Desmoid Tumor (Aggressive Fibromatosis)

• 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

• 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

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

• 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

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

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

• 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)

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

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

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

• 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

• 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)

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

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

• Cheap, oral, low toxicity, and for decades the default opening move
• But the supporting data are entirely uncontrolled, and in a disease where roughly a quarter of tumours regress on observation alone the reported "response rates" cannot be separated from natural history
• Retains a role where the tumour is indolent and mildly symptomatic, where the randomised-evidence agents are unavailable or unaffordable, or where a patient declines them - not because it is known to be better

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

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

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

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

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

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

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

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

• 2-year progression-free survival 81% vs 36% with placebo (hazard ratio 0.13, 95% CI 0.05-0.31, P less than 0.001)
• Objective response 33% (sorafenib) vs 20% (placebo) - note how high the placebo response is, and see the warning above about interpreting uncontrolled series
• Responses were slow: median time to response 9.6 months on sorafenib (13.3 months on placebo). Do not abandon treatment at 3 months for lack of shrinkage

• Rash 73%
• Fatigue 67%
• Hypertension 55%
• Diarrhoea 51%
• Hand-foot skin reaction is the classic dose-limiting effect of sorafenib and commonly forces dose reduction

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

an oral gamma-secretase inhibitor. Gamma-secretase cleaves the Notch receptor to release its intracellular domain, so inhibiting it blocks Notch signalling; Notch and Wnt/beta-catenin cross-talk in desmoid fibroblasts. It is not a direct beta-catenin inhibitor, which is a common misconception.

• Hazard ratio for progression or death 0.29 (95% CI 0.15-0.55, P less than 0.001)
• 2-year event-free 76% vs 44% with placebo
• Objective response 41% vs 8% (P less than 0.001), with complete response in 7% vs 0%
• Median time to response 5.6 months - faster than sorafenib's 9.6 months
• Significant improvements in pain, symptom burden, physical and role functioning and quality of life (all P at or below 0.01) - the endpoints that matter most in a non-metastasising disease

diarrhoea 84%, nausea 54%, fatigue 51%, hypophosphataemia 42%, maculopapular rash 32% - but 95% of adverse events were grade 1 or 2.

among women of childbearing potential, 27 of 36 (75%) developed adverse events consistent with ovarian dysfunction, which resolved in 20 of 27 (74%). This must be discussed before starting in a young woman - and desmoid tumours peak in exactly that group.

the first agent ever approved specifically for desmoid tumours (FDA, 2023).

• 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

• 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

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

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

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

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

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

• 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