The efficacy of Mohs micrographic surgery over the traditional wide local excision surgery in the cure of dermatofibrosarcoma protuberans

Usually most patients with dermatofibrosarcoma protuberans (DFSP) may present rather late when the tumor is in protuberant phase due to its rarity and indolent onset. It has a high propensity for local recurrence and destructive nature. Management of DFSP requires a biopsychosocial and Multidisplinary approach regardless of the clinical or immunohistochemical variant. Surgery is the Gold standard management of localized disease. DFSP rarely exhibits any lymphatic or hematogenous dissemination. It is because of its high recurrence rate associated with Wide Local Excision (WLE), the introduction of Mohs micrographic surgery (MMS) has really helped in reducing the rates of recurrence of DFSP. Thus, the aim of this meta-analysis and systemic review is to advocate for MMS over WLE for DFSP and other cutaneous malignancies using DFSP as a prototype. The objective of this study were to conduct a meta-analysis on comparative surgical methods used in the cure of DFSP with regards to WLE verses MMS, to evaluate the cure rates with relation to recurrence rates, offer a recommendation on the various treatment modalities based on the location of lesion, and use of adjuvant therapy in different clinical-medical setups. A comprehensive retrospective analysis search in EMBASE, Google Scholar and Medline (PubMed) for studies published from 2008 to 2018 containing the surgical management of DFSP with WLE verses MMS were reviewed. Five studies of moderate-quality evidence (level B) with a pooled patient load of 684 was analyzed and found for recurrence of DFSP after WLE and MMS to be 9.10% and 2.72% respectively after an average follow-up time for both groups of 5.32 years with a female predominance of 1.58. The trunk is the commonest site for the DFSP lesion which was at 52.80% then the upper and lower extremities zones and the head and neck zones at 31.75% and 15.45% respectively. The pooled adjusted odds ratio (OR) analysis indicated that there was a direct relationship with regards the reduced recurrence rate of DFSP in the MMS group compared to the WLE group (OR:0.31;95%; CI :0.17-0.56). Furthermore, there was significant association between the reduced recurrence rate with the MMS in DFSP patients with a statistical P-value of 0.0001 at 95% CI. The expected increased recurrence rate by zones was in WLE head and neck zone at 38.19% then trunk and extremities zone at 13.34%. In the MMS group it was at of 23.4% as compared to 16.0% in the head and neck zone. Mohs Micrographic Surgery (MMS) is more efficacious in the cure rate and recurrence reduction of DFSP and should be advocated for as first line therapy especially in high recurrence prone zones.


Introduction
Dermatofibrosarcoma protuberans (DFSP) is one of the rare, indolent, spindle cell mesenchymal sarcoma or malignancy of low-grade aggressiveness, that arises in the dermis and can extend to the deep subcutaneous tissue and can also affect other under lying structures like muscles and bones in un intervened cases and often stains positive for CD34 [1-3]. It was first described by Darier and Ferrand however Hoffman officially coined the term dermatofibrosarcoma protuberans [4]. DFSP, described as a slow-growing low-grade cutaneous sarcoma [5] that often presents or has a predilection on the following sites: trunk and proximal extremities [6], less frequently on the head and neck regions [2,7,8]. DFSP has a very low potential to metastasize but with significant subclinical tentacular extensions and great capacity for local destruction as evidenced by Acosta et al. [9]. Usually patients may present rather late when the tumor is already several centimeters in size due to its indolent onset.
Misdiagnoses of the tumor for a simple scar, keloid [10], or cyst, lump is often the case [11]. As it has been shown to arise from regions or areas of previous trauma. Even when allowed to grow for many years, the tumor usually remains asymptomatic. Cytogenetically, these tumors have been associated with chromosomal translocation at position 17:22 leading to an overexpression of tyrosine kinase PDGFB, which can be targeted with Imatinib, a tyrosine kinase inhibitor [12].
This rare cutaneous tumor, constitutes of not more than 0.1% of all malignancies and approximately 1% of all soft-tissue sarcomatous tumors [8,13]. It is a locally aggressive sarcoma of intermediate malignancy that favors young to middle-aged individuals of all sexes [14]. There has been reports of lesions that are present at birth or with an early onset during childhood [15,16]. Loghdey MS et al. describes DFSP as the most common skin tumor with prevalence of about 0.8 to 4.2 cases per million persons per year and it roughly accounts for between 2 and 6% of all soft tissue sarcomas [17]. The incidence of DFSP ranges between 0.5 and 1:100,000, thus it is considered as the most common cutaneous sarcoma. There seems not to be a gender or racial predilection for the tumor. However, the pigmented variant (referred to as Bednar's tumor) is more common in black population [18]. The hypothesized pathogenesis of DFSP is largely due to protooncogenes which are as a result or is associated by either; marked by chromosomal translocation t (17;22) (q11; q13.1) or an extra ring of chromosome derived from the t (17;22) which ends in the formation of COL1A1-PDGFB fusion gene in the greater number of cases of DFSP [19][20][21]. The chromosomal translocation is found in more than 90% of cases, and involves 17q22 and 22q13 [3,22]. The chimeric protein COL1A1-PDGFB, is processed into a functional beta platelet-derived growth factor (PDGFB) ligand that in turn causes PDGFRB signaling activation through an autocrine stimulation loop in tumor cells as evidenced by Simon et al. [23][24][25].
The COL1A1-PDGFB fusion gene, exhibit growth factor activity, this furthers on the proliferation on tumor cells [26]. Molecular studies have shown that fusion genes are crucial as the initiating factors of tumorigenesis in many translocation-related sarcoma subtypes [24,27]. Once PDGFB is cleaved from the COL1A1-PDGFB chimeric protein, it stimulates tumor cells to go into an autocrine fashion, thus, leading to proliferation transformation [ [31].
The clinical presentation is somewhat uniform with a few variations in racial and individual genetic variations. The tumor is more often commonly affects the trunk in about 40%-50% of cases, the proximal extremities (30%-40%), and the least being head and neck at 10%-15% of cases [32,33]. Involvement of the limbs is usually on the proximal aspects. Presentation on the hands and feet, particularly on the digits, is very rare. Clinically, classical DFSP tumors start as a plaque, which sometimes may be atrophic in nature. It may begin in early adulthood as one or more small, firm, painless, flesh-colored or erythematous dermal nodules [34]. Their progression is most of the time very slow and may occur over many months to years; a significant proportion of these tumors only become protuberant after a long period of time. Jonathan et al. classified DFSP into three different forms: the initial phase as morphea-like form resembling a scar, morphea, morphea-form basal cell carcinoma. Secondly, dermatofibroma plaque; this is an atrophoderma-like form similar to atrophoderma or an anetoderma. Finally, an angioma-like form resembling vascular malformations [35]. Subsequently, one or multiple nodules may mushroom in the protuberant phase. These nodules grow, extend and coalesce, becoming more redder or bluish as they enlarge to form an irregular protuberant swelling. At this phase, the base of the tumor is a hard-indurated plaque of irregular outline. In advanced stages, a proportion of some lesions become painful and may be associated rapid growth, ulceration and exudation [36]. Typically, DFSP lesions ranges between 1 to about 6 cm in size.
However, in some occasions, and if not remedied earlier, these tumors may grow to as much as 20 cm in diameter with multiple satellite nodules. The overlying skin is fixed to the tumor, but not to deeper structures. However, it has been documented that long-standing or recurrent tumors may invade deeper structures like fascia, muscle, periosteum, and even bone tissues [37,38]. On physical exam, initially the tumor is freely moveable from the underlying surface. As the tumor subsequently evolves in size, it becomes adherent to the underlying surface. At this stage the overlying epidermis may be thinned and telangiectasias appear. Bleeding and ulceration are uncommon. DFSP may less frequently present like a non-protuberant, violaceous and atrophic lesion similar to a sclerosing like basal cell carcinoma or morphea; which is a common presentation in childhood.
The pigmented variant of DFSP is termed Bednar tumor.
Diagnosis of DFSP can be achieved according to clinical, histopathological and immunohistochemical findings in any case variant of DFSP. After a tentative diagnosis of DFSP, a comprehensive evaluation of the patient is crucial for an effective management of the patient. Rarely does DFSP exhibits any hematogenous or lymphatic dissemination as observed by Gloster et al. [39,40]. Prior any surgical procedure, magnetic resonance imaging (MRI) is important, which is extremely sensitive than physical examination, for ascertaining tumor for the diagnosis of DFSP. It is approximated that over 80% to 100% of DFSP express this marker, although between 10% and 20% are negative, as mostly noted in the fibrosarcomatous type [44,45].
Nonetheless,CD34 expression has been increasingly reported in other non DFSP sarcomas [46,47], such as myofibrosarcoma [48], nuchaltype fibroma [49], inflammatory myofibroblastic tumor, epithelioid, or angiosarcoma. Positive CD34 has been reported in some benign fibrohistiocytic lesions, like in the solitary fibrous tumor, sclerotic fibroma, cellular digital fibromas [50], superficial acral fibromyxomas [47], and dermatofibromas [51]. As such, this marker may soon be considered less specific for DFSP but a careful clinical and immunohistochemical evaluation is thus essential in the definitive diagnosis of DFSP. In the management of DFSP a biopsychosocial and

Methods
This Meta-analysis was done according to the preferred Reporting items for systematic reviews and meta-analyses known as the PRISMA statement [56]. Inclusion criteria: eligibility to our study were any RCTs comparing a 10-year recurrence rates of WLE to MMS in patients having primary or secondary DFSP on any part of body. In an advent that inadequate number of RCTs were found, non-randomized trials (NRTs) were to be included as long as they compared recurrence rates associated with MMS vs WLE (comparative NRTs) or reported only recurrence rates associated with MMS (noncomparative NRTs). The study should include more than ten patients.
Exclusion criteria: any studies involving adjuvant therapy (Radiotherapy or chemotherapy), fewer than 10 patients, incomplete data outcomes or either poor methodological design, duplicate publications, review articles and those conducted over 10years ago were excluded. Also, case reviews, pre-clinical studies, titles, abstracts and expert opinions were not accepted in our meta-analysis.   we retrieved the full text of 100 studies. Of these, 53 articles were further excluded because they were older than 10 years. Further 37 articles were excluded because they were review articles as well as case studies and others had less than 10 subjects in their studies.
Articles without eligible data or not in English were three. Articles including adjuvant therapy to WLE and also recurrence case were two.
Consequently, five studies were eligible for this meta-analysis review.
Due to the aforementioned reasons, none of the included studies were randomized controlled trial. All articles were retrospective comparative NCTs studies. The characteristics and patient demographic information from each of the five studies included in our meta-analysis are shown in However, the quality of included studies was level B grade according to criteria by Robinson et al. [71]. The study also labored to analyze The trunk and extremities zone in the WLE were at 13.34%. This is slightly half that in the head and neck zone.

Conclusion
Our study reviewed that MMS has better outcomes that WLE in terms

Competing interests
The authors declare no competing interests.

Authors' contributions
All authors had full access to all the data in the study and take