10. Desmoid Fibromatosis

Presentation

Desmoid tumours (DTs) are rare, accounting for 0.03% of all neoplasms and < 3% of all soft tissue tumours.
Desmoid tumours or aggressive fibromatosis are classified as benign tumours 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 behaviour. Some desmoid tumours 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 desmoid tumours.
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 desmoid tumours.
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 desmoid tumours 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 desmoid tumours are associated with good outcomes overall.

Antecedent trauma

Desmoid tumours have been associated with antecedent trauma, particularly surgical intervention, as noted in patients with FAP and pregnancy-associated desmoid tumours, but also with sporadically occurring desmoid tumours.
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 harbour inactivating mutations in either CTNNB1 (90% somatic - sporadic ) or APC (9% germline - hereditary).
Desmoid tumours in FAP arise from APC inactivation and subsequent beta-catenin accumulation in cells.
Sporadic desmoid tumours 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 tumour 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 tumour, although it should be noted that nuclear beta-catenin is not completely specific, being occasionally seen in other entities (eg. Solitary fibrous tumour and synovial sarcoma) and not all desmoid tumours 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 desmoid tumours 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 tumour especially an intra-abdominal desmoid.

Treatment

Active surveillance

Desmoid tumours 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 desmoid tumours.
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.
Tumour 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 desmoid tumours 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 tumours.

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 desmoid tumours 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 tumours.
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 tumours.
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 neoplasms: history and state of the art. Curr Rev Muskuloskelet Med 2015;8:353-360.