biology and treatment of aggressive fibromatosis or ... · fibromatosis or desmoid tumor keith m....

Biology and Treatment of Aggressive

Fibromatosis or Desmoid Tumor

Keith M. Skubitz, MD

Abstract

Aggressive fibromatosis, also known as desmoid-type fibromatosis (DTF) or desmoid tumor, is an uncommonlocally invasive tumor. Because of its low incidence and variable behavior, DTF is often first seen byphysicians who are not familiar with it, and recent advances in understanding this disease have led tochanges in treatment approaches. The Wnt (b-catenin) pathway appears to play a key role in DTFpathogenesis, and recent studies of DTF biology suggest a possible model of DTF pathogenesis.Histologically, DTF shows a poorly circumscribed proliferation of myofibroblast-like cells with variablecollagen deposition, similar to the proliferative phase of wound healing, and DTF has been associated withtrauma and pregnancy. Desmoid-type fibromatosis may be a useful model of the tumor stroma incarcinomas as well as other fibrosing diseases such as progressive pulmonary fibrosis. The clinical courseof DTF can vary greatly among patients, complicating the determination of the optimal treatmentapproach. Treatment options include surgery, nonsteroidal anti-inflammatory drugs with or withouthormonal manipulation, chemotherapy, radiation therapy, and other forms of local therapy. Manytreatments have been used, but these are not without toxicities. Because of the variable nature of thedisease and the potential morbidity of treatment, some cases of DTF may do better without treatment;simple observation is often the best initial treatment. This review used a PubMed search from January 1,1980, through October 31, 2016, using the terms fibromatosis and desmoid and discusses DTF diseasecharacteristics, pathophysiology, and treatment options as well as examines several cases illustrating keypoints in the biology and treatment of this heterogeneous disease.

ª 2017 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2017;92(6):947-964

The term fibromatosis encompasses 2general groups of tumors: superficialand deep fibromatoses. The superficial

fibromatoses include palmar fibromatosis orDupuytren contracture, plantar fibromatosis,and penile fibromatosis or Peyronie disease.Deep or aggressive fibromatosis, also knownas desmoid-type fibromatosis (DTF) or des-moid tumor, is a clonal locally invasive tumorthat does not metastasize.1-8 However,although uncommon, DTF may be multifocal.The word desmoid derives from the Greekdesmos meaning “bandlike, bond, orfastening.”9,10 Desmoid-type fibromatosis wasoriginally described by McFarlane in 183211

and termed “desmoid tumor” by Mueller in1838. By 1904, about 400 cases had beenreported.10-13 The term fibromatosis was laterintroduced by Stout.14 This review used aPubMed search from January 1, 1980, throughOctober 31, 2016, using the terms fibromatosisand desmoid.

Histologically, DTF shows a poorlycircumscribed proliferation of myofibroblast-like cells with variable collagen deposition.These myofibroblastic cells are histologicallysimilar to the proliferative phase of woundhealing, and DTF has been associated withtrauma, pregnancy, and oral contraceptiveuse.3 Trauma is a common inciting agent forthe development of DTF,3,15-17 and surgerymay sometimes promote growth of DTF. Thenatural history of DTF is highly variable.This review discusses DTF disease characteris-tics, pathophysiology, and treatment optionsas well as examines several cases illustratingkey points in the biology and treatment ofthis heterogeneous disease.

EPIDEMIOLOGY OF DTF

Desmoid-type fibromatosis most commonlyarises between the ages of 15 and 60 years,with a female predominance of 2- to3-fold.18,19 The incidence of DTF is about 2

From the Department of

Medicine, University of

Minnesota Medical School,

Minneapolis.

REVIEW

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to 4 per million per year in the general popu-lation.20-23 In contrast, the incidence of DTFhas been reported to be about 1000-foldhigher in patients with familial adenomatouspolyposis (FAP), in which the adenomatouspolyposis coli gene (APC) is mutated.24-26

Familial adenomatous polyposiseassociatedDTF is more frequently abdominal, especiallyin the Gardner variant of FAP, which ischaracterized by intestinal polyposis, oste-omas, fibromas, and epidermal inclusion(“sebaceous”) cysts.9,27-29 Desmoid-type fibro-matosis develops in approximately 5% to 30%of patients with FAP, usually in the mesen-tery.20,21,25,30-32 In some studies, FAP-associated DTF represents about 2% of DTFcases9; in 1 Dutch study, nearly 10% ofpatients with DTF have or will developFAP.21,33 With aggressive follow-up ofpatients with FAP and in those receiving pro-phylactic colectomy, DTF has been reported tobe the most common cause of death.32,34,35

Kindreds of familial DTF without the colonicfeatures of FAP have also been reported inwhich mutations occur in a different regionof APC.36,37 Genetic predisposition to DTFin patients with FAP independent of germ

line APC mutation has also been described,suggesting the existence of genes independentof APC that influence DTF formation in FAP.38

Although common in patients with FAP, mostcases occur sporadically in young adults15,18

and are associated with a mutation inb-catenin (CTNNB1).19,39-44 Desmoid-typefibromatosis and a related disease, infantileaggressive fibromatosis, may also differ be-tween children and adults.45,46 Infantile fibro-matosis (so-called diffuse or mesenchymaltype of fibromatosis) is not discussed hereand usually occurs before the age of 2,most commonly in the first few months oflife; it may recur locally, but does notmetastasize.

HISTOLOGY OF DTF

Histologically, DTF appears as a poorly cir-cumscribed proliferation of myofibroblasticcells with variable collagen deposition. Typi-cally, the margins of the tumor are difficultto assess at the time of surgery, and the finalmargins are often positive. Desmoid-typefibromatosis tumors are morphologically het-erogeneous and may exhibit striking morpho-logical intra- and intertumoral heterogeneity(Figure 1, A). In some areas tumors mayresemble fibroblasts of inactive fibrous tissue,whereas other areas resemble the active fibro-blasts of wound healing. This morphologicalheterogeneity covers a spectrum rangingfrom areas in which cells have oval nuclei con-taining pale-staining vesicular euchromatinand small nucleoli to areas in which cellshave elongated nuclei that stain darkly withhematoxylin, reflecting heterochromatin.47,48

Cells with more euchromatin are presumablymore “transcriptionally active,” whereas cellswith more heterochromatin are felt to bemore “transcriptionally inactive.”47 Figure 1,B, shows an area that appears inactive, withsparse cells with narrow, darker-stainingnuclei and few mitoses, in which in generalthere is more collagen deposition, impartinga more pink (collagenous) coloration to theseinactive areas. Typically the areas with more“transcriptionally inactive” cells are often sepa-rated by extensive collagen.48 Figure 1, C,from the same tumor shows an area that ap-pears histologically active, characterized bycells with plump, light-staining oval nuclei,

ARTICLE HIGHLIGHTS

d The clinical course of desmoid-type fibromatosis (DTF), an

uncommon locally invasive tumor, can vary greatly among pa-

tients, complicating the determination of the optimal treatment

approach.

d The Wnt (b-catenin) pathway appears to play a key role in DTF

pathogenesis.

d Treatment options include surgery, nonsteroidal anti-

inflammatory drugs with or without hormonal manipulation,

chemotherapy, radiation therapy, and other forms of local

therapy. Many treatments have been used, but these are not

without toxicities.

d Because of the variable nature of the disease and the potential

morbidity of treatment, some cases of DTF may do better

without treatment; simple observation is often the best initial

treatment.

d Desmoid-type fibromatosis may be a useful model of the tumor

stroma in carcinomas as well as other fibrosing diseases such as

progressive pulmonary fibrosis.

MAYO CLINIC PROCEEDINGS

948 Mayo Clin Proc. n June 2017;92(6):947-964 n http://dx.doi.org/10.1016/j.mayocp.2017.02.012

www.mayoclinicproceedings.org



greater cell density, increased mitotic activity,and less collagen. Digital assessment of chro-matin density and average nuclear size andpathological assessment of tumor activitywere strongly correlated in 1 study,48 andthere was a spatial correlation of proteinexpression of genes overexpressed in DTFand nuclear morphology.48

GENETIC CHANGES IN DTF

The Wnt (b-catenin) pathway appears to playa key role in DTF pathogenesis,2,41-43,49-51

with a mutation in the b-catenin gene inmost sporadic cases,39,41,42,45,49,50,52-56 or amutation in APC, which regulates b-catenindegradation, in cases associated withFAP.2,15,24,25,30,32,36,37,57-59 In 1 study a

FIGURE 1. Hematoxylin and eosin staining of desmoid-type fibromatosis specimens. A, Desmoid-type

fibromatosis samples exhibit striking morphological intra- and intertumoral heterogeneity. B, Some

tumor areas appear inactive, with sparse cells with narrow, darker-staining nuclei and few mitoses. In

general, more collagen deposition is evident in regions in which cells appeared inactive, imparting a more

pink (collagenous) coloration to these inactive areas. C, Other areas appeared histologically active,

characterized by cells with plump, light-staining oval nuclei, greater cell density, increased mitotic activity,

and less collagen.

AGGRESSIVE FIBROMATOSIS OR DESMOID TUMOR


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CTNNB1 mutation was found in 223 of 254sporadic DTF cases (88%),42 with only 3 mu-tations reported: S45P, S45F, and T41A. S45Fand T41A were the most common, with S45Pseen in less than 10% of cases. Several cases ofAPC mutations have also been found in spo-radic cases of DTF.2,43 Clonal chromosomalchanges have been reported in about 45%of cases of deep DTF and approximately10% of superficial fibromatosis cases,60 withseveral recurrent chromosomal changesreported.41-43,60 In a study of 17 FAP-associated DTF and 38 sporadic DTF casesusing comparative genomic hybridizationand multiple ligation-dependent probe ampli-fication, a limited number of genetic changeswas observed in 44% of tumors.43,61 A higherfrequency of copy number abnormalities wasseen in FAP-associated DTF (59%) ascompared with sporadic DTF (37%).61 Theincidence and severity of DTF in FAP is relatedto the site of APC mutation.62

MOLECULAR BIOLOGY OF DTF

Desmoid-type fibromatosis exhibits a mono-clonal proliferation of myofibroblasts, present-ing a true neoplastic process,6-8 and asdescribed above, the Wnt or b-cateninpathway has been strongly implicated inDTF pathogenesis.2,3,41-44,49-51,54,57,63,64 Inaddition, induction of stabilized b-catenin ina transgenic mouse model leads to hyper-plastic cutaneous wounds and the develop-ment of DTF, providing further evidence thatb-catenin plays a role in these fibroprolifera-tive diseases.63 Similarly, mice with germ linemutations in APC have a high incidence ofDTF.65 Abnormal growth factor production(including transforming growth factor [TGF]and platelet-derived growth factor [PDGF])has been associated with hereditary gingivalfibromatosis and plantar fibromatosis66-68

and may play a role in DTF as well. Murinestudies suggest that DTF can originate inmesenchymal stem cells, in some cases derivedfrom pericytes.69,70

b-Catenin, encoded by the CTNNB1 gene,is also mutated or overexpressed in variouscancers71 and has 2 recognized functions. Itis part of the cadherin complex involved incell-cell adhesion, in which it binds the cyto-plasmic domain of cadherin,72 and also, aspart of the Wnt signaling pathway, can

translocate to the nucleus in which it regulatesgene transcription.73,74 b-Catenin is regulatedby a destruction complex (Figure 2) includingAPC, which has multiple b-catenin bindingsites, axin, b-catenin, casein kinase 1 (CK1),glycogen synthase kinase 3b (GSK3), and pro-tein phosphatase 2A. b-Catenin is phosphory-lated in this complex by GSK3 after a“priming” phosphorylation by CK1, whichleads to ubiquitination and subsequent degra-dation in the proteasome.74 Wnt signalingfrom the cell surface leads to disruption ofthe APC/axin/GSK3 complex and thus inhibitsb-catenin phosphorylation by the complex,leading to increased nuclear b-catenin.74

Nuclear b-catenin can act as a transcriptionalactivator when bound to a member ofthe T-cell factor/lymphocyte enhancerfamily, leading to the formation of nuclearb-catenin/T-cell factor/lymphocyte enhancercomplexes, changing the way they bind pro-motor regions of DNA and altering gene tran-scription.73,74 The hedgehog signalingpathway and b-catenin signaling pathwaysregulate each other’s activity, and 1 studyfound that hedgehog signaling is activated inhuman and murine desmoid tumors.75

Four genesda disintegrin and metallopro-teinase gene 12 (ADAM12), fibroblast activa-tion protein 1a (Fap-1a), Wnt 1 induciblesignaling pathway protein-1 (WISP1), andSRY-box 11 (SOX11)dhave been reported tobe overexpressed in DTF compared with 16nonneoplastic tissues,51 and immumohisto-chemistry studies have exhibited proteinexpression of ADAM12, Fap-1a, WISP1, andSOX11 in DTF.48 Fap-1a is a serine proteaselocalized to the cell surface and cytoplasm.Fap-1a has been found in tumor stroma andseveral fibrotic diseases including idiopathicpulmonary fibrosis.76 ADAM12 plays a rolein cell-cell and cell-matrix interactions andregulates integrin signaling77,78; ADAM12expression has also been found in Dupuytrendisease79 and idiopathic pulmonary fibrosis(reviewed in reference 80). ADAM12 identifiesa proinflammatory subset of PDGF receptor-a(PDGFR-a)epositive stromal cells residing inthe perivascular space that can be activatedby acute injury and can differentiate into myo-fibroblasts and act as progenitors for a largefraction of the collagen-producing cells gener-ated in scarring; these cells are progressively






eliminated during normal wound healing.80

WISP1 is a secreted protein that can act as agrowth factor and regulate various cellularfunctions.81 WISP1 has been detected in anumber of tumors, including the desmoplastictumor stroma of carcinomas82 andDTF.48,51,83,84 WISP1 is up-regulated in idio-pathic pulmonary fibrosis and stimulatesextracellular matrix (ECM) deposition by fi-broblasts.85 SOX11 is a nuclear transcriptionfactor that is temporally regulated in develop-ment and not expressed in most adult tissues.SOX11 is deregulated in various tumors86 andoverexpressed in liposarcomas.87 SOX11 ismore highly expressed in mesenchymal stem

cell lines than in fibroblasts and may aidmesenchymal stem cell proliferation andpluripotent potential retention.88

Thus, the available data suggest a possiblemodel of DTF pathogenesis, in which an acti-vating stimulus, such as trauma with associ-ated inflammation and growth factorproduction, in the setting of deregulationof b-catenin, leads to up-regulation ofb-catenin48 (Figure 3, right side). Reactive ox-ygen species produced by neutrophils havebeen shown to have the potential to inducemutations in DNA. In rare cases the incitingevent may stimulate a progenitor cell thatdoes not have baseline b-catenin dysregulation

Wnt

Cadherin

Membrane

Nucleus

β-Catenin

β-Catenin

β-Catenin

β-Catenin P04

Axin

CK1 GSK3β

Proteasome

PP2AAPC

TCF

DNA

FIGURE 2. b-Catenin forms part of the cadherin complex involved in cell-cell adhesion, in which it

binds the cytoplasmic domain of cadherin. As part of the Wnt signaling pathway, b-catenin can also

translocate to the nucleus, in which it regulates gene transcription. b-Catenin is regulated by a

destruction complex including adenomatous polyposis coli gene (APC), axin, b-catenin, casein kinase 1

(CK1), glycogen synthase kinase 3b (GSK3), and protein phosphatase 2A (PP2A). b-Catenin is

phosphorylated by GSK3 and CK1, leading to ubiquitination and subsequent degradation in the

proteasome. Wnt signaling from the cell surface leads to disruption of the APC/axin/GSK3 complex

and thus inhibits b-catenin phosphorylation by the complex, leading to increased nuclear b-catenin.

Nuclear b-catenin can act as a transcriptional activator when bound to a member of the T-cell factor

(TCF)/lymphocyte enhancer (LEF) family, changing the way they bind promotor regions of DNA and

altering gene transcription.






(left-hand-side of the figure). b-Catenin canthen translocate to the nucleus, complexto transcription factors, bind the WISP1promotor, and increase WISP1 production.WISP1 may then bind its receptor and induceb-catenin nuclear translocation,89 resulting ina prosurvival signal, and further stimulateWISP1 production, and production of ECMproteins including collagen, leading to fibrosis.WISP1 binding to the tumor cells can thenfurther stimulate tumor growth. Myofibro-blasts are functionally heterogeneous and canbe generated from multiple cell types.80

WISP1, by binding to its receptor on othercells, may also recruit nonclonal (normal) pro-fibrotic ADAM12-positive cells from a PDGFR-positive precursor pool,80 potentially addingnonclonal normal myofibroblasts to the

tumor. These recruited cells, whether normalor part of the true clonal tumor, are Fap-1 pos-itive and produce a number of ECM proteins,including collagen, leading to fibrosis.Although the role of SOX11 is not clear,studies have reported that SOX11 assistsmesenchymal stem cell proliferation andretention of pluripotent potential.88 In somecases DTF tumors, and their constituent cells,may stabilize or regress, with a decrease inexpression of ADAM12, FAP-1a, WISP1, andSOX11 (Figure 4). In most cases of DTF,different areas of the tumor show either activeor inactive areas,48 indicating that the balanceof these factors leading to progression orregression operate differently in different partsof the tumor. The mechanisms regulatingthese factors are unknown.

Profibrotic ADAM12 +

PDGFR-α + precursor

WISP1 Production

ProliferationECM protein production

β-Catenin dysregulation

Increase in β-Catenin

β-Catenin translocationto the nucleus

Inflammation, growth factors,reactive oxygen species

Trauma

β-Catenin translocation to the nucleusWISP1 productionSOX11 (mesenchymal cell proliferation)ADAM12 (modify signals)FAP-1 (protease)α

FIGURE 3. A possible model of desmoid-type fibromatosis pathogenesis, in which an activating stimulus,

such as trauma with associated inflammation and growth factor production, in the setting of deregulation

of b-catenin, leads to up-regulation of b-catenin. b-Catenin can then translocate to the nucleus, complex

to transcription factors, bind the WISP1 promotor, and increase WISP1 production. WISP1 may then bind

its receptor and induce b-catenin nuclear translocation, resulting in a prosurvival signal, and further

stimulate WISP1 production and production of extracellular matrix (ECM) proteins including collagen,

leading to fibrosis. WISP1 binding to the tumor cells can also further stimulate tumor growth. WISP1,

by binding to its receptor on other cells, may also recruit nonclonal (normal) profibrotic ADAM12-positive

cells from a PDGFR-a-positive precursor pool, potentially adding nonclonal normal myofibroblasts to the

tumor. These recruited cells, whether normal or part of the true clonal tumor, are Fap-1 positive and

produce a number of ECM proteins, leading to fibrosis. In rare cases, an inciting stimulus may activate cells

that lack b-catenin dysregulation (left-hand-side of the figure). The exact role of ADAM12 and Fap-1 are

unknown, but may modify signaling via protease activity. Although the role of SOX11 is also not clear,

studies have reported that SOX11 assists mesenchymal stem cell proliferation and retention of pluripotent

potential.






EVIDENCE FOR CLINICAL TREATMENTS OF

DTF

The natural clinical course of DTF can varygreatly among patients, complicating the deter-mination of the optimal treatment approach.Clinical trials exhibiting the best approach ina particular patient are lacking. Treatment op-tions include surgery, nonsteroidal anti-inflammatory drugs with or without hormonalmanipulation, chemotherapy, radiation ther-apy, and other forms of local therapy. Manytreatments have been used, but these are notwithout toxicities. Because of the variablecourse of the disease and the potentialmorbidity of treatment with the result thatsome cases of DTF may do better without treat-ment, Lewis et al,90 Mitchell et al,91 and Rocket al92 were among the first to suggest that sim-ple observation may often be the best initialapproach, and this recommendation hasbecome more common.93-103 Some studiessuggest that approximately 50% of cases willhave an indolent course93 and that patientswith DTF who have stable disease for morethan 1 year are unlikely to require activetreatment.96,104 The therapeutic approach of

adults with DTF and children with eitherDTF or infantile aggressive fibromatosis mayalso differ.45,46

Abdominal wall desmoids are mostcommonly associated with pregnancy andcould relate to “trauma” of stretching theabdominal wall musculature or possibly hor-monal changes or both.14 However, pregnancyis also associated with changes in circulatinggrowth factors and immune modulators,including vascular endothelial growth factor,TGF-b, and insulin-like growth factor 1; theseall could also be involved.105-108 Spontaneousregression of cases of abdominal wall DTFoccurred in about 30% of patients in 1 seriesof 122 patients not treated with surgery forDTF.96 In another study of 147 patients,97% of whom were young women withabdominal wall DTF, 102 underwent initialobservation; of these, 29 had spontaneousregression and only 16% went to surgery by3 years.95 Although the rate of progression ofDTF diagnosed during pregnancy is high, itsprognosis is generally good,109 and is notnecessarily, a contraindication for furtherpregnancies.110

Trauma, as from surgery, may worsen DTF,and DTF has a high risk of local recurrence aftersurgery ranging from about 25% to 60% at 5years.19,31,59,94,111-120 Inflammation from othertypes of trauma also may augment or stimulaterecurrence; however, DTF does not metastasize.Although a marginal resection is associated witha worse outcome than a complete resection, thenature of the surgical procedure is stronglyinfluenced by tumor location and associatedanatomical and functional consequences.94 Ina retrospective study of a subgroup of patients,the 3-year event-free survival with a nonsurgicalapproach was similar to that after a completeresection.94 A multivariate analysis of 495 pa-tients undergoing gross resection found thatonly age, tumor size, and tumor location sitewere associated with recurrence, with youngerage having a worse prognosis.121 In anothermultivariate analysis of 426 cases of sporadicDTF, 87% of cases were treated surgically, andabout 50% of cases recurred; only age, tumorsize, and tumor site were independent prog-nostic factors of recurrence.102 Tumors of theextremity recurred more frequently and micro-scopic assessment of the surgical margin hadno influence on recurrence.102,121 The high

Stimulus

β-Catenin dysregulation

Proliferation

Regression ProgressionStabilizationDecreased

ADAM12, WISP1,

FAP-1 , SOX11

pro-inflammatory

and/or profibrotic stimuli

α

FIGURE 4. Variable progression of desmoid-

type fibromatosis (DTF). In some cases of

DTF, a stimulus, such as trauma with associated

inflammation, in the setting of b-catenin dysre-

gulation can induce proliferation of clonal

myofibroblasts, forming a DTF tumor. These

tumors may progress, but in some cases DTF

tumors, and their constituent cells, may stabilize

or regress, with a decrease in expression of

ADAM12, FAP-1a, WISP1, and SOX11.






recurrence rate after surgery suggests that aclinical trial of an adjuvant tolerable chemo-therapy or other treatment shortly after surgerymight be worthy of study in some cases.41 Adju-vant chemotherapy after surgery might beparticularly useful after abdominal surgery inpatients at high risk of DTF, such as patientswith Gardner syndrome, although it has notbeen well studied.

In some cases radiation therapy can beuseful97,103,112,122-127; although radiationtherapy has been reported to decrease localrecurrence after marginal surgery in severaluncontrolled studies, other retrospectivestudies have found no benefit.128 The role ofradiation therapy among the varioustreatment options remains controversialbecause of long-term sequelae, includingedema, pain, and second malignantneoplasm.4,19,94,97,103,112,116,121,123,129-131 In1 study of 6 radiation-induced sarcomas inpatients with DTF whose original tumor hada mutation in CTNNB1, 3 had the sameCTNNB1 mutation as the original DTF, and3 had no CTNNB1 mutation, suggesting thatsome cases of DTF were not derived fromthe original DTF tumor clone.132

Cryoablation has also been used in anattempt to decrease the trauma associatedwith more extensive surgery, although itsrole remains to be defined.133

Various medical therapies have been usedfor DTF, ranging from those with lowtoxicity such as nonsteroidal anti-inflammatorydrugs9,18,134-136 or hormonal therapy9,18,31,137-140

to aggressive combination chemotherapy.141-148

Colchicine has also been used,149 and a casereport suggests a possible response to1,2-dihydroxyvitamin D3.

150 Comparative evalua-tion of different therapies is hindered by the factthat most case series are not randomized; the vari-able natural history of DTF further complicates theinterpretation of these studies. In cases thatrespond to drug, the optimal length of treatmentis unknown. Treatment approaches range fromholding treatment at an arbitrary time in the settingof stable disease to prolonged treatment in re-sponders, followed by abrupt cessation of therapyor gradually weaning treatment intervals or dose.

Magnetic resonance imaging (MRI) is thebest imaging technique for diagnosis and moni-toring of DTF.151-154 In some cases MRI mayreveal changes associated with increased

collagen deposition and decreased cellularity,such as a loss of T2 signal, suggesting either aresponse to treatment or a spontaneous decreasein disease activity.155,156 Changes in contrastenhancement may provide similar information.

Expression of estrogen receptor b is oftenpresent and, along with the occasional rela-tionship of DTF activity to pregnancy, pro-vides some rationale for hormonaltherapy.9,31,97,138-140,157-159 It has been re-ported that estrogen treatment can inducethe formation of desmoid tumors that regressafter discontinuing the drug or after addingprogesterone.160 In 1 study of 25 patientswith DTF (8 sporadic and 17 associated withFAP), a regimen of tamoxifen (120 mg/d)and sulindac (300 mg/d) was not highly effec-tive in preventing DTF recurrence after sur-gery, but was still felt to be potentially usefulin other settings, in which stable disease wasthe most common response.9 The optimaldose of tamoxifen for DTF is not well defined,and a range of doses has been used.9 Nonste-roidal anti-inflammatory drugs, typicallyibuprofen or sulindac, have also been usedwith some efficacy.9,18,134-136,158 Desmoid-type fibromatosis also expresses androgen re-ceptors; testosterone can stimulate DTF cellgrowth in vitro and DTF development inmouse models, suggesting androgen blockadeas another potential hormonal approach.161

A combination of methotrexate andvinblastine was one of the first chemotherapyregimens widely used for DTF, with responserates ranging from 30% to 50%.162-165

Because this regimen does have considerabletoxicity, vinorelbine has largely replacedvinblastine in this regimen.166 Methotrexatecombined with vinblastine or vinorelbine ismore difficult to deliver over a prolongedcourse in adults because of toxicity.143,167

Other agents include more aggressive chemo-therapy such as anthracyclines, gemcitabine,and even ifosfamide in rarecases.18,129,130,141,145-147,168,169 Tyrosine ki-nase inhibitors also have activity in someDTF cases, and meaningful responses havebeen described.64,155,156,169-174 In at least 1case the tumor was responsive to sunitinibbut not imatinib at the usual doses,169 suggest-ing that in some cases efficacy may be dueto effects on targets other than KIT (kitproto-oncogene receptor tyrosine kinase).






TABLE. Ongoing Trials for Desmoid-Type Fibromatosis

Intervention Title Phase Location Clinical trial identifier Status

Sirolimus A pilot study evaluating the use of mTor

inhibitor sirolimus in children and young

adults with desmoid-type fibromatosis

Pilot phase 1/II Maine Medical Center NCT01265030 Recruiting

Cryotherapy Evaluation of the cryodestruction of non

abdominopelvic desmoid tumors in patients

progressing despite medical treatment

Phase II University Hospital, Strasbourg NCT02476305 Recruiting

PF-03084014 Phase II trial of the gamma-secretase inhibitor

PF-03084014 in adults with desmoid

tumors/aggressive fibromatosis

Phase II National Cancer Institute NCT01981551 Closed to accrual

Pazopanib Pazopanib efficacy and tolerance in desmoid

tumors

Randomized phase II:

pazopanib vs

methotrexate-vinblastine

Institut Bergonié NCT01876082 Recruiting

Imatinib Imatinib in patients with desmoid tumor and

chondrosarcoma

Phase II Italian Sarcoma Group NCT00928525 Closed to accrual

Sulindac and

tamoxifen

Sulindac and tamoxifen in treating patients

with desmoid tumor

Phase II Children’s Oncology Group NCT00068419 Closed to accrual

Sorafenib Sorafenib tosylate in treating patients with

desmoid tumors or aggressive fibromatosis

Phase II National Cancer Institute NCT02066181 Closed to accrual

Observation till-

progression

Tailored beta-catenin mutational approach in

extra-abdominal sporadic desmoids tumor

patients

Observational Fondazione IRCCS Istituto

Nazionale dei Tumori, Milano

NCT02547831 Recruiting

Imatinib Study to evaluate imatinib in desmoid tumors Phase II Heidelberg University NCT01137916 Closed to accrual

5-Aminolevulinic

acid (5-ALA)

and photodynamic

therapy

Safety and efficacy study using 5-ALA oral

administration as an adjuvant therapy on the

rate of local tumor recurrence in patients

who have desmoid tumors

Phase II adjuvant Tel-Aviv Sourasky Medical Center NCT01898416 Recruiting

Imatinib A trial of imatinib for patients with aggressive

desmoid tumor (aggressive fibromatosis)

Phase II Yonsei University NCT02495519 Closed to accrual

AGGRESSIVEFIB

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Trials of tyrosine kinase inhibitors in DTF areongoing (Table). Pegylated-liposomal doxoru-bicin (PLD) is particularly attractive, given itsefficacy and low toxicity profile and isbecoming widely used.18,129,130,169

Antibodies to WISP1 inhibit fibrosis inmouse models of bleomycin lung toxicity,suggesting this as a potential target for thefuture treatment of select cases of DTF aswell. Similarly, the beneficial response ofDTF to certain chemotherapy approachessuggests that a similar approach could beuseful in severe cases of idiopathic pulmo-nary fibrosis. Altering Notch signaling withg-secretase inhibition is also under study,and an adenosine monophosphateeactivatedprotein kinase activator inhibits peritonealfibrosis (a complication of peritonealdialysis) in a mouse model.175 Preliminarydata suggest activity of a g-secretase inhibi-tor in DTF. Some ongoing trials for DTFare listed in the Table.

In some cases DTF tumors, and their con-stituent cells, may stabilize or regress, with adecrease in expression of biochemical markersof disease activity (Figure 4). The observationthat DTF tumors sometimes stabilize orregress implies that the tumor myofibroblastsretain sensitivity to a regulatory system, likelyan autocrine or more likely paracrine signalingsystem, similar to that of wound healing. ThatDTF tumors may still subsequently becomeactive again after stabilization or regression im-plies that a population of cells remains that re-tains the ability to respond to someproinflammatory and/or profibrotic stimuli,in some cases induced by trauma, associatedinflammation, or other physiological condi-tions, such as pregnancy. The degree to whichrecruited normal myofibroblasts contribute tothe mass of clonal myofibroblasts in an indi-vidual DTF tumor could potentially affect thetumor behavior.

PREDICTING DTF BEHAVIOR

Predicting which treatment is most appro-priate for a particular patient, such as theobservation approach, would be useful. Anomogram using tumor size, location, and pa-tient age has been reported to be useful in pre-dicting recurrence after surgery.121 Somestudies, but not all, have suggested that thelocation of the b-catenin mutation correlates

with differences in clinical course of sporadicDTF. For example, tumors with S45F muta-tions in CTNNB1 may be at a higher risk ofrecurrence.40-42,45,49,53,56,102 One study foundthat DTF tumors with an S45 b-catenin muta-tion had a higher progression arrest rate thandid wild-type tumors when treated with imati-nib,176 and a European position paper encour-aged b-catenin mutation testing in DTF.177

Another study found that higher nuclearb-catenin expression (>20% of tumor cellsexpressing nuclear b-catenin) had a higherrecurrence rate than did lower expression.178

Trisomy 8 has also been associated with ahigher risk of recurrence.179 In 1 study,immunohistochemical staining for ADAM12,Fap-1a, and WISP1 correlated with nuclearchromatin density and was higher in patientswith an early recurrence (<1 year after surgerycompared with no recurrence at 5 years).48

Other studies suggest that gene expressionpatterns may also correlate with biologicalbehavior48,51,180,181 and might be useful inidentifying patients who would more likelybenefit from therapy.

DESMOID-TYPE FIBROMATOSIS AS A

MODEL FOR THE ROLE OF TUMOR

STROMA IN OTHER DISEASES

The tumor stroma in invasive carcinomasfrequently exhibits a desmoplastic responsewith proliferation of myofibroblasts, andtumors have been described as “wounds thatdo not heal.”182,p1650 Fibroblasts and myofi-broblasts in neoplasms can secrete varioustrophic, mitogenic, and proinflammatorygrowth factors including hepatocyte growthfactor, epidermal growth factor, TGF-b, andinsulin-like growth factor 1 (reviewed inreference 183), possibly influencing growthof the clonal neoplastic cells. Because oftheir potential contribution to tumor biology,targeting the normal stromal myofibroblastsin tumors is an interesting potential approachto cancer treatment.184 As DTF closely resem-bles wound healing, it may be a potentiallyuseful model to study the role of tumorstroma. Indeed, some studies suggest thatgene signatures similar to that seen in DTFcorrelate with clinical outcome in somemalignancies.84,185-188 Desmoid-type fibro-matosis may also provide a model for






other fibrosing diseases such as progressivepulmonary fibrosis.

DESMOID-TYPE FIBROMATOSIS CASE

EXAMPLES

As described above, DTF can have a differentcourse in different patients. Thirteen cases ofDTF are summarized here (10 in SupplementalMaterials, Supplemental Figure 2, availableonline at http://www.mayoclinicproceedings.org) to illustrate important principles of DTFbiology and treatment.

Case 1: Slow Spontaneous Regression of an

Extra-Abdominal DTF in a Man

A28-year-oldmannoted a smallmass inhis rightchest near the sternum. He developed psoriaticarthritis 8 months later and began treatmentwith methotrexate. A year after initiating metho-trexate, etanercept was added. At presentation 8months after starting etanercept, he was not surethe mass had grown over the part year, but henow had occasional twinges of pain lasting afew seconds, from none to several times a day.Thus, the tumor progressed symptomaticallywhile on methotrexate. Examination revealed afirm, fixed, nontender parasternal mass.Computed tomography revealed a massinvolving the sternumgrowing through the chestwall (Figure 5, top panel) and a biopsy revealedDTF. Consultation at another institution recom-mended surgical removal of the chest wall mass;however, he was observed, and 3 months laterhis symptoms and imaging of the mass were un-changed. Ten months after the biopsy, the masswas slightly smaller and symptoms were un-changed. At 35 months after the biopsy, hissymptoms had resolved and the mass wassmaller (Figure 5, bottom panel). He remainssymptom free 50 months after the biopsy andcontinues the observation. This case exhibitsslow spontaneous regression of an extra-abdominalDTF in aman, not related to estrogen.

Case 2: DTF Caused by Local Trauma/

Inflammation and Stable Disease After

Methotrexate and Vinblastine

A 33-year-old man presented with a painfulmass in the arm. He had an influenza shot1.5 years before presentation, and shortlythereafter he became aware of a persistentdiscomfort in the region of the injection sitethat gradually progressed, and a painful mass

developed. The size of the mass and degreeof pain progressed markedly over the 2months before presentation. Examinationrevealed a slightly tender warm 10 cm hardmass fixed to the underlying tissue in theproximal right arm. Magnetic resonance imag-ing revealed a 7�5�8.5 cm mass along the tri-ceps muscle that was hyperintense on a fluid-sensitive image with some areas of heterogene-ity (Supplemental Figure 1, available online athttp://www.mayoclinicproceedings.org). Atru-cut biopsy revealed DTF, and an openbiopsy performed to exclude a low-grade sar-coma also revealed DTF. Surgical treatmentwas felt to require shoulder disarticulation. Assurgical treatment was felt to result in signifi-cant morbidity, chemotherapy with metho-trexate and vinblastine was begun. At 6 weeksof treatment, there was no clear evidence ofchange in tumor size or symptoms, and hemoved to a different state in which chemo-therapy was continued for 2 more monthswithout change in tumor size. The tumor wasthen surgically excised. He was sent for consid-eration of postoperative radiation therapy andthereafter lost to follow-up. This case exhibitsDTF development after local trauma/inflamma-tion, potential significant morbidity of treat-ment (shoulder disarticulation or more limiteddisfiguring surgery), and disease stabilizationwith methotrexate and vinblastine.

Case 3: Aggressive Multifocal DTF

Controlled With PLD

A 32-year-old man with Gardner syndromepresented with painful extra-abdominal des-moid tumors as well as large intra-abdominaldesmoids requiring opiates. He also had a pul-monary embolus and venous thrombosis andwas taking coumadin. He had been treated ayear earlier with tamoxifen for 8 weeks, buttumors grew during this period. He begantreatment with PLD and had a good response.Treatment was held after 6 cycles. Desmoid-type fibromatosis progression was noted 10months after the last chemotherapy, and hereceived imatinib 400 mg/d orally, but it pro-gressed. He began treatment with PLD andnoted stabilization of pain after 1 month andsome tumor shrinkage at 3 months. Threemonths later, imaging revealed further tumorregression, and the interval between PLDtreatments was increased. Subsequent imaging









revealed continued gradual tumor shrinkageand then stabilization, and PLD was discontin-ued after 1.5 years of treatment. Imagingfound stable disease at 3 years after reinitiatingPLD, but 4 months later (40 months after firstinitiating chemotherapy) he developedincreasing pain and progression of DTF on im-aging, and PLD was reinitiated. One monthlater he developed small bowel obstruction,bacteremia, and renal failure and had adecompressive gastrostomy tube placed. Hissubsequent course was complicated, and heeventually entered a hospice program anddied 5.3 years after initial chemotherapy.This case exhibits aggressive multifocal DTF,long-term control with PLD, and severeDTF-associated morbidity.

FUTURE STUDIES

Controlled trials are needed to better defineoptimal treatment approaches. Future clinicaltrials must consider several aspects of DTFbiology. First, because of the highly variableclinical course of DTF, patients must be care-fully stratified at entry. Factors to considerinclude rate of tumor growth (tumor growthrate should be quantitated before treatment).Other stratification variables should includeage at diagnosis, tumor location (mesenteric,abdominal wall, central extra-abdominal, andextremity), b-catenin mutation and APC muta-tion status, relation to pregnancy, symptoms,and tumor size. Samples should be obtainedfor future, more detailed genetic analysis;consideration should be given to obtainingcore biopsies from different parts of the tumor,if possible, given the known intratumoral vari-ability. Watchful waiting should be the firsttreatment, if possible, and when treatment isinitiated, randomization to 2 treatments isneeded. The “standard” treatment can bedebated, but given its efficacy, tolerability,and increasing popularity, PLD would be oneconsideration. Finally, a decision on howlong to treat a responding tumor and how toquantify tumor response must be considered.RECIST (Response Evaluation Criteria In SolidTumors) is known to be a poor measure ofresponse in DTF, but some measure of size(optimally careful analysis of tumor volume)and tumor “activity” (possibly determined by

FIGURE 5. Slow spontaneous regression of an extra-abdominal desmoid-

type fibromatosis (DTF) in a man. A 28-year-old man developed a firm,

fixed, nontender parasternal mass. Computed tomography revealed a mass

involving the sternum growing through the chest wall (top panel), and a

biopsy revealed DTF. He was observed, and 10 months after the biopsy the

mass was slightly smaller. At 35 months after the biopsy, his symptoms had

resolved and the mass was smaller.






contrast enhancement or changes in T1/T2signal on MRI) need to be considered. Becausetumor stabilization can be a beneficialoutcome, a measure of symptoms experiencedby the patient should be included as well,including a quality of life assessment such asQLQ-C30 or FACTG. Perhaps better thannonlinear subjective variables such as a “painscale” are clear measures such as the following:is a pain medication required, how much painmedication is used, does the tumor interferewith sleep (yes/no), how far can the patientwalk before tumor pain limits the activity(this could be objectively determined at eachclinic visit for cases with serious symptoms),and what is the range of motion of the affectedbody part. Only with carefully controlled trialsthat use careful stratification based on knownvariables can the best treatment approaches forDTF be determined.

SUMMARY

Because of the heterogeneity of the biologicalbehavior of DTF, the optimal approach totreatment is unclear. Historically, surgery wasthe mainstay of treatment, but recurrence aftersurgery is common.9,31,59,111,113,115 In addi-tion, trauma can stimulate DTF growth, andsurgery is a form of trauma associated withinflammation and production of variousgrowth factors important in wound healingthat may also stimulate clonal DTF cells; thisis especially true in the case of FAP-associated mesenteric DTF.3,9,31,58,119,189

Although surgery remains an option for theinitial treatment in which the expectedmorbidity is low and the chance of completeremoval is high, given the usually slow pro-gression of DTF, a regimen with low toxicityis the preferred initial approach and observa-tion has become more standard.91,93-102 Ofcourse, the appropriate clinical decision de-pends on the particular case, and some requireaggressive chemotherapy initially.

CONCLUSION

Desmoid-type fibromatosis is an uncommonlocally invasive tumor. Because of the variablenature of the disease and the potentialmorbidity of treatment, some cases of DTFmay do better without treatment; simpleobservation is often the best initial treatment.

ACKNOWLEDGMENTS

We thank Shelly Marette, MD, for assistance ininterpreting magnetic resonance images,Michael Franklin, MS, for editorial assistance,and J. Carlos Manivel, MD, for a critical reviewof the manuscript.

SUPPLEMENTAL ONLINE MATERIAL

Supplemental material can be foundonline at: http://www.mayoclinicproceedings.org. Supplemental material attached to journalarticles has not been edited, and the authorstake responsibility for the accuracy of all data.

Abbreviations and Acronyms: APC = adenomatous

polyposis coli gene; CK1 = casein kinase 1; DTF = desmoid-

type fibromatosis; ECM = extracellular matrix; FAP = familial

adenomatous polyposis; Fap-1a = fibroblast activation

protein 1a; GSK3 = glycogen synthase kinase 3; MRI =

magnetic resonance imaging; PDGF = platelet-derived

growth factor; PDGFR-a = platelet-derived growth factor

receptor-a; PLD = pegylated-liposomal doxorubicin; TGF =

transforming growth factor

Correspondence: Address to Keith M. Skubitz, MD,

Department of Medicine, University of Minnesota Medical

School, Box 286 University Hospital, Minneapolis, MN

55455 ([email protected]).

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