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10. Desmoid Fibromatosis

Presentation
  • Desmoid tumors (DTs) are rare, accounting for 0.03% of all neoplasms and < 3% of all soft tissue tumors.
  • Desmoid tumors or aggressive fibromatosis are classified as benign tumors because of their lack of metastatic potential and low risk of mortality.
  • DTs are locally infiltrative and may result in significant morbidity and, very rarely, death.
  • DTs can occur in any anatomic location, but frequently arise in the abdominal wall, neurovascular bundle of the limb and shoulder girdle, root of the mesentery, and head and neck structures.
  • Depending on location, presentation can vary from asymptomatic to severe pain, deformity, swelling, loss of function, bowel obstruction or perforation, and/or threat to vital organs.
  • DTs usually affect individuals between 15-60 years of age.
  • There is a slight female preponderance.
  • DTs are characterized by variable clinical behavior. Some desmoids may grow progressively larger over time, while others may experience indolent growth or periods of growth arrest and spontaneous regression.
  • There is also variability in the propensity to recur after definitive therapy.

Risk Factors

FAP and Gardner syndrome
  • Most DTs are sporadic.
  • About 5-15% are associated with familial adenomatous polyposis (FAP), while 10-20% of patients with FAP will develop desmoids.
  • FAP is caused by mutations in the APC gene on chromosome 5q21-q22.
  • Gardner syndrome is a variant of FAP, characterized by intestinal polyposis and various bone and soft tissue lesions, including osteomas, epidermal inclusion cysts, lipomas, fibromas and desmoid fibromatoses.
  • Most DTs associated with FAP are abdominal (intra-abdominal or abdominal). 
  • Screening colonoscopy can be considered in patients with newly diagnosed DTs especially if they are a young, have intra-abdominal or abdominal wall desmoid, or multiple desmoids.
  • With the increasing use of prophylactic colectomy in patients with FAP, DTs have become an important cause of morbidity and mortality.
Pregnancy
  • DTs have been associated with high estrogen states.
  • Extra-abdominal and abdominal desmoids can occur in women during or following pregnancy. Trauma related to the pregnancy (including scar from prior Cesarean section) and exposure to elevated hormone levels may both be contributory.
  • Pregnancy-associated desmoids are associated with good outcomes overall.
Antecedent trauma
  • Desmoid tumors have been associated with antecedent trauma, particularly surgical intervention, as noted in patients with FAP and pregnancy-associated desmoids, but also with sporadically occurring desmoids.
  • There may be a molecular connection between wound healing processes and fibroproliferative disorders of mesenchymal tissue. 
Molecular pathogenesis
  • The molecular events leading to desmoid formation are incompletely understood.
  • Virtually all patients with DTs harbor inactivating mutations in either CTNNB1 (90% somatic - sporadic ) or APC (9% germline - hereditary).
  • Desmoids in FAP arise from APC inactivation and subsequent beta-catenin accumulation in cells.
  • Sporadic desmoids arise from mutations in gene for beta-catenin, CTNNB1, while APC mutations are uncommon.

Diagnostic workup

Imaging
  • MRI is preferred for truncal and extremity DTs for defining relationship of the tumor to adjacent structures to assess resectability and need for treatment.
  • CT can also adequately evaluate DTs.
Biopsy
  • Core needle biopsy is usually sufficient to make a diagnosis in the hands of an experienced pathologist.
Pathology
  • Positive immunohistochemistry for nuclear beta-catenin supports the diagnosis of desmoid tumor, although it should be noted that nuclear beta-catenin is not completely specific, being occasionally seen in other entities (eg. Solitary fibrous tumor and synovial sarcoma) and not all desmoid tumors will stain for nuclear beta-catenin (cytoplasmic staining is more sensitive, but less specific). 
  • Genomic sequencing reveals a very low mutational burden with no consistent genetic changes, except in Gardner syndrome cases.
Endoscopy
  • Given the association of desmoids with FAP, it is important to obtain an accurate family history, especially of colon cancer. 
  • Colonoscopy may be recommended for all patients diagnosed with desmoid tumor especially an intra-abdominal desmoid.

Treatment

Active surveillance
  • Desmoids have an unpredictable clinical course, encompassing progression, stability or even spontaneous regression. 
  • Close observation, in consultation with the sarcoma team, is an acceptable strategy for stable, asymptomatic primary or recurrent desmoids.
  • Active surveillance may not be appropriate if progression could be life-threatening or pose a risk to  critical adjacent structures (eg. nerves or vessels)
  • Patients should be monitored clinically and with imaging every 3-6 months. If disease is stable, then monitoring intervals can be extended.
Surgery
  • Surgery, when medically and technically feasible with negative margins, is an acceptable treatment option for patients who are symptomatic or experiencing rapid or life-threatening progression.
  • Tumor location and size, and patient’s age are factors associated with recurrence risk.
  • The relationship between surgical margin status and local recurrence rate is unclear. 
  • Thus, aggressive attempts at achieving widely negative margins are not warranted, especially if they result in increased risk of morbidity.
  • Intra-abdominal/mesenteric desmoids that develop in patients with FAP are often unresectable as they tend to be large, infiltrative and/or multiple in nature. Attempted resections can result in substantial morbidity. For these patients, a multidisciplinary approach, which may include initial medical therapy, is recommended. 
Radiation Therapy
  • Radiation therapy is an effective and reasonable primary therapeutic option for symptomatic patients who are not candidates for surgical or systemic therapies. 
  • Given the unclear relationship between margin status and local recurrence risk, the role of post-operative radiation is also unclear and tends to be avoided in this generally younger patient population.
  • Radiation therapy is not usually recommended for retroperitoneal or intra-abdominal desmoid tumors.

Other local therapies:

Cryoablation
  • Cryosurgery/cryoablation may be considered as an adjunct or stand-alone treatment for local control or palliation of musculoskeletal neoplasms.
  • Patients presenting with aggressive or symptomatic benign bone or soft tissue neoplasm may benefit from cryoablation while minimizing morbidity compared for eg, with surgery or radiation.
  • An advantage of cryoablation for desmoids is that it allows conservative treatment of a benign process and the ability to re-treat if necessary with decreased chance of significant morbidity.
  • Cryotherapy should only be attempted in a specialized setting in experienced hands. There is local experience with cryotherapy at Vancouver General Hospital under Dr. Peter Munk.
Systemic therapy
  • There are a variety of options for systemic therapy depending on patient and disease factors such as resectability, disease indolence, symptomatic disease, urgency to induce response, prior local therapy and potential morbidity of local therapy. 
  • A wide class of drugs has shown variable degrees of activity.
  • Initial treatment with hormonal agents (tamoxifen) with or without NSAIDs (sulindac or celecoxib) may be suitable for patients with less aggressive, minimally symptomatic disease in whom an urgent response is not required. 
  • The risk of cardiovascular events may be increased in patients receiving celecoxib, and this information should be considered when prescribing celecoxib to individual patients, weighing risks versus benefits, especially in patients with risk factors for cardiovascular disease. 
  • Tyrosine kinase inhibitors (Imatinib, Sorafenib) have demonstrated activity in the treatment of desmoid tumors.
  • Chemotherapy is generally reserved for slowly progressing, symptomatic disease that have failed prior therapies or, rapidly progressing, unresectable disease.
  • Doxorubicin-based chemotherapy, including single agent liposomal doxorubicin, has been effective in patients with recurrent and unresectable tumors.
  • The combination of  low dose methotrexate with vinorelbine or vinblastine has also shown activity with durable clinical benefit 
Duration of therapy: 
  • There is no strong evidence to guide duration of therapy.
  • Duration of therapy should be based on toxicity and response. 
  • Response to systemic therapy can be slow to manifest, sometimes taking 6 to 8 moths or more. 
  • Imaging every 2 -3 cycles (or every 2-3 months) to monitor response or disease stability, and ensure non-progression is reasonable.
  • Non-cytotoxic therapies could be continued in the absence of toxicity and based on the patient’s response and wishes for treatment breaks.
  • Doxorubicin-based therapies are limited by cumulative cardiotoxicity and myelosuppression.
  • The weekly Methotrexate plus vinblastine combination tends to be less toxic and often administered for one year.
Surveillance
  • Consensus-based guidelines from NCCN suggest history and physical with imaging (CT or MRI) every 3-6 months for 2-3 years then annually.

References

  • Gounder MM, Thomas DM, Tap WD. Locally aggressive connective tissue tumors. J CLin Oncol 2018;36(2):202-209.
  • Fletcher JA, Bridge JA, Hogendoorn PCW et al. Desmoid-type fibromatoses.
  • WHO Classification of Tumors of Soft Tissue and Bone. Lyon: IARC Press 2013; 72–73.
  • Alberta Health Services Clinical Practice guidelines. Desmoid tumors. July 2017. https://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-sar004-desmoid.pdf
  • Gronchi A, Casali PG, Mariani L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003: 21:1390-1397.
  • Skapek SX, Anderson JR, Hill DA, et al: Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: Results of a Children’s Oncology Group (COG) phase II study. Pediatr Blood Cancer 60:1108-1112, 2013
  • Kasper B, Baumgarten C, Bonvalot S, et al: Management of sporadic desmoid-type fibromatosis: A European consensus approach based on patients’ and professionals’ expertise—A sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative. Eur J Cancer 51:127-136, 2015
  • Fiore M, Colombo C, Radaelli S, et al: Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis. Eur J Cancer 51: 2800-2807, 2015
  • Tsukada K, Church JM, Jagelman DG, et al. Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum. 1992;35(1):29.
  • Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive 37. Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res. 2010;16(19):4884. Epub 2010 Aug 19.
  • Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011;17(12):4082. Epub 2011 Mar 29.
  • Garbay D, Le Cesne A, Penel N, et al. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012;23:182-186. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21444357.
  • Constantinidou A, Jones RL, Scurr M, et al. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009;45:2930-2934. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19767198.
  • Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer. 2001;92(5):1259.
  • Rose PS, Morris JM. Cryosurgery/cryoablation in musculoskeletal neolams: history and state of the art. Curr Rev Muskuloskelet Med 2015;8:353-360.




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