REVIEW

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 uncommon locally invasive tumor. Because of its low incidence and variable behavior, DTF is often first seen by physicians who are not familiar with it, and recent advances in understanding this disease have led to changes in treatment approaches. The Wnt (b-catenin) pathway appears to play a key role in DTF pathogenesis, 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 variable collagen deposition, similar to the proliferative phase of wound healing, and DTF has been associated with trauma and pregnancy. 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. The clinical course of DTF can vary greatly among patients, complicating the determination of the optimal treatment approach. 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. 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. This review used a PubMed search from January 1, 1980, through October 31, 2016, using the terms fibromatosis and desmoid and discusses DTF disease characteristics, pathophysiology, and treatment options as well as examines several cases illustrating key points 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

he term fibromatosis encompasses 2 Histologically, DTF shows a poorly general groups of tumors: superficial circumscribed proliferation of myofibroblast- and deep fibromatoses. The superficial like cells with variable collagen deposition. From the Department of T Medicine, University of fibromatoses include palmar fibromatosis or These myofibroblastic cells are histologically Minnesota Medical School, Dupuytren contracture, plantar fibromatosis, similar to the proliferative phase of wound Minneapolis. and penile fibromatosis or Peyronie disease. healing, and DTF has been associated with Deep or aggressive fibromatosis, also known trauma, pregnancy, and oral contraceptive as desmoid-type fibromatosis (DTF) or des- use.3 Trauma is a common inciting agent for moid tumor, is a clonal locally invasive tumor the development of DTF,3,15-17 and surgery that does not metastasize.1-8 However, may sometimes promote growth of DTF. The although uncommon, DTF may be multifocal. natural history of DTF is highly variable. The word desmoid derives from the Greek This review discusses DTF disease characteris- desmos meaning “bandlike, bond, or tics, pathophysiology, and treatment options fastening.”9,10 Desmoid-type fibromatosis was as well as examines several cases illustrating originally described by McFarlane in 183211 key points in the biology and treatment of and termed “desmoid tumor” by Mueller in this heterogeneous disease. 1838. By 1904, about 400 cases had been reported.10-13 The term fibromatosis was later EPIDEMIOLOGY OF DTF introduced by Stout.14 This review used a Desmoid-type fibromatosis most commonly PubMed search from January 1, 1980, through arises between the ages of 15 and 60 years, October 31, 2016, using the terms fibromatosis with a female predominance of 2- to and desmoid. 3-fold.18,19 The incidence of DTF is about 2

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line APC mutation has also been described, ARTICLE HIGHLIGHTS suggesting the existence of genes independent of APC that influence DTF formation in FAP.38 d The clinical course of desmoid-type fibromatosis (DTF), an Although common in patients with FAP, most uncommon locally invasive tumor, can vary greatly among pa- cases occur sporadically in young adults15,18 tients, complicating the determination of the optimal treatment and are associated with a mutation in approach. b-catenin (CTNNB1).19,39-44 Desmoid-type fi d The Wnt (b-catenin) pathway appears to play a key role in DTF bromatosis and a related disease, infantile fi pathogenesis. aggressive bromatosis, may also differ be- tween children and adults.45,46 Infantile fibro- d Treatment options include surgery, nonsteroidal anti- matosis (so-called diffuse or mesenchymal inflammatory drugs with or without hormonal manipulation, type of fibromatosis) is not discussed here chemotherapy, radiation therapy, and other forms of local and usually occurs before the age of 2, therapy. Many treatments have been used, but these are not most commonly in the first few months of without toxicities. life; it may recur locally, but does not metastasize. 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 HISTOLOGY OF DTF treatment. Histologically, DTF appears as a poorly cir- cumscribed proliferation of myofibroblastic d Desmoid-type fibromatosis may be a useful model of the tumor cells with variable collagen deposition. Typi- fi stroma in carcinomas as well as other brosing diseases such as cally, the margins of the tumor are difficult progressive pulmonary fibrosis. to assess at the time of surgery, and the final margins are often positive. Desmoid-type fibromatosis tumors are morphologically het- to 4 per million per year in the general popu- erogeneous and may exhibit striking morpho- lation.20-23 In contrast, the incidence of DTF logical intra- and intertumoral heterogeneity has been reported to be about 1000-fold (Figure 1, A). In some areas tumors may higher in patients with familial adenomatous resemble fibroblasts of inactive fibrous tissue, polyposis (FAP), in which the adenomatous whereas other areas resemble the active fibro- polyposis coli gene (APC) is mutated.24-26 blasts of wound healing. This morphological Familial adenomatous polyposiseassociated heterogeneity covers a spectrum ranging DTF is more frequently abdominal, especially from areas in which cells have oval nuclei con- in the Gardner variant of FAP, which is taining pale-staining vesicular euchromatin characterized by intestinal polyposis, oste- and small nucleoli to areas in which cells omas, fibromas, and epidermal inclusion have elongated nuclei that stain darkly with (“sebaceous”) cysts.9,27-29 Desmoid-type fibro- hematoxylin, reflecting heterochromatin.47,48 matosis develops in approximately 5% to 30% Cells with more euchromatin are presumably of patients with FAP, usually in the mesen- more “transcriptionally active,” whereas cells tery.20,21,25,30-32 In some studies, FAP- with more heterochromatin are felt to be associated DTF represents about 2% of DTF more “transcriptionally inactive.”47 Figure 1, cases9; in 1 Dutch study, nearly 10% of B, shows an area that appears inactive, with patients with DTF have or will develop sparse cells with narrow, darker-staining FAP.21,33 With aggressive follow-up of nuclei and few mitoses, in which in general patients with FAP and in those receiving pro- there is more collagen deposition, imparting phylactic colectomy, DTF has been reported to a more pink (collagenous) coloration to these be the most common cause of death.32,34,35 inactive areas. Typically the areas with more Kindreds of familial DTF without the colonic “transcriptionally inactive” cells are often sepa- features of FAP have also been reported in rated by extensive collagen.48 Figure 1,C, which mutations occur in a different region from the same tumor shows an area that ap- of APC.36,37 Genetic predisposition to DTF pears histologically active, characterized by in patients with FAP independent of germ cells with plump, light-staining oval nuclei,

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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.

greater cell density, increased mitotic activity, GENETIC CHANGES IN DTF and less collagen. Digital assessment of chro- The Wnt (b-catenin) pathway appears to play matin density and average nuclear size and a key role in DTF pathogenesis,2,41-43,49-51 pathological assessment of tumor activity with a mutation in the b-catenin gene in were strongly correlated in 1 study,48 and most sporadic cases,39,41,42,45,49,50,52-56 or a there was a spatial correlation of protein mutation in APC, which regulates b-catenin expression of genes overexpressed in DTF degradation, in cases associated with and nuclear morphology.48 FAP.2,15,24,25,30,32,36,37,57-59 In 1 study a

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CTNNB1 mutation was found in 223 of 254 translocate to the nucleus in which it regulates sporadic DTF cases (88%),42 with only 3 mu- gene transcription.73,74 b-Catenin is regulated tations reported: S45P, S45F, and T41A. S45F by a destruction complex (Figure 2) including and T41A were the most common, with S45P APC, which has multiple b-catenin binding seen in less than 10% of cases. Several cases of sites, axin, b-catenin, casein kinase 1 (CK1), APC mutations have also been found in spo- glycogen synthase kinase 3b (GSK3), and pro- radic cases of DTF.2,43 Clonal chromosomal tein phosphatase 2A. b-Catenin is phosphory- changes have been reported in about 45% lated in this complex by GSK3 after a of cases of deep DTF and approximately “priming” phosphorylation by CK1, which 10% of superficial fibromatosis cases,60 with leads to ubiquitination and subsequent degra- several recurrent chromosomal changes dation in the proteasome.74 Wnt signaling reported.41-43,60 In a study of 17 FAP- from the cell surface leads to disruption of associated DTF and 38 sporadic DTF cases the APC/axin/GSK3 complex and thus inhibits using comparative genomic hybridization b-catenin phosphorylation by the complex, and multiple ligation-dependent probe ampli- leading to increased nuclear b-catenin.74 fication, a limited number of genetic changes Nuclear b-catenin can act as a transcriptional was observed in 44% of tumors.43,61 A higher activator when bound to a member of frequency of copy number abnormalities was the T-cell factor/lymphocyte enhancer seen in FAP-associated DTF (59%) as family, leading to the formation of nuclear compared with sporadic DTF (37%).61 The b-catenin/T-cell factor/lymphocyte enhancer incidence and severity of DTF in FAP is related complexes, changing the way they bind pro- to the site of APC mutation.62 motor regions of DNA and altering gene tran- scription.73,74 The hedgehog signaling MOLECULAR BIOLOGY OF DTF pathway and b-catenin signaling pathways Desmoid-type fibromatosis exhibits a mono- regulate each other’s activity, and 1 study clonal proliferation of myofibroblasts, present- found that hedgehog signaling is activated in ing a true neoplastic process,6-8 and as human and murine desmoid tumors.75 described above, the Wnt or b-catenin Four genesda disintegrin and metallopro- pathway has been strongly implicated in teinase gene 12 (ADAM12), fibroblast activa- DTF pathogenesis.2,3,41-44,49-51,54,57,63,64 In tion protein 1a (Fap-1a), Wnt 1 inducible addition, induction of stabilized b-catenin in signaling pathway protein-1 (WISP1), and a transgenic mouse model leads to hyper- SRY-box 11 (SOX11)dhave been reported to plastic cutaneous wounds and the develop- be overexpressed in DTF compared with 16 ment of DTF, providing further evidence that nonneoplastic tissues,51 and immumohisto- b-catenin plays a role in these fibroprolifera- chemistry studies have exhibited protein tive diseases.63 Similarly, mice with germ line expression of ADAM12, Fap-1a, WISP1, and mutations in APC have a high incidence of SOX11 in DTF.48 Fap-1a is a serine protease DTF.65 Abnormal growth factor production localized to the cell surface and cytoplasm. (including transforming growth factor [TGF] Fap-1a has been found in tumor stroma and and platelet-derived growth factor [PDGF]) several fibrotic diseases including idiopathic has been associated with hereditary gingival pulmonary fibrosis.76 ADAM12 plays a role fibromatosis and plantar fibromatosis66-68 in cell-cell and cell-matrix interactions and and may play a role in DTF as well. Murine regulates integrin signaling77,78; ADAM12 studies suggest that DTF can originate in expression has also been found in Dupuytren mesenchymal stem cells, in some cases derived disease79 and idiopathic pulmonary fibrosis from pericytes.69,70 (reviewed in reference 80). ADAM12 identifies b-Catenin, encoded by the CTNNB1 gene, a proinflammatory subset of PDGF receptor-a is also mutated or overexpressed in various (PDGFR-a)epositive stromal cells residing in cancers71 and has 2 recognized functions. It the perivascular space that can be activated is part of the cadherin complex involved in by acute injury and can differentiate into myo- cell-cell adhesion, in which it binds the cyto- fibroblasts and act as progenitors for a large plasmic domain of cadherin,72 and also, as fraction of the collagen-producing cells gener- part of the Wnt signaling pathway, can ated in scarring; these cells are progressively

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Cadherin Wnt

Membrane

Nucleus

β-Catenin

β-Catenin

TCF β-Catenin DNA

APC Axin PP2A

CK1 GSK3β

β-Catenin P04

Proteasome

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.

eliminated during normal wound healing.80 cell lines than in fibroblasts and may aid WISP1 is a secreted protein that can act as a mesenchymal stem cell proliferation and growth factor and regulate various cellular pluripotent potential retention.88 functions.81 WISP1 has been detected in a Thus, the available data suggest a possible number of tumors, including the desmoplastic model of DTF pathogenesis, in which an acti- tumor stroma of carcinomas82 and vating stimulus, such as trauma with associ- DTF.48,51,83,84 WISP1 is up-regulated in idio- ated inflammation and growth factor pathic pulmonary fibrosis and stimulates production, in the setting of deregulation extracellular matrix (ECM) deposition by fi- of b-catenin, leads to up-regulation of broblasts.85 SOX11 is a nuclear transcription b-catenin48 (Figure 3, right side). Reactive ox- factor that is temporally regulated in develop- ygen species produced by neutrophils have ment and not expressed in most adult tissues. been shown to have the potential to induce SOX11 is deregulated in various tumors86 and mutations in DNA. In rare cases the inciting overexpressed in liposarcomas.87 SOX11 is event may stimulate a progenitor cell that more highly expressed in mesenchymal stem does not have baseline b-catenin dysregulation

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Trauma Inflammation, growth factors, reactive oxygen species β-Catenin dysregulation

Profibrotic ADAM12 + Increase in β-Catenin PDGFR-α + precursor WISP1 Production β-Catenin translocation to the nucleus

β-Catenin translocation to the nucleus WISP1 production SOX11 (mesenchymal cell proliferation) ADAM12 (modify signals) FAP-1α (protease)

Proliferation ECM protein production

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.

(left-hand-side of the figure). b-Catenin can tumor. These recruited cells, whether normal then translocate to the nucleus, complex or part of the true clonal tumor, are Fap-1 pos- to transcription factors, bind the WISP1 itive and produce a number of ECM proteins, promotor, and increase WISP1 production. including collagen, leading to fibrosis. WISP1 may then bind its receptor and induce Although the role of SOX11 is not clear, b-catenin nuclear translocation,89 resulting in studies have reported that SOX11 assists a prosurvival signal, and further stimulate mesenchymal stem cell proliferation and WISP1 production, and production of ECM retention of pluripotent potential.88 In some proteins including collagen, leading to fibrosis. cases DTF tumors, and their constituent cells, WISP1 binding to the tumor cells can then may stabilize or regress, with a decrease in further stimulate tumor growth. Myofibro- expression of ADAM12, FAP-1a, WISP1, and blasts are functionally heterogeneous and can SOX11 (Figure 4). In most cases of DTF, be generated from multiple cell types.80 different areas of the tumor show either active WISP1, by binding to its receptor on other or inactive areas,48 indicating that the balance cells, may also recruit nonclonal (normal) pro- of these factors leading to progression or fibrotic ADAM12-positive cells from a PDGFR- regression operate differently in different parts positive precursor pool,80 potentially adding of the tumor. The mechanisms regulating nonclonal normal myofibroblasts to the these factors are unknown.

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adults with DTF and children with either Stimulus DTF or infantile aggressive fibromatosis may also differ.45,46 β-Catenin dysregulation Abdominal wall desmoids are most commonly associated with pregnancy and Proliferation could relate to “trauma” of stretching the abdominal wall musculature or possibly hor- monal changes or both.14 However, pregnancy Stabilization is also associated with changes in circulating RegressionDecreased Progression ADAM12, WISP1, growth factors and immune modulators, FAP-1α , SOX11 including vascular endothelial growth factor, TGF-b, and insulin-like growth factor 1; these 105-108 pro-inflammatory all could also be involved. Spontaneous and/or profibrotic stimuli regression of cases of abdominal wall DTF occurred in about 30% of patients in 1 series FIGURE 4. Variable progression of desmoid- of 122 patients not treated with surgery for type fibromatosis (DTF). In some cases of DTF.96 In another study of 147 patients, DTF, a stimulus, such as trauma with associated 97% of whom were young women with fl b in ammation, in the setting of -catenin dysre- abdominal wall DTF, 102 underwent initial gulation can induce proliferation of clonal observation; of these, 29 had spontaneous myofibroblasts, forming a DTF tumor. These regression and only 16% went to surgery by tumors may progress, but in some cases DTF 95 tumors, and their constituent cells, may stabilize 3 years. Although the rate of progression of or regress, with a decrease in expression of DTF diagnosed during pregnancy is high, its 109 ADAM12, FAP-1a, WISP1, and SOX11. prognosis is generally good, and is not necessarily, a contraindication for further pregnancies.110 Trauma, as from surgery, may worsen DTF, EVIDENCE FOR CLINICAL TREATMENTS OF and DTF has a high risk of local recurrence after DTF surgery ranging from about 25% to 60% at 5 The natural clinical course of DTF can vary years.19,31,59,94,111-120 Inflammation from other greatly among patients, complicating the deter- types of trauma also may augment or stimulate mination of the optimal treatment approach. recurrence; however, DTF does not metastasize. Clinical trials exhibiting the best approach in Although a marginal resection is associated with a particular patient are lacking. Treatment op- a worse outcome than a complete resection, the tions include surgery, nonsteroidal anti- nature of the surgical procedure is strongly inflammatory drugs with or without hormonal influenced by tumor location and associated manipulation, chemotherapy, radiation ther- anatomical and functional consequences.94 In apy, and other forms of local therapy. Many a retrospective study of a subgroup of patients, treatments have been used, but these are not the 3-year event-free survival with a nonsurgical without toxicities. Because of the variable approach was similar to that after a complete course of the disease and the potential resection.94 A multivariate analysis of 495 pa- morbidity of treatment with the result that tients undergoing gross resection found that some cases of DTF may do better without treat- only age, tumor size, and tumor location site ment, Lewis et al,90 Mitchell et al,91 and Rock were associated with recurrence, with younger et al92 were among the first to suggest that sim- age having a worse prognosis.121 In another ple observation may often be the best initial multivariate analysis of 426 cases of sporadic approach, and this recommendation has DTF, 87% of cases were treated surgically, and become more common.93-103 Some studies about 50% of cases recurred; only age, tumor suggest that approximately 50% of cases will size, and tumor site were independent prog- have an indolent course93 and that patients nostic factors of recurrence.102 Tumors of the with DTF who have stable disease for more extremity recurred more frequently and micro- than 1 year are unlikely to require active scopic assessment of the surgical margin had treatment.96,104 The therapeutic approach of no influence on recurrence.102,121 The high

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recurrence rate after surgery suggests that a collagen deposition and decreased cellularity, clinical trial of an adjuvant tolerable chemo- such as a loss of T2 signal, suggesting either a therapy or other treatment shortly after surgery response to treatment or a spontaneous decrease might be worthy of study in some cases.41 Adju- in disease activity.155,156 Changes in contrast vant chemotherapy after surgery might be enhancement may provide similar information. particularly useful after abdominal surgery in Expression of estrogen receptor b is often patients at high risk of DTF, such as patients present and, along with the occasional rela- with Gardner syndrome, although it has not tionship of DTF activity to pregnancy, pro- been well studied. vides some rationale for hormonal In some cases radiation therapy can be therapy.9,31,97,138-140,157-159 It has been re- useful97,103,112,122-127; although radiation ported that estrogen treatment can induce therapy has been reported to decrease local the formation of desmoid tumors that regress recurrence after marginal surgery in several after discontinuing the drug or after adding uncontrolled studies, other retrospective progesterone.160 In 1 study of 25 patients studies have found no benefit.128 The role of with DTF (8 sporadic and 17 associated with radiation therapy among the various FAP), a regimen of tamoxifen (120 mg/d) treatment options remains controversial and sulindac (300 mg/d) was not highly effec- because of long-term sequelae, including tive in preventing DTF recurrence after sur- edema, pain, and second malignant gery, but was still felt to be potentially useful neoplasm.4,19,94,97,103,112,116,121,123,129-131 In in other settings, in which stable disease was 1 study of 6 radiation-induced sarcomas in the most common response.9 The optimal patients with DTF whose original tumor had dose of tamoxifen for DTF is not well defined, a mutation in CTNNB1, 3 had the same and a range of doses has been used.9 Nonste- CTNNB1 mutation as the original DTF, and roidal anti-inflammatory drugs, typically 3 had no CTNNB1 mutation, suggesting that ibuprofen or sulindac, have also been used some cases of DTF were not derived from with some efficacy.9,18,134-136,158 Desmoid- the original DTF tumor clone.132 type fibromatosis also expresses androgen re- Cryoablation has also been used in an ceptors; testosterone can stimulate DTF cell attempt to decrease the trauma associated growth in vitro and DTF development in with more extensive surgery, although its mouse models, suggesting androgen blockade role remains to be defined.133 as another potential hormonal approach.161 Various medical therapies have been used A combination of methotrexate and for DTF, ranging from those with low vinblastine was one of the first chemotherapy toxicity such as nonsteroidal anti-inflammatory regimens widely used for DTF, with response drugs9,18,134-136 or hormonal therapy9,18,31,137-140 rates ranging from 30% to 50%.162-165 to aggressive combination chemotherapy.141-148 Because this regimen does have considerable Colchicine has also been used,149 and a case toxicity, vinorelbine has largely replaced report suggests a possible response to vinblastine in this regimen.166 Methotrexate 150 1,2-dihydroxyvitamin D3. Comparative evalua- combined with vinblastine or vinorelbine is tion of different therapies is hindered by the fact more difficult to deliver over a prolonged that most case series are not randomized; the vari- course in adults because of toxicity.143,167 able natural history of DTF further complicates the Other agents include more aggressive chemo- interpretation of these studies. In cases that therapy such as anthracyclines, gemcitabine, respond to drug, the optimal length of treatment and even ifosfamide in rare is unknown. Treatment approaches range from cases.18,129,130,141,145-147,168,169 Tyrosine ki- holding treatment at an arbitrary time in the setting nase inhibitors also have activity in some of stable disease to prolonged treatment in re- DTF cases, and meaningful responses have sponders, followed by abrupt cessation of therapy been described.64,155,156,169-174 In at least 1 or gradually weaning treatment intervals or dose. case the tumor was responsive to sunitinib Magnetic resonance imaging (MRI) is the but not imatinib at the usual doses,169 suggest- best imaging technique for diagnosis and moni- ing that in some cases efficacy may be due toring of DTF.151-154 In some cases MRI may to effects on targets other than KIT (kit reveal changes associated with increased proto-oncogene receptor tyrosine kinase).

954 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 www.mayoclinicproceedings.org aoCi Proc. Clin Mayo TUMOR DESMOID OR FIBROMATOSIS AGGRESSIVE n ue2017;92(6):947-964 June

TABLE. Ongoing Trials for Desmoid-Type Fibromatosis Intervention Title Phase Location Clinical trial identifier Status Sirolimus A pilot study evaluating the use of mTor Pilot phase 1/II Maine Medical Center NCT01265030 Recruiting inhibitor sirolimus in children and young fi n adults with desmoid-type bromatosis

http://dx.doi.org/10.1016/j.mayocp.2017.02.012 Cryotherapy Evaluation of the cryodestruction of non Phase II University Hospital, Strasbourg NCT02476305 Recruiting abdominopelvic desmoid tumors in patients progressing despite medical treatment PF-03084014 Phase II trial of the gamma-secretase inhibitor Phase II National Cancer Institute NCT01981551 Closed to accrual PF-03084014 in adults with desmoid tumors/aggressive fibromatosis Pazopanib Pazopanib efficacy and tolerance in desmoid Randomized phase II: Institut Bergonié NCT01876082 Recruiting tumors pazopanib vs methotrexate-vinblastine Imatinib Imatinib in patients with desmoid tumor and Phase II Italian Sarcoma Group NCT00928525 Closed to accrual chondrosarcoma Sulindac and Sulindac and tamoxifen in treating patients Phase II Children’s Oncology Group NCT00068419 Closed to accrual tamoxifen with desmoid tumor Sorafenib Sorafenib tosylate in treating patients with Phase II National Cancer Institute NCT02066181 Closed to accrual desmoid tumors or aggressive fibromatosis Observation till- Tailored beta-catenin mutational approach in Observational Fondazione IRCCS Istituto NCT02547831 Recruiting progression extra-abdominal sporadic desmoids tumor Nazionale dei Tumori, Milano patients Imatinib Study to evaluate imatinib in desmoid tumors Phase II Heidelberg University NCT01137916 Closed to accrual 5-Aminolevulinic Safety and efficacy study using 5-ALA oral Phase II adjuvant Tel-Aviv Sourasky Medical Center NCT01898416 Recruiting acid (5-ALA) administration as an adjuvant therapy on the and photodynamic rate of local tumor recurrence in patients therapy who have desmoid tumors Imatinib A trial of imatinib for patients with aggressive Phase II Yonsei University NCT02495519 Closed to accrual desmoid tumor (aggressive fibromatosis) 955 MAYO CLINIC PROCEEDINGS

Trials of tyrosine kinase inhibitors in DTF are with differences in clinical course of sporadic ongoing (Table). Pegylated-liposomal doxoru- DTF. For example, tumors with S45F muta- bicin (PLD) is particularly attractive, given its tions in CTNNB1 may be at a higher risk of efficacy and low toxicity profile and is recurrence.40-42,45,49,53,56,102 One study found becoming widely used.18,129,130,169 that DTF tumors with an S45 b-catenin muta- Antibodies to WISP1 inhibit fibrosis in tion had a higher progression arrest rate than mouse models of bleomycin lung toxicity, did wild-type tumors when treated with imati- suggesting this as a potential target for the nib,176 and a European position paper encour- future treatment of select cases of DTF as aged b-catenin mutation testing in DTF.177 well. Similarly, the beneficial response of Another study found that higher nuclear DTF to certain chemotherapy approaches b-catenin expression (>20% of tumor cells suggests that a similar approach could be expressing nuclear b-catenin) had a higher useful in severe cases of idiopathic pulmo- recurrence rate than did lower expression.178 nary fibrosis. Altering Notch signaling with Trisomy 8 has also been associated with a g-secretase inhibition is also under study, higher risk of recurrence.179 In 1 study, and an adenosine monophosphateeactivated immunohistochemical staining for ADAM12, protein kinase activator inhibits peritoneal Fap-1a, and WISP1 correlated with nuclear fibrosis (a complication of peritoneal chromatin density and was higher in patients dialysis) in a mouse model.175 Preliminary with an early recurrence (<1 year after surgery data suggest activity of a g-secretase inhibi- compared with no recurrence at 5 years).48 tor in DTF. Some ongoing trials for DTF Other studies suggest that gene expression arelistedintheTable. patterns may also correlate with biological In some cases DTF tumors, and their con- behavior48,51,180,181 and might be useful in stituent cells, may stabilize or regress, with a identifying patients who would more likely decrease in expression of biochemical markers benefit from therapy. of disease activity (Figure 4). The observation that DTF tumors sometimes stabilize or regress implies that the tumor myofibroblasts DESMOID-TYPE FIBROMATOSIS AS A retain sensitivity to a regulatory system, likely MODEL FOR THE ROLE OF TUMOR an autocrine or more likely paracrine signaling STROMA IN OTHER DISEASES system, similar to that of wound healing. That The tumor stroma in invasive carcinomas DTF tumors may still subsequently become frequently exhibits a desmoplastic response active again after stabilization or regression im- with proliferation of myofibroblasts, and plies that a population of cells remains that re- tumors have been described as “wounds that tains the ability to respond to some do not heal.”182,p1650 Fibroblasts and myofi- proinflammatory and/or profibrotic stimuli, broblasts in neoplasms can secrete various in some cases induced by trauma, associated trophic, mitogenic, and proinflammatory inflammation, or other physiological condi- growth factors including hepatocyte growth tions, such as pregnancy. The degree to which factor, epidermal growth factor, TGF-b,and recruited normal myofibroblasts contribute to insulin-like growth factor 1 (reviewed in the mass of clonal myofibroblasts in an indi- reference 183), possibly influencing growth vidual DTF tumor could potentially affect the of the clonal neoplastic cells. Because of tumor behavior. their potential contribution to tumor biology, targeting the normal stromal myofibroblasts PREDICTING DTF BEHAVIOR in tumors is an interesting potential approach Predicting which treatment is most appro- to cancer treatment.184 As DTF closely resem- priate for a particular patient, such as the bles wound healing, it may be a potentially observation approach, would be useful. A useful model to study the role of tumor nomogram using tumor size, location, and pa- stroma. Indeed, some studies suggest that tient age has been reported to be useful in pre- gene signatures similar to that seen in DTF dicting recurrence after surgery.121 Some correlate with clinical outcome in some studies, but not all, have suggested that the malignancies.84,185-188 Desmoid-type fibro- location of the b-catenin mutation correlates matosis may also provide a model for

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other fibrosing diseases such as progressive developed. The size of the mass and degree pulmonary fibrosis. of pain progressed markedly over the 2 months before presentation. Examination DESMOID-TYPE FIBROMATOSIS CASE revealed a slightly tender warm 10 cm hard EXAMPLES mass fixed to the underlying tissue in the As described above, DTF can have a different proximal right arm. Magnetic resonance imag- course in different patients. Thirteen cases of ing revealed a 7Â5Â8.5 cm mass along the tri- DTF are summarized here (10 in Supplemental ceps muscle that was hyperintense on a fluid- Materials, Supplemental Figure 2, available sensitive image with some areas of heterogene- online at http://www.mayoclinicproceedings. ity (Supplemental Figure 1, available online at org) to illustrate important principles of DTF http://www.mayoclinicproceedings.org). A biology and treatment. tru-cut biopsy revealed DTF, and an open biopsy performed to exclude a low-grade sar- Case 1: Slow Spontaneous Regression of an coma also revealed DTF. Surgical treatment Extra-Abdominal DTF in a Man was felt to require shoulder disarticulation. As A 28-year-old man noted a small mass in his right surgical treatment was felt to result in signifi- chest near the sternum. He developed psoriatic cant morbidity, chemotherapy with metho- arthritis 8 months later and began treatment trexate and vinblastine was begun. At 6 weeks with methotrexate. A year after initiating metho- of treatment, there was no clear evidence of trexate, etanercept was added. At presentation 8 change in tumor size or symptoms, and he months after starting etanercept, he was not sure moved to a different state in which chemo- the mass had grown over the part year, but he therapy was continued for 2 more months now had occasional twinges of pain lasting a without change in tumor size. The tumor was few seconds, from none to several times a day. then surgically excised. He was sent for consid- Thus, the tumor progressed symptomatically eration of postoperative radiation therapy and while on methotrexate. Examination revealed a thereafter lost to follow-up. This case exhibits firm, fixed, nontender parasternal mass. DTF development after local trauma/inflamma- Computed tomography revealed a mass tion, potential significant morbidity of treat- involving the sternum growing through the chest ment (shoulder disarticulation or more limited wall (Figure 5, top panel) and a biopsy revealed disfiguring surgery), and disease stabilization DTF. Consultation at another institution recom- with methotrexate and vinblastine. mended surgical removal of the chest wall mass; however, he was observed, and 3 months later Case 3: Aggressive Multifocal DTF his symptoms and imaging of the mass were un- Controlled With PLD changed. Ten months after the biopsy, the mass A 32-year-old man with Gardner syndrome was slightly smaller and symptoms were un- presented with painful extra-abdominal des- changed. At 35 months after the biopsy, his moid tumors as well as large intra-abdominal symptoms had resolved and the mass was desmoids requiring opiates. He also had a pul- smaller (Figure 5, bottom panel). He remains monary embolus and venous thrombosis and symptom free 50 months after the biopsy and was taking coumadin. He had been treated a continues the observation. This case exhibits year earlier with tamoxifen for 8 weeks, but slow spontaneous regression of an extra- tumors grew during this period. He began abdominal DTF in a man, not related to estrogen. treatment with PLD and had a good response. Treatment was held after 6 cycles. Desmoid- Case 2: DTF Caused by Local Trauma/ type fibromatosis progression was noted 10 Inflammation and Stable Disease After months after the last chemotherapy, and he Methotrexate and Vinblastine received imatinib 400 mg/d orally, but it pro- A 33-year-old man presented with a painful gressed. He began treatment with PLD and mass in the arm. He had an influenza shot noted stabilization of pain after 1 month and 1.5 years before presentation, and shortly some tumor shrinkage at 3 months. Three thereafter he became aware of a persistent months later, imaging revealed further tumor discomfort in the region of the injection site regression, and the interval between PLD that gradually progressed, and a painful mass treatments was increased. Subsequent imaging

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revealed continued gradual tumor shrinkage and then stabilization, and PLD was discontin- ued after 1.5 years of treatment. Imaging found stable disease at 3 years after reinitiating PLD, but 4 months later (40 months after first initiating chemotherapy) he developed increasing pain and progression of DTF on im- aging, and PLD was reinitiated. One month later he developed small bowel obstruction, bacteremia, and renal failure and had a decompressive gastrostomy tube placed. His subsequent course was complicated, and he eventually entered a hospice program and died 5.3 years after initial chemotherapy. This case exhibits aggressive multifocal DTF, long-term control with PLD, and severe DTF-associated morbidity.

FUTURE STUDIES Controlled trials are needed to better define optimal treatment approaches. Future clinical trials must consider several aspects of DTF biology. First, because of the highly variable clinical course of DTF, patients must be care- fully stratified at entry. Factors to consider include rate of tumor growth (tumor growth rate should be quantitated before treatment). Other stratification variables should include age at diagnosis, tumor location (mesenteric, abdominal wall, central extra-abdominal, and extremity), b-catenin mutation and APC muta- tion status, relation to pregnancy, symptoms, and tumor size. Samples should be obtained for future, more detailed genetic analysis; consideration should be given to obtaining core biopsies from different parts of the tumor, if possible, given the known intratumoral vari- ability. Watchful waiting should be the first treatment, if possible, and when treatment is initiated, randomization to 2 treatments is needed. The “standard” treatment can be debated, but given its efficacy, tolerability, and increasing popularity, PLD would be one consideration. Finally, a decision on how FIGURE 5. Slow spontaneous regression of an extra-abdominal desmoid- long to treat a responding tumor and how to fi fi type bromatosis (DTF) in a man. A 28-year-old man developed a rm, quantify tumor response must be considered. fi xed, nontender parasternal mass. Computed tomography revealed a mass RECIST (Response Evaluation Criteria In Solid involving the sternum growing through the chest wall (top panel), and a Tumors) is known to be a poor measure of 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 response in DTF, but some measure of size resolved and the mass was smaller. (optimally careful analysis of tumor volume) and tumor “activity” (possibly determined by

958 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 AGGRESSIVE FIBROMATOSIS OR DESMOID TUMOR

contrast enhancement or changes in T1/T2 ACKNOWLEDGMENTS signal on MRI) need to be considered. Because We thank Shelly Marette, MD, for assistance in tumor stabilization can be a beneficial interpreting magnetic resonance images, outcome, a measure of symptoms experienced Michael Franklin, MS, for editorial assistance, by the patient should be included as well, and J. Carlos Manivel, MD, for a critical review including a quality of life assessment such as of the manuscript. QLQ-C30 or FACTG. Perhaps better than nonlinear subjective variables such as a “pain SUPPLEMENTAL ONLINE MATERIAL scale” are clear measures such as the following: Supplemental material can be found is a pain medication required, how much pain online at: http://www.mayoclinicproceedings. medication is used, does the tumor interfere org. Supplemental material attached to journal with sleep (yes/no), how far can the patient articles has not been edited, and the authors walk before tumor pain limits the activity take responsibility for the accuracy of all data. (this could be objectively determined at each clinic visit for cases with serious symptoms), Abbreviations and Acronyms: APC = adenomatous and what is the range of motion of the affected polyposis coli gene; CK1 = casein kinase 1; DTF = desmoid- body part. Only with carefully controlled trials type fibromatosis; ECM = extracellular matrix; FAP = familial that use careful stratification based on known adenomatous polyposis; Fap-1a = fibroblast activation variables can the best treatment approaches for protein 1a; GSK3 = glycogen synthase kinase 3; MRI = magnetic resonance imaging; PDGF = platelet-derived DTF be determined. growth factor; PDGFR-a = platelet-derived growth factor receptor-a; PLD = pegylated-liposomal doxorubicin; TGF = transforming growth factor SUMMARY Because of the heterogeneity of the biological Correspondence: Address to Keith M. Skubitz, MD, behavior of DTF, the optimal approach to Department of Medicine, University of Minnesota Medical treatment is unclear. Historically, surgery was School, Box 286 University Hospital, Minneapolis, MN 55455 ([email protected]). the mainstay of treatment, but recurrence after surgery is common.9,31,59,111,113,115 In addi- tion, trauma can stimulate DTF growth, and REFERENCES surgery is a form of trauma associated with 1. Alman BA, Goldberg MJ, Naber SP, Galanopoulous T, inflammation and production of various Antoniades HN, Wolfe HJ. Aggressive fibromatosis. J Pediatr growth factors important in wound healing Orthop. 1992;12(1):1-10. 2. Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ. that may also stimulate clonal DTF cells; this Increased b-catenin protein and somatic APC mutations in is especially true in the case of FAP- sporadic aggressive fibromatoses (desmoid tumors). Am J associated mesenteric DTF.3,9,31,58,119,189 Pathol. 1997;151(2):329-334. 3. Bertario L, Russo A, Sala P, et al; Hereditary Colorectal Tu- Although surgery remains an option for the mours Registry. Genotype and phenotype factors as determi- initial treatment in which the expected nants of desmoid tumors in patients with familial morbidity is low and the chance of complete adenomatous polyposis. Int J Cancer. 2001;95(2):102-107. 4. Goldblum JR, Fletcher JA. Desmoid-type fibromatosis. In: removal is high, given the usually slow pro- Fletcher DM, Bridge JA, Hogendoorn P, Mertens F, eds. gression of DTF, a regimen with low toxicity WHO Classification of Tumors of Soft Tissue and Bone, 4th ed. is the preferred initial approach and observa- Lyon: IARC; 2013:72-73. 91,93-102 5. Hoos A, Lewis JJ, Antonescu CR, et al. Characterization of tion has become more standard. Of molecular abnormalities in human fibroblastic neoplasms: a course, the appropriate clinical decision de- model for genotype-phenotype association in soft tissue pends on the particular case, and some require tumors. Cancer Res. 2001;61(7):3171-3175. 6. Li M, Cordon-Cardo C, Gerald WL, Rosai J. Desmoid fibro- aggressive chemotherapy initially. matosis is a clonal process. Hum Pathol. 1996;27(9):939-943. 7. Lucas DR, Shroyer KR, McCarthy PJ, Markham NE, Fujita M, Enomoto TE. Desmoid tumor is a clonal cellular proliferation: CONCLUSION PCR amplification of HUMARA for analysis of patterns of Desmoid-type fibromatosis is an uncommon X-chromosome inactivation. Am J Surg Pathol. 1997;21(3): 306-311. locally invasive tumor. Because of the variable 8. Middleton SB, Frayling IM, Phillips RK. Desmoids in familial nature of the disease and the potential adenomatous polyposis are monoclonal proliferations. Br J morbidity of treatment, some cases of DTF Cancer. 2000;82(4):827-832. 9. Hansmann A, Adolph C, Vogel T, Unger A, Moeslein G. High- may do better without treatment; simple dose tamoxifen and sulindac as first-line treatment for des- observation is often the best initial treatment. moid tumors. Cancer. 2004;100(3):612-620.

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