Differential diagnosis and mutation stratification of desmoid-type fibromatosis on MRI using radiomics

Diagnosing desmoid-type fibromatosis (DTF) requires an invasive tissue biopsy with beta-catenin staining and CTNNB1 mutational analysis, and is challenging due to its rarity. The aim of this study was to evaluate radiomics for distinguishing DTF from soft tissue sarcomas (STS), and in DTF, for predicting the CTNNB1 mutation types. Patients with histologically confirmed extremity STS (non-DTF) or DTF and at least a pretreatment T1-weighted (T1w) MRI scan were retrospectively included. Tumors were semi-automatically annotated on the T1w scans, from which 411 features were extracted. Prediction models were created using a combination of various machine learning approaches. Evaluation was performed through a 100x random-split cross-validation. The model for DTF vs. non-DTF was compared to classification by two radiologists on a location matched subset. The data included 203 patients (72 DTF, 131 STS). The T1w radiomics model showed a mean AUC of 0.79 on the full dataset. Addition of T2w or T1w post-contrast scans did not improve the performance. On the location matched cohort, the T1w model had a mean AUC of 0.88 while the radiologists had an AUC of 0.80 and 0.88, respectively. For the prediction of the CTNNB1 mutation types (S45 F, T41A and wild-type), the T1w model showed an AUC of 0.61, 0.56, and 0.74. Our radiomics model was able to distinguish DTF from STS with high accuracy similar to two radiologists, but was not able to predict the CTNNB1 mutation status.

Desmoid tumors are rare, benign, and locally aggressive neoplasms that stem from connective tissue that have high rates of recurrence after surgery. Intra-abdominal desmoid-type fibromatosis can arise in 2 forms: sporadic or hereditary (associated with familial adenomatous polyposis and Gardner syndrome). The diagnosis of desmoid-type tumors is based on imaging modalities and histopathological examination. The primary treatment is resection surgery. We report a 64-year-old male with a distal pancreatic desmoid tumor. We focus on tumor management by the application of radiological modalities and pathological analysis.

This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a gamma-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.

We present a case of a 50-year-old female with a left thigh vastus medialis intramuscular mass which underwent imaging work-up and subsequent core needle ultrasound-guided biopsy showing results of desmoid-type fibromatosis. Following biopsy, the tumor showed prompt, complete regression with complete MRI resolution 2 months following biopsy. The patient showed no evidence of disease recurrence out to one year on MRI surveillance. To our knowledge there have been no reported cases of DF spontaneous regression 2 months following a core needle biopsy. Understanding the variable behavior of desmoid-type fibromatosis can assist the radiologist in guiding management of these lesions with the goal of optimizing clinical outcomes and preventing unnecessary aggressive treatments for stable or regressing disease.

Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression, in order to avoid the short- and long-term complications of local treatments. We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute. Only patients with documented progressive disease (PD) according to RECIST v1.1 over 3 months (±2 weeks) before treatment initiation were included. From 2009 to 2019, of 438 patients with DF, 90 were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34, for a median duration of 6.7 months. A partial response was observed in 29%, and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women (HR: 2.16, 95%CI: 1.06-4.37, p = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared to p.T41A or wild type tumors (HR : 2.78, 95%CI: 1.23-6.27, p = 0.04). Toxicity profile was favorable, without grade 3-4 toxicity but one grade 3 neutropenia. Oral vinorelbine is an effective, affordable and well tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.

Low-dose methotrexate (MTX) plus vinblastine (VBL) chemotherapy is an effective treatment for desmoid-type fibromatosis (DF). However, previous reports have described a weekly regimen, with no reports available on a biweekly one. The aim of this study was to determine the clinical outcomes of a biweekly regimen in a cohort prospectively treated in our single institution. Since 2010, we have prospectively treated refractory DF patients with biweekly MTX (30mg/m2) + VBL (6mg/m2). Efficacy, progression-free survival (PFS), and correlating factors were analyzed. Adverse events were recorded. In total, 38 patients received low-dose MTX + VBL therapy, and its efficacy was assessed in 37 of them. Nineteen (51%) patients showed partial response (PR). Clinical benefit rate was 95%. PFS at 5 years was 80.8 %. Only 3 adverse events of Grade 3/4 were observed. Tumor regrowth after MTX + VBL discontinuation was observed in 5 (20%) of 25 cases. Biweekly administration of MTX + VBL chemotherapy was well tolerated compared with weekly administration, and its efficacy was anticipated in DF patents, although the time needed to achieve a response may be relatively long. The treatment interval should be determined taking into account both the condition of the tumor and the patient’s preference.