Diagnostic utility of LEF1 and β-catenin in WNT pathway tumors with CTNNB1 mutation

OBJECTIVE: This study aimed to compare the expression of lymphoid enhancer factor 1 (LEF1) and β-catenin in basal cell adenoma (BA), desmoid-type fibromatosis (DF), and pancreatic solid pseudopapillary neoplasm (SPN) to evaluate their diagnostic utility in tumors associated with the WNT/β-catenin signaling pathway harboring the mutation of CTNNB1 gene 3 exon. METHODS: Eighty tumor patients, including 26 BAs, 30 DFs, and 24 SPNs, were analyzed. Immunohistochemical staining was identified positive (nuclear staining of LEF1 and β-catenin in > 50% of tumor cells). The diagnostic rate of LEF1 alone, β-catenin alone, and their combination were compared for each tumor type and all patients. RESULTS: Compared to β-catenin, when LEF1 alone was used for diagnosis, the diagnostic rate increased by 46.16% for BA, 16.67% for SPN, and 11.25% for all patients, but decreased by 23.34% for DF. The combined use of β-catenin and LEF1 significantly increased the diagnostic ratio in BA (46.16%), SPN (16.67%), and all patients (21.25%), but only marginally in DF (3.33%). In terms of all WNT pathway tumors with CTNNB1 gene mutation encompassed by our study, statistical analysis revealed no significant difference between LEF1 alone and β-catenin alone. However, their combined application was highly significant (P = 0.001) . CONCLUSION: While β-catenin is commonly used as a marker for WNT pathway tumors, its variable expression and localization can be challenging for diagnosis. Our study emphasizes the importance of LEF1 as a complementary marker to β-catenin in diagnosing BA, DF, SPN, and other WNT pathway tumors activated by exon 3 CTNNB1 gene mutation. The combined use of LEF1 and β-catenin enhances diagnostic accuracy and may help the identification of these tumor types.

Drug development for rare diseases can be long, complex, and costly. Desmoid tumors (DT), a rare type of soft-tissue tumor, are associated with substantial and debilitating burden, including disease-specific symptoms (e.g., pain, impaired mobility), reduce functioning for daily activities, and worsen quality of life for patients with this condition. These tumors can be potentially life-threatening when they invade surrounding tissues, affect vital structures, or interfere with the body’s functions. Until recently, there were no approved treatments specific to DT and little alignment on disease management. However, on November 27, 2023, the US Food and Drug Administration approved nirogacestat, an oral, targeted, and selective gamma secretase inhibitor, indicated for adult patients with progressing DT who require systemic treatment. This development milestone ascribes to nirogacestat the first approval of a gamma secretase inhibitor for human clinical use and the first therapy specifically indicated for treating patients with DT, thus addressing a long-term unmet need in this patient population. In the DeFi phase III trial of nirogacestat in adults with DT (NCT03785964), nirogacestat demonstrated statistically significant and clinically meaningful improvement in progression-free survival, objective response rate, DT-specific symptom burden (including pain), physical functioning, role functioning, and overall quality of life. This review chronicles the clinical development journey of nirogacestat from 2009 to the present day. Motivated to improve patient outcomes-and navigating considerable skepticism and uncertainty-the dedicated efforts of individuals within academic and medical institutions, industry, and patient advocacy groups shepherded nirogacestat through the development process, including those times when development stalled and might otherwise have been abandoned. Nirogacestat’s pathway to becoming a treatment for DT demonstrates how critically important collaboration and coordination are for identifying unique, creative solutions to overcome challenges in rare disease drug development.

Desmoid fibromatosis (DF) is defined as a borderline tumor of the soft tissues with a low malignant potential. The most common tumor sites are the extremity, trunk, abdominal cavity, and head and neck. Surgical resection has been the standard treatment for DF. However, there are concerns regarding long-term cosmetic outcomes or functional morbidity associated with surgery particularly in the head and neck. Recently, the use of the front-line wait-and-see strategy and pharmacologic treatment such as chemotherapy for progression has been proposed as tumors can spontaneously stabilize and regress. Herein, we report the efficacy of vinblastine (VBL) and methotrexate (MTX) in a childhood patients with DF. A 21-month-old female patient with a 4-cm tumor at the left lower jaw was diagnosed with DF. She did not initially receive any therapies (wait-and-see) according to the recent treatment guidelines. However, the tumor gradually progressed, and the patient was managed with COX2 inhibitor. Since the tumor was not controlled with such a treatment and tracheal exclusion caused by the mass was a cause of concern, the patient was managed with chemotherapy with VBL and MTX. VBL and MTX were administered weekly for 26 weeks, every other week, and further for 26 weeks. The tumor size gradually decreased with VBL and MTX. Magnetic resonance imaging revealed no evidence of the disease at the end of chemotherapy. Good cosmetic outcomes were achieved, and recurrence was not observed after 24 months of follow-up.

Desmoid tumors are uncommon soft tissue neoplasms that do not metastasize but are locally aggressive, often causing recurrence due to their infiltrative nature. This report discusses a case involving a symptomatic desmoid tumor in the right upper abdomen of a 23-year-old female patient. The diagnosis was established through clinical examination, ultrasonography, and computed tomography. A complete resection with a 2 cm margin followed by mesh placement for parietal reconstruction was carried out. Histopathological analysis confirmed the diagnosis of desmoid tumor. The patient was discharged on the fifth postoperative day and is recovering well. The wait and watch approach is suitable for asymptomatic patients, while surgical and systemic therapies are recommended for symptomatic individuals. Complete surgical excision with sufficient safety margins followed by parietal reconstruction using prosthetic reinforcement is advised when necessary.

Objectives: Because size-based imaging criteria poorly capture biologic response in desmoid-type fibromatosis (DF), changes in MRI T2 signal intensity are frequently used as a response surrogate, but remain qualitative. We hypothesized that absolute quantification of DF T2 relaxation time derived from parametric T2 maps would be a feasible and effective imaging biomarker of disease activity.

Methods: This IRB-approved retrospective study included 11 patients with DF, managed by observation or systemic therapy, assessed by 3T MRI. Tumor maximum diameter, volume, and T2-weighted signal intensity were derived from manual tumor segmentations. Tumor:muscle T2 signal ratios were recorded. Two readers measured tumor T2 relaxation times using a commercial T2 scanning sequence, manual ROI delineation and commercial calculation software enabling estimation of reader reliability. Objective response rates based on RECIST1.1 and best responses were compared between size-based and signal-based parameters.

Results: Median patient age was 52.6 years; 8 subjects were female (73%). Nine patients with longitudinal assessments were followed for an average of 314 days. Median baseline tumor diameter was 7.2 cm (range 4.4 – 18.2 cm). Median baseline T2 was 65.1 ms (range 40.4 – 94.8 ms, n=11); median at last follow-up was 44.3 ms (-32% from baseline; range 29.3 – 94.7 ms, n=9). T2 relaxation times correlated with tumor:muscle T2 signal ratios, Spearman p=0.78 (p<0.001). T2 mapping showed high inter-reader reliability, ICC=0.84. The best response as a percentage change in T2 values was statistically significant (mean -17.9%, p=0.05, paired t-test) while change in diameter was not (mean -8.9%, p=0.12). Conclusions: Analysis of T2 relaxation time maps of DF may offer a feasible quantitative biomarker for assessing the extent of response to treatment. This approach may have high inter-reader reliability.

With increasing multidisciplinary management and emphasis on masterly inactivity for abdominal fibromatosis (AF), the indications for surgery are evolving. This retrospective analysis looked at outcomes following surgery. Two groups of patients who underwent surgery for AF between November 2011 and August 2021 were identified-intra-abdominal fibromatosis (IAF) and abdominal wall fibromatosis (AWF). All treatment-related details and follow-up data were gathered from a database and analyzed. Sixteen patients underwent surgery for IAF. R0 resection (wide margin) was achieved in 13 patients (81.2%). Over a median follow-up period of 51.7 (range 5-103) months, 5 patients developed recurrence (31.2%). The conditional probabilities of OS and DFS at 5 years were 80% (95% CI 58.7-100) and 42.2% (95% CI 20.3-87.8), respectively. Ten patients with AWF underwent surgery. R0 resection was achieved at 70% (7/10). Over a median follow-up period of 54.8 (range 12.9-96.7) months, 2 patients (20%) developed recurrence. The conditional probabilities of OS and DFS at 5 years were 88.9% (95% CI 70.6-100) and 77.8% (95% CI 54.9-87.8), respectively. Surgery has a vital role in the management of AF presenting with progressive/symptomatic lesions, especially when watchful waiting is not an option, and must be considered as one of the first-line active therapy. Timely curative surgery avoids disease progression and its morbidity with acceptable recurrence rates and provides durable remissions.