Desmoid Fibromatosis

Not clinically relevant

The majority (90–95%) of sporadic desmoid tumors result from three different point mutations in two codons (41 and 45) of exon 3 of the gene that encodes β-catenin (CTNNB1): p.Thr41Ala, p.Ser45Pro, and p.Ser45Phe. p.Thr41Ala and p.Ser45Phe are the most common mutations. A smaller percentage of desmoid tumors arise in the setting of Gardner syndrome; affected patients harbor germline mutations in the APC tumor suppressor gene, specifically mutations at or beyond codon 1444, with subsequent loss of heterozygosity of the wildtype allele, and rare cases of desmoid tumors with sporadic APC mutations have also been described. The activating mutations in CTNNB1 or inactivating mutations in APC interfere with β-catenin proteasomal degradation, leading to nuclear β-catenin accumulation. Because β-catenin functions as part of the transcription apparatus in the nucleus, this increased activation of the WNT/β-catenin pathway is thought to ultimately promote cell proliferation and survival and appears to drive tumorigenesis. A subset of the neoplastic population of desmoid fibromatosis may harbor trisomies for chromosomes 8 and/or 20; however, these aberrations are unlikely to play a substantial role in pathogenesis or behavior.

Gross examination reveals a solid mass with a wide size range and a whitish-tan, coarsely trabecular or whorled cut surface. Most lesions appear poorly circumscribed with ill-defined margins and infiltration into adjacent tissues. Intra-abdominal desmoid fibromatosis tends to present as a large mass, often as large as 10 cm in diameter, with a whorled cut surface.

Desmoid fibromatosis is characterized by long, sweeping fascicles of bland fibroblasts and myofibroblasts with infiltration into surrounding soft tissues. The fascicles often span an entire 10× objective field, and lymphoid aggregates are often appreciated at the advancing edge of the lesion. The tumor cells demonstrate pale eosinophilic cytoplasm and lack nuclear hyperchromasia or cytological atypia. Thin-walled blood vessels, occasionally with a gaping or staghorn appearance, are often prominent with variable perivascular edema. Mitotic figures are typically absent or rare, and atypical mitoses are lacking. A subset of tumors harbor densely eosinophilic stromal keloidal-type collagen, a finding most common in intra-abdominal tumors. Other morphological patterns include myxoid change, paucicellular hyalinized areas, and zones resembling nodular fasciitis. By immunohistochemistry, the lesional cells are positive for SMA and MSA. The majority of tumors (~80%) show nuclear β-catenin expression, although definite nuclear reactivity can be difficult to appreciate.

FNA (fine-needle aspiration) specimens are variably cellular and typically show loose clusters of bland or reactive-appearing fibroblasts and myofibroblasts without substantial cytological atypia or nuclear hyperchromasia. The relatively nonspecific findings make desmoid tumors difficult to diagnose by FNA.

The natural course of desmoid fibromatosis in individual patients is variable, with unpredictable growth, stabilization, and regression. Tumor-related deaths are rare but seem to be more common in patients with familial adenomatous polyposis. Although primary surgery with negative surgical margins was classically considered to be the standard of care, local recurrence does not consistently correlate with margin status. Approximately one third of patients experience recurrence after resection; extensive surgery can be morbid; and spontaneous regression has been observed in a subset of advanced, unresectable tumors. For these reasons, a watchful waiting approach with a period of initial observation has been advocated for asymptomatic patients. When surgery is considered for patients with desmoid tumors, higher rates of local recurrence are associated with extra-abdominal location, younger age, larger tumor size, and mutation status. Studies have suggested that tumors harboring CTNNB1 p.Ser45Phe mutations have a greater risk for local recurrence. It is unclear whether similar molecular or clinicopathological factors predict progression during active observation.

CTNNB1 mutation analysis may be helpful in small biopsy specimens, when diagnostic morphological features are not readily apparent, and/or when β-catenin immunostaining is equivocal or challenging to interpret.

Essential: long, sweeping fascicles of bland fibroblasts and myofibroblasts without substantial cytological atypia; infiltrative growth.

Desirable: nuclear β-catenin expression; characteristic CTNNB1 mutation (in challenging cases or small biopsies).