The patients presented no local trauma before the DFSP appeared (wound, burn, local infection, or scar). No patient benefited from an additional imaging examination to assess tumour infiltration. None of our patients presented a surgically unresectable DFSP. We did not use any neoadjuvant treatment before surgery. On the surgical plan (Fig. 2), 85% (n = 30) of patients benefited from general anaesthesia and 15% (n = 5) from a local anaesthesia. The median size of the excision was 37.11 cm2 (range 12.37: 109.95). A direct closure after excision was possible in 83% of cases (n = 29), a controlled wound healing was necessary in 11% of cases (n = 4), and a skin graft or a local flap was performed in 6% of cases (n = 2). In this last case, the DFSP excision had a diameter of 12 cm and closure with a local flap was the optimal solution. The mean size of the excision when we could not directly suture was 95 mm long (65-120) and 70 mm large (50—100), i.e. 66.5 cm2 in average (32.5—108). Minor postoperative complications were reported in 11% of cases (n = 4) (a delay of wound healing, a diastasis recti, a haematoma, and one scar dehiscence). The median time to get the anatomopathological results was 5 days (range 0: 13). Apart from the initial biopsy, the mean number of surgeries was 1.4 (median 1, range 1: 3). In 17% of cases, two surgeries were necessary because the first biopsy was positive, and in 11% of cases a third surgery was performed because the second biopsy was still positive. Our median clinical excision margins were 17 mm (tumour excision margins + thickness of the 3-dimensional excision) (range 11.0: 30.0). No local or distant recurrence was highlighted nor metastasis. No patient was displeased by the management duration. The median duration of follow-up was 46 months (range 35.2: 60.2).
Figure 1 Lateral thoracic DFS (left). Surgical view: the lesion is delimited. Excision of 1 cm that we practice compared to 5 cm margins that could be used. Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Figure 2 The procedure: we first perform the excision of the lesion. We remove the visible tumor with a layer of surrounding tissue (A). A 3-dimensional exeresis is performed with a thickness as close as possible to 3 mm to be easily put into a histocassette by the pathologist (B). The surgical specimens are oriented and inked to realize a precise mapping by the pathologist (C). Immediate closure of the wound (D).
Discussion DFSP is a rare dermal tumour presenting a high risk of local recurrence, which remains the main difficulty regarding its management. The risk factors for DFSP are still unknown. Taylor reported 16.5% of local traumas [4] but we did not highlight pre-existing traumas to the DFSP appearance in our series. The development of DFSP is not concentric compared to other tumours, which is why wide excision does not seem to be the best technique to manage these tumours, as it would obviously sacrifice too much healthy tissue. It is
Table 2
accepted that the risks of recurrence decrease when the margins increase [5—8] (Table 2). However, no correlation was made between the size of the tumour and the required excision margins [9]. MMS is currently the main alternative to a wide excision (Table 3). The aim of MMS is to reduce as much as possible the surgical excision margins while limiting local tumour recurrences. The modified MMS or slow-Mohs using paraffin-embedded sections was first described by Breuninger et al. in 1988 [10]. It consists like Mohs technique of a histological 3D analysis of
Mohs micrographic surgery.
Study/Authors
Recurrence rate (%)
Follow-up (months)
7
0
60
Breuninger et al. (1994) [32]
23
0
60
Parker et al. (1995) [20]
20
0
40.8
Dawes et al. (1996) [33]
24
8.3
61.2
Ratner et al. (1997) [34]
58
1.7
57.6
Huether et al. (2001) [35]
33
3
45.6
Ah-Weng et al. (2002) [9]
21
0
47
Dubay et al. (2003) [21]
11
0
48.4
Snow et al. (2004) [13]
29
0
60
Meguerditchian et al. (2010) [36]
20
0
40.4
Tan et al. (2011) ‘‘Slow mohs’’ [17]
35
0
29.5
1.2
55
Mohs (1978) [31]
Total
Number of patients
281
Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
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Wide local excision.
Study/Authors
Number of Patients
Margins (cm)
Recurrence rate (%)
Follow-up (months) 105
Smola et al. (1991) [37]
20
1—5
30
Rutgers et al. (1992) [27]
19
2—3
0
158.4
Arnaud et al. (1997) [38]
107
5
2.1
61
Bowne et al. (2000) [26]
159
NC
Joucdar et al. (2001) [39]
65
5
Chang et al. (2004) [40]
60
Dubay et al. (2004) [21] Behbahani et al. (2005) [41]
21
57
7.6
60
>3
16.7
59
43
NC
0
48.4
34
3
0
60
NC
3.7
NC
Fiore et al. (2005) [42]
218
Popov et al. (2007) [43]
40
3
0
40
Heuvel et al. (2009) [44]
38
2-3
7
89
Meguerditchian et al. (2010) [36]
28
2
3.6
49.9
Farma et al. (2010) [45]
206
2
1
64
Total
865
N/A
7.5
73
the margins thanks to a peripheral surgical incision. Conventional histological analysis techniques do not examine 100% of the margins whereas 3-dimensional excision is analysed in its entirety (Fig. 3). Compared to MMS, slow-Mohs technique embeds the sections from the 3-dimensional excision in paraffin and does not analyse frozen sections. Unlike of the United States, where the surgeons analyze the tumour themselves, in Europe we need pathologists. They consider, however, slow-Mohs as a time-consuming procedure and on this specific point the cancer centers such as Claudius Regaud institute seem more favorable. Moreover, the valorisation by the health insurance remains insufficient [11,12]. In our unit, wide excision with margins of 5 cm was the standard technique, but the arrival of a plastic surgeons team at the institute has given a new impetus to the management of DFS. We decided to use slow-Mohs technique as for us it was easy to perform in daily practice. The pathologists were told of the procedure the day before to be in optimal conditions. Although, this is a more expensive and timeconsuming procedure, it seems to be more reliable in terms of histological analysis. Many authors have reported a higher
Figure 3
difficulty to differentiate healthy tissue from tumour tissue on frozen sections [13—16]. In fact, Tan et al. reported a higher recurrence of DFSP in MMS using a frozen section analysis than in those using paraffin embedded sections [17]. This might be due to very small residues, which are more difficult to differentiate from healthy dermal tissue after being frozen, which can alter the tissue architecture [18]. Situations where paraffin-embedded sections clearly showed the presence of tumour were also reported, although frozen sections coming from the same sections were healthy [17]. The fusiform organisation of DFSP cells associated to the tumour infiltrates scattered in the healthy dermis as well as the common presence of scar tissue or of granulation secondary to biopsies or to the initial surgery are many negative factors which make reading frozen sections more difficult. The input of CD34 immunostaining helped increase the frozen sections’ screening sensitivity, but many false positives remained [17,19]. Our study conducted on 35 patients with DFSP highlighted a noticeable reduction compared to the margins recommended in the literature with wide excision. We never performed total margins above 2 cm at first (tumour clinical
Histologic procedure. The tissues are cut and put into cassette before paraffin embedding.
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margins + thickness of the 3-dimensional excision) in order to spare tissue. A smaller excision also means less postsurgical complications. The aim was to perform a direct closure in every case and to wait for the results. Our median clinical excision margins were 17 mm with a 0% recurrence rate at 46 months. We noticed the thickness of the 3dimensional excision is quite variable as it is a complex procedure where it is sometimes difficult to stay perfectly regular. Parker et al. reported their experience of MMS with 15 mm margins for DFSP below 2 cm, and performed a complete excision in 80% of cases [20]. Nouri et al. reported a 0% recurrence rate on 20 patients with a median follow-up of 56.4 months [16] and Dubay et al. reported a 0% recurrence rate on 11 patients with a median follow-up of 52.8 months [21]. We noticed that many authors described very low recurrence rates (0-8.3%) with MMS. The articles about slow-Mohs are less numerous, but recently Tan et al. reported their experience on 35 patients over a median follow-up of 29.5 months with a 0% recurrence rate [17]. In the literature on wide excision, the teams who practised margins below 3 cm reported important recurrence rates [19]. We understand that wide excision seems interesting for many surgical teams as it is fast, cheaper, and easier to perform than MMS. Monnier et al. showed a significant difference of recurrence depending on margins in 66 patients over 9.6 years. They found 47% of recurrences with margins lower than 3 cm and 7% between 3 and 5 cm [22]. To maintain the patients’ comfort, we frequently chose general anaesthesia (85%). In 83% of cases, we could perform a direct closure and the patients did not come back home with an open wound. It is sometimes reproached to the slowMohs technique to be uncomfortable for patients, but in our study the procedure was well tolerated, and for us the advantages of this technique remain more important than this inconvenience [23]. Recurrences of DFSP would be more frequent on the face [21,24,25], maybe because the surgeons hesitate to perform wide excisions on these areas. Metastases are exceptional but described: 1% for Browne et al. in 159 patients [26], up to 4% of metastases reported by Rutgers et al. in a series of 913 patients [27]. In our series, no lesion was unresectable. Here, we must underline the importance of a multidisciplinary management with the oncologist, the radiotherapist, and the pathologist, who in addition to the surgeon can give their opinion concerning management planning. For large tumours on the face or very deep tumours, there is a hope with neoadjuvant treatments, which are being developed. Imatinib mesylate (GLIVEC1) and Pazopanib (VOTRIENT1) are targeted treatments, which are efficient on tumour reduction [28]. The translocation t(17:22) resulting from the fusion of the COL1A1-PDGFB gene is present in 95% of patients and plays a role in the targeted treatments’ efficiency [3]. For Kerob et al. in a multicentre phase II study conducted on 25 patients, imatinib mesylate targeting the breceptor of the platelet-derived growth factor would reduce by 20% the size of the tumour in more than a third of the DFSP cases receiving a neoadjuvant treatment [3]. The radiotherapy alone or associated to surgery showed moderate efficiency in the treatment of DFSP [29]. This tumour remains however radiosensitive. It can be used to manage an unresectable or incompletely resected tumour to limit local recurrences [2]. Sun et al. even recommended radiotherapy
as a systematic adjuvant treatment to decrease the risk of local recurrence [30]. The role of radiotherapy and of targeted treatments (Imatinib mesylate, Pazopanib) still needs to be assessed before being systematically suggested. To conclude, our management with slow-Mohs enabled us within reasonable periods of time to suggest a DFSP excision to our patients with median clinical excision margins of 17 mm. This management was confirmed on a series of 35 patients presenting a DFSP with a median follow-up of 46 months without recurrence. We suggest a systematic management of DFSP using the slow-Mohs technique, a procedure which proved to be efficient to spare tissue and to limit recurrences. The functional areas (periorificial, periarticular, or genital) as well as the face and nose are special candidate sites for this type of procedure. If MMS is unavailable, surgery with 3-cm lateral margins have to be recommended [19].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Please cite this article in press as: Chaput B, et al. Dermatofibrosarcoma protuberans: Margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients. Ann Chir Plast Esthet (2014), http://dx.doi.org/10.1016/j.anplas.2013.11.001
