Stefano Radaelli

Epithelioid sarcoma: Prognostic factors and survival in a series of patients treated at a single institution

BackgroundEpithelioid sarcoma (ES) is a rare subtype of soft-tissue sarcoma of unknown histogenesis. Typically, it occurs superficially as single/multiple nodules (nodular ES), or in deeper tissues as a mass. The correlation between initial presentation and clinical outcome was investigated.MethodsFifty-four consecutive patients surgically treated at a single referral center were retrospectively reviewed. Thirty-six patients presented with a primary and 18 with a recurrent tumor. Potential prognostic clinicopathological variables, including macroscopic features at first presentation, were tested by univariable and multivariable analysis with respect to overall (OS), metastasis-free (MFS), and local recurrence-free survival (LRFS).ResultsThe 10-year OS was 61.8% for the whole series. Thirty patients relapsed; in detail, local and distant failure occurred in 14 (25.9%) and 24 (44.4%) patients, respectively. The lymph node involvement rate was 16/54 (29.6%). In both the whole series and the subset of patient with primary ES, single localized tumor correlated with increased OS at multivariable analysis; occurrence of nodal involvement during postoperative follow-up correlated to worse OS and MFS. Nodular ES was an independent predictor of worse LRFS. In univariable analysis, nodular ES was associated with smaller tumor size, distal limb locations, earlier classification of malignant tumor (TNM) stage, and higher amputation rate. A statistical difference in the pattern of failure between nodular and mass ES was found.ConclusionsPrimary tumor macroscopic features seem to correlate to different local aggressiveness and failure patterns. Better prognosis is associated with single localized disease stage and no occurrence of locoregional spread.

Emerging therapies for adult soft tissue sarcoma

Soft tissue sarcoma (STS) are a broad group of rare tumors. Cornerstone of treatment is surgery. Complementary radiotherapy is recommended in high-risk STS arising from extremities. Doxorubicine ± ifosfamide based cytotoxic chemotherapy, explored in few randomized trials, showed a certain degree of activity, playing an established role only in unresectable disease. Since peculiar chemosensitivity towards alternative drugs was described for different metastatic subtypes in second or further lines, the modern concept of ‘histology-driven chemotherapy’ has been accepted and employed: gemicitabine ± dacarbazine, trabectedin and taxanes used respectively in patients with leiomyosarcoma, solitary fibrous tumor, myxoid/round cell liposarcoma, angiosarcoma. Recent discoveries about molecular pathways involved in STS tumorogenesis led to develop molecular targeted agents such as imatinib used in advanced dermatofibrosarcoma protuberans (DFSP) or metastatic DFSP-related fibrosarcoma, pazopanib, approved as second line regimen in advanced non-adipocitic STS and recently sunitinib in solitary fibrous tumors, alveolar soft part sarcoma and extraskeletal myxoid chondrosarcoma.

Imatinib in advanced chordoma: A retrospective case series analysis

INTRODUCTION Imatinib showed activity in 50 chordoma patients treated within a Phase II study. In that study, 70% of patients remained with stable disease (SD), median progression free survival (PFS) was 9 months and median overall survival (OS) was 34 months. We now report on a retrospective series of PDGFB/PDGFRB positive advanced chordoma patients treated with imatinib as a single agent within a compassionate-use programme at Istituto Nazionale Tumori, Milan, Italy (INT) between August 2002 and November 2010, when the programme was closed. METHODS 48 patients were consecutively treated with imatinib 800 mg/d. All patients had inoperable and progressive disease before starting imatinib. Demographics, treatment duration, toxicity and response rate by Response Evaluation Criteria in Solid Tumors (RECIST) were retrospectively recorded. RESULTS The median duration of therapy was 7 months (1-46.5). No patient is on therapy at present. 46 patients were evaluable for response. No partial responses were detected. Best response was: stable disease 34 (74%), progressive disease 12 (26%). At a median follow-up of 24.5 months (0.5-117), median PFS was 9.9 months (95% confidence interval (CI) 6.7-13). Eight patients (16.5%) remained on therapy >18 months and 10 patients (21%) remained progression-free >18 months. Median OS was 30 months (95% CI 20-40), with 24 (50%) patients dead at the time of the present analysis. CONCLUSIONS We confirm the activity of imatinib in locally advanced and metastatic chordoma, in terms of >70% tumour growth arrest in previously progressive patients. Median duration of response lasted almost 10 months, with >20% of patients progression-free at 18+ months.

Sacral Chordoma: Long-term outcome of a large series of patients surgically treated at two reference centers

Study Design. Retrospective case series. Objective. To report on the natural history and long-term outcome of a large series of consecutive primary sacral chordoma patients surgically treated at two reference centers. Summary of Background Data. Sacral chordomas are rare tumors with poor long-term prognosis mainly caused by local failure. Till date, a few large series with long follow up are available in literature. Methods. All consecutive patients affected by primary localized sacral chordoma operated on at two Italian reference centers between 1981 and 2012 were included. Overall survival (OS), disease free survival (DFS), crude cumulative incidence (CCI) of local recurrence (LR), and distant metastases (DM) were calculated. Multivariable analyses for OS, DFS, LR, and DM were performed. Results. A total of 99 patients were identified: 65 males and 34 females. Median age was 59 years (range 22–77 yrs), median tumor size was 9 cm (range 4–22). Nineteen patients received pre- or postoperative radiotherapy (RT). Wide (R0) surgical margins were achieved in 46 patients, marginal (R1) margins in 43 patients and intralesional (R2) margins in 10 patients. At a median follow up of 8.7 years (range 1–23.8 yrs) 30 patients died of disease, 31 patients developed local relapse, 16 patients developed distant metastasis, whereas 51 patients are alive without disease. OS and DFS at 5, 10, and 15 year were 92% and 63%, 45% and 62%, 36% and 21%, respectively, without any evidence of a plateau in the curves.CCI of LR and DM were 30% and 9% at 5 years, 46% and 18% at 10 years, 56% and 23% at 15 years. Size of the tumor and quality of surgical margins were the only significant predictors of long-term outcome. DFS for 15 years was, in fact, 49% for R0 and 7% for R1, respectively. Conclusion. In this series, long-term outcome of resected sacral chordoma was poor, with less than 25% patients were disease-free at 15 years. Interestingly, only half of the patients treated with R0 resection had no evidence of recurrence at 15 years. When surgical margins are expected to be positive other treatment modalities should be considered, especially when expected sequelae are substantial as in the case of more cephalad levels of resection. Level of Evidence: 3

Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis.

INTRODUCTION Many patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and β-catenin pathways. MATERIAL AND METHODS We retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed. RESULTS Forty-four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G≥2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients. DISCUSSION Present series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results.

Vascular resection en-bloc with tumor removal and graft reconstruction is safe and effective in soft tissue sarcoma (STS) of the extremities and retroperitoneum.

BACKGROUND To analyze the outcome of a series of patients who underwent vascular resection as part of an excision of a soft tissue sarcoma (STS). STUDY DESIGN All consecutive patients affected by localized STS of an extremity or retroperitoneum treated between January 2000 and December 2013 with surgery including vascular resection were considered. Overall survival (OS), crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were estimated by Kaplan-Meier. Long-term vascular graft patency rate was assessed. RESULTS 2692 patients received an operation for localized disease with 105 (3.9%) cases undergoing vascular resection. Median FU was 32 months. 5-year OS, CCI of LR and DM were 62%, 12% and 58% respectively. Vascular reconstructions consisted of 52 arterial and 16 venous grafts in extremities; 12 arterial and 33 venous grafts in the retroperitoneum. Graft thrombosis occurred in 16 patients (7/64 arterial and 9/49 venous reconstructions). Arterial occlusions occurred at a median of 36 months after surgery and were treated by prosthesis replacement (3), Fogarty catheter embolectomy (2), percutaneous angioplasty (1) and observation (1). One patient eventually required amputation. Venous occlusions occurred at a median of 4 months post surgery and were all treated conservatively. Overall arterial and venous reconstruction patency rates were 89% and 82% respectively. CONCLUSIONS Vascular resection to facilitate resection of STS has an acceptable long term patency rate. However it was associated to a high risk of distant spread. Although the encasement of the vascular bundle does not represent a contraindication to surgery there is an association with a high metastatic risk by virtue of the locally advanced nature of the disease and this should be considered when planning treatment.

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial-Mesenchymal Transition-like Process and 22q Loss

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target. Mol Cancer Res; 14(9); 820–9. ©2016 AACR.

Soft Tissue Tumors of the Groin and Inguinal Region

Soft tissue sarcomas (STSs) are rare tumors accounting for 1% of all adult malignancies. Due to their histological variety and heterogeneous anatomical presentation, treatment may be extremely complex, requiring peculiar expertise. Before planning any therapeutic approach, core needle percutaneous biopsy is mandatory and although surgery with negative margins is the mainstay of cure, complementary chemo and radiation therapies are often advocated, especially in high grade tumors. STSs of the groin and inguinal region account between 5 and 10% of all soft tissue malignancies, arising from the inguinal canal, the spermatic cord and the anatomical structures within the femoral triangle. Exceptionally giant retroperitoneal sarcoma may herniate through the abdo-inguinal ring. All these presentations are frequently misdiagnosed as inguinal or crural hernia, enlarged lymph nodes or testicular malignancies. Given the particular constraints of the inguinal region, in order to achieve adequate margins to increase the chance of locoregional control, surgery usually requires extensive soft tissue and visceral resections often combined with vascular and plastic complex reconstructions. In the very rare cases of lymphatic metastases, radical groin lymph node dissection may be performed, potentially with curative intent. Due to the rarity of the disease and the complexity of the diagnostic and therapeutic process, patients presenting with suspicious of STSs must always adressed to national referral centers.

Retroperitoneal Sarcoma Involving the Inferior Vena Cava

Soft tissue sarcomas (STS) are a group of rare diseases that account for less than 1 % of all adult cancers, with an estimated incidence of 4–5/100,000/year in Europe. Approximately 15 % of them arise in the retroperitoneum. The vast majority of STS originate from the connective tissue, while only a minority arises from viscera, with vessels included.

Neoplastic lymphangiosis of the upper aerodigestive tract simulating field cancerization: histopathological analysis, surgical limits and literature review.

Neoplastic lymphangiosis is defined as extensive embolic spread of cancer cells in the lymphatic vessels often without any evidence of a mass. Instead, field cancerization is defined by the presence of multifocal neoplastic lesions in a mucosal field previously exposed to mutagenic factors. In this case report, this oncological entity was suggested by the wide extent and multifocality of the disease and by the patients exposure to risk factors. Instead, the pathological slides revealed the integrity of the mucosa and the presence of widespread embolic metastasis to lymphatic vessels. Thus, the diagnosis was changed to neoplastic lymphangiosis. This clinical presentation is a negative prognostic factor, and surgical treatment is ineffective because of the impossibility to obtain adequate free margins. The present case underlines the poor prognosis of such locally advanced cancer and the importance of recognizing it early so that the treatment approach can be adapted.