19.7.1.2 Mohs Micrographic Surgery

MMS has several advantages over WLE which include

(1) inspection of 100% of tissue margins for residual tumor, (2) intraoperative pathologic assessment of three-dimensional view of clinical margins, (3) preservation of maximum amount of normal tissue, and (4) functional and cosmetic sensitivity in anatomically challenging areas [73–75].

The decision to treat DFSP with MMS versus WLE depends on the anatomic location, tumor size, availability of MMS, and physician preference. The efficacy of MMS in the treatment of DFSP has been well documented in the literature. Recurrence rates as low as 0–6.6% have been reported with MMS [76–79]. In the most recent study evaluating MMS as the sole treatment for DFSP, MMS yielded a local recurrence rate of 0% at an average of 39 months follow-up in 39 DFSP cases. Four cases were recurrent tumors and 31 were primary [78]. Another study by Nelson et al. reported no tumor recurrence in their series of 44 DFSP patients over a 3.3 years average follow-up [79]. Deep margin resection during MMS should go down to and include fascia or periosteum [66].

Only three studies formally examine the utility of MMS compared to WLE, and each study reported different recurrence rates between the two modalities. The Mayo Clinic case series consisting of 84 DFSP patients reported lower recurrence rates of 6.6% for MMS and 10% for WLE at 36 and 40 months followup, respectively. Only 15 patients (18%) underwent MMS. The study also included 56% of patients with recurrent tumors which may not allow for an unbiased assessment of the true efficacy of MMS in comparison to WLE [80]. Dubay et al. described 63 DFSP cases with no recurrence in any of the three groups of patients assigned to three different treatment regimens: 11 (17%) cases of MMS, 44 (70%) cases of WLE, and 9 (14%) cases of combination treatment (MMS and/or WLE and/or radiation). Two WLE cases received additional treatment with radiation after maximal excision for positive microscopic margins. This study also included least 11 recurrent DFSP tumors, 8 of which were treated with WLE, 1 with MMS, and 2 with combination treatment [3].

A third case series with 48 DFSPs reported 3.6% recurrence rate with WLE (28/48 cases, 58%) versus 0% with MMS (20/48 cases, 42%) at a median followup of 49.9 and 40.4 months, respectively. The authors of the study commented that although WLE resulted in more frequent positive margin resection, local control was ultimately similar for both surgical modalities.

They also noted that WLE proved to be a more timeefficient procedure with significantly lower operative time at 77 min versus 257 min for MMS. However, the opportunity to perform definitive resection in the case of positive margins on the same day was lost. The authors concluded that the choice of WLE versus MMS should be based on patients and tumor characteristics as well as institutional expertise in these modalities [74].

Postoperative defect sizes can be large requiring advanced reconstruction. Nelson et al. reported defect sizes ranging from 7.2 to 168.0 cm2 in their series of 44 DFSP patients treated with MMS. Fifty percent of the patients underwent plastic reconstruction, while the rest underwent primary closure by the Mohs surgeon [69]. Multidisciplinary approach is often needed for tumors adjacent to or involving vital structures on scalp, face, breast, and eyes, among others. Several cases in the literature have illustrated the joint efforts of specialties such as ophthalmology, plastic surgery, and head and neck surgery in optimal reconstruction of tissue defects [3, 66, 81–83].

Adjuvant immunohistochemistry can facilitate the accurate delineation of DFSP margins intraoperatively during MMS. The most common and practical immunohistochemical marker used in MMS is CD34, an antigen typically found in hematopoietic stem cells, endothelium, dermal dendritic cells, and endoneuronal dendritic cells. Staining tumor specimens with CD34 has enhanced the yield of negative margins by clearly delineating the extent of tumor involvement and unmasking areas of tumor cells surrounded by inflammation [84, 85]. The increased time for immunostaining limits its practical use during MMS. Alternatively, after complete excision of the tumor with MMS via frozen sections, a final layer can be sent for permanent sections to be stained with CD34, thereby providing more corroboratory means of assessing margin control [86, 87]. Caution must be exercised since DFSP cells may have variable CD34 expression depending on tumor characteristics of plaque or nodular components [88].

19.7.2 Radiotherapy

The role of radiation therapy for DFSP remains controversial. In combination with surgery, radiotherapy has been utilized in patients who cannot undergo invasive procedures due to medical or technical reasons. Eternal beam radiation therapy (EBRT) is usually administered in the range of 59–65 gray (Gy) [89]. Dagan et al. reported disease-free follow-up ranging from 1.8 to

15.5 years in ten DFSP patients who underwent resection before EBRT. Four patients had negative surgical margins, while the rest had either or <5 mm of microscopically positive margins. Only one patient, who had the FS variant of DFSP, experienced local recurrence 3 months after treatment [90]. In another case series of 35 DFSP patients who underwent surgery alone (24 patients) and combined surgery with radiation (11 patients), local control rates after 7-year follow-up were 28% and 80%, respectively. One of the 11 patients receiving adjuvant radiation initially had inoperable tumor and received palliative preoperative radiation. The remaining ten patients underwent radiation due to either surgeon’s preference (four patients) or inadequate resection margins (six patients) [91].

Radiation-induced DFSP has also been reported in the literature. DFSP should be included in the differential diagnosis of postradiation fibrohistiocytic tumors [92–94]. The pathogenesis of postradiation DFSP is not clear. It has been speculated that fibroblasts transform into DFSP cells under long-term stimulation by various radiation-induced cytokines, especially transforming growth factor-B (TGF-B) [95].

19.7.3 Molecularly Targeted Therapy

Imatinib mesylate (imatinib, STI 571) is a low-molecular weight, synthetic, 2-phenylaminopyridine derivative, and a tyrosine kinase inhibitor. Initially developed to inhibit the tyrosine kinase BCR-ABL, imatinib also showed clinical efficacy against ABL-related kinase, KIT, PDGFRs. It is marketed as Gleevec® in North America and Glivec® in Europe by Novartis Pharmaceuticals and is available as 100 and 400 mg capsules [96]. Imatinib has revolutionized treatment of chronic myelogenous leukemia (CML) as well as gastrointestinal stromal tumors (GISTs). It is clinically indicated and approved by the Food and Drug Administration (FDA) for Philadelphia (Ph) chromosome positive CML, refractory Ph chromosome positive acute lymphoblastic leukemia, hypereosinophilic syndrome, systemic mastocytosis, myelodysplastic disorders, GISTs, and DFSP. Imatinib has become the model of targeted therapy in oncology and a novel treatment modality for DFSP [27, 97].

The introduction of imatinib-targeted therapy into the treatment of DFSP was possible due to the advances in the understanding of the molecular pathogenesis of DFSP. PDGFB is overexpressed in DFSP and constitutively stimulates its tyrosine kinase receptor, PDGFR. The adenosine triphosphate (ATP) binding site of

COL1A1 PDGFB

PDGFR

ATP

ATP Imatinib

Fig. 19.7 Pathomechanism of imatinib mesylate. Imatinib inhibits the tyrosine phosphorylation of proteins involved in COL1A1-PDGFB related signal transduction by binding to the adenosine triphosphate (ATP) binding site of PDGFR. ADP adenosine diphosphate, ATP adenosine triphosphate, PDGFB platelet-derived growth factor B, PDGFR kinase platelet-derived growth factor receptor

PDGFR is inhibited by imatinib, a tyrosine kinase inhibitor. By competing for the ATP binding site of the kinase, imatinib inhibits the tyrosine phosphorylation of proteins involved in COL1A1-PDGFB related signal transduction (Fig. 19.7). It is hypothesized that imatinib reduces proliferation of DFSP cells, causing a decrease in tumor size [24–26].

Initial use of off-label imatinib involved cases of unresectable or metastatic DFSP to the lungs. Some cases showed a treatment response characterized by reduction in tumor size or tumor resolution with a dose of 400 mg daily [98–100]. These results led to a phase II open label study in 2004 using imatinib 800 mg daily (400 mg bid) in ten patients, eight patients with primary DFSP, and two patients with metastatic disease. All nine of nine cases of DFSP with t(17;22), including one case of metastatic DFSP, showed either partial or complete response. The one case lacking PDGFB rearrangement also had metastatic disease and showed no improvement [101]. Based on the results of this study and other case reports, the FDA approved imatinib for use in adults patients with (1) unresectable DFSP, (2) recurrent DFSP, if additional resection would lead to unacceptable functional or cosmetic outcomes, and (3) metastatic DFSP [8].

Additional clinical trials have demonstrated the effectiveness and safety of imatinib in inducing partial or complete remission. A phase II clinical study on 25 DFSPs (longest diameter: 25 cm, median diameter: 4.5 cm) using 600 mg/day imatinib daily for 2 months demonstrated clinical response rate of 36%. The primary

endpoint was a decrease in tumor size by at least 30%. The COL1A1-PDGFB fusion gene was detected in 21 patients, 13 of which failed to respond to imatinib [102].

A nearly 50% response rate was demonstrated in pooled analysis of two phase II clinical trials on 24 DFSP patients for 14–16 weeks. No significant difference in efficacy was noted between imatinib doses of 400 or 800 mg daily. The use of neoadjuvant imatinib in facilitating complete surgical excision has also been substantiated. Four patients achieved complete remission after WLE in an EORTC (European Organisation for Research and Treatment of Cancer) study using 800 mg of imatinib for 14 weeks. Rutkowski et al. reported disease-free survival of 47% in 7 out of 15 patients undergoing WLE after 400–800 mg imatinib daily. The median time from the initiation of imatinib therapy to WLE of residual tumor was 3.3 months (range: 3–8 months) [103].

Several pediatric DFSP case reports have illustrated the use of adjuvant imatinib mesylate therapy in the management of DFSP [104–106]. The largest pediatric case series to date used 400–500 mg/m2/day imatinib over 6–12 months as preoperative management in three children (age range: 1–14 years old). The patients had previous history of multiple recurrences or anatomically challenging tumor location. Partial response, as defined by response evaluation criteria in solid tumors (RECIST), was noted in all three patients. The patients remain free of disease at an average of 2-year follow-up [104].

Imatinib has a favorable safety profile with most patients experiencing mild-moderate and well-toler- ated side effects of edema, asthenia, nausea, and maculopapular rash. These were easily managed by supportive medical management, dose reduction or interruption. Rare serious adverse event has included transaminitis, anemia, neutropenia, leukopenia thrombocytopenia, and Stevens–Johnson syndrome [8, 107].

Clinical benefit of imatinib is lacking in DFSP without t(17;22) as these tumors may not be dependent on signal transduction through PDGFRs. As a result, the National Comprehensive Cancer Network (NCCN) guidelines recommend that cytogenetic analysis may be useful prior to the institution of imatinib therapy. Cytogenetic confirmation for the tyrosine kinase receptor may be done via FISH or RT-PCR [8, 108]. The use of neoadjuvant imatinib therapy to reduce tumor burden prior to surgery may also have its limitations. It has been suggested that the therapeutic actions of imatinib on DFSP may be non-uniform. The resultant skip areas of tumor could potentially be missed during surgery with margin control [8, 109].

For appropriately selected patients, imatinib may minimize functional and cosmetic disfigurement while enhancing surgical outcomes. The optimal duration of preoperative imatinib therapy in DFSP patients is unknown. Further studies are needed to evaluate imatinib’s clinical efficacy and long-term outcomes with respect to local control and disease-free survival in DFSP.

19.7.4 Imaging Studies

The extent of DFSP involvement cannot be ascertained based solely on clinical examination. Large tumor size does not necessarily indicate subclinical extension. Several imaging modalities are being used to characterize tumor size and extent including ultrasound and magnetic resonance imaging (MRI).

Shin et al. described the ultrasonographic features of four DFSPs as a subcutaneous mass abutting the skin with lobulated margin and hypoechogenicity or an irregular margin and mixed echogenicity. The study also correlated the pathologic findings with the corresponding sonographic aspects of DFSP [110, 111]. A hypoechoic DFSP exhibits high cellularity, with spindle cells arranged in a distinct storiform pattern, whereas the hyperechoic areas are a mixture of DFSP cells and fibrous tissue infiltrating the subcutaneous fat. The sensitivity and specificity of ultrasound for detection of DFSP is, however, unknown at the present [110, 111].

Perioperative MRI has been utilized to assess muscle and tendon involvement. MRI appears to be the superior imaging modality for DFSP because of its high soft tissue resolution and contrast. In the largest study to date evaluating the utility of MRI in DFSP assessment, three out of ten histologically confirmed DFSPs with clinically obscure extent of tumor demonstrated fascial and muscle involvement. The actual tumor size ranged from 2 to 8 cm with an average of 4 cm. Either T1 or T2-weighted MRI images may be used. DFSP is isointense or slightly hypointense compared with skeletal muscle with a lower intensity signal than subcutaneous fat on T1-weighted images. T2-weighted imaging portrays DFSP as hyperintense or isointense compared with fat. Fat suppression techniques are routinely used in T1-weighted images since the brightness of the fat signal can obscure DFSP [112, 113].

Studies suggest that preoperative MRI may play a role in evaluation of DFSP with large tumor size, history of recurrence, location in critical anatomic regions, or in cases of re-excision with positive surgical margins.