GMKA
Support

Desmoid tumors

Oncology
Read in Ukrainian

Introduction

Desmoid Tumors (DTs) are locally aggressive but non-metastasizing, deep-seated, monoclonal fibroblastic neoplasms with an annual incidence of 5 to 6 cases per million [1]. Recognition of their unpredictable biological behavior that may lead to spontaneous regression or asymptomatic stability has led to major shifts in management strategies away from upfront treatment toward initial front-line active surveillance [2,3]. Indications for treatment interventions are based on progressive growth or symptoms.

Clinical features and diagnosis

DTs most commonly arise in the extremities and buttock (30%), abdomen (30% [abdominal wall 20%, intra-abdominal 10%]), chest 30%, and head and neck (10%) [4]. The median age at diagnosis is around 40 years of age and female/male sex ratio is 2:1, except for abdominal wall DTs where the median age is younger (~34 years) and the sex ratio is 35:1 [5].
A previous history of trauma or surgery in the area of the DT is reported in approximately 10% of patients [4]. Recent or current pregnancy is reported in 15% of females [1]. Trauma, surgery, and pregnancy alter levels of some growth factors that may lead to the development and/or the progression of DTs. DTs may affect 10-25% of familial adenomatous polyposis (FAP) patients [6]. FAP patients generally present with mesenteric or retroperitoneal masses that can become life-threatening and cause death.
DTs infiltrate muscle, deep tissues, and along muscle planes [1] producing a mass that can compress or invade nerves which causes pain. Mesenteric or retroperitoneal DTs may present with nonspecific digestive symptoms or mechanical complications (most commonly intestinal obstruction, intussusception, fistulation and/or perforation, and mesenteric ischemia) [7]. Magnetic resonance imaging (MRI) imaging usually shows a poorly delineated, T2 hyper-intense lesion [8].
According to the European Society of Medical Oncology (ESMO) guidelines, core needle biopsy using a coaxial technique and a needle of adequate diameter (16 gauge) is the standard of care [3]. A percutaneous route is recommended when possible (peripheral or bulky DTs). If a percutaneous biopsy is not feasible, laparoscopic biopsy versus surveillance should be discussed in the multidisciplinary tumor board (MTB) with consideration of the patient’s imaging and clinical context.
Surgical biopsy has the disadvantage of potentially activating tumor growth and local progression and should be avoided [3,7]. Several samples must be collected for molecular analysis. Molecular genomic testing for beta-catenin (CTNNB1) and APC genes is recommended when diagnostic morphological features are atypical and/or when beta-catenin immunostaining is equivocal [1]. Mutations in these two genes are mutually exclusive in DTs. If a somatic mutation of CTNNB1 is described, FAP is excluded. Conversely, CTNNB1 wild-type tumors and APC mutated tumors require a complete assessment including colonoscopy when a diagnosis of FAP was previously unknown.
The Desmoid Tumor Working Group (DTWG) [2] recommends molecular testing to confirm the diagnosis and guide the clinical workup. Diagnosis should be confirmed by an expert pathologist because the risk of misdiagnosis is high. In a National database, 28% of patients had received discordant diagnoses after review by an expert pathologist [9]. A progressive DT without a molecular test confirming the diagnosis should raise the possibility of another malignant mesenchymal entity and an incorrect diagnosis of DT.

Rationale for active surveillance

Until the last decade, surgery was the standard of care when feasible. Active surveillance was first proposed for unresectable tumors or recurrences where limb salvage was not possible [10]; stabilization or spontaneous regression of DTs was observed in more than half of the cases. This strategy was then offered to patients with primary resectable tumors, first reported in a single institution series [11] and later in larger multi-center series of DTs in various anatomic locations and with longer patient follow-up [5,12,13,14].
In these series, more than half of the patients were observed to have stabilization or spontaneous regression of their DTs. In a randomized double-blind study comparing sorafenib to placebo in progressing DTs, two-thirds of patients in the placebo group had tumor stabilization or regression. Of these, 20% were significant according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. [15]. Furthermore, retrospective studies on intra-abdominal desmoids have shown that the risk of an event (disease progression or recurrence) is the same whether patients undergo surgery or active surveillance [16]. This unpredictable biological behavior of DTs and the very high rates of recurrence following resection prompted international experts to re-evaluate the holistic management of DTs.
Currently, ESMO [3] and DTWG [2] guidelines recommend active surveillance when the DT size does not pose a vital risk to the patient and otherwise propose medical treatment as the first-line strategy in select patients who truly require aggressive local treatment to avoid over-treating a large proportion of patients with DTs.
Patients should be advised to avoid unnecessary surgery, such as cosmetic surgery, since DT may arise from these scars and that another location may appear [7].

Surveillance monitoring

Monitoring with computed tomography (CT) or MRI imaging according to the tumor location should be performed closely after the diagnosis to avoid missing a significant progression. The first surveillance exam is typically performed one or two months after the initial imaging [2,3]. When disease stabilization or regression is first observed, imaging can be performed three to four months later and then every six months for two or three years. In patients with DT progression, it is recommended to confirm ongoing progression on several scans before deciding to intervene, as the tumor may progress further after diagnosis and then stop growing.
In cases of ongoing or significant tumor growth, the decision to treat is made based on the tumor location and initial size. Indeed, DTs in some locations (head and neck, intraabdominal) may require treatment earlier due to symptoms or threat to nearby critical structures. Conversely, greater progression of DTs in the abdominal wall location can be tolerated without risk to or change in available treatment options, particularly if the initial lesion was small.

Indications for treatment

In addition to tumor progression, other indications for treatment include the development of symptoms or complications as sequelae of a DT such as intestinal obstruction, perforation, and/or mesenteric ischemia [7]. When management of DT-associated complications involves surgery, resection of the tumor should be performed synchronously to the treatment of the complications when feasible without excessive bowel resection. If DT resection would result in a significant risk of intestinal insufficiency, it is preferable to treat the complication and leave the tumor in situ, only performing a biopsy to obtain histological confirmation (if DT not previously known) and decide upon systemic treatment postoperatively.
This strategy is particularly suitable in patients who previously underwent colo-proctectomy for FAP, in whom intestinal resections would be significantly more morbid, and the preservation of an ileal reservoir could be jeopardized [7]. DTs causing major aesthetic damages are also potential candidates for surgical treatment [2].
For the patients under active surveillance, treatment decisions are based on significant tumor growth or progressive symptoms [2,3]. A shared decision should be taken with the patient. When initiation of treatment is decided, recent guidelines recommend commencing medical treatment [2], which may stop the progression and avoid permanent sequelae. Surgery and radiotherapy have the disadvantage that they generate irreversible sequelae and surgery is no longer recommended as first-line treatment. An exception is an abdominal wall DT, where surgery may be relatively limited avoiding medical treatments whose adverse events and long-term effects are not negligible.
Cryotherapy is an interventional radiology freezing technique and may be considered before surgery or medical treatment in DTs with compatible locations (extremity or abdominal wall DT) and tumor sizes [17]. It may be limited by large tumor size and proximity of vascular and nervous structures. In a recent phase 2 including patients with progressive DT, 86% of patients had non-progressive disease at 12 months, with reduced pain and better functional status. Grade 1 and 2 toxicity occurred in 32.8% and 44.5% of patients, grade 3-4 in 22%, and no grade 5 toxicity was observed, making this strategy relatively safe [18].
Following medical treatment or cryotherapy failure, superficial sites of DTs – particularly abdominal wall DTs- represent the best indications for surgery in cases of continuous progression [2, 7]. Indeed, even considering the morbidity and loss of function from a full-thickness abdominal wall resection which may be required – especially in a young woman of child-bearing age which is an additional reason for carefully selecting patients – complete resection at surgery is relatively well tolerated if the reconstruction is performed optimally, and future pregnancies are possible even with a prosthetic mesh repair.
Between 15 and 20% of patients suffering from abdominal wall DT eventually undergo surgery [5]. Thoracic wall DTs allow complete surgery in the most favorable locations (lateral and located distantly from the cervico-thoracic outlet), but morbidity is potentially greater, and indications should be discussed in the MTB [7]. Following unsuccessful medical treatment and/or cryotherapy, surgery may also be considered in the event of progression in breast DTs [19] and in extremities when morbidity is acceptable and function can be maintained [7].
In limbs, isolated limb perfusion is another option [20] offered in some expert centers, but joint stiffness and soft tissue sclerosis may be long-term sequelae of this technique. In the abdomen, surgery should be carefully considered as imaging systematically underestimates the extent of mesentery involved, and resections are often macroscopically incomplete [16,7]. Macroscopically incomplete surgery is often deleterious compared to non-surgical strategies [2,3,11].
The results of historic retrospective studies that investigated the impact of microscopic margins are contradictory. Indeed, they included various proportions of indolent DT, for which the impact of margins may be irrelevant, in addition to progressive DT, for which achieving a negative margin might have a favorable impact. Moreover, a precise study of the margins is not always feasible retrospectively because of the poorly delineated margins and the limited numbers of sections reviewed or available for re-review. Accordingly, when proposed in the management of progressive DT, the goal of surgery should be an R0 resection when the expected morbidity is low, but a marginal resection may be acceptable when aesthetic or function is an issue [2].
Radiotherapy is an effective option in the event of a contraindication or failure of medical treatments and in locations where surgery would be mutilating and incomplete (e.g. limb girdles, mediastinum, pelvic wall) and not amenable to cryotherapy. A phase 2 trial validated radiotherapy for these indications, demonstrating local control in more than 80% of patients [21].
The long-term morbidity of radiotherapy (fibrosis, fracture, lymphoedema, radiation-induced malignancies) limits its indications to the most unfavorable situations, especially in young patients. The combination of surgery and radiotherapy does not achieve better local control than definitive radiotherapy alone [22]. As a result, definitive radiotherapy is preferred after medical treatments fail when surgery is expected to be potentially mutilating and incomplete [2].
In younger patients and those with axial DT adjacent to critical organs, proton therapy is an option as the dosimetric advantages may mitigate some of the toxicity associated with conventional photon-based radiotherapy [23].
When a marginal resection is performed upfront despite current recommendations, active surveillance should be proposed with an initial close follow-up [2]. As there is a chance that the DT might be indolent, this surgery can be sufficient and there is no indication for a re-operation or for adjuvant radiotherapy. Although adjuvant radiotherapy increases local control following marginal resection, routine use in the adjuvant setting could over-treat a large proportion of patients with indolent DT [2]. ‘Whoops surgery’ may cause a flare-up with a rapid local recurrence by the production of growth and pro-inflammatory factors during healing which can stabilize after a period of active surveillance.
The management strategy of DT recurrences is identical to that of primary tumors [2]. Recurrent DTs have also a chance of regression, as shown in a two-center study and confirmed by the placebo arm analysis in the randomized trial of Gounder [12,16].

Medical treatments

Many historic series were performed without strict inclusion criteria based on progression and included patients with both progressive and indolent DTs. Thus, reported response rates and progression-free survival (PFS) may not report accurate responses to treatment. Therefore, interpretation of historic studies is difficult and the author recommends that only relatively recent studies that included progressive DTs should be selected.
There is only one randomized phase 3 comparing sorafenib and placebo in patients presenting progressive or recurrent DTs [15]. The two-year PFS was significantly better in the sorafenib group (81% versus 36% in the placebo group), with durable responses. Two-thirds of patients in the placebo group experienced tumor stabilization or regression, validating front-line active surveillance also in recurrent DTs.
A randomized phase 2 trial compared pazopanib to an intravenous regimen combining methotrexate (30 mg/m2 per dose) and vinblastine (5 mg/m2 per dose) in patients with progressive DT [24]. Six-month PFS of patients who received pazopanib was 83·7% versus 45% in the methotrexate-vinblastine arm. Phase 2 studies have reported encouraging results with imatinib [25, 26]. Kinase inhibitors have also been successfully used in a pediatric population [27].
In a recent series including progressive DTs before starting chemotherapy, regimens containing methotrexate (MTX) + vinblastine (40% of patients), MTX + vinorelbine (57% of patients), or vinorelbine alone (3% of patients) achieved complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) in 1%, 47%, 51%, and 1% of patients, and the median PFS was 75 months [28]. In a series including patients with advanced, progressive DT treated with oral vinorelbine (90 mg once weekly), 6- and 12-month PFS were 88.7% and 77.5%; PR was observed in 29% of patients and SD in 57% [29].
Doxorubicin-based and liposomal doxorubicin chemotherapy have also been used successfully, especially when a rapid and significant tumor response must be achieved, such as in the case of some mesenteric desmoids [30,31,32]. All respective adverse events of these drugs and their long-term safety profile must be balanced with the need for symptom control and tumor response, especially in life-threatening DT. The use of hormonal therapy and anti-inflammatory agents is more controversial since most of the studies were limited to few patients, included both indolent and progressive DTs, and were performed before active surveillance was the recommended front-line [2].
New drugs acting on the Notch signaling are in evaluation such as Nirogacestat, a gamma-secretase inhibitor that has shown promising efficacy in adults [33] and has been evaluated in a randomized trial comparing it with placebo in adult patients with progressing DT (ClinicalTrials.gov Identifier: NCT03785964). This trial is closed to accrual and results are pending. Another drug inhibiting the Wnt pathway, which has a central role in DT, is currently in evaluation. Tegavivint, which interferes with the binding of beta-catenin to TBL1, is currently being evaluated in a phase 1/2 study for the treatment of recurrent or refractory solid tumors, including DT (ClinicalTrials.gov Identifier: NCT04851119).

Pain and pregnancy

Surprisingly, pain is not always proportional to tumor size, in that small DT may be significantly painful with a serious impact on health-related quality of life (HRQoL). Endometriosis occasionally coexists in rectus muscle tumor sites, and this can be another determining factor for pain. Nerve compression and tumour-related deformations are the most common causes of pain. This pain justifies primary medical treatment that, if there is no imminent risk, should start with concomitant analgesia, starting by the least aggressive option [2,7]. Surgery should be avoided as it causes postoperative residual pain and sequelae.
Pregnancy, as both hormone and growth factor secretion increase, can cause the appearance of a DT (frequently within abdominal peritoneal location) or the progression of a pre-existing tumour. On the basis of a retrospective collaborative study and expert practice, it is now well established that progression risk during pregnancy is high, but a spontaneous decrease is seen in most cases after delivery [34]. Among non-at-risk tumour sites, simple close ultrasound monitoring should be proposed during pregnancy. Pregnancy is no longer contraindicated in the majority of patients with DTs.

Conclusion

Active surveillance with planned imaging has become the first-line management in DT. A risk-benefit discussion in the setting of a specialized MTB should be conducted to determine DT management strategy. Initiation of any DT treatment should consider potential adverse events and long-term safety.

References

  1. WHO classification of tumours, 5th edition, volume 3: Soft tissue and bone tumours. (2020). Accessed : August 24, 2021: https://www.iarc.who.int/news-events/publication-of-the-who-classification-of-tumours-5th-edition-volume-3-soft-tissue-and-bone-tumours/
  2. Desmoid Tumor Working Group. The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020 Mar; 127:96-107.
  3. Gronchi A, Miah AB, Dei Tos AP, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Nov; 32(11):1348-1365.
  4. Salas S, Dufresne A, Bui B, et al. Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.  J Clin Oncol. 2011 Sep 10;29(26):3553-8.
  5. Bonvalot S, Ternès N, Fiore M, et al. Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought. Ann Surg Oncol 2013;20(13):4096–102.
  6. Campos FG, Martinez CA, Novaes M, et al. Desmoid tumors: clinical features and outcome of an unpredictable and challenging manifestation of familial adenomatous polyposis. Fam Cancer. 2015 Jun;14(2):211-9.
  7. Improta L, Tzanis D, Bouhadiba T, Abdelhafidh K, Bonvalot S. Desmoid tumours in the surveillance era: What are the remaining indications for surgery?  Eur J Surg Oncol. 2020 Jul;46(7):1310-1314.
  8. Sheth PJ, Del Moral S, Wilky BA, et al. Desmoid fibromatosis: MRI features of response to systemic therapy.  Skeletal Radiol. 2016 Oct;45(10):1365-73.
  9. Penel N, Coindre JM, Bonvalot S, et al.  Management of desmoid tumours: A nationwide survey of labelled reference centre networks in France.  Eur J Cancer. 2016 May;58:90-6.
  10. Lewis JJ, Boland PJ, Leung DH, et al. The enigma of desmoid tumors. Ann Surg 1999; 229(6):866–72.
  11. Bonvalot S, Eldweny H, Haddad V, et al. Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients. Eur J Surg Oncol 2008;34(4):462–8.
  12. Fiore M, Rimareix F, Mariani L, et al. Desmoid- type fibromatosis: a front-line conservative approach to select patients for surgical treatment. Ann Surg Oncol 2009;16(9):2587–93.
  13. Colombo C, Miceli R, Le Péchoux C, et al. Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients. Eur J Cancer 2015;51(2):186–92.
  14. Penel N, Le Cesne A, Bonvalot S, et al. Surgical versus non-surgical approach in primary desmoid-type fibromatosis patients: A nationwide prospective cohort from the French Sarcoma Group. Eur J Cancer 2017; 83:125–31.
  15. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for Advanced and Refractory Desmoid Tumors. N Engl J Med 2018; 379(25):2417–28.
  16. Burtenshaw SM, Cannell AJ, McAlister ED, et al. Toward Observation as First-line Management in Abdominal Desmoid Tumors. Ann Surg Oncol 2016;23(7):2212–9.
  17. Vora BMK, Munk PL, Somasundaram N, et al. Cryotherapy in extra-abdominal desmoid tumors: A systematic review and meta-analysis.  PLoS One. 2021 Dec 23;16(12):e0261657.
  18. Kurtz JE, Buy X, Deschamps F, et al. CRYODESMO-O1: A prospective, open phase II study of cryoablation in desmoid tumour patients progressing after medical treatment Eur J Cancer. 2021 Jan; 143:78-87. 
  19. Duazo-Cassin L, Le Guellec S, Lusque A, et al. Breast desmoid tumor management in France: toward a new strategy. Breast Cancer Res Treat 2019; 176(2):329–35.
  20. van Broekhoven DL, Deroose JP, Bonvalot S, et al. Isolated limb perfusion using tumour necrosis factor α and melphalan in patients with advanced aggressive fibromatosis. Br J Surg. 2014 Dec; 101(13):1674-80.
  21. Keus RB, Nout RA, Blay JY, et al. Results of a phase II pilot study of moderate dose radio- therapy for inoperable desmoid-type fibromatosis–an EORTC STBSG and ROG study (EORTC 62991-22998). Ann Oncol 2013;24(10):2672–6.
  22. Nuyttens JJ, Rust PF, Thomas CR Jr, et al. Surgery versus radiation therapy for patients with aggressive fibromatosis or desmoid tumors: A comparative review of 22 articles.  Cancer. 2000 Apr 1;88(7):1517-23.
  23. Looi WS, Indelicato DJ, Rutenberg MS. The Role of Radiation Therapy for Symptomatic Desmoid Tumors.  Curr Treat Options Oncol. 2021 Mar 1;22(4):34.
  24. Toulmonde M, Pulido M, Ray-Coquard I, et al. Pazopanib or methotrexate-vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study. Lancet Oncol. 2019 Sep;20(9):1263-1272.
  25. Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG).  Eur J Cancer. 2017 May; 76:60-67.
  26. Penel N, Le Cesne A, Bui BN, et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up.  Ann Oncol. 2011 Feb;22(2):452-7.
  27. Sparber-Sauer M, Orbach D, et al. Rationale for the use of tyrosine kinase inhibitors in the treatment of paediatric desmoid-type fibromatosis. Br J Cancer. 2021 May;124(10):1637-1646.
  28. Palassini E, Frezza AM, Mariani L, et al. Long-term Efficacy of Methotrexate Plus Vinblastine/Vinorelbine in a Large Series of Patients Affected by Desmoid-Type Fibromatosis.  Cancer J. 2017 Mar/Apr; 23(2):86-91.
  29. Mir O, Honoré C, Chamseddine AN, et al. Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status.  Clin Cancer Res. 2020 Dec 1;26(23):6277-6283.
  30. Lynch HT, Fitzgibbons R Jr, Chong S, et al. Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner’s syndrome. Dis Colon Rectum. 1994 Mar;37(3):260-7.
  31. de Camargo VP, Keohan ML, D’Adamo DR, et al. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).  Cancer. 2010 May 1;116(9):2258-65.
  32. Constantinidou A, Jones RL, Scurr M, Al-Muderis O, Judson I. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis.  Eur J Cancer. 2009 Nov;45(17):2930-4.
  33. Kummar S, O’Sullivan Coyne G, Do KT, et al. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults with Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569
  34. Fiore M, Coppola S, Cannell AJ et al. Desmoid-type fibromatosis and pregnancy: a multi-institutional analysis of recurrence and obstetric risk.  Ann Surg. 2014 May; 259(5):973-8.