In 1838, Muller named Aggressive Fibromatosis (AF) as Desmoid tumor, also known as Desmoid-type fibromatosis, etc. In 2002, the WHO defined AF as a clonal fibroblastic proliferative tumor occurring in deep tendinous tissue, characterized by abundant collagen fibers. It is characterized by the production of abundant collagen fibers and involves skeletal tendon membranes and fascia, with progressive invasion of the surrounding muscle and soft tissue, a tendency for local recurrence, and no metastatic ability. Extended resection is the most effective treatment modality. Its non-peritoneal infiltrative growth characteristics lead to the difficulty of achieving negative cut margins, and it is often difficult to resect or even life-threatening when important organs are involved, and adjuvant therapy such as radiotherapy reduces the recurrence rate. This is a literature review of recent advances in the understanding and treatment of this disease at home and abroad.
1.Characteristics of the disease
(1) Epidemiology and etiology: The incidence of AF accounts for only 3% of soft tissue tumors and 0.03% of all malignant tumors, with an annual incidence of 2-4/100,000 in the U.S. There is still a lack of epidemiological data on domestic AF. It can develop at any age, with youth being the most prevalent age and no significant gender difference. Mostly solitary, about 5% are multiple, with a predilection for children on the extremities and adults on the trunk. The cause is unknown and may be related to endocrine, connective tissue growth regulation abnormalities and genetic defects. Estrogen-induced mitosis of fibroblasts may be involved in the development of AF. Molecular studies have identified activation of the Wnt signaling pathway as the main mechanism of AF: AF is characterized by mutations in the adenomatous polyposis coli (APC) gene, or mutations in the CTNNB1 gene, which encodes β-catenin, resulting in abnormally high expression of β-catenin protein. . Elevated levels of intracytoplasmic free β-catenin protein play an important role in wound healing and fibroproliferative diseases and AF development. Increased expression of platelet growth factor receptor (PDGFR,α&β) and its ligands are also involved in AF.
(2) Typing: AF is classified according to the site of occurrence: extra-abdominal (about 50-60%), abdominal wall (about 25%) and intra-abdominal (about 15%).
The abdominal wall type AF: it occurs in the neck and shoulder, chest wall and lower limbs, and even requires amputation if the joints are involved.
(3) Biological behavior: Between fibroblastoma and fibrosarcoma, malignant tendency is reflected by aggressive growth and persistent recurrence after surgery. The pathological and MRI signal characteristics of recurrent foci are mostly the same as those of the primary foci, but the growth is more rapid and the invasion is more extensive, even invading vital organs and endangering life. Nakayama believes that nearly 50% of AF may be self-limiting, stable for a long time without progression or gradually resolving on its own.
(4) Pathology and immunohistochemistry.
Visually: the swelling is located in the muscle connected with tendon membrane and deep fascia, with irregular shape, unclear border, no envelope, pale and hard texture, woven texture in the cut surface, and no necrosis inside. Those occurring in the mesentery or pelvis may have interstitial mucus-like changes.
Microscopic view: AF consists of spindle-shaped fibroblasts and myofibroblasts in different stages of proliferation, arranged in parallel bundles, with collagen fibers interspersed, and more collagen content than well-differentiated fibrosarcoma; there is no degenerative necrosis, and the cell nuclei are stained in dotted color, with one to three small nucleoli, without pathological nuclear division and heterotypy. The tumor margins often contain infiltrated muscle tissue.
Immunohistochemistry: the characteristic cytoplasm and nucleus were diffusely positive for β-catenin, vimentin, SMA (smooth muscle actin), androgen receptor, cathepsin D, growth inhibitory hormone, Ki-67, and 80% of AF were positive for estrogen receptor (ER) β; while S 100, CD34, ERα, progesterone receptor, Her2, desmin, cytokeratins, and c-kit were often negative. Other fibroblastic tumors were negative for β-catenin in the nucleus; isolated fibrous tumors were positive for CD34; and GIST was positive for CD34, c-kit.
(5) Clinical manifestations: painless masses with indistinct borders, hard texture and no fluctuation that cannot be pushed, normal skin and no lymph node enlargement are palpable on the trunk or limbs. The size of the tumor is related to the site of occurrence, duration of disease and growth rate, with a diameter of several to tens of centimeters; symptoms may appear when it compresses or involves adjacent organs or nerves, blood vessels and joints. The patient should pay attention to the combination of FAP and Gardner’s syndrome.
2.Diagnosis and differential diagnosis
(1) Diagnosis: Diagnosis is confirmed based on imaging features and histopathology. Because of the rare and aggressive growth of AF, it is difficult to accurately identify other soft tissue tumors despite its imaging features, and the preoperative misdiagnosis rate is high. Any soft tissue mass should be thought of as a possible AF. Patients who have been diagnosed with “fibroma” and have recurred after surgery should review the original pathology and not misdiagnose AF as a simple fibroma.
MRI is preferred in combination with DWI (diffusion-weighted imaging) to preoperatively assess the extent of invasion, whether it involves peripheral blood vessels, bone destruction or invasion of organs, to formulate surgical plan and as an accurate follow-up tool. T1WI showed equal or slightly low signal; T2WI showed slightly high signal, and dynamic enhancement MRI showed obvious continuous enhancement or progressive delayed enhancement, accompanied by the presence of dense collagen with shuttle-shaped low signal and no enhancement in each sequence, which has important differential diagnostic value, while most malignant tumors only showed high signal in T2WI. CT showed unclear tumor boundary, uniform density on scan, and inhomogeneous enhancement after enhancement, and saw trabeculae in line with the direction of muscle fibers. The tumor is not well-defined and has homogeneous density on plain scan and uneven enhancement after enhancement, with trabecular and spindle-shaped hypodense areas scattered in the same direction as muscle fibers. Ultrasound or CT-guided aspiration cytology (FNAC) with immunohistochemical staining (at least β-catenin, c-kit, CD-34, desmin) can confirm the diagnosis preoperatively.
(2) Differential diagnosis: The site of AF should be considered and should be differentiated from fibroma, fibrosarcoma, malignant fibrous histiocytoma, neurogenic tumor, ossifying myositis, nodular fasciitis; gastrointestinal mesenchymal tumor, tumor of uterine or ovarian origin, lymphoma, smooth muscle sarcoma, retroperitoneal fibrosis, etc.
3.Treatment.
(1) Surgery: surgical resection is still the most effective treatment for AF, but because of its non-envelope and infiltrative growth characteristics, it is difficult to confirm the tumor boundary and clearly distinguish scar and connective tissue during surgery. Most scholars advocate that the cut edge should be 2-3 cm from the tumor to expand the resection, and the affected muscle, tendon membrane, periosteum and bone should be removed together to ensure negative cut edge (R0). The observation specimen should be free of hard tissue at the cut edge, and intraoperative multi-point cryopathology of the cut edge should be performed to confirm R0. AF occurring in specific areas such as mesentery, neck and mediastinum often causes fatal complications and should be aggressively surgically resected. The extent of resectability and the status of the incisional margin are related to the site of occurrence: for example, AF is closely related to nerves, blood vessels, organs, and periosteum, and the extent of resection is often limited due to the need to preserve the structural function of limbs or organs, and reconstruction is difficult to achieve R0 resection. There was still a 12% to 27% local recurrence rate; a 42% to 68% recurrence rate for positive microscopic margins (R1); and a 100% recurrence rate for positive naked eye margins (R2), with an overall postoperative recurrence rate of approximately 40%. Almost all recurrences were in situ or adjacent to the tendon membrane, with a mean recurrence time of 13-23 months and 95% occurring within 5 years; the recurrence rate was higher for reoperation, and the recurrence rate was higher for disseminated abdominal ectopic AF, with a high recurrence rate and shorter interval in children. Initial positive margins are highly susceptible to recurrence in a short period of time, allowing cells with possible genetic mutations to be placed in a tissue trauma repair environment, playing a recurrence-promoting factor. However, AF is after all different from malignancy and recurrence does not mean a runaway outcome. Regular postoperative review of ultrasound and MRI is emphasized, and patients with recurrence should be aggressively reoperated after MRI assessment of lesion resectability, striving for negative cut margins.
The extent of surgical resection is still controversial, and some scholars do not emphasize aggressive enlargement of resection, suggesting that functional-sparing resection plus postoperative radiotherapy should be retained when R0 resection is difficult to achieve. The PFS (progression-free survival) was 62.5% at 5 years for R0 resection, while there was no significant difference in PFS for R0 versus R1, and R2 had a significantly poorer prognosis. Wait-and-see is recommended for patients with recurrence but no progression and where reoperation would produce complications such as severe disability (especially of the extremities).
(2) Adjuvant therapy: Although enlarged resection may be theoretically curative, the clinical practice is still accompanied by a high rate of postoperative recurrence, and adjuvant therapy such as radiotherapy, chemotherapy, NSAIDs, selective estrogen receptor modulators (SERMs), kinase inhibitors TKI (tyrosine Marco Fiore retrospectively analyzed 142 AF cases and proposed a front-line nonaggressive policy, which attempts to achieve optimal local control of the tumor while ensuring the best quality of life through a staged approach: observation alone for asymptomatic patients → drug therapy → extended resection surgery and radiotherapy. →The 5-year PFS was 49.9% in the wait-and-see group and 58.6% in the drug-only group (P = 0.3196).
No radiotherapy was required for R0, while radiotherapy was recommended for both high-risk patients and those with positive cut margins or inoperable resection. It is recommended to give 50 Gy to 60 Gy to R1 patients. Shin concluded that postoperative radiotherapy significantly delayed recurrence but did not seem to improve the long-term prognosis.
The application of SERMs tamoxifen (triamcinolone, Tamoxifen) or raloxifene (Raloxifene) is 40% effective. Celecoxib (Celebrex), a COX-2 (cyclooxygenase-2) inhibitor, is effective in controlling disseminated extra-abdominal AF.
Imatinib (Imatinib) inhibits the targets of c-KIT, ABL, ARG and PDGFR-A&B kinase. Since AF does not have typical mutations above, the overall response rate to Imatinib is 10-23%, and it is only used as salvage therapy.
4. Prognosis and influencing factors: Regardless of the treatment taken, the average relapse rate of AF was 24-77%. 10- and 20-year survival rates were 94% and 86%, and 8% of AF patients died due to invasion of vital organs or large blood vessels. Multifactorial analysis found that AF site of origin, depth of lesion size, age, and gender were not associated with recurrence, and positive margins and history of surgical resection were independent influencing factors for postoperative recurrence. It has also been suggested that the individual biological behavior of AF will determine the prognosis to a greater extent. The S45F mutation on exon 3 of CTNNB1, the gene encoding β-catenin, has been shown to be a molecular predictor of high postoperative recurrence in disseminated AF.
5, Conclusion: Because of the rarity of invasive fibromatosis, most of the studies are currently retrospective or preliminary, and there is a lack of prospective multicenter joint studies and accumulation of evidence-based experience from randomized controlled trials. Accurate intraoperative determination of the extent of resection and striving to achieve R0 resection for the first time are important tools to improve the complete remission rate and reduce the recurrence rate. Surgery plus adjuvant radiotherapy is the effective treatment of choice, and individualized regimens such as NSAIDs, anti-estrogen drugs, chemotherapy, and targeted therapy have emerged as new adjuvant treatment options.