Desmoid Tumors: Current Perspective and Treatment.

OPINION STATEMENT: Desmoid tumors are rare tumors with a tendency to infiltrate locally. The lack of a standard treatment approach makes choosing the most appropriate treatment for patients challenging. Most experts recommend watchful observation for asymptomatic patients as spontaneous regression of tumor is observed in up to 20% of patients. Upfront resection of the desmoid tumor has fallen out of favor due to high morbidity and high relapse rates associated with the tumor. Systemic therapy has evolved over several decades. Where chemotherapy, hormonal therapy, and non-steroidal anti-inflammatory drugs were used over the last several decades, tyrosine kinase inhibitors came to the forefront within the last decade. Most recently, gamma-secretase inhibitors have shown significant clinical benefit in patients with desmoid tumors, bringing forth an entirely new mechanistic approach. Several Wnt pathway inhibitors are also under development. Invasive approaches like cryoablation have also shown clinical benefit in patients with extra-abdominal desmoid tumors in recent years. The recent approval of nirogacestat has ushered in a new era of treatment for patients diagnosed with desmoid tumors. Several new molecules are expected to be approved over the coming years.

Desmoid fibromatosis-a diagnostic dilemma.

PURPOSE: Desmoid fibromatosis in head and neck is infrequent and poses a significant challenge to the clinicians due to its non-specific characteristics. METHODS: This case report focuses on a 69-year-old male who presented to a tertiary healthcare center in Karnataka, India with a swelling in the oral cavity. RESULTS: Despite initial suspicions of malignancy based on clinical examination and findings on computed tomography imaging, subsequent histopathology and immunohistochemistry revealed an unexpected finding. CONCLUSION: The case highlights the importance of clinical suspicion and histopathological evaluation as well as the need for greater awareness to facilitate early diagnosis and appropriate management of desmoid fibromatosis. We also present a literature review of varied presentations of desmoid tumors afflicting various subsites of the head and neck.

[A Case of Desmoid-Type Fibromatosis of the Mesentery of Small Intestine].

Desmoid-type fibromatosis is a relatively rare disease, often associated with familial adenomatous polyposis and a history of abdominal surgery. A 43-year-old male patient presented with abdominal pain and contrast-enhanced CT showed a mass in the lower abdomen. The mass was a 4×4×3 cm white, dense tumor with a wreath-like arrangement of eosinophilic spindle-shaped cells. Immunostaining showed KIT(-), CD34(-), desmin(-), ß-catenin(+), SMA(few+), and the diagnosis was desmoid-type fibrosis. Six months after surgery, there was no apparent recurrence.

The variable histogenesis and biology of selected bland fibroblastic lesions of the breast - pitfalls in the differential diagnostics and optimal therapeutic approach (three case reports).

Presented are three casuistics of seemingly identical breast lesions which even by adopting advanced laboratory techniques may represent diagnostic challenge. Microscopic features of some bland spindle cell lesions of different histogenesis (epithelial or mesenchymal) are misleading and a potential source of unaware errors, which might affect optimal therapeutic strategy. In the setting of three diverse entities (low-grade spindle cell metaplastic carcinoma, desmoid fibromatosis and phyllodes tumor) is documented both demanding diagnostic algorithm and revealing molecular landscape on one side as well as evolving predictive/prognostic parameters on the other one. Close interdisciplinary cooperation is inevitable for accurate interpretation/understanding of revealed diagnostic facts which is required for adjustment of competent rational and individualized therapy.

GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

PURPOSE: The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. METHODS: The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. RESULTS: DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. CONCLUSION: GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. TRIAL REGISTRATION NUMBER AND REGISTRATION DATE: NCT03785964; December 24, 2018.

Intra-abdominal desmoid fibromatosis mimicking tumour recurrence after the operation: A case series.

INTRODUCTION: Desmoid fibromatosis is a multifactorial disorder classified as a category of intermediate, locally aggressive behaviour, which might be associated with CTNNB1 or APC mutations, trauma, surgery, or pregnancy. CASE REPORTS: We present two cases of postoperative intra-abdominal desmoid fibromatosis. The first case occurred 14 months after the resection of a retroperitoneal gastrointestinal stromal tumour. The second case was located in the mesentery, as evidenced on an 18-month followup after a laparoscopy-assisted anterior resection for adenocarcinoma at the rectosigmoid junction. Under the clinical diagnosis of recurrence, tissue excisions were conducted. Microscopically, the tissue was composed of bland spindle cells without cytological atypia, admixed with collagen bundles. Both tumours exhibited nuclear expression of ß-catenin on immunohistochemical staining, which is a desirable criterion for desmoid fibromatosis. DISCUSSION: Although positron emission tomography aids the diagnosis of recurrence, the radiological features of desmoid fibromatosis in computed tomography or magnetic resonance images are nonspecific and preoperative diagnosis of desmoid fibromatosis is difficult. The histological diagnosis of desmoid fibromatosis is difficult, especially when the specimen is small. The histological differential diagnosis of desmoid fibromatosis includes other myofibroblastic or fibroblastic tumours or lesions. Additional studies, such as ß-catenin immunohistochemistry or CTNNB1 mutation analysis, can enable accurate diagnosis of desmoid fibromatosis. A correct diagnosis is essential, because the current therapeutic strategy is a "waitand- watch" approach, which is significantly different from those of the other locally aggressive, intermediate soft tissue neoplasms. We have summarised the clinicopathological, histological and immunohistochemical features of the post-operative desmoid fibromatosis.

Desmoid-type fibromatosis of the mesentery: a clinicopatho-logical and genetic analysis of 9 cases. / è‚ ç³»è†œéŸ§å¸¦æ ·çº¤ç»´ç˜¤ç— æ‚£è€ ä¸´åºŠç— ç†å­¦åˆ†æž.

Nine cases of mesenteric desmoid-type fibromatosis were diagnosed and treated in Taizhou Hospital, Wenzhou Medical University between January 2010 and May 2022, including 2 females and 7 males, aged 16 to 59 years. The lesions were in the mesentery of small intestine with 7 cases, ileocecal junction with 1 cases and transverse colon with 1 case. The tumors had an unclear boundary and no envelope, the section was solid, gray and tough. The mean maximum diameter was (10.7±8.5) cm (range 3.5-33.0 cm). Microscopically, fusiform fibroblasts and myofibroblasts were parallel, bunched or staggered, buried in a large amount of extracellular collagen. The cell morphology was relatively consistent, without obvious atypia, and mitosis was rare. Immunohistochemistry showed that the tumor cells were positive for vimentin (9/9), ß-catenin (9/9), while smooth muscle actin (5/9) stains were focally positive. Ki-67 proliferation index was 1%-10%. Cytokeratin Pan, S-100, STAT6, CD117, DOG1, CD34, desmin and anaplastic lymphoma kinase stains were negative. Genetic analysis showed that there were 7 cases of c.121G>A(p.Thr41Ala) mutation of CTNNB1 gene, 1 case of c.121G>A(p.Thr41Ala) and 1 case of c.134C>T(p.Ser45Phe) double mutation, and 1 case of wild type. Tumors were surgically resected in all 9 cases. Eight cases had no recurrence or metastasis, 1 case had recurrence 6 months later, and no recurrence or metastasis after additional surgical resection.

[A Case of Giant Abdominal Desmoid Tumor in a Young Man].

Desmoid tumor is a rare tumor of the soft tissue. The frequency of occurrence is 2.4 to 4.3 cases per year per million people, which is a very rare disease. We experienced a huge intra-abdominal desmoid tumor which is thought to be the primary mesentery. The case was a male in his 20s. He visited a nearby doctor with a complaint of abdominal bloating and abdominal pain. Abdominal contrast CT revealed a huge abdominal mass with a clear boundary of 35×25 cm in size extending from the upper right abdomen to the pelvis. Surgery was performed with a diagnosis of an intra-abdominal mass. Open abdominal tumor resection. Due to infiltration into the duodenum, transverse colon, and pancreas, right hemicolectomy and duodenal combined resection were performed. The pathological diagnosis was a diagnosis of desmoid tumor.

Evolving strategies for management of desmoid tumor.

Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for ß-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of ß-catenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracycline-based or methotrexate-based regimens). A newer class of agents, γ-secretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients.

Treatment of Orbital Desmoid-type Fibromatosis With Sorafenib.

Desmoid-type fibromatosis is a rare tumor, particularly in the orbit, with fewer than 10 cases of primary orbital desmoid-type fibromatosis reported in the literature. The authors present a case of an infant who presented with rapid onset of OD proptosis, disc edema, and hyperopic shift who was found to have a retrobulbar desmoid-type fibromatosis. After initial biopsy, due to risk of vision loss with complete excision, the tumor was treated with sorafenib, a tyrosine kinase inhibitor. During the course of treatment with sorafenib, the tumor stabilized and then regressed in size. To the authors' knowledge, this is the first reported case of orbital desmoid-type fibromatosis to be treated with sorafenib.

Giant mesenteric fibromatosis associated with non-Hodgkin lymphoma. A case report and literature review.

BACKGROUND: Mesenteric fibromatosis is a benign locally-aggressive mesenchymal neoplasm that lacks the potential for metastasis. It is related to Gardner's Syndrome, previous trauma, abdominal surgery, and prolonged intake of oestrogen. Differentially diagnosing this from similar tumours is crucial in order for establishing the appropriate treatment and only immunohistochemical features can be used for a definitive diagnosis. Although medical therapies play a role in the treatment of mesenteric fibromatosis, surgical resection is the gold-standard procedure. METHODS: Our case study is a 40-year-old male with a concomitant diagnosis of non-Hodgkin lymphoma and mesenteric fibromatosis, not associated with any of the risk factors mentioned above. We performed CT and PET scans and observed a vascularised and well-defined mesenteric centre-abdominal hypermetabolic solid mass in contact with the gastric body, duodenum, body and tail of the pancreas, transverse colon, and spleen. An ultrasound-guided tru-cut biopsy revealed features suggestive of mesenteric fibromatosis. RESULTS: An elective laparotomy was carried out and a giant mass, arising from mesentery, was excised, including a partial gastrectomy and segmental resection of the transverse colon. Distal pancreatectomy, small bowel resection and successive splenectomy were performed due to a large hypertensive component. The postoperative period was uneventful. The histopathology of the surgical pieces was compatible with intra-abdominal desmoid fibromatosis. CONCLUSION: As far as we know from the literature, this is the largest mesenteric fibromatosis tumour ever to be excised. We also noticed that this is the first reported case of the concomitant presence of mesenteric fibromatosis and non-Hodgkin lymphoma that is not related to any of the described risk factors. Further research is needed to establish what type of association this presentation may indicate.

[A Case of Solitary Desmoid Tumor after Laparoscopic Sigmoid Colon Cancer Resection].

A 71-year-old man with pathological Stage Ⅰ(pT1bN0M0)underwent laparoscopic sigmoid colon cancer resection. After 18 months postoperatively, follow-up computed tomography(CT)showed a 30 mm enhanced soft tissue tumor near the anastomotic site. Considering the magnetic resonance imaging(MRI)and positron emission tomography(PET)results, we diagnosed sigmoid colon cancer with local recurrence. Laparoscopic radical resection of the colon and intestine, including the tumor, was performed. Pathologically, the tumor comprised spindle-shaped cells with collagen fibers and was diagnosed as a desmoid tumor by immunostaining(ß-catenin+, c-kit-, CD34-, α-SMA-, and DOG-1-). We report a case of intra-abdominal desmoid tumor near the anastomotic site after laparoscopic sigmoid colon cancer resection.

[A Case of Intra-Abdominal Desmoid Tumor after Laparoscopic Resection of Colon Cancer].

An 84-year-old man underwent laparoscopic descending colon resection for colon cancer with stage Ⅰ. Follow-up computed tomography(CT), 18 months after surgery showed a soft tissue density nodular mass, 30 mm in size, in the small intestinal mesentery. The surgical resection of the tumor was performed after a thorough examination. Histopathological examination showed spindle-shaped fibroblasts and abundant collagen fibers. Immunohistochemical staining was negative for c-kit and CD34 and positive for α-SMA and ß-catenin. From the above, this tumor was diagnosed as intra-abdominal desmoid tumor.

Extra-abdominal desmoid tumor fibromatosis: a multicenter EMSOS study.

BACKGROUND: Extra-abdominal desmoid tumor fibromatosis (DTF) is a rare, locally aggressive soft tissue tumour. The best treatment modality for this patient cohort is still object of debate. QUESTIONS/PURPOSE: This paper aimed to (1) to compare the outcomes of DTF after different treatment modalities, (2) to assess prognostic factors for recurrence following surgical excision, and (3) to assess prognostic factors for progression during observation. METHODS: This was a retrospective multicenter study under the patronage of the European Musculoskeletal Oncology Society (EMSOS). All seven centres involved were tertiary referral centres for soft tissue tumours. Baseline demographic data was collected for all patients as well as data on the diagnosis, tumour characteristics, clinical features, treatment modalities and whether they had any predisposing factors for DTF. RESULTS: Three hundred eighty-eight patients (240 female, 140 male) with a mean age of 37.6 (±18.8 SD, range: 3-85) were included in the study. Two hundred fifty-seven patients (66%) underwent surgical excision of ADF, 70 patients (18%) were observed without therapy, the residual patients had different conservative treatments. There were no significant differences in terms of tumour recurrence or progression between the different treatment groups. After surgical excision, younger age, recurrent disease and larger tumour size were risk factors for recurrence, while tumours around the shoulder girdle and painful lesions were at risk of progression in the observational group. CONCLUSION: Local recurrence rate after surgery was similar to progression rates under observation. Hence, observation in DTF seems to be justified, considering surgery in case of dimensional progression in 2 consecutive controls (3 and 6 months) and in painful lesions, with particular attention to lesions around the shoulder girdle.

Desmoid Fibromatosis: Management in an Era of Increasing Options.

PURPOSE OF REVIEW: Desmoid fibromatosis (DF) is a locally aggressive clonal neoplasm with locally aggressive behavior and no metastatic potential. Historical treatment of DF has consisted primarily of up-front surgery when feasible. In recent years, recognition that DF can spontaneously stabilize or involute has allowed for many patients to be managed with watchful waiting rather than intervention. This review is intended to review recent developments in the treatment of DF. RECENT FINDINGS: Recent studies have demonstrated prospectively that patients with DF often have improvement in their lesions without intervention, enabling an initial period of surveillance as a standard option for patients with mild symptoms. Given the lengthening list of effective systemic treatments, including sorafenib, pazopanib, and experimental agents, there has been a less reliance on local therapies for those patients who require treatment. For patients with DF that require treatment, there is a growing list of options that includes radiation therapy (RT), percutaneous ablation, and a growing list of systemic agents with favorable toxicity profiles.

The Role of Radiation Therapy for Symptomatic Desmoid Tumors.

OPINION STATEMENT: Desmoid tumors have a variable clinical course that ranges from indolence or spontaneous regression to an aggressive pattern marked by local invasion. Up to half may remain stable or regress; watchful waiting is the preferred approach in the initial management of desmoid tumors. Symptomatic or progressive tumors or those that may affect adjacent critical structures require surgery, radiotherapy, or systemic therapy. Although radiotherapy effectively controls desmoid tumors in most cases, concerns regarding late toxicity exist. Definitive radiotherapy for macroscopic disease is indicated when a non-morbid complete surgical resection cannot be accomplished and provides similar control rates to surgery plus radiotherapy but avoids toxicity from combined-modality treatment (surgery and radiotherapy). Adjuvant radiotherapy can be considered for microscopically involved margins, particularly for recurrent cases or when a future recurrence may be challenging to treat. Large size, extremity site, and younger age are poor prognostic factors after radiotherapy. In the extremity, radiotherapy may have superior outcomes to surgery. Younger patients, especially children, are challenging to manage as they are at particular risk for late toxicity due to the number of potential years at risk. For patients under 20 years old, for whom a non-morbid complete resection is not possible, we recommend systemic therapy as the first line of treatment. Although the long-term efficacy of systemic therapy is unproven, this strategy allows additional time for growth and development prior to radiotherapy. In younger patients and those with axial desmoid tumors adjacent to critical organs, consideration should be given to using proton therapy as the dosimetric advantages may mitigate some of the toxicity associated with conventional radiotherapy.

Desmoid fibromatosis: is the current picture changing?

Desmoid fibromatosis is a locally aggressive tumor with an unpredictable clinical course. Surgery was once the mainstay of treatment, but the treatment protocol has been constantly evolving and currently active surveillance is the front-line approach. There have been significant insights into the molecular biology with the addition of mutational analysis of CTNNB1 adding to prognostic information. We present a review of the literature with current practice guidelines, also including novel therapeutic targets and ongoing clinical trials, to unravel the next step in the management of sporadic desmoid fibromatosis.

Lay abstract Desmoid fibromatosis is an aggressive local tumor with continuously changing treatment paradigms. It requires MRI with biopsy for diagnosis and follow-up. Usually the tumor responds to a 'wait and watch' approach in most patients with either stable disease or regression on follow-up; a surgical plan is made only after multidisciplinary discussion, as surgery does not provide additional benefit in most patients. After a period of wait and watch, if there is disease progression, patients can be kept on medical management such as chemotherapy. Currently we have novel drugs for medical management like tyrosine kinase inhibitors, which result in disease stabilization in a majority of patients. In order to reduce the morbidity of treatment, it is essential for the patient to be on continuous follow-up and for clinicians to be updated with the continuously changing management of this disease.

Cutaneous desmoid-type fibromatosis: A rare case with molecular profiling.

Fibromatoses encompass a broad group of histopathologically similar fibroblastic/myofibroblastic proliferations with divergent clinical manifestations and behavior. Deep (desmoid-type) fibromatoses are typically large, rapidly growing, and locally aggressive tumors that occur in the abdominal wall, mesentery, and extra-abdominal soft tissue, principally the musculature of the trunk and extremities. Most sporadic cases of desmoid fibromatosis harbor inactivating mutations in CTNNB1, the gene encoding beta-catenin. Tumors occurring in the context of familial adenomatous polyposis and Gardner syndrome bear inactivating mutations in APC. By contrast, mutations in CTNNB1 or APC have not been identified in cases of superficial fibromatosis. Cutaneous involvement by desmoid fibromatosis is exceedingly rare. Here we present a 78-year-old male with desmoid-type fibromatosis arising in the dermis of the right medial calf with a pathogenic mutation in CTNNB1 and a variant of unknown significance in APC.

Trends in diagnostic and therapeutic strategies for extra-abdominal desmoid-type fibromatosis: Japanese musculoskeletal oncology group questionnaire survey.

OBJECTIVE: The mainstay of treatment modality for extra-abdominal desmoid-type fibromatosis (DF) has shifted from surgery, which often impairs ADL/QOL, to conservative treatment including active surveillance. In the present study, we conducted a longitudinal survey on the diagnosis and treatment of DF at facilities belonging to the Japanese Musculoskeletal Oncology Group, which is a research group of facilities specializing in the treatment of bone and soft tissue tumors in Japan to clarify the transition of medical care for extra-abdominal DF. METHODS: The same questionnaire was administered in 2015 and 2018, and responses were obtained from 46 (69%) of 67 facilities and 42 (53%) of 80 facilities in 2015 and 2018, respectively. RESULTS: Although immunostaining for ß-catenin was often used for the pathological diagnosis in both 2015 and 2018, CTNNB1 mutation analysis was not performed either in 2015 or in 2018. As for the treatment strategy for resectable cases, surgical treatment including wide resection was selected at 11 facilities (24% of respondents) in 2015, and further decreased to 5 facilities (12%) in 2018. Conservative treatment with active surveillance or medical treatment was the most common treatment for both resectable and difficult-to-resect cases. COX-2 inhibitors and tranilast were often used in the drug treatment of both resectable and difficult-to-resect cases. Few facilities provided radiotherapy, methotrexate and vinblastine, or DOX-based chemotherapy for refractory cases in both 2015 and 2018. CONCLUSIONS: A good trend was found in the questionnaire survey. It will be further necessary to disseminate clinical practice guidelines to physicians more widely, and to have them understand and implement the most up-to-date medical practice strategies for this rare disease.

A comparison of the usefulness of nuclear beta-catenin in the diagnosis of desmoid-type fibromatosis among commonly used anti-beta-catenin antibodies.

Desmoid-type fibromatosis (DF) is a locally aggressive but non-metastatic (myo)fibroblastic neoplasm. A hallmark of the tumor is nuclear positivity for beta-catenin in immunohistochemistry due mostly to CTNNB1 mutations. However, a recent study has reported that even beta-catenin 'nuclear-negative' DFs can harbor CTNNB1 mutations and that the positive ratio of nuclear beta-catenin in DF is different among antibodies. Here, we reviewed soft tissue lesions for which the possibility of DF was considered and compared the sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF among commonly used anti-beta-catenin antibodies, i.e., clone beta-catenin 1, 17C2 and 14. We analyzed 26 cases of DF, 28 cases of benign fibroblastic lesions, and 27 cases of other soft tissue tumors. The sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF were different among antibodies; 54% and 98% in clone beta-catenin 1, 85% and 84% in 17C2, and 96% and 62% in 14. IHC of LEF1 showed comparable results with IHC of beta-catenin, with a sensitivity of 88% and specificity of 76%. Additionally, when beta-catenin 1 was used, DFs showed characteristic dotted cytoplasmic staining, often appearing as rings. Our results might be helpful for making a correct diagnosis of DF.