Neoadjuvant treatment of Dermatofibrosarcoma Protuberans of pancreas with Imatinib: case report and systematic review of literature

Dermatofibrosarcoma Protuberans (DFSP) is a rare fibrohistiocytic tumor of the skin or subcutaneous tissue that is often locally infiltrative but rarely metastatic[1, 2]. Cytogenetically, DFSP is characterized by a pathognomonic translocation t(17;22) (22;q13) with fusion of the COL1A1 gene on chromosome 17 with the PDGFB gene on chromosome 22[3]. This event results in constitutive expression of ligand PDGFB creating an autocrine stimulatory loop that drives cell proliferation and fibrosis. Clinically, it commonly presents in younger adults growing slowly over many years[2, 4]. Microsatellite instability and p53 mutations are involved in tumor progression to the fibrosarcomatous variant (DFSP-FS)[5]. Although the major recurrence risk for DFSP is local relapse, DFSP-FS subtype is associated with an aggressive clinical course, more likely to develop distant metastases[6, 7]. Several case reports in the literature have demonstrated that DFSP can metastasize to the lungs[8‐10], as well as, pancreatic or retroperitoneal spaces similar to the current case[11‐13]. The optimal treatment of primary and metastatic DFSP is complete surgical resection with negative margins[14]. Over 90% of DFSPs, demonstrate a constitutive activation of platelet-derived growth factor receptor, making inhibition with a promiscuous tyrosine kinase inhibitor (TKI), Imatinib a good option for unresectable, recurrent, or metastatic disease[15]. There have been several reports of neoadjuvant Imatinib for locally advanced primary tumors and adjuvant Imatinib for resected margin positive primary disease and metastatic disease[16‐20]. There have been no published reports of neoadjuvant Imatinib for unresectable metastatic DFSP to the pancreas successfully treated and subsequently resected. Here, we present the first reported case of unresectable metastatic DFSP to the pancreas, successfully resected following neoadjuvant Imatinib. Additionally, we conducted a systematic review of the literature for pancreatic metastases of DFSP and use of Imatinib in DFSP.

A 31 year old African American male was diagnosed with DFSP of the skin and soft tissue of the anterior left chest wall and shoulder in 2005 and underwent local excision at an outside facility in December, 2005. Grossly, the excised specimen consisted of a 22.0 × 18.0 × 9.5 cm portion of skin & subcutaneous tissue that contained a multinodular and glistening dermal & subcutaneous mass. Histologically, this revealed a neoplasm consisting of atypical spindled cells arranged in a storiform pattern that invaded the dermis and subcutaneous tissue (Figure 1A). Large parts of this tumor showed areas histologically reminiscent of fibrosarcoma (at least 75% of the tumor), characterized by spindled mesenchymal cells with high grade cytologic atypia arranged in broad fascicles forming a “Herringbone” pattern (Figure 1B), with more than 10 mitotic figures per high powered field. This neoplasm showed expression of CD34 by immunohistochemistry (Figure 1C), but was negative for Desmin, S100, Pan-cytokeratin, BCL-2, and CD117 expression. The deep margin of resection was focally positive for the neoplasm. A diagnosis of dermatofibrosarcoma protuberans with fibrosarcomatous transformation (DFSP-FS) was rendered.The patient received no other therapy at that time and did well until October 2007, when he presented to the emergency department with severe anemia and a hemoglobin of 4 g/dL. Surgical Oncology was consulted after an abdominal CT scan revealed a heterogeneous mass in the left upper quadrant involving the pancreas, spleen, adrenal, left lobe of liver, and stomach measuring 17 × 18 × 23 cm (Figure 2A). A core biopsy of this retroperitoneal mass was obtained that showed spindle shaped mesenchymal cells with high grade cytologic atypia (Figure 2B) essentially identical to the fibrosarcomatous areas that were seen in the 2005 chest wall DFSP-FS. These malignant cells showed an identical immunophenotype as the original chest wall tumor (see above). A dual fusion DNA FISH probe set for the COL1A1 (17q21) and PDGFB (22q13) genes was positive for a COL1A1-PDGFB translocation (Figure 2C), consistent with DFSP-FS metastasis to the retroperitoneum.Radiographically, this retroperitoneal tumor was unresectable and the patient was started on Imatinib therapy 400 mg BID. The patient tolerated this dose without any reported side effects and after 18 months of Imatinib therapy, the tumor exhibited a dramatic response with a 70% size reduction and radiographically appeared to be amenable to margin negative (R0) surgical resection (Figure 3). A left upper quadrant exenteration (en-bloc resection including a subtotal distal pancreatectomy, splenectomy, left adrenalectomy, and subtotal gastrectomy) was performed with negative margins on September 1, 2009 (Figure 4A-C). Post-Imatinib, this resected tumor showed dramatically altered histology, revealing primarily hyalinized and myxoid fibrous differentiated stroma (Figure 5A) with focal atypical spindle cells (Figure 5B-C) that revealed a COL1A1-PDGFB fusion by interphase FISH analysis, consistent with a dramatic gross and histologic response of the metastatic DFSP-FS to the Imatinib. The lymph nodes were negative for tumor.

The patient resumed adjuvant Imatinib for 6 months and remained free of disease for 14 months, off therapy. His imaging at 14 months revealed para-aortic nodal disease without evidence of local recurrence that responded to reinstitution of Imatinib at the same dose. The patient is now five years out from the initial diagnosis of metastatic disease and remains in remission on Imatinib.

To our knowledge, this is the first case report where an unresectable pancreatic metastasis was treated in a neoadjuvant fashion with Imatinib and an R0 resection was successfully performed. Consistent with findings observed in neoadjuvant therapy for primary cutaneous disease, when a clinical and radiographic reduction in tumor size is observed, it corresponds with the histologic findings of markedly decreased cellularity as evidenced by fewer CD34+ cells, along with significant hyalinization of dermal collagen as seen in our case (Figure 5A-C). In the current case, neoadjuvant Imatinib resolved the presenting symptoms (GI bleeding, anemia, and pain) and enabled R0 resection of an unresectable metastasis. The dose of 400 mg BID was selected based on the only published phase II study, B2225 at that time in 2007[40]. This study reported a 100% response rate in eight locally advanced t (17;22) positive DFPS tumors with four patients (50%) exhibiting complete responses. Additionally McArthur et al. reported 7/8 (88%) patients tolerated the therapy with only one patient requiring dose reduction to 600 mg. Since B2225 three additional phase II trials (Additional file4) have been conducted evaluating 400 mg, 600 mg and 800 mg doses which have reported similar efficacy and tolerance profiles[46, 49].

In this case 400 mg BID Imatinib followed by resection facilitated excellent local control evident now 5 years post metastatectomy, 10-years from primary cutaneous diagnosis without resection bed recurrence. Although, the patient did develop distant, para-aortic nodal metastasis 14 months post-resection, metastatic disease remained Imatinib responsive and demonstrated radiographic resolution with therapy. Importantly the patient did not report any significant gastrointestinal or other side effects during neoadjuvant therapy or subsequent therapy for nodal recurrence.

In conclusion, given the intrinsic biological sensitivity of COL1A1/PDGFB positive DFSP to Imatinib, neoadjuvant therapy with this medication may not only be an important tool in managing locally advanced and recurrent cutaneous disease but equally valuable in unresectable or marginally resectable metastatic DFSP; facilitating margin negative resection, improving local control, and extending disease free and overall survival. The response observed following neoadjuvant Imatinib may also be useful as an in vivo test of tumor’s responsiveness and may be useful in determine the best post-operative adjuvant therapy. Neoadjuvant and adjuvant Imatinib is well established in Gastrointestinal Stromal Tumors (GIST), unlike in DFSP. The results from the closed clinical trial NCT00243191/SARC004 will provide insight into the value of short course therapy in cutaneous disease but additional trials are needed to address the value in the setting of metastatic DFSP. This report highlights the value of neoadjuvant Imatinib in facilitating surgical resection and the continued response of distant disease sites in a patient now over 5-years with metastatic DFSP.