Desmoid-type fibromatosis: toward a holistic management.

PURPOSE OF REVIEW: Desmoid-type fibromatosis, a rare locally aggressive fibroblastic proliferation, is a treatment challenge. This review aimed to explore recent data about the management of desmoid-type fibromatosis. RECENT FINDINGS: New data underline the role of kinases and ɣ-secretase in stimulating cell proliferation and invasiveness in desmoid-type fibromatosis. This explains the proven activity of multikinase inhibitors (sorafenib or pazopanib) in the management of desmoid-type fibromatosis or the emerging role of a ɣ-secretase inhibitor. An international guideline for management was recently published, and this guideline take into account patient point of view. Lastly, recent studies highlight the multidimensional burden of desmoid-type fibromatosis, particularly health-related quality of life (HRQoL). SUMMARY: Active surveillance with planned MRI is the first-line management in desmoid-type fibromatosis. A site-specific and stepwise approach should be considered for progressive desmoid-type fibromatosis. Further, a risk-benefit analysis that considers the side effects and long-term sequelae should be conducted before deciding to start any treatment. A less aggressive approach should be considered. Multikinase inhibitors are effective, but their tolerability and side effects should be discussed with the patients. The symptoms and HRQoL should be integrated in decision-making. Desmoid-type fibromatosis patients should be offered support to address their needs supportive care.

Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor.

BACKGROUND: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in ß-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. METHODS: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. RESULTS: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. CONCLUSIONS: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.

Desmoid tumor-associated pain is dependent on mast cell expression of cyclooxygenase-2.

BACKGROUND: This study aimed to investigate the expression profile of cyclooxygenase-2 (COX-2) in desmoid tumor specimens and to evaluate the correlation of intratumoral COX-2 expression with pain status. METHODS: Sixteen patients with histologically proven desmoid tumors who attended our institution between 2003 and 2010 were enrolled in this study. COX-2 protein expression in desmoid tumors was determined by immunohistochemistry. COX-2 - positive cells had similar morphology to that of mast cells, and therefore, immunohistochemical staining for tryptase was performed in co-localized sections. The number of COX-2 -positive cells in 10 consecutive fields was counted at 400× magnification. Patients were stratified into 2 groups according to the number of COX-2- positive cells, the COX-2 -positive group (≧10 COX-2 -positive cells) and the COX-2 -negative group (<10 COX-2 -positive cells). The prevalence of painful tumors was compared between the 2 groups. RESULTS: COX-2 was expressed in 9 patients (56%). COX-2 proteins were expressed not in tumor cells but in tryptase-positive mast cells in the stroma of desmoid tumors. 6 of 9 patients in COX-2 -positive group had painful tumors. This difference was statistically significant according to the chi-squared test (p = 0 .036), suggesting a positive correlation between COX-2 expression and tumor-associated pain. CONCLUSIONS: Our results indicated that COX-2 secretion from mast cells modulates desmoid tumor-associated pain. In addition, mast cells may at least in part contribute to the pathogenesis of desmoid tumors. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1490389349103056.

Immunohistochemical and molecular analysis of tyrosine kinase activity in desmoid tumors.

BACKGROUND: Optimal surgical and medical therapy for the treatment of desmoid tumors (DT) is still undefined. Partial response to tyrosine kinase inhibitors (TKI) has previously been described. Here, we examined the role of the tyrosine kinases c-Src and c-Kit in driving desmoid tumorigenesis. METHODS: Six consecutive DT and matched normal tissues were collected from the operating room. Tissues were embedded in paraffin for immunohistochemical analysis, and protein lysates were prepared for immunoblot and immunoprecipitation. RESULTS: We found increased levels of ß-catenin in five of six (83%) DT relative to matched normal tissue by immunoblot analysis. By immunohistochemistry, ß-catenin expression was also increased in DT and localized to the nucleus. In contrast, we observed variable levels of total and activated c-Src and c-Kit expression in DT compared with normal tissue. Finally, ß-catenin tyrosine phosphorylation (p-Y) among tumors was variably increased, despite the increased amount of total ß-catenin in tumors. CONCLUSIONS: Our results suggest that c-Src and c-Kit activity in DT is variable, consistent with the heterogeneous nature of this disease. Clinical response to TKI in DT may be via alternative mechanisms unrelated to c-Src or c-Kit activity. Further insight into DT biology will help identify novel drug regimens to limit the morbidity and mortality associated with this disease.

Telomere length and telomerase activity in extra-abdominal desmoid tumors.

The telomere biology of extra-abdominal desmoids was investigated. In 12 specimens, telomere length was assessed by Southern-blot analysis and telomerase activity was measured using a PCR-based TRAP assay. There was a significant correlation between telomere length and tumor size, with telomeres being shorter with increasing tumor size (p = 0.049), and between telomere length and PCNA-positive cell rate, with telomere shortening with increased positive cell rate (p = 0.017). There was a significant correlation between telomerase activity and age at surgery, with increased activity with younger age (p = 0.015). Telomere length increased with recurrence, but telomerase activity decreased, and rate of PCNA-positive cells became lower, whenever the tumors were recurrent. Decreasing telomere length correlated with tumor size, probably due to increased duration of proliferation in the tumor, and tumor aggressiveness. Recurrent case results may be due to a lower rate of cell division and the presence of telomerase activity.

Invasion and MMP expression profile in desmoid tumours.

Desmoid tumours are locally invasive soft tissue tumours in which beta-catenin mediated TCF-dependent transcription is activated. The role of soluble factors secreted by the myofibroblastic desmoid tumour, which could stimulate tumour invasiveness, was investigated. Using collagen gel invasion assays, the presence of factors stimulating invasion in desmoid conditioned media (CM) could be established. Since matrix metalloproteinases (MMPs) have been implicated in the process of tumoral invasion, the expression levels of the MMP family members were evaluated. Quantitative reverse transcription-PCR was used to determine the expression levels of MMP1, MMP2, MMP3, MMP7, MMP11, MMP12, MMP13, MMP14 and the inhibitors TIMP1, TIMP2 and TIMP3. Besides overexpression of MMP7, a known TCF-dependent target gene, a striking upregulation of the expression levels of MMP1, MMP3, MMP11, MMP12 and MMP13 in desmoid tumours, compared to unaffected fibroblasts from the same patients, was found. Treating the CM of desmoids with a synthetic and a physiologic MMP inhibitor reduced the invasion-stimulating capacity of the desmoid CM by approximately 50%. These results suggest the involvement of soluble factors, released by the desmoid cells, in stimulating invasion and implicate the MMPs as facilitators of invasion.

Lack of telomerase in desmoids occurring sporadically and in association with familial adenomatous polyposis.

BACKGROUND: Telomerase activity may be required for unlimited growth of cells and is repressed in most somatic tissues, but is detectable in immortal cell lines, germ cells, many malignancies and some benign lesions. Desmoids are proliferative, locally invasive, non-metastasizing fibromatous tumours which rarely regress. They occur frequently in familial adenomatous polyposis (FAP), causing significant morbidity and death. Telomerase activity was assayed in desmoids from patients with and without FAP to assess the role of telomerase in the development of these lesions, and its potential as a prognostic marker and possible target for treatment. METHODS: Protein extracts from 11 desmoids from nine patients with FAP, and ten desmoids from ten patients without FAP, were analysed for telomerase activity by the telomeric repeat amplification protocol, a sensitive polymerase chain reaction-based assay. Six fibrosarcomas and a fibrosarcoma cell line were used as positive controls; all displayed telomerase activity. RESULTS: No telomerase activity was detected in any of the 21 desmoids studied. CONCLUSION: These results indicate that desmoid tumours are one of the intriguing exceptions to the emerging view that re-expression of telomerase activity accompanies the development of preneoplastic and neoplastic tissues, and suggest that alternative mechanisms may operate in these proliferative neoplasms.