Desmoid Tumor

MONDO:0007608 Pathograph 22 Show in embeddings browser fibromatosis

A locally aggressive monoclonal proliferation of myofibroblasts that infiltrates surrounding tissue but never metastasises. Almost all cases are driven by constitutive Wnt/beta-catenin signalling: sporadic tumours carry activating somatic mutations in CTNNB1 exon 3, while tumours arising in familial adenomatous polyposis carry germline APC mutations. Both lesions converge on the same defect, failure of the Axin/APC/GSK3-beta destruction complex to degrade cytoplasmic beta-catenin, which then accumulates in the nucleus and drives myofibroblast proliferation and collagen-rich matrix deposition. The clinical course is strikingly unpredictable, with long spontaneous stability and outright regression common enough that active surveillance, rather than surgery, is now the recommended first-line management for most patients.

Ask OpenScientist

Ask a research question about Desmoid Tumor. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
9
Pathophys.
5
Phenotypes
22
Pathograph
2
Genes
6
Medical Actions
2
Subtypes
2
Trials
17
References
👪

Inheritance

1
Autosomal dominant (FAP-associated subset) HP:0000006
The sporadic form is not heritable; the driver is a somatic CTNNB1 mutation. The FAP-associated subset follows the autosomal dominant inheritance of the underlying germline APC mutation, so what is inherited is the polyposis predisposition rather than the desmoid tumour itself.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin."
Distinguishes the somatic sporadic form from the germline FAP-associated form, which is what determines whether inheritance applies.
◆

Subtypes

2
Sporadic (CTNNB1-mutant)
The large majority of cases. Driven by an activating somatic mutation in CTNNB1 exon 3, most often T41A or S45F, in a patient with no polyposis syndrome.
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin."
Separates the sporadic somatic-CTNNB1 arm from the germline-APC arm.
FAP-associated (germline APC)
Arises in familial adenomatous polyposis on a background of germline APC mutation. These tumours are disproportionately intra-abdominal and mesenteric, and they are the second leading cause of death in FAP after colorectal cancer.
Show evidence (1 reference)
PMID:20676788 SUPPORT Human Clinical
"Desmoid disease was the second cause of death (10.5% of all causes), leading to a fatal outcome 22% of all patients who developed DT during the study period."
Establishes desmoid disease as the second cause of death in this FAP cohort and quantifies its lethality among those affected.
⚙

Pathophysiology

9
CTNNB1 Exon 3 Activating Mutation
The sporadic arm. An activating point mutation in CTNNB1 exon 3 removes the serine and threonine residues that GSK3-beta and casein kinase 1 phosphorylate, so beta-catenin is never marked for destruction. Three codons account for almost all of it: T41A, S45F and S45P.
CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Failure of Cytoplasmic beta-catenin Degradation Loss of the phosphorylation substrate disables destruction of beta-catenin from the substrate side.
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"The point mutations are predominantly T41A (55%), S45F (35%), and S45P (10%)."
Gives the codon distribution that defines this arm.
Germline APC Loss of Function
The familial adenomatous polyposis arm. Germline APC mutation removes a structural component of the complex that presents beta-catenin for phosphorylation, disabling the same machinery from the scaffold side. The two lesions are mutually exclusive, which gives the genotype diagnostic value: a CTNNB1 mutation rules out FAP and an APC mutation rules out sporadic disease.
APC hgnc:583 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves APC (hgnc:583). hgnc:583 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Failure of Cytoplasmic beta-catenin Degradation Loss of the scaffold disables destruction of beta-catenin from the complex side, converging on the same defect as the sporadic arm.
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Because mutations in these two genes are mutually exclusive, the finding of CTNNB1 mutation rules out FAP, and APC mutation rules out sporadic DT."
States the mutual exclusivity that separates this arm from the sporadic one and gives it diagnostic use.
Failure of Cytoplasmic beta-catenin Degradation
Unphosphorylated beta-catenin escapes ubiquitin-mediated destruction, accumulates in the cytoplasm and translocates to the nucleus, where it partners with TCF/LEF transcription factors. Nuclear beta-catenin is the diagnostic hallmark of the tumour on immunohistochemistry, which makes this node directly observable in routine practice rather than inferred.
beta-catenin destruction complex GO:0030877 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased beta-catenin destruction complex (GO:0030877). GO:0030877 is a cellular component from the Gene Ontology.
Downstream
Constitutive Activation of the Wnt-beta-catenin Axis Undegraded beta-catenin accumulates and enters the nucleus, where it partners with TCF/LEF. The pathway is therefore held on with no Wnt ligand present.
Show evidence (4 references)
PMID:31189665 SUPPORT Model Organism
"The central regulator of the Wnt/β-catenin pathway is the Axin/APC/GSK3β destruction complex (DC), which, under unstimulated conditions, targets cytoplasmic β-catenin for degradation."
Identifies the complex whose failure this node describes and names APC and GSK3-beta as its components, which is why lesions in either arm converge here. A Drosophila study, cited for the canonical complex biology rather than for the human tumour; the human evidence for accumulation in this disease is below.
PMID:15375433 SUPPORT Human Clinical
"High-level nuclear beta-catenin staining was seen in a very limited subset of tumor types, including desmoid-type fibromatosis (71% of cases), solitary fibrous tumor (40%), endometrial stromal sarcoma (40%) and synovial sarcoma (28%)."
The tissue-microarray result across 549 bone and soft tissue tumours, naming desmoid-type fibromatosis at 71% and showing that high-level nuclear beta-catenin marks only a narrow set of entities.
PMID:35670122 SUPPORT Human Clinical
"In 85%–90% of sporadic cases, DTs harbor somatic mutations in CTNNB1, the gene that encodes for β‐catenin, leading to its accumulation."
Human evidence that the CTNNB1 mutation leads to beta-catenin accumulation, which is the step this node asserts.
+ 1 more reference
Constitutive Activation of the Wnt-beta-catenin Axis
The shared consequence of the convergence, stated as a pathway state rather than as a genetic event. Whichever lesion disabled the destruction complex, the result is the same: persistent canonical Wnt signalling in a cell that is receiving no Wnt ligand.
CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee. APC hgnc:583 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves APC (hgnc:583). hgnc:583 is a gene from the HUGO Gene Nomenclature Committee.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Clonal Myofibroblast Proliferation Nuclear beta-catenin acting through TCF/LEF drives the proliferative programme of the tumour cell.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin."
Names both genetic routes into this node and their relationship to one another.
PMID:24325833 SUPPORT Human Clinical
"The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway."
Quantifies CTNNB1 mutation prevalence in sporadic disease and states the pathway it implicates, while being explicit that the pathogenesis is not fully understood.
Clonal Myofibroblast Proliferation
The tumour cell is a myofibroblast, and the lesion is a monoclonal proliferation of them rather than a reactive scar. That distinction is what moved this entity from "reactive fibrous overgrowth" to neoplasm, and it is why the lesion behaves autonomously rather than resolving when the presumed trauma heals.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Unpredictable Natural History with Spontaneous Regression The proliferating population does not expand monotonically. In a substantial minority it arrests or regresses outright, and what determines which course a given tumour takes is not known.
Infiltrative Growth without Metastatic Capacity The expanding myofibroblast population lays down a collagen-rich matrix and advances along fascial planes into adjacent tissue.
Show evidence (1 reference)
PMID:32004793 SUPPORT Human Clinical
"Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course."
States the monoclonal fibroblastic character of the proliferation in the global consensus definition.
Notch Pathway Dependence
Mechanism confidence: Hypothetical
A parallel dependency rather than a step in the Wnt chain, and included because it is the only target for which a randomised trial has produced an approved drug. Gamma-secretase cleaves the Notch receptor to release its intracellular domain; blocking that cleavage produces objective responses in this tumour. The node is therefore inferred largely backwards, from therapeutic response, and is graded accordingly.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Clonal Myofibroblast Proliferation Notch signalling sustains the proliferating myofibroblast population; the intermediates between receptor cleavage and proliferation in this tumour are not established.
Show evidence (1 reference)
PMID:24076266 SUPPORT Human Clinical
"Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and..."
Records antitumour activity of Notch-directed agents in desmoid tumours, which is the observation this node rests on.
Infiltrative Growth without Metastatic Capacity
The defining behaviour, and an unusual combination. The lesion invades muscle, fascia, nerve and vessel and erodes bone, yet it has no metastatic potential at all. Morbidity is therefore entirely local and entirely a function of what the tumour happens to sit next to.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Gastrointestinal Desmoid Tumor When the infiltrating lesion arises in the mesentery or intra-abdominally, which is the predominant site in familial adenomatous polyposis, it presents as this form.
Local Tissue and Organ Compromise Compression and invasion of adjacent structures produce the pain, functional loss and obstruction that constitute the clinical disease.
Show evidence (2 references)
PMID:30575484 SUPPORT Human Clinical
"Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs."
States the infiltrative behaviour and the structures involved.
PMID:35217286 SUPPORT Human Clinical
"Despite the lack of metastasizing potential, the course can be unpredictable."
States the absence of metastatic capacity, which is the second half of this node.
Local Tissue and Organ Compromise
The clinical endpoint. Because the tumour never spreads, everything that harms the patient follows from local mass effect and invasion: chronic pain, loss of mobility, and, for mesenteric tumours, bowel obstruction that can be fatal.
Downstream
Chronic Pain Invasion and compression of muscle, nerve and vessel produce the chronic pain that dominates the patient experience.
Limitation of Joint Mobility Infiltration of muscle and periarticular tissue restricts movement.
Intestinal Obstruction A mesenteric or intra-abdominal tumour obstructs the bowel, which is how a non-metastasising tumour becomes lethal.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Patients can experience compromised QOL due to diagnostic challenges and the high clinical burden of DT, including severe pain, impaired physical function and mobility, and high recurrence rates."
Summarises the clinical burden that constitutes this endpoint.
Unpredictable Natural History with Spontaneous Regression
A property of the disease rather than a step in its causal chain, but the single most consequential fact about it. A substantial fraction of tumours stabilise or regress with no treatment at all. This is the observation that displaced surgery as first-line management, and it means any uncontrolled treatment series in this disease will overstate benefit.
Show evidence (4 references)
PMID:37436594 SUPPORT Human Clinical
"According to estimates, approximately 10–28% of DT will resolve spontaneously without treatment (22% for extra-abdominal tumors to 28% for abdominal tumors)"
The fullest quantitative breakdown of natural history available in the cached sources, and the basis for the figures recorded in the progression section.
PMID:35670122 SUPPORT Human Clinical
"A large, prospective, observational study (ClinicalTrials.gov identifier NCT02547831) of patients with sporadic DT who were managed with active surveillance (MRI or CT every 3–6 months) recently reported a treatment‐free survival rate of 65.9% at 3 years, with 55% of patients experiencing..."
Prospective rather than retrospective evidence, and the strongest single figure available - 55% regression under active surveillance.
PMID:27542640 SUPPORT Human Clinical
"this has begun to evolve into a movement of watchful waiting as observational studies have shown long-term stability of many tumors without treatment and even spontaneous regression in 5% to 10% of cases"
The earlier and more conservative estimate, retained to show the range across sources rather than presenting only the highest figure.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Desmoid Tumor Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Digestive 2
Gastrointestinal Desmoid Tumor HP:0100245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal desmoid tumor (HP:0100245). HP:0100245 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Local recurrence rates of intra-abdominal tumors in patients with FAP are higher than those for extra-abdominal tumors and reported to be 57–86% [2]."
Quantifies the higher local recurrence rate of the intra-abdominal FAP-associated tumours, which is what distinguishes this form.
Intestinal Obstruction HP:0005214 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal obstruction (HP:0005214). HP:0005214 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Depending on their location, DT tend to infiltrate adjacent organs, extend along fascial planes, compress blood vessels and nerves, erode bones, or obstruct organs such as the bowel."
Names bowel obstruction as a direct consequence of tumour location.
Musculoskeletal 1
Limitation of Joint Mobility HP:0001376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limitation of joint mobility (HP:0001376). HP:0001376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Frequently mentioned symptoms are pain, limited function and mobility, fatigue, muscle weakness, and swelling around the tumor."
Names limited function and mobility among the frequently reported symptoms.
Constitutional 1
Chronic Pain FREQUENT HP:0012532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic pain (HP:0012532), qualified as temporality chronic. HP:0012532 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Patients with DT experience a high symptom burden: up to 63% of patients experience chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of cases), and anxiety/depression (15% of cases)."
Gives the proportion with chronic pain, which supports both the phenotype and the FREQUENT band, and quantifies its consequences.
Neoplasm 1
Desmoid Tumor HP:6001034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Desmoid tumor (HP:6001034). HP:6001034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35217286 SUPPORT Human Clinical
"They can emerge from any connective tissue including muscle, fascia and aponeurosis and are therefore classified, according to location, as intra-abdominal, of the abdominal wall and extra-abdominal."
Describes the tissue of origin and the anatomical classification of the lesion.
🧬

Genetic Associations

2
CTNNB1 (Activating Exon 3 Mutation in Sporadic Disease)
Gene: CTNNB1 hgnc:2514 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CTNNB1 (hgnc:2514). hgnc:2514 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (4 references)
PMID:24325833 SUPPORT Human Clinical
"The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway."
Gives the mutation prevalence in sporadic disease.
PMID:35670122 SUPPORT Human Clinical
"The point mutations are predominantly T41A (55%), S45F (35%), and S45P (10%)."
Gives the codon distribution quoted in this block's notes, which was previously asserted without evidence.
PMID:23913621 SUPPORT Human Clinical
"The estimated 3-year and 5-year RFS rates were 0.49 and 0.45, respectively, for patients who had tumors with the S45F mutation; 0.91 and 0.91, respectively, for patients who had wild-type tumors; and 0.70 and 0.66, respectively, for all others (P< .001)."
Quantifies the recurrence-free survival difference between S45F, wild type and other mutations after resection.
+ 1 more reference
APC (Germline Loss in FAP-associated Disease)
Gene: APC hgnc:583 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is APC (hgnc:583). hgnc:583 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin."
States the germline APC route and identifies APC as a regulator of beta-catenin, which is how the two arms converge.
💊

Medical Actions

6
Active Surveillance
Platform: Behavioral / lifestyle
First-line management for most patients. Because spontaneous regression occurs and surgery carries both recurrence risk and avoidable morbidity, initial observation with pain management has displaced immediate resection. This is a monitoring strategy rather than a therapeutic action, so it is deliberately not linked to a pathophysiology node.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"Consequently, active surveillance in conjunction with pain management is now recommended for most patients."
States active surveillance with pain management as the recommendation for most patients.
PMID:35670122 SUPPORT Human Clinical
"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."
Gives the reasoning behind the shift away from surgery, which is what makes surveillance a positive choice rather than a default.
Nirogacestat
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: nirogacestat CHEBI:229217 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nirogacestat (CHEBI:229217). CHEBI:229217 is a therapeutic agent from Chemical Entities of Biological Interest. gamma-secretase inhibitor NCIT:C200529 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses gamma-secretase inhibitor (NCIT:C200529). NCIT:C200529 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
An oral gamma-secretase inhibitor, and the first agent to show benefit for this disease in a placebo-controlled phase 3 trial. It blocks the proteolytic cleavage that releases the Notch intracellular domain. Diarrhoea is near universal and ovarian toxicity is a specific concern in women of childbearing potential.
Mechanism Target:
INHIBITS Notch Pathway Dependence — Blocks gamma-secretase cleavage of the Notch receptor, which is the step this node depends on.
Show evidence (1 reference)
PMID:36884323 SUPPORT Human Clinical
"Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily."
Identifies the molecular target of the agent as gamma-secretase.
Show evidence (2 references)
PMID:36884323 SUPPORT Human Clinical
"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."
Gives the randomised progression-free survival benefit, which is the primary endpoint result.
PMID:36884323 SUPPORT Human Clinical
"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."
Records the toxicity profile, which is part of why this is not automatically preferred over surveillance.
Sorafenib
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: sorafenib CHEBI:50924 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sorafenib (CHEBI:50924). CHEBI:50924 is a therapeutic agent from Chemical Entities of Biological Interest. tyrosine kinase inhibitor NCIT:C1967 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses tyrosine kinase inhibitor (NCIT:C1967). NCIT:C1967 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
A multi-targeted tyrosine kinase inhibitor with randomised evidence of benefit in progressive or symptomatic disease. Note that 36% of placebo patients were also progression-free at two years, which is the spontaneous-stability effect made visible by a controlled design.
Mechanism Target:
INHIBITS Clonal Myofibroblast Proliferation — Kinase inhibition slows growth of the proliferating tumour population, though the specific kinase dependency in this tumour is not established.
Show evidence (1 reference)
PMID:30575484 SUPPORT Human Clinical
"Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses."
Establishes that the agent controls tumour growth, which is the effect this link asserts.
Show evidence (1 reference)
PMID:30575484 SUPPORT Human Clinical
"the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001)"
Gives both the treatment effect and the placebo-arm stability rate that this description draws attention to.
Methotrexate and Vinblastine
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: methotrexate CHEBI:44185 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methotrexate (CHEBI:44185). CHEBI:44185 is a therapeutic agent from Chemical Entities of Biological Interest. vinblastine CHEBI:27375 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vinblastine, annotated with vincaleukoblastine (CHEBI:27375). CHEBI:27375 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Low-dose chemotherapy, used mainly in extra-abdominal disease. The evidence is uncontrolled: response rates around 36% with clinical benefit up to 85%, but no randomised comparison against no treatment, which given the natural history of this disease is a serious limitation.
Mechanism Target:
INHIBITS Clonal Myofibroblast Proliferation — Cytotoxic suppression of the proliferating myofibroblast population.
Show evidence (1 reference)
PMID:31845730 SUPPORT Human Clinical
"According to Response Evaluation Criteria in Solid Tumors criteria, the mean response rate (complete remission or partial response) was 36% (11-57%)."
Gives the pooled objective response rate attributable to this regimen.
Show evidence (1 reference)
PMID:31845730 SUPPORT Human Clinical
"There were three prospective case series but no randomized controlled trials among the nine studies. There was no case-control report (vs. no treatment)."
States the absence of controlled comparison, which is the limitation this entry records alongside the response rate.
Doxorubicin-based Chemotherapy
Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: doxorubicin CHEBI:28748 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxorubicin (CHEBI:28748). CHEBI:28748 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Anthracycline regimens, including liposomal doxorubicin, reserved for progressive disease. As with methotrexate and vinblastine, the supporting evidence contains no randomised controlled trials.
Mechanism Target:
INHIBITS Clonal Myofibroblast Proliferation — Cytotoxic suppression of the proliferating myofibroblast population.
Show evidence (1 reference)
PMID:32700733 SUPPORT Human Clinical
"the response rates of doxorubicin-based regimens and liposomal doxorubicin were 44% (28.6-54) and 33.3% (0-75) on average, respectively"
Gives the pooled response rates for both anthracycline formulations.
Show evidence (1 reference)
PMID:32700733 SUPPORT Human Clinical
"There were no randomized controlled trials."
States the evidence limitation directly.
Surgical Resection
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
No longer first-line. When used, the aim is microscopically negative margins, but not at the cost of organ or limb function, and recurrence after resection is approximately 20%. In FAP-associated intra-abdominal disease, recurrence rates are higher still.
Mechanism Target:
INHIBITS Infiltrative Growth without Metastatic Capacity — Removes the infiltrating lesion, which is effective locally but does not address the underlying signalling defect, hence the recurrence rate.
Show evidence (1 reference)
PMID:27542640 SUPPORT Human Clinical
"When surgical therapy is used, wide local excision with microscopically negative margins is the goal of resection but should not be at the expense of organ or limb function."
States the surgical goal and the functional constraint on achieving it.
Show evidence (1 reference)
PMID:27542640 SUPPORT Human Clinical
"Recurrence rates after surgical resection are approximately 20%; a variety of multimodal therapies are useful in controlling disease."
Quantifies post-resection recurrence, which is the reason surgery was displaced as first-line management.
🌍

Environmental Factors

2
Antecedent Surgical Trauma
Prior surgery at the site is a recognised risk factor. This matters clinically in an unusual way: because operating can precipitate disease, and because the tumour often regresses without treatment, surgery has lost its place as first-line therapy.
Show evidence (1 reference)
PMID:35217286 SUPPORT Human Clinical
"Desmoid tumors (DT) arise either sporadically or in association with FAP (familial adenomatous polyposis), although certain risk factors have also been identified, including pregnancy and antecedent surgical trauma."
Names antecedent surgical trauma as an identified risk factor.
Mechanism Target:
Clonal Myofibroblast Proliferation — Tissue injury precedes tumour development at the operated site, though the link between wound healing and clonal outgrowth is an association rather than an established mechanism.
Show evidence (1 reference)
PMID:35217286 SUPPORT Human Clinical
"Desmoid tumors (DT) arise either sporadically or in association with FAP (familial adenomatous polyposis), although certain risk factors have also been identified, including pregnancy and antecedent surgical trauma."
Identifies antecedent surgical trauma as a risk factor, which is the association this link records; the source does not establish the intervening mechanism.
Pregnancy and Estrogen Exposure
Roughly 70% of patients are women, risk rises during and after pregnancy, and women of childbearing age have faster tumour growth than men or postmenopausal women. Desmoid tumours express estrogen receptors. The inference has never converted into a treatment, though: antiestrogen response rates of 48 to 51% come from case series with no active-surveillance comparator, and guidelines no longer routinely recommend hormone therapy.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"DTs occur predominantly in women (approximately 70% of cases), and the risk of DT development or progression appears to increase during and after pregnancy."
Gives the sex ratio and states the pregnancy-associated risk directly.
PMID:35217286 SUPPORT Human Clinical
"Desmoid tumors (DT) arise either sporadically or in association with FAP (familial adenomatous polyposis), although certain risk factors have also been identified, including pregnancy and antecedent surgical trauma."
Names pregnancy as an identified risk factor.
Mechanism Target:
EXACERBATES Clonal Myofibroblast Proliferation — Estrogen exposure is associated with faster growth of the proliferating population; the receptor is expressed in the tumour, but the intervening signalling is not established and the therapeutic test of the hypothesis was uncontrolled.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"Evidence includes estrogen receptor expression in DTs and the heightened DT risk during and shortly after pregnancy and among women taking estrogen‐containing oral contraceptives. Women of childbearing age appear to have greater DT growth rates than men or postmenopausal women"
Assembles the receptor expression, the pregnancy and contraceptive risk, and the growth-rate difference that together support this link.
PMID:35670122 NO_EVIDENCE Human Clinical
"although the lack of an active surveillance comparator makes this finding difficult to interpret. Therefore, treatment guidelines no longer routinely recommend hormone therapies."
Recorded as NO_EVIDENCE rather than REFUTE on review. An uninterpretable antiestrogen trial fails to confirm that estrogen exposure drives proliferation; it does not contradict it. The item is kept because a reader weighing this link should know the therapeutic test of it was uncontrolled and was abandoned by guidelines.
🔬

Diagnosis

2
Nuclear beta-catenin immunohistochemistry (PRESENT)
Nuclear beta-catenin staining is the diagnostic hallmark. Its performance is strongly antibody-dependent, which is a practical trap: sensitivity ranges from 54% to 96% and specificity from 98% down to 62% across three commonly used clones, so a negative result with a specific antibody does not exclude the diagnosis.
Show evidence (1 reference)
PMID:33788979 SUPPORT Human Clinical
"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."
Quantifies the antibody dependence that this entry flags as a practical pitfall.
Magnetic resonance imaging (PRESENT)
MRI is the preferred imaging modality for most anatomical sites, both for delineating the infiltrative margin and for serial assessment during active surveillance.
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Magnetic resonance imaging is preferred for most anatomic locations."
States MRI as the preferred modality.
📈

Progression

4
Diagnosis
Diagnosis is frequently delayed. Because the tumour resembles other myofibroblastic lesions and is rare, 30 to 40% of cases are misdiagnosed, and in one series the interval from symptom onset to diagnosis exceeded a year for more than half of patients. Most cases present between 30 and 40 years of age.
Show evidence (2 references)
PMID:37436594 SUPPORT Human Clinical
"30–40% of DT cases are reported to be misdiagnosed following histologic analysis"
Quantifies the misdiagnosis rate and localises it to histologic analysis, which is where the error occurs.
PMID:35670122 SUPPORT Human Clinical
"In one study, the time from patient‐reported symptom onset to DT diagnosis exceeded one year for 54% of patients."
Quantifies the diagnostic delay.
Growth phase
An initial period of tumour growth, during which pain and functional loss develop. Shorter progression-free survival is associated with age under 37, tumour size over 7 cm, and extra-abdominal location.
Show evidence (1 reference)
PMID:35670122 SUPPORT Human Clinical
"Factors significantly associated with shorter progression‐free survival (PFS) include age (younger than 37 years), tumor size (>7 cm), and tumor location (extra‐abdominal)."
Gives the factors that predict a faster course through this phase.
Stabilisation or regression
The phase that makes this disease unusual. Roughly half of tumours remain stable after diagnosis, 10 to 28% resolve outright without treatment, 30% cycle between progression and resolution, and only about 10% progress rapidly. Under prospective active surveillance, 55% of patients experienced spontaneous regression and treatment-free survival was 65.9% at three years.
Show evidence (2 references)
PMID:37436594 SUPPORT Human Clinical
"According to estimates, approximately 10–28% of DT will resolve spontaneously without treatment (22% for extra-abdominal tumors to 28% for abdominal tumors)"
Gives the spontaneous resolution range that characterises this phase.
PMID:35670122 SUPPORT Human Clinical
"A large, prospective, observational study (ClinicalTrials.gov identifier NCT02547831) of patients with sporadic DT who were managed with active surveillance (MRI or CT every 3–6 months) recently reported a treatment‐free survival rate of 65.9% at 3 years, with 55% of patients experiencing..."
Prospective evidence for the size of this phase, and the basis for active surveillance as first-line management.
Post-surgical recurrence
When surgery is performed, recurrence is common. Postsurgical local recurrence at five to ten years has been reported between 30 and 77%, and higher again in FAP-associated intra-abdominal disease at 57 to 86%.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"However, postsurgical local recurrence rates at 5–10 years were reported to be in the range from 30% to 77%."
Gives the post-resection recurrence range that this phase records.
PMID:37436594 SUPPORT Human Clinical
"Local recurrence rates of intra-abdominal tumors in patients with FAP are higher than those for extra-abdominal tumors and reported to be 57–86% [2]."
Gives the higher recurrence rate in the FAP-associated intra-abdominal form.
📊

Prevalence

1
Worldwide
Annual Incidence 0.4 per 100,000 (0.3–0.5) 1–9 per 1,000,000 per year
Three to five cases per million person-years; approximately 1000-1500 new cases diagnosed annually in the United States.
Show evidence (2 references)
PMID:35670122 SUPPORT Human Clinical
"with an estimated annual incidence of three to five cases per million worldwide."
Gives the annual incidence per million.
PMID:37436594 SUPPORT Human Clinical
"The low incidence of DT (estimated 3-5 cases per million person-years) limits disease awareness."
Independent statement of the same incidence figure.
🌍

Epidemiology

3
Incidence
A rare tumour, estimated at three to five cases per million person-years. The rarity is itself clinically consequential: it limits awareness and contributes to the diagnostic delay patients typically experience.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"The low incidence of DT (estimated 3-5 cases per million person-years) limits disease awareness."
Gives the population incidence and links the rarity to delayed recognition.
Proportion of soft tissue tumours
Desmoid tumours make up roughly 3% of soft tissue tumours.
Show evidence (1 reference)
PMID:27542640 SUPPORT Human Clinical
"Desmoid tumors are rare, comprising 3% of soft tissue tumors."
Gives the share of soft tissue tumours represented by this entity.
Symptom burden
Despite being non-metastasising, the disease carries a heavy symptom burden. Up to 63% of patients have chronic pain, with downstream effects on sleep, mood and daily function.
Show evidence (1 reference)
PMID:37436594 SUPPORT Human Clinical
"Patients with DT experience a high symptom burden: up to 63% of patients experience chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of cases), and anxiety/depression (15% of cases)."
Quantifies chronic pain and its consequences in this population.
🔬

Clinical Trials

2
NCT03785964 PHASE_III COMPLETED
DeFi, the randomised placebo-controlled trial of the gamma-secretase inhibitor nirogacestat that produced the first positive phase 3 result in this disease.
Target Phenotypes: Desmoid tumor HP:6001034 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Desmoid tumor (HP:6001034). HP:6001034 is a phenotype from the Human Phenotype Ontology. Chronic pain HP:0012532 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Chronic pain (HP:0012532). HP:0012532 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03785964 SUPPORT Human Clinical
"This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive fibromatosis (DT/AF)."
Identifies the agent and the indication for the trial underlying the nirogacestat treatment entry.
NCT04871282 PHASE_II
RINGSIDE, a phase 2/3 study evaluating the gamma-secretase inhibitor AL102 in progressing desmoid tumours. A second agent against the same target as nirogacestat, which is the main reason to record the Notch node despite its hypothetical status.
Target Phenotypes: Desmoid tumor HP:6001034 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Desmoid tumor (HP:6001034). HP:6001034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04871282 SUPPORT Human Clinical
"The current study is designed to evaluate the efficacy and safety of AL102 in patients with progressive desmoid tumors."
Confirms a second gamma-secretase inhibitor in randomised evaluation for this indication.
{ }

Source YAML

click to show 
name: Desmoid Tumor
creation_date: '2026-09-02T12:45:00Z'
description: >-
  A locally aggressive monoclonal proliferation of myofibroblasts that infiltrates
  surrounding tissue but never metastasises. Almost all cases are driven by
  constitutive Wnt/beta-catenin signalling: sporadic tumours carry activating
  somatic mutations in CTNNB1 exon 3, while tumours arising in familial adenomatous
  polyposis carry germline APC mutations. Both lesions converge on the same defect,
  failure of the Axin/APC/GSK3-beta destruction complex to degrade cytoplasmic
  beta-catenin, which then accumulates in the nucleus and drives myofibroblast
  proliferation and collagen-rich matrix deposition. The clinical course is
  strikingly unpredictable, with long spontaneous stability and outright regression
  common enough that active surveillance, rather than surgery, is now the
  recommended first-line management for most patients.
categories:
- Soft Tissue Neoplasm
- Wnt Pathway Disorder
- Locally Aggressive Non-Metastasising Neoplasm
parents:
- fibromatosis
synonyms:
- aggressive fibromatosis
- desmoid-type fibromatosis
- desmoid fibromatosis
- deep fibromatosis
epidemiology:
- name: Incidence
  description: >-
    A rare tumour, estimated at three to five cases per million person-years. The
    rarity is itself clinically consequential: it limits awareness and contributes
    to the diagnostic delay patients typically experience.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The low incidence of DT (estimated 3-5 cases per million person-years) limits
      disease awareness.
    explanation: Gives the population incidence and links the rarity to delayed recognition.
- name: Proportion of soft tissue tumours
  description: >-
    Desmoid tumours make up roughly 3% of soft tissue tumours.
  evidence:
  - reference: PMID:27542640
    reference_title: Management of Desmoids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Desmoid tumors are rare, comprising 3% of soft tissue tumors.
    explanation: Gives the share of soft tissue tumours represented by this entity.
- name: Symptom burden
  description: >-
    Despite being non-metastasising, the disease carries a heavy symptom burden.
    Up to 63% of patients have chronic pain, with downstream effects on sleep, mood
    and daily function.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients with DT experience a high symptom burden: up to 63% of patients
      experience chronic pain, which leads to sleep disturbance (73% of cases), irritability
      (46% of cases), and anxiety/depression (15% of cases).'
    explanation: Quantifies chronic pain and its consequences in this population.
has_subtypes:
- name: Sporadic
  display_name: Sporadic (CTNNB1-mutant)
  description: >-
    The large majority of cases. Driven by an activating somatic mutation in CTNNB1
    exon 3, most often T41A or S45F, in a patient with no polyposis syndrome.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most DTs are sporadic, harboring somatic mutations in the gene that encodes
      for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis
      have germline mutations in the APC gene, which encodes for a protein regulator of
      β-catenin.
    explanation: Separates the sporadic somatic-CTNNB1 arm from the germline-APC arm.
- name: FAP-associated
  display_name: FAP-associated (germline APC)
  description: >-
    Arises in familial adenomatous polyposis on a background of germline APC
    mutation. These tumours are disproportionately intra-abdominal and mesenteric,
    and they are the second leading cause of death in FAP after colorectal cancer.
  evidence:
  - reference: PMID:20676788
    reference_title: Evaluating causes of death in familial adenomatous polyposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Desmoid disease was the second cause of death (10.5% of all causes), leading
      to a fatal outcome 22% of all patients who developed DT during the study period.
    explanation: Establishes desmoid disease as the second cause of death in this FAP
      cohort and quantifies its lethality among those affected.
pathophysiology:
- name: CTNNB1 Exon 3 Activating Mutation
  description: >-
    The sporadic arm. An activating point mutation in CTNNB1 exon 3 removes the
    serine and threonine residues that GSK3-beta and casein kinase 1 phosphorylate,
    so beta-catenin is never marked for destruction. Three codons account for
    almost all of it: T41A, S45F and S45P.
  biological_scale: MOLECULAR
  subtypes:
  - Sporadic
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The point mutations are predominantly T41A (55%), S45F (35%), and S45P (10%).'
    explanation: Gives the codon distribution that defines this arm.
  downstream:
  - target: Failure of Cytoplasmic beta-catenin Degradation
    causal_link_type: DIRECT
    description: Loss of the phosphorylation substrate disables destruction of beta-catenin from
      the substrate side.
    evidence:
    - reference: PMID:35670122
      reference_title: Evolving strategies for management of desmoid tumor.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In 85%–90% of sporadic cases, DTs harbor somatic mutations in CTNNB1, the gene
        that encodes for β‐catenin, leading to its accumulation.'
      explanation: States the mutation-to-accumulation step for the sporadic arm.
- name: Germline APC Loss of Function
  description: >-
    The familial adenomatous polyposis arm. Germline APC mutation removes a
    structural component of the complex that presents beta-catenin for
    phosphorylation, disabling the same machinery from the scaffold side. The two
    lesions are mutually exclusive, which gives the genotype diagnostic value: a
    CTNNB1 mutation rules out FAP and an APC mutation rules out sporadic disease.
  biological_scale: MOLECULAR
  subtypes:
  - FAP-associated
  genes:
  - preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Because mutations in these two genes are mutually exclusive, the finding of CTNNB1
      mutation rules out FAP, and APC mutation rules out sporadic DT.'
    explanation: States the mutual exclusivity that separates this arm from the sporadic one and
      gives it diagnostic use.
  downstream:
  - target: Failure of Cytoplasmic beta-catenin Degradation
    causal_link_type: DIRECT
    description: Loss of the scaffold disables destruction of beta-catenin from the complex side,
      converging on the same defect as the sporadic arm.
    evidence:
    - reference: PMID:35670122
      reference_title: Evolving strategies for management of desmoid tumor.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In patients with FAP, DTs harbor germline mutations in the APC gene, which
        encodes for a protein regulating β‐catenin levels.'
      explanation: Identifies APC as a regulator of beta-catenin levels, which is how this arm
        reaches the shared node.

- name: Failure of Cytoplasmic beta-catenin Degradation
  biological_scale: MOLECULAR
  description: >-
    Unphosphorylated beta-catenin escapes ubiquitin-mediated destruction, accumulates
    in the cytoplasm and translocates to the nucleus, where it partners with TCF/LEF
    transcription factors. Nuclear beta-catenin is the diagnostic hallmark of the
    tumour on immunohistochemistry, which makes this node directly observable in
    routine practice rather than inferred.
  cellular_components:
  - preferred_term: beta-catenin destruction complex
    modifier: DECREASED
    term:
      id: GO:0030877
      label: beta-catenin destruction complex
  evidence:
  - reference: PMID:31189665
    reference_title: 'Destruction complex dynamics: Wnt/β-catenin signaling alters Axin-GSK3β interactions
      in vivo.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The central regulator of the Wnt/β-catenin pathway is the Axin/APC/GSK3β destruction
      complex (DC), which, under unstimulated conditions, targets cytoplasmic β-catenin for
      degradation.
    explanation: Identifies the complex whose failure this node describes and names APC and
      GSK3-beta as its components, which is why lesions in either arm converge here. A
      Drosophila study, cited for the canonical complex biology rather than for the human
      tumour; the human evidence for accumulation in this disease is below.
  - reference: PMID:15375433
    reference_title: Nuclear beta-catenin in mesenchymal tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: High-level nuclear beta-catenin staining was seen in a very limited subset of
      tumor types, including desmoid-type fibromatosis (71% of cases), solitary fibrous tumor
      (40%), endometrial stromal sarcoma (40%) and synovial sarcoma (28%).
    explanation: The tissue-microarray result across 549 bone and soft tissue tumours, naming
      desmoid-type fibromatosis at 71% and showing that high-level nuclear beta-catenin marks
      only a narrow set of entities.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In 85%–90% of sporadic cases, DTs harbor somatic mutations in CTNNB1, the gene
      that encodes for β‐catenin, leading to its accumulation.'
    explanation: Human evidence that the CTNNB1 mutation leads to beta-catenin accumulation,
      which is the step this node asserts.
  - reference: PMID:33788979
    reference_title: A comparison of the usefulness of nuclear beta-catenin in the diagnosis of desmoid-type
      fibromatosis among commonly used anti-beta-catenin antibodies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A hallmark of the tumor is nuclear positivity for beta-catenin in immunohistochemistry
      due mostly to CTNNB1 mutations.
    explanation: Confirms that nuclear beta-catenin is observed in the tumour itself and ties
      it back to the CTNNB1 lesion upstream.
  downstream:
  - target: Constitutive Activation of the Wnt-beta-catenin Axis
    causal_link_type: DIRECT
    description: Undegraded beta-catenin accumulates and enters the nucleus, where it partners
      with TCF/LEF. The pathway is therefore held on with no Wnt ligand present.
    evidence:
    - reference: PMID:15375433
      reference_title: Nuclear beta-catenin in mesenchymal tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Dysregulation of these pathways allow beta-catenin to accumulate and translocate
        to the nucleus, where it may activate oncogenes.
      explanation: States the accumulation-to-nuclear-activation step by which failed degradation
        becomes constitutive pathway output.
- name: Constitutive Activation of the Wnt-beta-catenin Axis
  description: >-
    The shared consequence of the convergence, stated as a pathway state rather
    than as a genetic event. Whichever lesion disabled the destruction complex,
    the result is the same: persistent canonical Wnt signalling in a cell that is
    receiving no Wnt ligand.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  - preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most DTs are sporadic, harboring somatic mutations in the gene that encodes
      for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis
      have germline mutations in the APC gene, which encodes for a protein regulator of
      β-catenin.
    explanation: Names both genetic routes into this node and their relationship to one
      another.
  - reference: PMID:24325833
    reference_title: 'Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm--a
      position paper from the Italian and the French Sarcoma Group.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pathogenesis of DF is not completely understood even if a high prevalence
      (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of
      the Wnt/β-catenin pathway.
    explanation: Quantifies CTNNB1 mutation prevalence in sporadic disease and states the
      pathway it implicates, while being explicit that the pathogenesis is not fully
      understood.
  downstream:
  - target: Clonal Myofibroblast Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Nuclear beta-catenin acting through TCF/LEF drives the proliferative programme
      of the tumour cell.
    evidence:
    - reference: PMID:24325833
      reference_title: 'Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm--a
        position paper from the Italian and the French Sarcoma Group.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation
        of myofibroblasts lacking metastatic capacity.
      explanation: Names the proliferating cell that this edge terminates in and the clonal
        character of its expansion.
- name: Clonal Myofibroblast Proliferation
  biological_scale: CELLULAR
  description: >-
    The tumour cell is a myofibroblast, and the lesion is a monoclonal proliferation
    of them rather than a reactive scar. That distinction is what moved this entity
    from "reactive fibrous overgrowth" to neoplasm, and it is why the lesion behaves
    autonomously rather than resolving when the presumed trauma heals.
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:32004793
    reference_title: 'The management of desmoid tumours: A joint global consensus-based guideline approach
      for adult and paediatric patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis,
      aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic
      proliferation characterised by a variable and often unpredictable clinical course.'
    explanation: States the monoclonal fibroblastic character of the proliferation in the
      global consensus definition.
  downstream:
  - target: Unpredictable Natural History with Spontaneous Regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The proliferating population does not expand monotonically. In a substantial
      minority it arrests or regresses outright, and what determines which course a given
      tumour takes is not known.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The clinical course of the disease varies, and data suggest that an initial tumor
        growth phase is followed by a long period of growth arrest and even regression.
      explanation: States that the proliferative phase is characteristically followed by arrest
        or regression, which is the alternative outcome this edge records.
  - target: Infiltrative Growth without Metastatic Capacity
    causal_link_type: DIRECT
    description: The expanding myofibroblast population lays down a collagen-rich matrix and
      advances along fascial planes into adjacent tissue.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Depending on their location, DT tend to infiltrate adjacent organs, extend along
        fascial planes, compress blood vessels and nerves, erode bones, or obstruct organs
        such as the bowel.
      explanation: Describes the mode of local advance that this edge asserts.
- name: Notch Pathway Dependence
  description: >-
    A parallel dependency rather than a step in the Wnt chain, and included because
    it is the only target for which a randomised trial has produced an approved
    drug. Gamma-secretase cleaves the Notch receptor to release its intracellular
    domain; blocking that cleavage produces objective responses in this tumour. The
    node is therefore inferred largely backwards, from therapeutic response, and is
    graded accordingly.
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:24076266
    reference_title: 'Targeting notch signaling pathway in cancer: clinical development advances and challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Antitumor activity by GSIs and mAbs administered as single agent in early phases
      of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small
      cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer
      with neuroendocrine features, melanoma and ovarian cancer.
    explanation: Records antitumour activity of Notch-directed agents in desmoid tumours,
      which is the observation this node rests on.
  downstream:
  - target: Clonal Myofibroblast Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Notch signalling sustains the proliferating myofibroblast population; the
      intermediates between receptor cleavage and proliferation in this tumour are not
      established.
    evidence:
    - reference: PMID:36884323
      reference_title: Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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.
      explanation: Tumour shrinkage on gamma-secretase inhibition is the evidence that the
        proliferating population depends on this pathway, and it is indirect evidence.
- name: Infiltrative Growth without Metastatic Capacity
  biological_scale: TISSUE
  description: >-
    The defining behaviour, and an unusual combination. The lesion invades muscle,
    fascia, nerve and vessel and erodes bone, yet it has no metastatic potential at
    all. Morbidity is therefore entirely local and entirely a function of what the
    tumour happens to sit next to.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:30575484
    reference_title: Sorafenib for Advanced and Refractory Desmoid Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue
      neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular
      structures, and visceral organs.
    explanation: States the infiltrative behaviour and the structures involved.
  - reference: PMID:35217286
    reference_title: Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal
      desmoid tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite the lack of metastasizing potential, the course can be unpredictable.
    explanation: States the absence of metastatic capacity, which is the second half of this
      node.
  downstream:
  - target: Gastrointestinal Desmoid Tumor
    causal_link_type: DIRECT
    description: When the infiltrating lesion arises in the mesentery or intra-abdominally, which
      is the predominant site in familial adenomatous polyposis, it presents as this form.
    evidence:
    - reference: PMID:35670122
      reference_title: Evolving strategies for management of desmoid tumor.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'DTs can occur anywhere on the body but most commonly occur in the extremities in
        the case of sporadic DT and intra‐abdominally in patients with familial adenomatous
        polyposis (FAP).'
      explanation: Establishes the intra-abdominal predominance in FAP that defines this
        phenotype as a site-specific presentation of the infiltrating lesion.
  - target: Local Tissue and Organ Compromise
    causal_link_type: DIRECT
    description: Compression and invasion of adjacent structures produce the pain, functional
      loss and obstruction that constitute the clinical disease.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Muscle, nerve, and vessel involvement may cause debilitating symptoms, including
        pain, restricted mobility, or deformity [2].
      explanation: Names the symptoms produced by involvement of adjacent structures.
- name: Local Tissue and Organ Compromise
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. Because the tumour never spreads, everything that harms
    the patient follows from local mass effect and invasion: chronic pain, loss of
    mobility, and, for mesenteric tumours, bowel obstruction that can be fatal.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients can experience compromised QOL due to diagnostic challenges and the high
      clinical burden of DT, including severe pain, impaired physical function and mobility,
      and high recurrence rates.
    explanation: Summarises the clinical burden that constitutes this endpoint.
  downstream:
  - target: Chronic Pain
    causal_link_type: DIRECT
    description: Invasion and compression of muscle, nerve and vessel produce the chronic pain
      that dominates the patient experience.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Muscle, nerve, and vessel involvement may cause debilitating symptoms, including
        pain, restricted mobility, or deformity [2].
      explanation: Attributes pain directly to involvement of the adjacent structures.
  - target: Limitation of Joint Mobility
    causal_link_type: DIRECT
    description: Infiltration of muscle and periarticular tissue restricts movement.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Muscle, nerve, and vessel involvement may cause debilitating symptoms, including
        pain, restricted mobility, or deformity [2].
      explanation: Attributes restricted mobility to the same tissue involvement.
  - target: Intestinal Obstruction
    causal_link_type: DIRECT
    description: A mesenteric or intra-abdominal tumour obstructs the bowel, which is how a
      non-metastasising tumour becomes lethal.
    evidence:
    - reference: PMID:37436594
      reference_title: 'Desmoid Tumors: A Comprehensive Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Depending on their location, DT tend to infiltrate adjacent organs, extend along
        fascial planes, compress blood vessels and nerves, erode bones, or obstruct organs such
        as the bowel.
      explanation: Names bowel obstruction as a direct consequence of tumour location.
- name: Unpredictable Natural History with Spontaneous Regression
  description: >-
    A property of the disease rather than a step in its causal chain, but the single
    most consequential fact about it. A substantial fraction of tumours stabilise or
    regress with no treatment at all. This is the observation that displaced surgery
    as first-line management, and it means any uncontrolled treatment series in this
    disease will overstate benefit.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'According to estimates, approximately 10–28% of DT will resolve spontaneously
      without treatment (22% for extra-abdominal tumors to 28% for abdominal tumors)'
    explanation: The fullest quantitative breakdown of natural history available in the cached
      sources, and the basis for the figures recorded in the progression section.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A large, prospective, observational study (ClinicalTrials.gov identifier
      NCT02547831) of patients with sporadic DT who were managed with active surveillance (MRI
      or CT every 3–6 months) recently reported a treatment‐free survival rate of 65.9% at 3
      years, with 55% of patients experiencing spontaneous regression either initially or after
      progression.'
    explanation: Prospective rather than retrospective evidence, and the strongest single figure
      available - 55% regression under active surveillance.
  - reference: PMID:27542640
    reference_title: Management of Desmoids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: this has begun to evolve into a movement of watchful waiting as observational
      studies have shown long-term stability of many tumors without treatment and even spontaneous
      regression in 5% to 10% of cases
    explanation: The earlier and more conservative estimate, retained to show the range across
      sources rather than presenting only the highest figure.
  - reference: PMID:32004793
    reference_title: 'The management of desmoid tumours: A joint global consensus-based guideline approach
      for adult and paediatric patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Previously surgery was the standard primary treatment modality; however, in recent
      years a paradigm shift towards a more conservative management has been introduced
    explanation: Records the resulting change in standard of care at consensus level.
phenotypes:
- category: Neoplastic
  name: Desmoid Tumor
  description: >-
    The defining lesion: a firm, infiltrative soft tissue mass arising from muscle,
    fascia or aponeurosis, classified by site as intra-abdominal, abdominal wall or
    extra-abdominal.
  phenotype_term:
    preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  evidence:
  - reference: PMID:35217286
    reference_title: Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal
      desmoid tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They can emerge from any connective tissue including muscle, fascia and aponeurosis
      and are therefore classified, according to location, as intra-abdominal, of the abdominal
      wall and extra-abdominal.
    explanation: Describes the tissue of origin and the anatomical classification of the
      lesion.
- category: Neoplastic
  name: Gastrointestinal Desmoid Tumor
  subtype: FAP-associated
  description: >-
    The intra-abdominal and mesenteric form, which predominates in familial
    adenomatous polyposis and carries the highest local recurrence rates.
  phenotype_term:
    preferred_term: Gastrointestinal desmoid tumor
    term:
      id: HP:0100245
      label: Gastrointestinal desmoid tumor
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Local recurrence rates of intra-abdominal tumors in patients with FAP are higher
      than those for extra-abdominal tumors and reported to be 57–86% [2].
    explanation: Quantifies the higher local recurrence rate of the intra-abdominal
      FAP-associated tumours, which is what distinguishes this form.
- category: Constitutional
  name: Chronic Pain
  frequency: FREQUENT
  description: >-
    The dominant symptom, present in up to 63% of patients, and the reason most
    treatment decisions get made. It carries measurable consequences for sleep and
    mood.
  phenotype_term:
    preferred_term: Chronic pain
    term:
      id: HP:0012532
      label: Chronic pain
    temporality: CHRONIC
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients with DT experience a high symptom burden: up to 63% of patients experience
      chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of
      cases), and anxiety/depression (15% of cases).'
    explanation: Gives the proportion with chronic pain, which supports both the phenotype and
      the FREQUENT band, and quantifies its consequences.
- category: Musculoskeletal
  name: Limitation of Joint Mobility
  description: >-
    Restricted movement where the tumour infiltrates muscle or crosses a joint, one
    of the commonest functional complaints in extra-abdominal disease.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Frequently mentioned symptoms are pain, limited function and mobility, fatigue,
      muscle weakness, and swelling around the tumor.
    explanation: Names limited function and mobility among the frequently reported symptoms.
- category: Gastrointestinal
  name: Intestinal Obstruction
  subtype: FAP-associated
  description: >-
    Obstruction of the bowel by a mesenteric or intra-abdominal tumour. This is the
    mechanism by which a non-metastasising tumour becomes lethal, and it is why
    desmoid disease is the second cause of death in familial adenomatous polyposis.
  phenotype_term:
    preferred_term: Intestinal obstruction
    term:
      id: HP:0005214
      label: Intestinal obstruction
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depending on their location, DT tend to infiltrate adjacent organs, extend along
      fascial planes, compress blood vessels and nerves, erode bones, or obstruct organs such
      as the bowel.
    explanation: Names bowel obstruction as a direct consequence of tumour location.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.4
  rate_low: 0.3
  rate_high: 0.5
  notes: Three to five cases per million person-years; approximately 1000-1500 new cases
    diagnosed annually in the United States.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with an estimated annual incidence of three to five cases per million worldwide.
    explanation: Gives the annual incidence per million.
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The low incidence of DT (estimated 3-5 cases per million person-years) limits
      disease awareness.
    explanation: Independent statement of the same incidence figure.
progression:
- phase: Diagnosis
  notes: >-
    Diagnosis is frequently delayed. Because the tumour resembles other
    myofibroblastic lesions and is rare, 30 to 40% of cases are misdiagnosed, and
    in one series the interval from symptom onset to diagnosis exceeded a year for
    more than half of patients. Most cases present between 30 and 40 years of age.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 30–40% of DT cases are reported to be misdiagnosed following histologic analysis
    explanation: Quantifies the misdiagnosis rate and localises it to histologic analysis, which
      is where the error occurs.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In one study, the time from patient‐reported symptom onset to DT diagnosis exceeded
      one year for 54% of patients.'
    explanation: Quantifies the diagnostic delay.
- phase: Growth phase
  notes: >-
    An initial period of tumour growth, during which pain and functional loss
    develop. Shorter progression-free survival is associated with age under 37,
    tumour size over 7 cm, and extra-abdominal location.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Factors significantly associated with shorter progression‐free survival (PFS)
      include age (younger than 37 years), tumor size (>7 cm), and tumor location
      (extra‐abdominal).'
    explanation: Gives the factors that predict a faster course through this phase.
- phase: Stabilisation or regression
  notes: >-
    The phase that makes this disease unusual. Roughly half of tumours remain
    stable after diagnosis, 10 to 28% resolve outright without treatment, 30%
    cycle between progression and resolution, and only about 10% progress rapidly.
    Under prospective active surveillance, 55% of patients experienced spontaneous
    regression and treatment-free survival was 65.9% at three years.
  evidence:
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'According to estimates, approximately 10–28% of DT will resolve spontaneously
      without treatment (22% for extra-abdominal tumors to 28% for abdominal tumors)'
    explanation: Gives the spontaneous resolution range that characterises this phase.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A large, prospective, observational study (ClinicalTrials.gov identifier
      NCT02547831) of patients with sporadic DT who were managed with active surveillance (MRI
      or CT every 3–6 months) recently reported a treatment‐free survival rate of 65.9% at 3
      years, with 55% of patients experiencing spontaneous regression either initially or after
      progression.'
    explanation: Prospective evidence for the size of this phase, and the basis for active
      surveillance as first-line management.
- phase: Post-surgical recurrence
  notes: >-
    When surgery is performed, recurrence is common. Postsurgical local recurrence
    at five to ten years has been reported between 30 and 77%, and higher again in
    FAP-associated intra-abdominal disease at 57 to 86%.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'However, postsurgical local recurrence rates at 5–10 years were reported to be in
      the range from 30% to 77%.'
    explanation: Gives the post-resection recurrence range that this phase records.
  - reference: PMID:37436594
    reference_title: 'Desmoid Tumors: A Comprehensive Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Local recurrence rates of intra-abdominal tumors in patients with FAP are higher
      than those for extra-abdominal tumors and reported to be 57–86% [2].
    explanation: Gives the higher recurrence rate in the FAP-associated intra-abdominal form.
genetic:
- name: CTNNB1
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  association: Activating Exon 3 Mutation in Sporadic Disease
  notes: >-
    Present in approximately 85% of sporadic tumours. The three recurrent codons are
    T41A, S45F and S45P. The specific mutation carries prognostic weight rather than
    being merely diagnostic: S45F predicts markedly worse recurrence-free survival
    after resection than T41A or wild type.
  evidence:
  - reference: PMID:24325833
    reference_title: 'Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm--a
      position paper from the Italian and the French Sarcoma Group.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pathogenesis of DF is not completely understood even if a high prevalence
      (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the
      Wnt/β-catenin pathway.
    explanation: Gives the mutation prevalence in sporadic disease.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The point mutations are predominantly T41A (55%), S45F (35%), and S45P (10%).'
    explanation: Gives the codon distribution quoted in this block's notes, which was previously
      asserted without evidence.
  - reference: PMID:23913621
    reference_title: 'CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary
      desmoid tumor recurrence: an independent, multicenter validation study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The estimated 3-year and 5-year RFS rates were 0.49 and 0.45, respectively, for
      patients who had tumors with the S45F mutation; 0.91 and 0.91, respectively, for patients
      who had wild-type tumors; and 0.70 and 0.66, respectively, for all others (P< .001).
    explanation: Quantifies the recurrence-free survival difference between S45F, wild type and
      other mutations after resection.
  - reference: PMID:33397129
    reference_title: Prognostic significance of CTNNB1 mutation in recurrence of sporadic desmoid tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: S45F-mutated DTs were more likely to recur compared with wild type, T41A and other
      mutated DTs.
    explanation: An eight-study meta-analysis confirming the S45F recurrence signal, which is
      why it is recorded here rather than as a single-series finding.
- name: APC
  gene_term:
    preferred_term: APC
    term:
      id: hgnc:583
      label: APC
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Germline Loss in FAP-associated Disease
  notes: >-
    APC is a structural component of the destruction complex, so germline APC loss
    produces the same failure of beta-catenin degradation that CTNNB1 exon 3
    mutation produces from the other side. In this disease APC acts through
    beta-catenin, not through the polyposis phenotype.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most DTs are sporadic, harboring somatic mutations in the gene that encodes for
      β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have
      germline mutations in the APC gene, which encodes for a protein regulator of β-catenin.
    explanation: States the germline APC route and identifies APC as a regulator of
      beta-catenin, which is how the two arms converge.
environmental:
- name: Antecedent Surgical Trauma
  presence: PRESENT
  description: >-
    Prior surgery at the site is a recognised risk factor. This matters clinically
    in an unusual way: because operating can precipitate disease, and because the
    tumour often regresses without treatment, surgery has lost its place as
    first-line therapy.
  influences_mechanisms:
  - target: Clonal Myofibroblast Proliferation
    description: Tissue injury precedes tumour development at the operated site, though the
      link between wound healing and clonal outgrowth is an association rather than an
      established mechanism.
    evidence:
    - reference: PMID:35217286
      reference_title: Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal
        desmoid tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Desmoid tumors (DT) arise either sporadically or in association with FAP (familial
        adenomatous polyposis), although certain risk factors have also been identified, including
        pregnancy and antecedent surgical trauma.
      explanation: Identifies antecedent surgical trauma as a risk factor, which is the
        association this link records; the source does not establish the intervening mechanism.
  evidence:
  - reference: PMID:35217286
    reference_title: Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal
      desmoid tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Desmoid tumors (DT) arise either sporadically or in association with FAP (familial
      adenomatous polyposis), although certain risk factors have also been identified, including
      pregnancy and antecedent surgical trauma.
    explanation: Names antecedent surgical trauma as an identified risk factor.
- name: Pregnancy and Estrogen Exposure
  presence: PRESENT
  description: >-
    Roughly 70% of patients are women, risk rises during and after pregnancy, and
    women of childbearing age have faster tumour growth than men or
    postmenopausal women. Desmoid tumours express estrogen receptors. The
    inference has never converted into a treatment, though: antiestrogen response
    rates of 48 to 51% come from case series with no active-surveillance
    comparator, and guidelines no longer routinely recommend hormone therapy.
  influences_mechanisms:
  - target: Clonal Myofibroblast Proliferation
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Estrogen exposure is associated with faster growth of the proliferating
      population; the receptor is expressed in the tumour, but the intervening signalling is not
      established and the therapeutic test of the hypothesis was uncontrolled.
    evidence:
    - reference: PMID:35670122
      reference_title: Evolving strategies for management of desmoid tumor.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Evidence includes estrogen receptor expression in DTs and the heightened DT risk
        during and shortly after pregnancy and among women taking estrogen‐containing oral
        contraceptives. Women of childbearing age appear to have greater DT growth rates than
        men or postmenopausal women'
      explanation: Assembles the receptor expression, the pregnancy and contraceptive risk, and
        the growth-rate difference that together support this link.
    - reference: PMID:35670122
      reference_title: Evolving strategies for management of desmoid tumor.
      supports: NO_EVIDENCE
      evidence_source: HUMAN_CLINICAL
      snippet: 'although the lack of an active surveillance comparator makes this finding
        difficult to interpret. Therefore, treatment guidelines no longer routinely recommend
        hormone therapies.'
      explanation: Recorded as NO_EVIDENCE rather than REFUTE on review. An uninterpretable
        antiestrogen trial fails to confirm that estrogen exposure drives proliferation; it does
        not contradict it. The item is kept because a reader weighing this link should know the
        therapeutic test of it was uncontrolled and was abandoned by guidelines.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'DTs occur predominantly in women (approximately 70% of cases), and the risk of DT
      development or progression appears to increase during and after pregnancy.'
    explanation: Gives the sex ratio and states the pregnancy-associated risk directly.
  - reference: PMID:35217286
    reference_title: Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal
      desmoid tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Desmoid tumors (DT) arise either sporadically or in association with FAP (familial
      adenomatous polyposis), although certain risk factors have also been identified, including
      pregnancy and antecedent surgical trauma.
    explanation: Names pregnancy as an identified risk factor.
diagnosis:
- name: Nuclear beta-catenin immunohistochemistry
  presence: PRESENT
  description: >-
    Nuclear beta-catenin staining is the diagnostic hallmark. Its performance is
    strongly antibody-dependent, which is a practical trap: sensitivity ranges from
    54% to 96% and specificity from 98% down to 62% across three commonly used
    clones, so a negative result with a specific antibody does not exclude the
    diagnosis.
  evidence:
  - reference: PMID:33788979
    reference_title: A comparison of the usefulness of nuclear beta-catenin in the diagnosis of desmoid-type
      fibromatosis among commonly used anti-beta-catenin antibodies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '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.'
    explanation: Quantifies the antibody dependence that this entry flags as a practical
      pitfall.
- name: Magnetic resonance imaging
  presence: PRESENT
  description: >-
    MRI is the preferred imaging modality for most anatomical sites, both for
    delineating the infiltrative margin and for serial assessment during active
    surveillance.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Magnetic resonance imaging is preferred for most anatomic locations.
    explanation: States MRI as the preferred modality.
treatments:
- name: Active Surveillance
  therapeutic_modality: BEHAVIORAL
  description: >-
    First-line management for most patients. Because spontaneous regression occurs
    and surgery carries both recurrence risk and avoidable morbidity, initial
    observation with pain management has displaced immediate resection. This is a
    monitoring strategy rather than a therapeutic action, so it is deliberately not
    linked to a pathophysiology node.
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consequently, active surveillance in conjunction with pain management is now
      recommended for most patients.
    explanation: States active surveillance with pain management as the recommendation for most
      patients.
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Gives the reasoning behind the shift away from surgery, which is what makes
      surveillance a positive choice rather than a default.
- name: Nirogacestat
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An oral gamma-secretase inhibitor, and the first agent to show benefit for this
    disease in a placebo-controlled phase 3 trial. It blocks the proteolytic
    cleavage that releases the Notch intracellular domain. Diarrhoea is near
    universal and ovarian toxicity is a specific concern in women of childbearing
    potential.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nirogacestat
      term:
        id: CHEBI:229217
        label: nirogacestat
    - preferred_term: gamma-secretase inhibitor
      term:
        id: NCIT:C200529
        label: Gamma-Secretase Inhibitor
  target_mechanisms:
  - target: Notch Pathway Dependence
    treatment_effect: INHIBITS
    description: Blocks gamma-secretase cleavage of the Notch receptor, which is the step this
      node depends on.
    evidence:
    - reference: PMID:36884323
      reference_title: Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor
        nirogacestat (150 mg) or placebo twice daily.
      explanation: Identifies the molecular target of the agent as gamma-secretase.
  evidence:
  - reference: PMID:36884323
    reference_title: Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Gives the randomised progression-free survival benefit, which is the primary
      endpoint result.
  - reference: PMID:36884323
    reference_title: Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Records the toxicity profile, which is part of why this is not automatically
      preferred over surveillance.
- name: Sorafenib
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A multi-targeted tyrosine kinase inhibitor with randomised evidence of benefit
    in progressive or symptomatic disease. Note that 36% of placebo patients were
    also progression-free at two years, which is the spontaneous-stability effect
    made visible by a controlled design.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sorafenib
      term:
        id: CHEBI:50924
        label: sorafenib
    - preferred_term: tyrosine kinase inhibitor
      term:
        id: NCIT:C1967
        label: Tyrosine Kinase Inhibitor
  target_mechanisms:
  - target: Clonal Myofibroblast Proliferation
    treatment_effect: INHIBITS
    description: Kinase inhibition slows growth of the proliferating tumour population, though
      the specific kinase dependency in this tumour is not established.
    evidence:
    - reference: PMID:30575484
      reference_title: Sorafenib for Advanced and Refractory Desmoid Tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib
        significantly prolonged progression-free survival and induced durable responses.
      explanation: Establishes that the agent controls tumour growth, which is the effect this
        link asserts.
  evidence:
  - reference: PMID:30575484
    reference_title: Sorafenib for Advanced and Refractory Desmoid Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the 2-year progression-free survival rate was 81% (95% confidence interval [CI],
      69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard
      ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001)
    explanation: Gives both the treatment effect and the placebo-arm stability rate that this
      description draws attention to.
- name: Methotrexate and Vinblastine
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Low-dose chemotherapy, used mainly in extra-abdominal disease. The evidence is
    uncontrolled: response rates around 36% with clinical benefit up to 85%, but no
    randomised comparison against no treatment, which given the natural history of
    this disease is a serious limitation.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
    - preferred_term: vinblastine
      term:
        id: CHEBI:27375
        label: vincaleukoblastine
  target_mechanisms:
  - target: Clonal Myofibroblast Proliferation
    treatment_effect: INHIBITS
    description: Cytotoxic suppression of the proliferating myofibroblast population.
    evidence:
    - reference: PMID:31845730
      reference_title: 'Efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with
        extra-abdominal desmoid-type fibromatosis: a systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'According to Response Evaluation Criteria in Solid Tumors criteria, the mean
        response rate (complete remission or partial response) was 36% (11-57%).'
      explanation: Gives the pooled objective response rate attributable to this regimen.
  evidence:
  - reference: PMID:31845730
    reference_title: 'Efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with
      extra-abdominal desmoid-type fibromatosis: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were three prospective case series but no randomized controlled trials among
      the nine studies. There was no case-control report (vs. no treatment).
    explanation: States the absence of controlled comparison, which is the limitation this entry
      records alongside the response rate.
- name: Doxorubicin-based Chemotherapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Anthracycline regimens, including liposomal doxorubicin, reserved for
    progressive disease. As with methotrexate and vinblastine, the supporting
    evidence contains no randomised controlled trials.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
  target_mechanisms:
  - target: Clonal Myofibroblast Proliferation
    treatment_effect: INHIBITS
    description: Cytotoxic suppression of the proliferating myofibroblast population.
    evidence:
    - reference: PMID:32700733
      reference_title: 'Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients
        with extra-abdominal desmoid-type fibromatosis: a systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the response rates of doxorubicin-based regimens and liposomal doxorubicin were
        44% (28.6-54) and 33.3% (0-75) on average, respectively
      explanation: Gives the pooled response rates for both anthracycline formulations.
  evidence:
  - reference: PMID:32700733
    reference_title: 'Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients
      with extra-abdominal desmoid-type fibromatosis: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were no randomized controlled trials.
    explanation: States the evidence limitation directly.
- name: Surgical Resection
  therapeutic_modality: SURGERY
  description: >-
    No longer first-line. When used, the aim is microscopically negative margins,
    but not at the cost of organ or limb function, and recurrence after resection is
    approximately 20%. In FAP-associated intra-abdominal disease, recurrence rates
    are higher still.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Infiltrative Growth without Metastatic Capacity
    treatment_effect: INHIBITS
    description: Removes the infiltrating lesion, which is effective locally but does not
      address the underlying signalling defect, hence the recurrence rate.
    evidence:
    - reference: PMID:27542640
      reference_title: Management of Desmoids.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: When surgical therapy is used, wide local excision with microscopically negative
        margins is the goal of resection but should not be at the expense of organ or limb
        function.
      explanation: States the surgical goal and the functional constraint on achieving it.
  evidence:
  - reference: PMID:27542640
    reference_title: Management of Desmoids.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Recurrence rates after surgical resection are approximately 20%; a variety of
      multimodal therapies are useful in controlling disease.
    explanation: Quantifies post-resection recurrence, which is the reason surgery was displaced
      as first-line management.
inheritance:
- name: Autosomal dominant (FAP-associated subset)
  description: >-
    The sporadic form is not heritable; the driver is a somatic CTNNB1 mutation. The
    FAP-associated subset follows the autosomal dominant inheritance of the
    underlying germline APC mutation, so what is inherited is the polyposis
    predisposition rather than the desmoid tumour itself.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:35670122
    reference_title: Evolving strategies for management of desmoid tumor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most DTs are sporadic, harboring somatic mutations in the gene that encodes for
      β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have
      germline mutations in the APC gene, which encodes for a protein regulator of β-catenin.
    explanation: Distinguishes the somatic sporadic form from the germline FAP-associated form,
      which is what determines whether inheritance applies.
references:
- reference: PMID:15375433
  title: "Nuclear beta-catenin in mesenchymal tumors."
- reference: PMID:20676788
  title: "Evaluating causes of death in familial adenomatous polyposis."
- reference: PMID:23913621
  title: "CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study."
- reference: PMID:24076266
  title: "Targeting notch signaling pathway in cancer: clinical development advances and challenges."
- reference: PMID:24325833
  title: "Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm--a position paper from the Italian and the French Sarcoma Group."
- reference: PMID:27542640
  title: "Management of Desmoids."
- reference: PMID:30575484
  title: "Sorafenib for Advanced and Refractory Desmoid Tumors."
- reference: PMID:31189665
  title: "Destruction complex dynamics: Wnt/\u03b2-catenin signaling alters Axin-GSK3\u03b2 interactions in vivo."
- reference: PMID:31845730
  title: "Efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with extra-abdominal desmoid-type fibromatosis: a systematic review."
- reference: PMID:32004793
  title: "The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients."
- reference: PMID:32700733
  title: "Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients with extra-abdominal desmoid-type fibromatosis: a systematic review."
- reference: PMID:33397129
  title: "Prognostic significance of CTNNB1 mutation in recurrence of sporadic desmoid tumors."
- reference: PMID:33788979
  title: "A comparison of the usefulness of nuclear beta-catenin in the diagnosis of desmoid-type fibromatosis among commonly used anti-beta-catenin antibodies."
- reference: PMID:35217286
  title: "Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal desmoid tumors."
- reference: PMID:35670122
  title: "Evolving strategies for management of desmoid tumor."
- reference: PMID:36884323
  title: "Nirogacestat, a \u03b3-Secretase Inhibitor for Desmoid Tumors."
- reference: PMID:37436594
  title: "Desmoid Tumors: A Comprehensive Review."
clinical_trials:
- name: NCT03785964
  phase: PHASE_III
  status: COMPLETED
  description: DeFi, the randomised placebo-controlled trial of the gamma-secretase inhibitor
    nirogacestat that produced the first positive phase 3 result in this disease.
  target_phenotypes:
  - preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  - preferred_term: Chronic pain
    term:
      id: HP:0012532
      label: Chronic pain
  evidence:
  - reference: clinicaltrials:NCT03785964
    reference_title: 'A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus
      Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid
      tumor/aggressive fibromatosis (DT/AF).
    explanation: Identifies the agent and the indication for the trial underlying the
      nirogacestat treatment entry.
- name: NCT04871282
  phase: PHASE_II
  description: RINGSIDE, a phase 2/3 study evaluating the gamma-secretase inhibitor AL102 in
    progressing desmoid tumours. A second agent against the same target as nirogacestat, which
    is the main reason to record the Notch node despite its hypothetical status.
  target_phenotypes:
  - preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  evidence:
  - reference: clinicaltrials:NCT04871282
    reference_title: 'RINGSIDE: A Phase 2/3, Randomized, Multicenter Study to Evaluate AL102 in Patients
      With Progressing Desmoid Tumors'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The current study is designed to evaluate the efficacy and safety of AL102 in
      patients with progressive desmoid tumors.
    explanation: Confirms a second gamma-secretase inhibitor in randomised evaluation for this
      indication.
disease_term:
  preferred_term: desmoid tumor
  term:
    id: MONDO:0007608
    label: desmoid tumor
notes: >-
  Scope. This entry describes desmoid tumour as a single disease with two etiologic
  arms that converge on one biochemical lesion. The Wnt/beta-catenin chain is well
  supported; the Notch node is not, and is marked HYPOTHETICAL because it is
  inferred backwards from the response to gamma-secretase inhibition rather than
  from direct pathway measurement in this tumour.

  Why the natural history is modelled as a node. Spontaneous regression and long
  stability without treatment are not incidental. They are the reason surgery lost
  its first-line role and the reason every uncontrolled treatment series here should
  be read sceptically. The sorafenib trial makes the point quantitatively: 36% of
  placebo patients were progression-free at two years. The two chemotherapy entries
  are recorded with their own evidence of having no randomised control, rather than
  with response rates alone.

  Ontology notes. HPO has an exact term for the lesion (HP:6001034 Desmoid tumor)
  and a separate term for the intra-abdominal form (HP:0100245 Gastrointestinal
  desmoid tumor); both are used rather than a generic soft tissue neoplasm parent.
  MAXO is not used in this repository, so treatments are bound to NCIT actions with
  CHEBI or NCIT therapeutic agents. No NCIT term for "watchful waiting" or "active
  surveillance" exists anywhere under NCIT:C25218, the root of this repository's
  TreatmentActionTerm enum, so Active Surveillance is deliberately left without a
  treatment_term rather than bound to a generic Observation Activity that would
  misrepresent it.

  Corrections, review round 1. Two claims in this section were wrong and are
  retracted here rather than silently deleted. The first said vinblastine has no
  CHEBI term; CHEBI:27375 vincaleukoblastine is vinblastine, was already in the
  committed cache, and was already used for this agent elsewhere in the knowledge
  base. It is now bound. The second said no quotable female-predominance ratio was
  available; PMID:35670122, a reference this entry cites repeatedly, states that
  desmoid tumours "occur predominantly in women (approximately 70% of cases)". The
  sex skew and the estrogen axis are now modelled as an environmental factor with
  an explicit influences_mechanisms link. Both errors have the same cause: the two
  large cached reviews are full-text rather than abstract-only, and they were read
  selectively for the specific claims being written rather than end to end. They
  have since been read in full, which is also where the codon frequencies, the
  prospective active-surveillance figures, the misdiagnosis rate and the two NCT
  identifiers came from.

  Why there is no conforms_to link. The obvious candidate module,
  sustaining_proliferative_signaling, does not fit. Its central node is defined as
  flux through "the RAS-RAF-MEK-ERK (MAPK) pathway" and "the PI3K-AKT-mTOR
  pathway" and is bound to GO:0007265 Ras protein signal transduction and the ERK
  cascade. Desmoid tumour is driven by canonical Wnt/beta-catenin, a
  transcriptional pathway sharing none of that machinery, so a conforming node
  here would carry none of the module's expected biological processes. Declaring
  conformance on the strength of "both are proliferative" would make the
  conformance check mean less. invasion_and_metastasis is likewise inapplicable,
  and for a more interesting reason: this tumour invades but provably never
  metastasises, so it satisfies half of that module and refutes the other half.

  Trial phase encoding. RINGSIDE (NCT04871282) is a phase 2/3 study. It is recorded
  as PHASE_II because the enum has no combined value and the phase 2 portion is
  what has reported; its recruitment status is deliberately absent because the
  cached ClinicalTrials.gov record carries no status field, and asserting one
  would be unattested.

  Known extension points: histopathology as a structured section (the cached
  reviews describe low-to-moderate cellularity, long fascicles of uniform cells,
  dense collagenous stroma, and an immunohistochemical panel of nuclear
  beta-catenin, SMA, vimentin and COX-2 positive with desmin, S100, CD34 and KIT
  negative); cryoablation, high-intensity focused ultrasound and radiotherapy as
  locoregional options; and pazopanib and vinorelbine, both with prospective data
  in the cached sources.

  Provenance. Curated directly from PubMed rather than from a deep-research report:
  both configured research providers were unavailable at the time of curation
  (openscientist.io returned CloudFront 403 on POST and 401 on authenticated GET;
  the cyberian backend returned 500). Every snippet below was fetched with
  just fetch-reference and verified as an exact substring of the cached abstract.
📚

References & Deep Research

References

17
PMID:15375433
Nuclear beta-catenin in mesenchymal tumors.
No top-level findings curated for this source.
PMID:20676788
Evaluating causes of death in familial adenomatous polyposis.
No top-level findings curated for this source.
PMID:23913621
CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.
No top-level findings curated for this source.
PMID:24076266
Targeting notch signaling pathway in cancer: clinical development advances and challenges.
No top-level findings curated for this source.
PMID:24325833
Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm--a position paper from the Italian and the French Sarcoma Group.
No top-level findings curated for this source.
PMID:27542640
Management of Desmoids.
No top-level findings curated for this source.
PMID:30575484
Sorafenib for Advanced and Refractory Desmoid Tumors.
No top-level findings curated for this source.
PMID:31189665
Destruction complex dynamics: Wnt/β-catenin signaling alters Axin-GSK3β interactions in vivo.
No top-level findings curated for this source.
PMID:31845730
Efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with extra-abdominal desmoid-type fibromatosis: a systematic review.
No top-level findings curated for this source.
PMID:32004793
The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients.
No top-level findings curated for this source.
PMID:32700733
Effectiveness of doxorubicin-based and liposomal doxorubicin chemotherapies for patients with extra-abdominal desmoid-type fibromatosis: a systematic review.
No top-level findings curated for this source.
PMID:33397129
Prognostic significance of CTNNB1 mutation in recurrence of sporadic desmoid tumors.
No top-level findings curated for this source.
PMID:33788979
A comparison of the usefulness of nuclear beta-catenin in the diagnosis of desmoid-type fibromatosis among commonly used anti-beta-catenin antibodies.
No top-level findings curated for this source.
PMID:35217286
Evaluation of diagnostic algorithm and therapeutic interventions for intra-abdominal desmoid tumors.
No top-level findings curated for this source.
PMID:35670122
Evolving strategies for management of desmoid tumor.
No top-level findings curated for this source.
PMID:36884323
Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.
No top-level findings curated for this source.
PMID:37436594
Desmoid Tumors: A Comprehensive Review.
No top-level findings curated for this source.