Desmoid Tumor (Aggressive Fibromatosis)

Sporadic Desmoid Tumors (85-90%)

CTNNB1 gene mutations (encoding beta-catenin) are the hallmark of sporadic desmoid tumors.

Molecular mechanism:

• Gene location: Chromosome 3p21
• Mutation sites: Exon 3, predominantly codons 41 (T41A) or 45 (S45F)
• Effect: Prevents beta-catenin phosphorylation and degradation
• Result: Nuclear beta-catenin accumulation

Pathway activation:

Normal state:

1. Beta-catenin is targeted by destruction complex (APC-Axin-GSK3beta)
2. Phosphorylation marks beta-catenin for ubiquitin-mediated degradation
3. Cytoplasmic levels remain low

Mutant state:

1. CTNNB1 mutation creates non-phosphorylatable beta-catenin
2. Destruction complex cannot target mutant protein
3. Beta-catenin accumulates and translocates to nucleus
4. Nuclear beta-catenin binds TCF/LEF transcription factors
5. Activates target genes promoting fibroblast proliferation

Genotype-phenotype correlation:

• T41A mutation: Associated with more aggressive behavior
• S45F mutation: May have better prognosis
• Codon 41 mutations: Higher recurrence risk in some studies

This molecular basis underlies nuclear beta-catenin immunostaining as diagnostic test.

FAP-Associated Desmoid Tumors (5-10%)

APC gene germline mutations cause familial adenomatous polyposis and associated desmoid tumors.

Molecular mechanism:

• Gene location: Chromosome 5q21-22
• Inheritance: Autosomal dominant germline mutation
• Function: APC is tumor suppressor component of beta-catenin destruction complex
• Effect: Loss of APC function prevents beta-catenin degradation
• Result: Same as CTNNB1 mutations - nuclear beta-catenin accumulation

FAP-desmoid characteristics:

• Occur in 10-20% of FAP patients
• Typically intra-abdominal (mesenteric) location
• Often multifocal
• Associated with prior abdominal surgery (colectomy)
• Generally more aggressive than sporadic desmoids
• Major cause of mortality in FAP after colectomy

Genotype correlation:

• APC mutations beyond codon 1400: Higher desmoid risk
• Mutations in codons 1310-1580: Greatest desmoid predisposition
• 3' APC mutations: Up to 25% desmoid incidence

FAP patients require counseling about desmoid risk before abdominal surgery.

Extra-Abdominal Desmoid (60%)

Typical presentation:

• Painless slowly enlarging mass over months to years
• Discovered incidentally or noted by patient
• Firm, non-mobile mass fixed to underlying structures
• Pain in 30% if nerve compression develops
• Functional limitation if large or involves shoulder/thigh

Common locations:

• Shoulder girdle (deltoid, pectoralis, scapular muscles)
• Thigh (quadriceps, adductors)
• Chest wall, back, gluteal region
• Head and neck (rare, 5-10% of extra-abdominal)

History points:

• Prior trauma to area in 30% (sports injury, surgery)
• Slow growth typical (months to years)
• May have periods of rapid growth then stabilization

Abdominal Wall Desmoid (25%)

Typical presentation:

• Firm mass in anterior abdominal wall, usually rectus muscle
• Often in postpartum women (40% pregnancy-associated)
• History of cesarean section or prior abdominal surgery (30%)
• Usually painless, cosmetic concern predominates
• Carnett sign positive (pain increases with rectus contraction)

Risk factors:

• Postpartum period (hormonal changes plus rectus trauma)
• Prior C-section or abdominal surgery
• Multiple pregnancies
• Female gender (strong association)

Intra-Abdominal Desmoid (15%)

Typical presentation:

• Abdominal pain, bloating, early satiety
• Bowel obstruction symptoms (if mesenteric)
• Palpable mass if large
• FAP history present in 50% of cases

Complications at presentation:

• Small bowel obstruction (20-30%)
• Ureteric obstruction with hydronephrosis (10%)
• Portal vein compression (rare)
• Gastrointestinal bleeding (rare)

FAP association:

• 50% of intra-abdominal desmoids occur in FAP patients
• Often develop after colectomy (surgery triggers tumor)
• May be multifocal
• Leading cause of death in FAP after prophylactic colectomy

Physical Examination

General examination:

• Firm to hard mass, non-tender unless nerve compression
• Poorly defined margins, infiltrative feel
• Fixed to underlying fascia or muscle, not freely mobile
• No overlying skin changes (unlike malignancy)
• No lymphadenopathy (benign tumor)

Abdominal wall specific:

• Carnett sign: Pain increases with abdominal muscle contraction
• Distinguishes abdominal wall mass from intra-abdominal pathology

Functional assessment:

• Range of motion for extremity lesions
• Neurological examination if nerve compression suspected
• Vascular examination if proximity to major vessels

T1-Weighted Features

Signal characteristics:

• Isointense to muscle (similar grey appearance)
• Poorly defined margins with irregular borders
• Infiltrates adjacent muscle (intramuscular extension)

Pathognomonic sign:

• Fascia sign (tail sign): Tumor extends along fascial planes as linear tail
• Highly suggestive of desmoid tumor
• Reflects predilection for aponeurotic structures

Structural evaluation:

• Relationship to neurovascular structures
• Extent of muscle involvement
• Bone contact (extraperiosteal, no invasion)

T1 sequences best for anatomical detail and surgical planning.

T2-Weighted Features

Variable signal intensity depending on cellularity and collagen content:

Pathognomonic finding:

• Low-signal bands within tumor mass
• Represent dense collagen bundles
• Create characteristic striped appearance
• Highly specific for desmoid tumor

Heterogeneous signal:

• Hypercellular areas: Intermediate to high T2 signal
• Fibrous/collagenous areas: Low T2 signal
• Overall heterogeneous appearance is typical

Clinical correlation:

• More low-signal areas: More fibrous, less cellular
• High T2 signal: More cellular, potentially more active
• Useful for assessing tumor activity on surveillance

T2 sequences best for tissue characterization and diagnosis.

Post-Gadolinium Enhancement

Enhancement pattern:

• Heterogeneous enhancement
• Cellular areas enhance (high T2 signal areas)
• Fibrous bands do not enhance (low T2 signal areas)
• No necrosis (absence helps exclude sarcoma)

Surveillance value:

• Increasing enhancement may indicate tumor activity
• Decreasing enhancement suggests regression/fibrosis
• Useful for serial monitoring on active surveillance

Differential diagnosis:

• Lack of necrosis helps exclude sarcoma
• Heterogeneous pattern typical for desmoid
• Peripheral enhancement may be seen

Contrast is helpful but not always required for diagnosis.

Intraoperative Margin Decisions

When tumor approaches critical structure:

Major nerve (median, ulnar, sciatic, femoral):

• Attempt preservation if greater than 1mm clearance possible
• If tumor encases nerve: Preserve nerve, accept positive margin
• Do NOT sacrifice major nerve for negative margin
• Functional loss from nerve sacrifice is permanent and devastating

Major vessel (femoral, popliteal, brachial):

• Dissect tumor off vessel if plane exists
• If tumor adherent: Preserve vessel, accept positive margin
• Vascular reconstruction possible but increases morbidity
• Accept positive margin rather than sacrifice vessel

Critical muscle:

• Non-critical muscle: Resection acceptable
• Functionally critical muscle: Preserve if possible
• Example: Preserve deltoid (shoulder function), can sacrifice sartorius

Bone contact:

• Extraperiosteal resection if abutting bone
• Do not resect bone for margin (benign tumor)

Frozen section:

• Rarely changes intraoperative management
• Positive margin often anticipated and accepted
• Document margin status for adjuvant therapy planning

Surgical decision-making prioritizes long-term function over margin status.

Resection Technique

Preoperative planning:

• Review MRI with radiology
• Identify neurovascular structures at risk
• Plan incision (extensile for adequate exposure)
• Consent: Discuss positive margin acceptance, recurrence risk

Surgical steps:

1. Exposure:

   • Wide exposure of entire tumor
   • Identify and protect critical structures early
   • Extensile incision, adequate working room

2. Dissection:

   • Attempt complete macroscopic excision
   • Dissect along tissue planes where possible
   • Tumor often densely adherent to fascia, muscle
   • Accept piecemeal resection if necessary to preserve function

3. Critical structure management:

   • Carefully dissect tumor from nerve/vessel
   • If encased: Preserve structure, leave tumor on surface
   • Neurolysis if nerve compressed but separable
   • Do NOT sacrifice structure for margin

4. Specimen handling:

   • Orient with sutures
   • Document margin concerns
   • Send for permanent sections (frozen rarely useful)

5. Reconstruction:

   • Primary closure if tension-free
   • Local flaps for soft tissue coverage
   • Abdominal wall: Mesh reconstruction if rectus excised
   • Drains for dead space

Postoperative care:

• Early mobilization
• Drain management (remove when under 30ml per 24 hours)
• Wound monitoring
• Await final pathology for margin status
• Plan surveillance or adjuvant therapy based on outcome

Technique emphasizes macroscopic excision with functional preservation.

NSAIDs Plus Tamoxifen (First-Line)

Rationale:

• Low toxicity, oral administration
• Combination more effective than monotherapy
• Well-tolerated, suitable for long-term use
• First-line for many centers

Mechanism:

• Sulindac (NSAID): COX-2 inhibition, anti-inflammatory
• Tamoxifen: Selective estrogen receptor modulator, anti-estrogenic

Dosing:

• Sulindac: 300mg daily (150mg twice daily)
• Tamoxifen: 20-40mg daily
• Continue for at least 12 months if responding

Response rates:

• Complete response: 5-10%
• Partial response: 20-30%
• Stable disease: 50%
• Progressive disease: 20-30%
• Overall disease control (CR + PR + SD): 70-80%

Toxicity:

• Generally well-tolerated
• GI upset (10-20%): Nausea, dyspepsia
• Hot flashes from tamoxifen (30%)
• Thromboembolic risk with tamoxifen (rare)
• Endometrial hyperplasia (monitor with tamoxifen)

Monitoring:

• MRI every 3-6 months
• Continue if stable or responding
• Consider discontinuation after 2 years if stable
• Restart if progression after stopping

NSAIDs plus tamoxifen is preferred first-line due to favorable toxicity profile.

Sorafenib (Tyrosine Kinase Inhibitor)

Rationale:

• Higher response rates than NSAIDs/tamoxifen
• Effective for progressive desmoids
• Reserved for failures of first-line therapy due to toxicity

Mechanism:

• Multi-kinase inhibitor
• Targets VEGFR, PDGFR, RAF kinases
• Anti-angiogenic and anti-proliferative

Dosing:

• 400mg daily (lower than oncologic dose of 800mg)
• Dose reduction common due to toxicity
• Oral administration

Response rates (Phase 3 trial):

• Objective response: 33% (sorafenib) vs 20% (placebo)
• Progression-free survival: Significantly longer with sorafenib
• Disease control rate: Greater than 80%

Toxicity (significant):

• Hand-foot syndrome: 50% (dose-limiting)
• Diarrhea: 30%
• Fatigue: 40%
• Hypertension: 20%
• Rash, alopecia: 20%
• Dose reductions required in 64% of patients

Monitoring:

• MRI every 3 months
• Blood pressure monitoring
• Dose reduce for grade 2-3 toxicity
• Median duration: 12-18 months

Sorafenib effective but toxicity limits use as first-line agent.

Alternative Systemic Therapies

Methotrexate + Vinblastine:

• Low-dose chemotherapy regimen
• Response rate: 30-40%
• Toxicity: Myelosuppression, nausea, alopecia
• Weekly IV administration (inconvenient)
• Alternative to sorafenib if NSAIDs/tamoxifen fail

Imatinib:

• Tyrosine kinase inhibitor (BCR-ABL, c-KIT, PDGFR)
• Variable responses, less effective than sorafenib
• Dose: 400-800mg daily
• May be tried before sorafenib

Nirogacestat (Gamma-Secretase Inhibitor):

• Investigational, promising results
• Targets Notch pathway
• Phase 3 trial showed significant response
• Not yet widely available, future option

Interferon-alpha:

• Historical option, rarely used now
• Significant toxicity (flu-like symptoms)
• Replaced by better-tolerated agents

Multiple options available, choice based on toxicity profile and availability.