Evaluating Management of Extra-Abdominal Desmoid Fibromatosis: A Retrospective Analysis of Treatments, Outcomes and Recurrence Patterns

Nationwide Trends in the Current Management of Desmoid (Aggressive) Fibromatosis

Desmoid tumor (DT), also known as desmoid fibromatosis, is a rare, locally proliferative tumor characterized by an overgrowth of myofibroblastic cells. Due to the varied clinical presentation of DT, there are a multitude of treatment options. This study provides our institutional experience in characterizing and treating DT as well as patient outcomes. A retrospective review was performed for 49 patients diagnosed with DT. Patient demographics, tumor characteristics, treatment characteristics, and tumor recurrence were reported. We reported our institution’s treatment trends over time, relative risk analysis for surgery, as well as univariate analysis for recurrence. Thirty-seven patients received surgery with an overall recurrence rate of 29.7% (11/37). In total, ten patients received medical therapy including tamoxifen/sulindac (n = 7), nirogacestat (n = 1), and sorafenib (n = 2). One patient has been followed with active surveillance. Relative risk for surgery and tumor recurrence was not significantly correlated with race, gender, location, or large tumor size > 5 cm. Four patients treated with medical therapy experienced tumor reduction and symptomatic improvement. Management of DT includes many surgical and non-surgical options. We noted a similar recurrence rate in patients who received surgical treatment to what has been reported in the literature roughly 33%. We also noted effective tumor control in patients receiving medical therapy. As such, surgery can be utilized in situations with well-demarcated DT which can be removed en bloc, while utilizing medical therapy for highly invasive tumors.

11513 Background: Desmoid fibromatosis (DF) often occurs during pregnancy/peripartum. Guidance for planning new pregnancies during active surveillance or following DF resection has been limited. Thus, we sought to evaluate outcomes and decision making in the peripartum. Methods: Women of child-bearing age with DF diagnosed between 2000 and 2020 were interviewed about procreation decisions, in a multicenter retrospective observational study (NCT05284305). Pregnancies simultaneous or after diagnosis were analyzed. Primary outcome was DF progression/recurrence within 1 yr postpartum. Secondary outcomes were spontaneous regression, switch to active treatment, and obstetric risks. To estimate probability of progression, a random intercept logistic model was fit to account for correlation of progression in multiple pregnancies in the same patient. Results: Of 483 pts interviewed, 120 (24.8%) postponed, 32 (6.6%) interrupted, and/or 232 (48%) avoided pregnancy (in 93.3%, 50%, and 72.9% of cases because of DF), respectively. 147 pregnancies in 131 pts were concurrent with or after diagnosis: 26 (17.7%, Group A) concurrent with diagnosis, 48 (32.7%, B) after DF resection, and 73 (49.7%, C) with DF on surveillance. Estimated probability of progression was 12.0% (CI 2.0 – 48.4) during pregnancy and 15.8% (5.6 – 37.5) postpartum; for pregnancies after diagnosis (Groups B and C), these rates were 5.1% (0.4 – 40.0) and 9.0% (1.8 – 35.0). On multivariate analysis, age at pregnancy and size of primary DF were significant risk factors for progression (Table). Estimated probability of spontaneous regression was 3.6% (CI 0.2-40.7) during pregnancy and 7.1% (CI 0.3 – 67.2) postpartum. 7/38 (18.4%) spontaneously regressed after pregnancy-related PD, 4/23 (17.4%) in Groups B and C. Treatment for progression was needed in 9/79 (11.4%) postpartum, in 4/63 (6.3%) in Groups B and C. Obstetric complications were comparable to population data in developed countries. Conclusions: After DF diagnosis, pregnancy is safe with a risk of progression of 5% during pregnancy and 9% postpartum. Treatment is needed in only 6%. Spontaneous regression is less common but occurs even after initial progression. Patients decision making about procreation appeared to be influenced by their DF diagnosis. This study supports counseling that fertility options should be fully explored with expert guidance as intervention rates are low. [Table: see text]

Desmoid fibromatosis: a clinicopathologic study of 25 children.

Pregnancy-associated desmoid fibromatosis: A Dutch multi-centre retrospective study

Introduction: Desmoid fibromatosis (DF) or Desmoid tumours are rare, benign musculoaponeurotic tumours. DF have no potential for metastatic spread but are locally aggressive and spread along fascial planes, leading to extensive patient morbidity. While germline Adenomatous Polyposis Coli (APC) mutations are associated with DF, it can also occur sporadically. Debate regarding the most appropriate treatment options exists in literature. Case summary: A 38 year old lady presented with a left hypochondrial swelling, night sweats and weight loss to the General Surgical Outpatients Department at our institution. This was noticed after the birth of her second child. No relevant family history was noted. A pre-operative ultrasound demonstrated a fusiform nodule within the left anterior abdominal transversalis oblique muscle, which had a focal hypervascular nidus. Surgical excision of the mass was performed under general anaesthetic and histologically the tumour was found to contain spindled myofibroblastic cells arranged in fascicles with perivascular lymphoid infiltrates. The diagnosis was DF with a positive margin status. Given the high risk of recurrence of this tumour type, the decision was made to undertake a further resection. Conclusion: DF is known to be a locally aggressive benign tumour of mesenchymal origin. The benefits and disadvantages of treatment options are debated within literature. Surgery is reported to have better or similar local control rates to radiotherapy but without radiation related complications. Given that DF is known to be locally aggressive, affecting young people and with a female preponderance, we believe that surgical excision with clear margins is the most appropriate treatment of choice.

Infantile desmoid fibromatosis of the submandibular region

Desmoid fibromatosis of the cruris: A rare case report

Objective To study the clinical effect of the postoperative abdominal wall reconstruction with synthetic mesh for abdominal desmoid type fibromatosis (DTF). Methods Clinical data of 11 patients with abdominal desmoid type fibromatosis during February 2012 to February 2016 in Beijing Chao-Yang Hospital were retrospectively collected. The abdominal wall of the patients who underwent tumor radical surgery were reconstructed with synthetic mesh. Results All the patients were successfully treated with synthetic mesh to reconstruct the abdominal wall. The mean operation time was 97±33 min, and the mean hospitalization was 19.2±3.1 days. All the patients recovered uneventfully. No wound infections and foreign body feelings were recorded in our study. Subcutaneous hydrops occurred in 1 patient who finally recovered uneventfully by puncture aspiration. During the follow-up time of 7-60 months (the median follow-up time was 31.8±18.5 months), there were no mortalities, and 1 patient suffered tumor recurrence. There were no mesh infections and mesh-related complications. No incisional hernias and intestinal obstructions were observed. Conclusion Abdominal wall reconstruction with synthetic mesh shows favorable clinical effect. Key words: abdominal desmoid type fibromatosis; abdominal reconstruction; synthetic mesh

Simple SummaryDesmoid tumors are benign neoplasms that invade locally, causing significant disability and morbidity. Historically, patients with desmoid tumors have been treated with surgery despite the significant morbidity associated with this modality. Less invasive treatments have emerged, including active surveillance, systemic therapy, radiotherapy, and local ablation. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed 262 patients with desmoid tumors treated at our institution over a period of 30 years. Our results suggest that initial active surveillance is a good option for patients with small and minimally symptomatic desmoid tumors, while tyrosine kinase inhibitors, local ablation, and surgery seem to be equally effective in those with more aggressive disease. The initial management of desmoid tumors (DTs) is shifting from surgery towards active surveillance, with systemic and locally ablative treatments reserved for enlarging and/or symptomatic disease. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed adult and pediatric patients with DTs treated at a tertiary academic cancer center between 1992 and 2022. Outcomes measured were progression-free survival (PFS) and time to next treatment (TTNT) after first-line therapy. A total of 262 treatment-naïve patients were eligible for analysis with a median age of 36.5 years (range, 0–87 years). The 5-year PFS and the median TTNT (months) after first-line treatment were, respectively: 50.6% and 69.1 mo for surgery; 64.9% and 149.5 mo for surgery plus adjuvant radiotherapy; 57.1% and 44.7 mo for surgery plus adjuvant systemic therapy; 24.9% and 4.4 mo for chemotherapy; 26.7% and 5.3 mo for hormonal therapy; 41.3% and 29.6 mo for tyrosine kinase inhibitors (TKIs); 44.4% and 8.9 mo for cryoablation and high intensity focused ultrasound; and 43.1% and 32.7 mo for active surveillance. Age 40 years (p < 0.001), DTs involving the extremities (p < 0.001), a maximum tumor diameter 60 mm (p = 0.04), and hormonal therapy (p = 0.03) predicted a higher risk of progression. Overall, our results suggest that active surveillance should be considered initially for patients with smaller asymptomatic DTs, while upfront TKIs, local ablation, and surgery achieve similar outcomes in those with more aggressive disease.

Desmoid fibromatosis is a locally aggressive clonal fibroblastic proliferation with high recurrence rates and no metastatic potential. Implicated molecular aberrations occur within the Wnt/β-catenin pathway (APC and β-catenin gene mutations). Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are profibrotic growth factors, downstream from nuclear translocation of β-catenin, that lead to increased fibrogenesis. CTGF (a downstream effector of TGF-β) is a matricellular protein that modulates the activity of growth factors, adhesion molecules, integrins, and extracellular matrix thus playing a central role in tissue remodeling and fibrosis. Recently there has been growing interest in use of extracellular matrix inhibitors for treatment of various fibrogenic diseases. Desmoid fibromatosis samples (n=15) were evaluated for expression of β-catenin, TGF-β, and CTGF using immunohistochemistry on formalin paraffin-embedded material. A control group comprising scar tissue and adjacent normal skin (n=10) were simultaneously immunostained with above mentioned markers. Real-time polymerase chain reaction was performed on frozen specimens of desmoid fibromatosis (n=6) and normal skin (n=2). All 15 desmoid tumors were positive for β-catenin (surrogate marker of Wnt/β-catenin pathway dysregulation) which was negative in control normal skin and scar samples. TGF-β and CTGF were negative in 9 of 10 normal skin controls. TGF-β and CTGF were positive in all cases of scar tissue. All 15 cases of desmoid tumors were positive for TGF-β and CTGF. The real-time polymerase chain reaction showed higher expression levels of TGF-β and CTGF in desmoid fibromatosis compared with normal skin. The high constitutive expression of β-catenin downstream effectors; TGF-β, CTGF has the potential for enabling targeted therapy.

Desmoid fibromatosis is a mesenchymal clonal proliferation, which lacks metastatic potential. Nevertheless, it has an infiltrative growth and thus implies a high morbidity1. Although the etiology remains unclear, mutations in the B-catenin or APC genes are involved. Some risk factors include pregnancy, hormonal exposure or surgery. Desmoid fibromatosis can be sporadic (80%) or FAP-associated2. In sporadic cases, it is caused by mutations in the B-catenin (CTNNB1) gene. Whether it is FAP-associated or not should be determined, as the treatment for each condition is different. A radiologic test is essential for diagnosis, although a biopsy is necessary for confirmation. With regard to treatment, there is a wide range of different alternatives such as observation only, medical treatment or even surgery3. However, a recurrence rate that ranges from 30% to 40% have been reported in the major published series4 and thus, conservative treatment is more common nowadays. We present the case of an 82-year-old male with constitutional syndrome. A computed tomography was performed, which identified a 69 x 52mm mass in the oesophago-gastric union. A computed tomography guided biopsy was performed and the histological analysis identified a fusocellular tumor compatible with desmoid fibromatosis. Treatment was started with indomethacin. However, a control computed tomography 3 months later showed that the mass had grown. Thus, indomethacin treatment was stopped and tamoxifen treatment was started. The patient has had an excellent performance status since symptom presentation. In conclusion, desmoid tumors are rare and most are sporadic. However, they may also be associated with familial adenomatous polyposis syndrome. It must be emphasized that our patient did not have any risk factors and the anatomical location in the oesophago-gastric union is not a common location. Desmoid fibromatosis supposes a clinical challenge for diagnosis and treatment and thus, management should be individualized.

Contrast enhanced ultrasound versus MRI for response assessment of extra-abdominal desmoid Fibromatosis- A feasibility study.

Desmoid tumors (DTs) are rare, fibroblastic cell proliferations that can exhibit locally aggressive behavior but lack metastatic potential. Initial management has traditionally involved upfront resection; however, contemporary guidelines and expert panels have increasingly advocated for prioritizing active surveillance strategies. A single-institution, retrospective chart review identified all patients diagnosed with a primary DT at any site from 2007 to 2020. The primary outcome was the initial management strategy over time. Secondary outcomes included treatment-free survival (TFS) and time to treatment (TTT) for those undergoing active surveillance, as well as recurrence-free survival (RFS) and time to recurrence for those undergoing resection. Overall, 103 patients were included, with 68% female and a median follow-up of 44 months [24-74]. The most common tumor locations included the abdominal wall (27%), intra-abdominal/mesenteric (25%), chest wall (19%), and extremity (10%). Initial management included resection (60%), systemic therapy (20%), active surveillance (18%), and cryoablation (2%). Rates of surgical resection significantly decreased (p<0.001) over time, from 69.6% prior to 2018 to 29.2% after 2018. For those treated with upfront resection, 5-year RFS was 41.2%, and for patients undergoing initial active surveillance, TFS was 66.7% at 2 years, with a median TTT of 4 months [4-10]. This single-institution cohort at a tertiary medical center spanning over a decade demonstrates the transition to active surveillance for initial management of DTs, and highlights salient metrics in the era of surveillance. This trend mirrors recommended treatment strategies by expert panels and consensus guidelines.

BACKGROUND Desmoid tumor (DT) is known as a locally aggressive tumor caused by altered Wnt/b-catenin signaling pathway. Although high frequency of mutations are observed in APC and CTNNB1, its values as a predictive marker of local recurrence is controversial and only serine to phenyalanie substitution at codone 45 (S45F) in CTNNB1 is reported. We designed a study to investigate candidate mutations which affect the local recurrence in DT. METHODS Tissues from 25 patients, treated with mass excision, were acquired and targeted gene sequencing (TGS) were performed for the 45 genes in COSMIC data set. Patients were divided into 2 groups, subjects with recurred DT and subjects without disease recurrence. Locus, previous reported in COSMIC data set, with altered frequency &amp;gt; 0.01 was considered as a significant alteration. Statistical significance of each altered locus and candidate genes were tested by Cox-regression analysis and fisher's exact test. Time to recurrence is used in survival analysis and P under 0.05 is considered as a significant result. Primary endpoint of this study is evaluating a hazard ratio (HR) for each alteration. RESULTS Out of 25 patients, 13 patients (52.0%) have recurred after initial treatment. APC mutation is observed in 13 patients (52.0%) and CTNNB1 mutation in 21 patients (84.0%) with no CTNNB1 S45F mutation observed. Median follow up duration was 72.3 months. More subjects were recurred with HRAS mutation (38.5% vs 0%, P = 0.039) and HR was increased (HR = 3.65, 95% confidential interval [CI] 1.09-12.15, P = 0.035). However, other genes, including CTNNB1 and APC, did not satisfied statistical significance. Among the 575 alterations detected by TGS, 9 missense mutation in 5 genes showed increased HR by Cox-proportional analysis and values are followed: (1) CTNNB1 S45G (HR 27.6, P = 0.007) (2) FGFR3 V266M (HR 14.8, P = 0.008); (3) CDKN2A P81L (HR 5.1, P = 0.020), D105E (HR 11.1, P = 0.049), R107C (HR 23.5, P = 0.026); (4) PTPN11 S502L (HR 23.5, P = 0.026); (5) TP53 A189V (HR 23.5, P = 0.026), C182Y (HR 23.5, P = 0.026), S96G (HR 23.5, P = 0.026). Out of 5 subjects with above alterations, 4 subjects recurred within 15.0 months and median time to relapse was shorter compared to the subjects without alteration (10.5 months vs 18 months, P = 0.057). CONCLUSIONS In this study, we identified 6 genes and 9 specific locus which are related with recurrence of desmoid tumor. Our result is coincidence with previous result that an alteration in codon 45 of CTNNB1 is related with desmoid tumor recurrence. Values of other significant alteration in our report should be validated with confirmatory studies. Citation Format: Sehhoon Park, Youngil Koh, Se-Hoon Lee, Chan-Young Ock, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo. Investigating candidate genomic alteration which affects the local recurrence in patients with desmoid fibromatosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4946. doi:10.1158/1538-7445.AM2015-4946