Functional analysis of young patients with desmoid-type fibromatosis: Initial surveillance does not jeopardize long term quality of life

With recent conservative strategies, prognosis of patients with desmoid-type fibromatosis (DTF) is about function preservation. We analyzed the long-term quality of life (QoL) of pediatric patients with DTF. All French young patients (<21years) treated between 2005 and 2016 for a DTF in the EpSSG NRSTS-05 study were analyzed. A first wait-and-see strategy was recommended. Patients’ QoL was analyzed with the internationally validated Child Health Questionnaire (CHQ). We focused on the relevant subscales scores: physical functioning (PF), role social limitations physical (RP), bodily pain (BP), general health perception (GH) and physical (PhS) and psychosocial (PsS) summary measures. Among the 81 patients, 52 families answered the CHQ (median delay since diagnosis = 6.2years; min2.2-max13.3 years). Median age at diagnosis was 11.5 years. Primary site: limbs (52%), head/neck (27%), or trunk (21%). Five year-Progression Free Survival was 39.1% (95%CI: 27.7-50.5%). As initial management for these 52 patients, 30 patients were first observed (57%), 13 had surgery (25%) and 9 received chemotherapy (18%). Total burden of therapy was exclusive surgery (9pts/18%), exclusive chemotherapy (18pts/35%), surgery + chemotherapy (13pts/25%), chemotherapy + radiotherapy (1 pt), surgery + chemotherapy + radiotherapy (1 pt), wait and see (10 pt). Regarding the parent forms, patients have significant lower PF (86.0vs.96.1; p = 0.03), RP (82.0vs.93.6; p = 0.04), GH (60vs.73; p < 0.005) and PhS (46.2 vs.53; p = 0.02) scores compared to healthy population. Comparison of QoL subscales scores according to initial strategy (wait-and-see vs.surgery/chemotherapy) did not reveal any difference (PF = 87.3vs.84.9; p = 0.80/RP = 83.4vs.78.7; p = 0.72/BP = 78.9vs.78.2; p = 0.95/GH = 59.7vs60; p = 0.97). Similar results were found using the children or adult forms. Initial wait-and-see strategy does not affect long term functional impairment.

We are discussing about a 40-year-old male presented with a concomitant diagnosis of non- Hodking lymphoma and mesenteric fibromatosis not associated with any of the risk factors mentioned above. CT and PET scan are performed visualizing a vascularized and well-defined mesenteric center- abdominal solid mass with hypermetabolism contacting with the gastric body, the duodenum, the body and the tail of the pancreas, the transverse colon and the spleen. Ultrasound-guided trucut biopsy showed features suggestive of mesenteric fibromatosis. Elective laparotomy was done and a giant mass arising from mesentery was excised including partial gastrectomy and segmental resection of the transverse colon. Distal pancreatectomy, small bowel resection and successive splenectomy are performed due to a large hypertensive component. The histopathology of the surgical pieces is compatible with intra-abdominal desmoid fibromatosis. As far as we know, it is the biggest case of mesenteric fibromatosis tumour excision reported in the literature. We also noticed that our case is the first reported case of concomitant presence of mesenteric fibromatosis and non-Hodgkin’s lymphoma that has not relation to any described risk factor. More research is needed to establish what type of association this presentation may indicate.

A 46-year-old gentleman was referred to our institution with a 6-month history of recurrent rectal bleeding. He had a strong family history of cancer with two brothers having died of colon cancer before the age of 50, and a son of brain tumor at the age of 2. Colonoscopy showed a large hypervascular pedunculated polyp (2×2.5 cm) in the sigmoid colon that was excised. Follow-up colonoscopy a year later, showed no recurrence at the polypectomy site, but another sessile 2×1 cm polyp was found and excised in the ascending colon. A laparoscopic right hemicolectomy with primary side-to-side ileo-transverse anastomosis was performed. Genetic testing confirmed the diagnosis of Hereditary Nonpolyposis Colorectal Cancer (HNPCC-Lynch syndrome). A follow-up CT scan of the abdomen and pelvis showed a speculated mesenteric mass of 2×1.7 cm in close proximity to the ileocolic anastomosis. A PET-CT scan was performed, and this showed the mass to have FDG uptake with SUV max of 4.67 (Mean Liver SUV based on body weight was 2.6). Findings were suggestive of local recurrence and an exploratory laparotomy was carried out. Histopathology showed no malignancy, but an ill-defined spindle cell proliferation within the pericolic fat, and mesentery arranged in short sweeping fascicles with long thin-walled blood vessels. Tumor cells were positive for beta catenin and negative for SMA, desmin and CD117, confirming the diagnosis of desmoid tumor and excluding other differential diagnoses of GIST, leiomyoma, neurofibroma and schwannoma. Two years’ surveillance workup showed no evidence of recurrence.

In this study, we aimed to assess the disease stabilization rate and identify predictive factors for disease stabilization of desmoid-type fibromatosis (DF) in patients with conservative treatment. We reviewed 76 patients with sporadic extra-abdominal DF who were managed with frontline conservative treatment in our institute. The minimum follow-up was 12 months. Stabilization was defined as radiological evidence of no change or continuous decrease in size of the tumor for six months or more. The primary endpoint was stabilization of DF. Possible patient-, disease-, and treatment-related factors predictive of disease stabilization were analyzed with multivariate analysis. At final follow-up, 54 of the 76 tumors (71%) were stable, and mean time to stabilization was 30.4 months (range, 7 to 112 months). On Kaplan-Meier survival analysis, the spontaneous stabilization rate was 25.4% at one year, 52.7% at two years, and 70.9% at three years. The mean time to spontaneous stabilization was longer in patients with ≤ 40 years of age (p = 0.022) or recurrence (p = 0.041). On multivariate analysis with the Cox proportional hazard method, recurrence (hazard ratio [HR], 1.79; p = 0.041) and younger age (HR, 2.04; p = 0.022) were identified as independent prognostic factors for longer time to disease stabilization. Frontline conservative treatment seems to be the optimal treatment for most patients with DF. Younger patients or those with recurrence may require longer time to spontaneous disease stabilization.

Genetic alterations affecting canonical Wnt/Beta-catenin signaling are reported in the majority of Desmoid-type fibromatosis (DTF, aggressive fibromatosis). While most sporadic DTF harbor somatic mutations in CTNNB1, germline mutations in adenomatous polyposis coli (APC) are known to occur in hereditary DTF types (FAP, Gardner-Syndrome). We performed targeted next-generation sequencing (NGS) in a large cohort of 204 formalin-fixed DTF samples, comprising 22 pediatric cases (patients age ≤18 years). The mutational status was correlated with clinicopathological characteristics. Overall, deleterious CTNNB1 mutations were detected in 89% of DTF, most frequently affecting the serine/threonine phosphorylation sites T41 and S45 of beta-catenin. While the T41A CTNNB1 mutation was significantly more often identified in the mesenterial localization, DTF originating from extra-intestinal sites more frequently harbored the S45P CTNNB1 alteration. Beyond common mutations in CTNNB1, additional SNVs were demonstrated in 7% of the DTF cohort and in 18% of the pediatric DTF subgroup. The mutational spectrum included deleterious mutations in AKT1 (G311S/D and T312I), ALK (R806H and G924S), AR (A159T), EGFR (P848L), ERBB2 (H174Y), IDH2 (H354Y), KIT (V559D), RET (T1038A), SDHA (R325M), and SDHD (R115W), as characterized by in silico prediction tools. In conclusion, our study indicates that DTF may harbor a broader mutational spectrum beyond CTNNB1 mutations, comprising targetable alterations including the herewith first reported imatinib-sensitive KIT V559D mutation in DTF.

This guideline was developed by the Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) and the Sarcoma Disease Site Group (DSG). The medline, embase, and Cochrane Library databases, main guideline websites, abstracts of relevant annual meetings, and PROSPERO databases were searched (January 2005 to October 2016). Based on the available evidence, we made three Strong Recommendations, 14 Recommendations, 9 Qualified Statements, and seven No Recommendations. The three Strong Recommendations include: i) MDM2 amplification by fluorescence in situ hybridization (FISH) is recommended as a sensitive and specific test to differentiate patients with atypical lipomatous tumour/well-differentiated liposarcoma, or dedifferentiated liposarcoma from lipoma or other STS in the differential diagnosis; ii) SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas; iii) CTNNB1 S45F mutation by polymerase chain reaction is recommended as a prognostic factor for poor recurrence-free survival in patients with desmoid tumours.This guideline may serve as a framework for the thoughtful implementation of molecular studies at cancer centres and other jurisdictions.