Pain in desmoid-type fibromatosis: Prevalence, determinants and prognosis value

The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P = .18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P = .013) and tumor site (P < .001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 [1.27-7.29]). Pain at baseline was significantly associated with poor quality of life (P < .001), depression (P = .02), lower performance status (P = .03) and functional impairment (P = .001); we also observed a nonsignificant association with anxiety (P = .10). In the univariate analysis, baseline pain was associated with poor EFS; the 3-year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 [1.23-2.68], P = .003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders.

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade.

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Desmoid fibromatosis is a myofibroblastic neoplasm of intermediate biologic potential, which has a strong predilection for local recurrence but does not metastasize. Arranged in long, sweeping fascicles with infiltrative borders, desmoid fibromatosis typically consists of uniform, bland myofibroblastic spindle cells that harbor mutation of CTNNB1 (or less often APC). In this report, we present a remarkable case of desmoid fibromatosis associated with striking nuclear pleomorphism. We hypothesize that this striking pleomorphism is due to a germline TP53 mutation, a finding first suspected due to strong and diffuse p53 staining by immunohistochemistry and subsequently confirmed by molecular testing. The combination of the pleomorphism and TP53 mutation in desmoid fibromatosis represents a novel finding unreported in the literature.

The patient is a 22-year-old, female. She had a family history of familial adenomatous polyposis(F.A.P.)and a prophylactic total colorectal resection was performed for FAP at age of 18. She presented with fever and abdominal distention and palpated a mass with tenderness in the right lower abdomen. Contrast-enhanced CT scan of the abdomen showed a heterogeneous contrast effect around the tumor margins. With the diagnosis of intra-abdominal desmoid tumor, a partial duodenal resection, small bowel mass resection, and right fallopian tube resection were performed along with the tumor, and an artificial anus was created with the jejunum. Contrast-enhanced CT scan of the abdomen 16 months after resection of desmoid tumor showed a 6.5 cm long desmoid tumor recurrence in the mesentery. She received 5 courses of doxorubicin (DOX)plus dacarbazine(DTIC)therapy followed by continued NSAIDs. Seven years after the operation, she has been able to maintain the shrinkage of the recurrent tumor and is still on medication. Long-term surveillance is necessary because of the possibility of the appearance of other associated lesions in the future.

Desmoid tumors are locally aggressive benign tumors arising from connective tissue and are classified as soft tissue sarcomas that do not metastasize. The name is derived from the Greek word desmos that means tendon-like. These tumors are also known as aggressive fibromatosis and have an unpredictable natural history that varies depending on risk factors. They are treated as sarcomas because of their locally aggressive nature and a high local recurrence rate. The causes behind desmoid tumor development are enigmatic and their clinical course is unpredictable. Disease progression also varies widely depending on multiple syndromic risk factors. At this time, there is no scientific consensus over best treatment practices for this tumor type. Treatment can potentially be a combination of observation, systemic therapy, surgery or radiation therapy. Here, we have described a case of a female patient with a sporadic desmoid tumor that successfully responded to tamoxifen and sulindac.