Curr. Treat. Options in Oncol.

(2017) 18:29
DOI 10.1007/s11864-017-0474-0

Sarcoma (SH Okuno, Section Editor)

Desmoid-Type Fibromatosis:
Who, When, and How to Treat
Javier Martı´nez Trufero, MD, PhD*
Isabel Pajares Bernad, MD, PhD
Irene Torres Ramón, MD
Jorge Hernando Cubero, MD
Roberto Pazo Cid, MD
Address
*
Medical Oncology Department, Hospital Universitario Miguel Servet, Avda Isabel
la Católica 1-3, 50009, Zaragoza, Spain
Email: jmtrufero@seom.org

* Springer Science+Business Media New York 2017

Javier Martínez Trufero and Isabel Pajares Bernad are active members of
Spanish Group of Sarcoma Research (GEIS).
Topical Collection on Sarcoma

Keywords Desmoid-type I Fibromatosis I Desmoid I Wait and see I Beta-catenin I CTNNB1

Opinion statement
Desmoid-type fibromatosis is a sarcoma subtype that gathers some singular characteris-
tics, making it a difficult challenge to face in clinical practice. Despite its excellent survival
prognosis, these tumors may be unpredictable, ranging from an asymptomatic indolent
course to persistent, local, and extended recurrences that significantly impair quality of
life. Although surgery was initially considered the first elective treatment, collected
published data during the past few years are now pointing to the “wait and see” approach
as a reasonable initial strategy because many patients can live a long life with the disease
without having symptoms. When symptoms appear or there is a risk of functional
impairment, a wide spectrum of therapies (local and systemic) can be useful in improving
symptoms and controlling the disease. Because of the low incidence of desmoid-type
fibromatosis, there is scarce scientific evidence supporting any specific treatment. None-
theless, if volumetric responses are needed, chemotherapy may be a reasonable early
option. However, if long-term control of disease is desirable, hormonal therapy, NSAIDs,
and TKIs are the likely treatments of choice. Recent new findings in the biologic devel-
opment of these tumors, such as the role of Wnt/β-catenin dependent pathway, have
shown that the prognostic information provided by specific CTNNB1 gene mutations and
other genetic profiles can lead to better methods of selecting patients as candidates for
other approaches. Based on recent research, the Notch pathway inhibition in DF is one of
the most promising potential targets to explore. As an orphan disease, it is mandatory that
as many patients as possible be included in clinical trials.
29 Page 2 of 12 Curr. Treat. Options in Oncol. (2017) 18:29

Introduction
Desmoid-type fibromatosis (DF), also known as
desmoid tumor or deep fibromatosis, is a locally aggres-
sive fibroblastic neoplasm that develops in musculoapo-
neurotic structures. It is characterized by infiltrative
growth and a tendency to relapse locally, but it has no
distant metastatic potential. Despite the prolonged long-
term survival, frequent recurrences and subsequent treat-
ment sequelae can considerably impair quality of life
[1].
DF accounts for 3% of all soft tissue sarcomas, and its
incidence is approximately 2.4–4.3/million/year. DF
typically occurs between the ages of 15 and 60 years,
with a peak age of onset of 30 years. There are two
different groups of patients based on their biological
behavior. Sporadic cases may be located in any anatom-
ical site, but they are predominantly located in the
shoulder, chest, abdominal wall, head, neck, and thigh.
Those located in the abdominal wall are especially com-
mon in female patients who are pregnant. The other
type occurs less frequently, mostly intraabdominally,
and is associated with familial adenomatous polyposis
(FAP) or Gardner syndrome, with predominance in the
mesentery [2].
DF pathogenesis is multifactorial, although there is
evidence of an underlying genetic basis due to the exis-
tence of familial cases and those associated with FAP.
Another hypothetical associated factor is trauma (most
often surgery) [3].
Pathological diagnoses are based on the presence of
poorly circumscribed and infiltrating lesions. Micro-
scopically, they are characterized by spindle cells of
uniform appearance with abundant collagen. Their nu-
clei are typically small, vesicular, pale, and sharply de-
fined. The immunophenotype shows positivity for MSA
and SMA and negativity for desmin, h-caldesmon, and
S-100. Seventy to 75% of cases show positivity for β-
catenin, but this is more frequent in FAP-associated
tumors [4].

Molecular and genetic characteristics (Fig. 1)

The biological development of DF is based on the Wnt/β-catenin-dependent
pathway that controls key developmental gene expression programs, modulat-
ing the intracellular amount of β-catenin and regulating its degradation, accu-
mulation, and translocation from the adherens junction and cytoplasm to the
nucleus. Although β-catenin plays a role as a cell adhesion molecule in
adherens junctions, in mesenchymal cells, such as those in DF, its main role
is being part of the transcription apparatus in the nucleus. Intracellular levels of
β-catenin are controlled by adenomatous polyposis coli (APC) complex that
phosphorylates β-catenin, inducing its destruction by the proteasome. In nor-
mal physiology, this process is inhibited by activation of the Wnt pathway,
which leads to inhibition of the kinase activity of the APC complex.
Nonphosphorylated β-catenin accumulates in the cytoplasm, then it translo-
cates to the nucleus and acts with other proteins, promoting transcription of
genes such as cyclin-D1 and c-myc, which facilitate proliferation, survival, and
differentiation. Accumulation of β-catenin protein in the cytoplasm and the
nucleus can be easily detected by immunohistochemistry, helping also in
pathological diagnosis. A protein encoded by exon 3 of the CTNNB1 gene
mediates phosphorylation of β-catenin, which also encodes β-catenin itself.
Other proteins that complete phosphorylation are casein kinase 1 (CK1) and
glycogen synthase kinase-3-b (GSK-3-β). Any interference of this process leads
to accumulation of β-catenin in the nucleus. In FAP syndrome, development of
DF is related to the presence of one inherited nonfunctional copy of APC and
the loss of the other. The mutation 3′ in codon 1444 of the APC gene is
Curr. Treat. Options in Oncol. (2017) 18:29 Page 3 of 12 29

Fig. 1. Canonical Wnt/β-catenin pathway.

particularly involved in such cases [5]. In sporadic DF, CTNNB1 mutations are
the most common route of activating the Wnt pathway. The largest and latest
studies on the prevalence of CTNNB1 mutations in DF show that at least 85% of
sporadic DF are carriers of mutations in this gene. Among all possible muta-
tions, only three (T41A, S45F, and S45P) were encountered in DF. This fact
makes it the only neoplasm with mutations in this gene that shows such
restrictions [6]. One study also found that the S45F mutation was an important
predictive factor of recurrence after surgical excision of the primary tumor, with
a relative risk of 3.5. This feature can likely be applied as a prognostic factor of
more aggressive behavior [7].
Transforming growth factor-β (TGF-β) and connective tissue growth factor
(CTGF) are profibrotic growth factors that play a role downstream from nuclear
translocation of β-catenin. CTGF is a downstream effector of TGF-β that mod-
ulates the activity of growth factors, adhesion molecules, integrins, and extra-
cellular matrix, holding a central function on tissue remodeling and fibrosis.
High expression of both molecules in DF has been described, which subse-
quently has been postulated as a potential therapeutic target [8].
However, the high expression of anti-apoptotic Bcl-2, Bcl-xL, survivin, and
the transcription factor NF-κB have been described in DF. These changes oc-
curred in the absence of cell proliferation, as shown by the absence of both Ki-
67 staining and increased telomerase activity. The fact that mitosis is unusual in
DF may reflect that proliferation is not affected but that apoptosis is largely
inhibited, giving a growth advantage to the tumor [9].
Recently, Salas et al. published a study analyzing the prognostic value of a
prognostic gene expression signature composed of 36 genes by cDNA microar-
rays. They found a robust correlation with progression-free survival (PFS) in a
29 Page 4 of 12 Curr. Treat. Options in Oncol. (2017) 18:29

sample of 115 patients with DF [10]. Similarly, Dufresne et al. defined that
overexpression of some specific miRNAs was correlated with clearly different
times to recurrence in a cohort of 15 patients who had DF treated with imatinib
[11]. These two studies provide a rationale to find biomarkers that may help to
assign patients to more or less conservative approaches depending on the risk of
progression.

Hormonal dependency
A higher incidence of DF in women has been documented, especially after
pregnancy, with an improvement after menopause. In fertile women, the
growth rate of DF is faster than observed in men. Preclinical studies supported
this hormonal dependency based on the development of DF in pigs after
prolonged administration of estrogens [12]. Although low expression of estro-
gen receptors (ER) has been described, when ER-β is specifically analyzed, the
percentage of positivity is almost 100% [13].

Treatment approaches
Wait and see approach
DF is often characterized by heterogeneous and variable natural history, with
unpredictable periods of growth, stabilization, or even regression in the absence
of any therapy. This characteristic indolent growth pattern, in addition to the
significant morbidity associated with surgery and radiotherapy, has made
“watchful waiting” a reasonable approach [14]. Two studies have specifically
highlighted this management. In the first study, Bonvalot et al. analyzed 142
patients with DF, 83 of whom were included in a “wait and see” approach and
59 of whom were treated upfront with medical therapy. There were no signif-
icant differences in 5-year progression-free survival between both groups (49.9
versus 58.6%) [15]. The other study, from Salas et al., analyzed the outcome of
426 patients with DF, 27 of whom were being observed without treatment,
showing that progressive disease developed in only 20% of them in follow-up.
Three different prognostic groups were described based on the presence of
adverse prognostic factors identified in multivariate analysis, which include
tumor size larger than 7 cm, extra-abdominal location, and age older than
37 years. Those groups stratify patients with different risks of relapse and may
be useful in differentiating patients who need to be treated early from those
who could be carefully followed conservatively [16].
Based on these data, the French and Italian sarcoma groups recommend the
wait and see strategy as the initial approach for most patients in order to
elucidate the specific behavior of the tumor. MRIs should be performed fre-
quently during the first year of follow-up to identify rapidly growing tumors
[17]. Similarly, the European Organization for Research and Treatment of
Cancer (EORTC) and the Soft Tissue and Bone Sarcoma Group (STBSG) pub-
lished a consensus approach recommending the same initial watchful waiting
period of 1 or 2 years as the first line of treatment [18].

Local treatment: surgery, radiotherapy, and invasive procedures

Local control of DF is a very difficult goal to achieve because local failure ranges
from 25 to 60% at 5 years in retrospective studies, despite radical treatment [19].
Curr. Treat. Options in Oncol. (2017) 18:29 Page 5 of 12 29

Classically, primary surgery with negative margins was considered the stan-
dard of care. However, due to the pattern of infiltrative growth, the scope of
resection needed to achieve negative margins could often lead to important
function impairments and cosmetic alterations, which are not acceptable in an
indolent disease. Furthermore, the efficacy of marginal R1 resections remains
unclear. A positive surgical margin was found to be an adverse predictor of worse
local control in some series, but not in others [20]. In the study by Salas et al.,
which is the largest study of sporadic DF, progression-free survival curves were
not significantly different based on the microscopic assessment of surgical resec-
tion quality (R0 versus R1), although R2 resections resulted in a significantly
poorer prognosis [16]. Other prognostic factors associated with poor PFS were
age younger than 37 years, tumor size larger than 7 cm, and extra-abdominal
localization, especially tumors found in the distal extremities. Based on these
data, the French and Italian sarcoma groups did not recommend surgery as
upfront therapy, except in case of patient’s preference [17]. Nonetheless, in our
experience, in a registry-based sample of 185 patients, quality of surgery along
with tumor size smaller than 8 cm were shown as independent predictors of
better PFS [21].
The benefit of radiotherapy has been described in several studies, mainly
retrospectively. A review that included 22 retrospective studies evaluating the
local treatment of DF (surgery, radiotherapy, or surgery plus radiotherapy)
showed that surgery plus radiotherapy or radiotherapy alone could result in a
better local control rate (75 and 78%, respectively) compared with surgery alone
(61% overall, 72% in cases with negative margins, and 41% in cases of positive
margins) [22].
For tumors located at critical sites (such as the head and neck, limb girdles,
and pelvis), for which surgery would involve functional impairment, or for
inoperable, symptomatic/progressive disease that did not respond to other ther-
apeutic approaches, radiotherapy alone could be preferable over other local
treatments [17].
Adjuvant radiotherapy is recommended for extremity/limb girdle disease after
R1/R2 resection for recurrent disease or following surgery at critical sites (i.e.,
head and neck), regardless of margins status.
Based on the published literature, the recommended dose of radiotherapy is
50–56 Gy in 2 Gy fractions while obtaining long-term control rates of 81% [23].
Doses higher than 56 Gy are associated with an increased risk of complications
(including fibrosis, soft-tissue necrosis, or even secondary malignancies) and may
result in no improvement of local control [24].
Other local treatments, such as isolated limb perfusion with tumor necrosis
factor alpha (TNFα) and melphalan, can be useful in tumors located in extrem-
ities or multifocal DF [25]. Cryoablation in small extra-abdominal tumors can
also be considered as an alternative treatment. However, larger studies are needed
to evaluate the effectiveness of those two treatments [26].

Systemic treatment
Several medical treatments have been explored for DF, but mostly in retrospec-
tive studies. Four treatment modalities stand out as possible alternatives when
local treatment fails or is contraindicated: cytotoxic chemotherapy, targeted
therapies, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal
29 Page 6 of 12 Curr. Treat. Options in Oncol. (2017) 18:29

therapy.
Considering the reported activity of most of chemotherapy regimen, it
seems clear that these treatments have the ability to achieve the highest rates
of volumetric responses. This characteristic can be useful in rapidly growing
tumors that cause pain or functional impairment or in those located in critical
sites. However, in most of cases, given the frequent indolent course of DF, the
first systemic approach would be the least toxic, with the possibility of long-
term maintenance. This goal probably can be achieved more easily with hor-
monal therapy, NSAIDs, or tyrosine kinase inhibitors (TKIs) [18].

Chemotherapy
Cytotoxic chemotherapy is usually the first treatment option for rapidly grow-
ing and symptomatic unresectable or advanced disease. In a retrospective
review, the French Sarcoma Group reported an 80% clinical benefit (stable
disease or objective response) in this group of patients [27]. The most frequent-
ly used regimens include methotrexate and vinblastine in combination and
anthracycline-based regimen.
Methotrexate plus vinblastine is one of the most frequently used regimens. It
was first tested in a phase II trial in a pediatric sample of 27 patients, 18 of
whom were free from progression at a median of 43 months [28]. However, this
regimen is highly toxic in adults because of frequent grades 3–4 neuropathy,
pneumonitis, and hepatitis [29]. Vinorelbine plus methotrexate can be a more
acceptable regimen, provided its more tolerable toxicity profile [30].
Anthracycline-based therapy was found to be the most active treatment for a
classic presentation [31]. First combinations included doxorubicin and
dacarbazine. In a small report of seven patients, all of them achieved response,
including three complete responses and a PFS of 74 months [32].
Pegylated liposomal doxorubicin, at a dose of 50 mg/m2 every 4 weeks, was
reported to have significant activity, and it is considered the treatment of choice
by many investigators. In a cohort of 12 patients, clinical benefit was achieved
in 11 patients. Treatment was mainly administered until maximum response,
maintaining it afterwards for more than 12 months. Most of the patients
required dose reduction due to toxicity [33]. The most representative published
active chemotherapy regimens used in DF are shown in Table 1.

Hormonal therapy
Based on the hormonal dependency previously described, anti-estrogens have
been tested in DF, although controlled clinical trials are scarce [37]. Tamoxifen
is the most commonly used drug in those studies. In retrospective series and
case reports, many responses have been documented, although its role as a
treatment option remains uncertain [12].
High-dose tamoxifen (120–200 mg/day) was more effective than low-dose
tamoxifen (10–40 mg/day) in a small retrospective study of 25 patients, but it
cannot be recommended as standard dose because of the lack of data from
randomized trials and the risk of toxicity [38]. Other hormonal agents such as
toremifene, testolactone, progesterone, and goserelin have shown efficacy, but
very limited evidence is available.
NSAIDs and hormonal therapy in combination have been tested mainly in
Curr. Treat. Options in Oncol. (2017) 18:29 Page 7 of 12 29

Table 1. Active chemotherapy regimens in DF

Author Drugs N CR PR SD PFS

(months)
Patel [28] Doxorubicin (60–90 mg/m2) + Dacarbazine 12 2 4 2 96
(750–1000 mg/m2)
Gega [32] Doxorubicin (20 mg/m2) + Dacarbazine (150 mg) 7 3 4 – 74
Constantinidou Pegylated liposomal doxorubicin (50 mg/m2) 12 – 4 7 14
[33]
Wehl [34] Pegylated liposomal doxorubicin (50 mg/m2) 4 – 4 – NA
2 2
Azzarelli [35] Vinblastine (6 mg/m ) + Methotrexate (30 mg/m ) 30 0 12 18 75
Skapek [36] Vinblastine (6 mg/m2) + Methotrexate (30 mg/m2) 27 – 8 10 15.9
Weiss [30] Vinorelbine (20 mg/m2) + Methotrexate (30 mg/m2) 13 2 4 2 6

N population, CR complete response, PR partial response, SD stable disease, PFS progression-free survival, NA not available

retrospective, uncontrolled series. One phase II trial testing sulindac plus ta-
moxifen in 55 pediatric patients found a low response rate of 8%, as noted
below, although toxicity was acceptable [39].

NSAIDs
Multiple case reports have shown regression of DFs with the use of NSAIDs [40,
41]. Theorized possible mechanism is the ability to regulate the β-catenin path-
way through inhibition of cyclooxygenase-2 (COX2) or prostaglandins [42].
Sulindac is a selective inhibitor of cyclooxygenase-2 with anti-inflammatory
activity, which has been studied in advanced and unresectable DF. The only
prospective phase II study published to date was conducted by the Children
Oncology Group (COG). The study tested the combination of sulindac, 3 mg/kg/
day and tamoxifen in a sample of 59 patients. A response rate of 8% (5/59) and
36% 2-year PFS were reported [39].

Targeted therapy
Many targeted drugs have been explored recently for advanced DF, although the
underlying molecular basis explaining their activity is not always clear (Table 2).
Imatinib was the first tested TKI for the treatment of DF. This drug targets
KIT, ABL, ARG, and platelet-derived growth factor receptor A/B (PDGFRA/B)
kinase. Two prospective, nonrandomized phase II studies have shown a high
rate of disease stabilization in approximately 60–80% of cases. Heinrich et al.
tested the efficacy of imatinib, 800 mg, in 19 patients. The response rate was
16% (3 partial responses (PR)), and stable disease was 21% (4 SD), showing a
PFS of 53 and 36.8% at 6 and 12 months, respectively. They speculated that
imatinib activity could rely on PDGFRB kinase activity inhibition [43]. Subse-
quently, Penel et al. published data of 35 patients who were treated with
imatinib, 400 mg/day, with a response rate of 11% (1 complete response
(CR), 3 PR) and 80% (28 SD), with a 2-year PFS of 55% [44].
The German Interdisciplinary Sarcoma Group has recently published data
29 Page 8 of 12 Curr. Treat. Options in Oncol. (2017) 18:29

Table 2. Published studies of targeted therapies in advanced DF

Author Drug Target Trial Daily N Response PFS

dose Rate (%)
Heinrich Imatinib ABL, ARG, Prospective 800 mg 19 pts 16% (3 PR) 36.8% at
et al. PDGFRA/B 21% (4 SD) 6 months
[43] kinase
Penel et al. Imatinib ABL, ARG, Prospective 400 mg 35 pts 11% (1 CR 3 PR) 80% at
[44] PDGFRA/B 80% SD 6 months
kinase
Kasper Imatinib ABL, ARG, Prospective 800 mg 37 pts 18% 65% at
et al. PDGFRA/B 6 months
[45] kinase
Gounder Sorafenib PDGFR, RAF, Retrospective 400 mg 26 pts 25% RP –
et al. RET, VEGFR 70% SD
[46] 1, 2, 3
Munhoz Sorafenib PDGFR, RAF, Retrospective 400 mg 79 pts 17.7% RP Median:
et al. RET, VEGFR 49% SD 48.2 months
[47] 1, 2, 3
Jo et al. Sunitinib FLT3 KIT, Prospective 37.5 mg 19 pts 26.3% (5) PR 74.1% at
[49] PDGFR, 42.1% (8 SD) 24 months
VEGFR-2
N population, CR complete response, PR partial response, SD stable disease, PFS progression-free survival, pts patients, VEGF vascular endothelial
growth factor, PDGFR platelet-derived growth factor, RET rearranged during transfection

on the GISG-01 phase II trial, which included 38 patients diagnosed with

advanced DF with documented previous RECIST progression who were treated
with imatinib, 800 mg/day. The response rate was 3% (1 PR), with 62% SD;
97% of patients showed tumor arrest at 6 months (primary end point). A
statistically significant correlation was showed, finding a higher progression
arrest at 6 months in patients who had the presence of the S45F mutation on
CTNNB1 versus wild-type (85 versus 43%) [45].
Sorafenib is another multitargeted inhibitor of PDGFR, RAF, RET, and
vascular endothelial growth factor receptors (VEGFRs) 1, 2, 3. A retrospec-
tive study of 26 patients reported symptomatic control in up to 70% of
cases, with a 25% response rate and 70% SD at 6 months [46]. A larger
cohort of 62 patients was recently presented with a similar response rate
and a median PFS of 48.2 months [47]. Sorafenib is currently undergoing
a phase III randomized, placebo-controlled study whose results could
potentially modify clinical practice in this type of tumor (https://
clinicaltrials.gov/ct2/show/NCT02066181).
Another multitarget TKI is pazopanib, which inhibits VEGF and
PDGFR. Clinical activity has been reported in some isolated clinical cases
[48]. An ongoing randomized, phase II study led by the French Sarcoma
Research group is testing pazopanib versus vinblastine and methotrexate in
advanced DF (https://clinicaltrials.gov/ct2/show/NCT01876082).
Sunitinib is a TKI that acts targeting FLT3, KIT, PDGFR, and angiogenesis. A
multicenter phase II trial has shown a 26.3% response rate and a 42.1% SD,
with a 2-year PFS of 74.7% [49].
Curr. Treat. Options in Oncol. (2017) 18:29 Page 9 of 12 29

Emerging and potential new treatments

There are several studies suggesting a crosstalk between β-catenin/Wnt and
Notch pathways [50, 51]. After ligand activation of the Notch receptor, the
Notch intracellular domain (NICD) is released, mediated by γ-secretase. The
NICD is translocated to the nucleus and activates transcriptional mediators
[52]. During the past few years, new γ-secretase inhibitors have emerged as
potential treatments [53, 54].
PF-03084014 is an oral reversible γ-secretase inhibitor. In a phase I trial that
involved 64 patients with multiple advanced solid tumors, a partial response
was observed among seven patients who were diagnosed with advanced DF.
The response rate was 71.4% [55]. Recently, a phase II trial with 17 patients
diagnosed with DF was presented. All patients had previously progressed to at
least one line of therapy. The response rate was 30%, with 71% stable disease.
No progression was detected after a median follow of 23 months. Treatment
lasted for more than 1 year in 12 patients and for more than 2years in two
patients. The most relevant toxicity was grade 3 hypophosphatemia in 47% of
patients [56]. Another potentially useful γ-secretase inhibitor is LY900009,
which has only been evaluated in a phase I study [57].

Compliance with ethical standards

Conflict of interest
The authors declare that they have no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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