Desmoid Fibromatosis

Desmoid fibromatosis is a clonal fibroblastic proliferation that does not metastasize but infiltrates locally and recurs after excision. It is a disease of the connective tissue stroma of muscle and fascia, with an incidence of 2 to 4 per million people a year and a peak at 30 to 40 years.

Pathology is bland spindle cells in long sweeping fascicles within collagen, with nuclear beta-catenin in most cases.

Genetics split the disease into two groups

• Sporadic disease (about 85%): somatic CTNNB1 mutations, most often T41A (the commonest, with a lower recurrence risk), S45F (the highest recurrence and progression risk) and S45P. About 5 to 10% are wild type for both CTNNB1 and APC.
• Familial adenomatous polyposis (about 5 to 10%): germline APC mutation, most often distal to codon 1444, giving a 1000-fold greater risk, with desmoids in 10 to 25% of carriers. About 10% of deaths in familial adenomatous polyposis come from desmoids.

Sites are extra-abdominal (shoulder girdle, chest wall, limbs, head and neck) and intra-abdominal (the root of the small bowel mesentery and retroperitoneum, which carry the greatest danger). Triggers are surgery and trauma (about 30 to 40% of intra-abdominal disease in familial adenomatous polyposis follows colectomy), pregnancy and estrogen exposure.

Natural history is variable: about 20 to 30% regress without treatment and many stabilize.

A staging system for familial adenomatous polyposis desmoids uses size, symptoms, growth and complications:

• stage I asymptomatic, under 10 cm and stable
• stage II symptomatic, under 10 cm and stable
• stage III 10 to 20 cm, or slowly growing
• stage IV over 20 cm, rapidly growing or with complications

Complications: intestinal ischemia and obstruction, perforation and fistula, ureteric obstruction, vascular encasement (the superior mesenteric vessels), neurovascular compression and joint contracture.

• Extra-abdominal: a firm, fixed, usually painless mass that enlarges over months, with pain, limb weakness, brachial plexus compression and joint stiffness
• Intra-abdominal: abdominal pain, a palpable mass, nausea, bloating, bowel obstruction, bleeding or ischemia
• Features of familial adenomatous polyposis: colonic polyposis, osteomas, epidermoid cysts, congenital hypertrophy of the retinal pigment epithelium, and a family history of colon cancer
• Red flags: abdominal pain with fever and peritonism (perforation), severe pain and distension (ischemia or obstruction), rapid growth, plexopathy and limb edema from venous compression

1. MRI for extra-abdominal tumors: infiltrative mass, T2 signal falling over time as collagen replaces cells, low-signal bands, fascial tail and a variable enhancement pattern.
2. CT with contrast, CT angiography or MRI enterography for mesenteric disease: a whorled soft tissue mass at the mesenteric root encasing the superior mesenteric artery and vein, with bowel wall thickening or ischemic change.
3. Core biopsy for extra-abdominal masses and for an unexpected mesenteric mass. In familial adenomatous polyposis with typical imaging, biopsy of a mesenteric mass is often avoided because of the risk of fistula.
4. Molecular testing: CTNNB1 sequencing on tissue (informs prognosis), and APC germline testing for patients with mesenteric disease, a young age or polyposis.
5. Colonoscopy for polyposis, and upper endoscopy for duodenal adenomas.

Differentials: fibrosarcoma, gastrointestinal stromal tumor, leiomyosarcoma, desmoplastic round cell tumor, retroperitoneal fibrosis, sclerosing mesenteritis, lymphoma, keloid.

Therapy depends on site, symptoms and growth. A policy of active surveillance is the first step for many patients.

1. Active surveillance: MRI or CT every 3 months for the first year, then every 6 months. About half stay stable. Treat if there is progression with symptoms, threatened organs or functional loss.
2. Systemic therapy for progressive or symptomatic disease:
   • Nirogacestat 150 mg orally twice daily, taken continuously (adverse effects: diarrhea, ovarian toxicity, rash, hypophosphatemia; contraindicated in pregnancy).
   • Sorafenib 400 mg orally once daily (adverse effects: hand-foot reaction, hypertension, diarrhea, raised liver tests).
   • Methotrexate 30 mg/m2 IV with vinblastine 5 mg/m2 IV every week for 26 weeks, then every 2 weeks. Check blood count, creatinine and liver tests before each dose.
   • Pegylated liposomal doxorubicin 50 mg/m2 IV every 4 weeks for 6 to 8 cycles for rapid or life-threatening mesenteric disease (check echocardiogram and watch for hand-foot syndrome).
   • Sulindac 150 mg orally twice daily with tamoxifen 20 mg orally twice daily for slowly progressive disease, with endometrial surveillance in women.
3. Local therapy for extra-abdominal disease: cryoablation, high-intensity focused ultrasound, and radiotherapy 50 to 56 Gy in 1.8 to 2 Gy fractions for unresectable disease or brachial plexus involvement. Avoid radiotherapy to the mesentery.
4. Surgery: limited to resectable extra-abdominal tumors where function can be saved, and to complications in the abdomen (obstruction, perforation, ischemia). Preserve bowel length. Avoid resection of a mesenteric mass encasing the superior mesenteric vessels, because short bowel and recurrence are common. Intestinal transplantation for life-threatening disease with intestinal failure. Cefazolin 2 g IV before incision (3 g if over 120 kg), and enoxaparin 40 mg SC daily for 7 days.
5. Familial adenomatous polyposis: plan timing of colectomy with surgeons who understand the desmoid risk, with attention to the trigger effect of laparotomy. Refer for genetic counseling and surveillance of relatives.
6. Pregnancy: observe, defer systemic therapy, and operate only for organ threat.

Follow-up for 5 years with MRI or CT at 3 to 6 month intervals, because recurrence is common. Counsel on the unpredictable course and on avoiding unnecessary operations.