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Biology and Treatment of Aggressive Fibromatosis or Desmoid Tumor

  • Keith M. Skubitz
    Correspondence
    Correspondence: Address to Keith M. Skubitz, MD, Department of Medicine, University of Minnesota Medical School, Box 286 University Hospital, Minneapolis, MN 55455.
    Affiliations
    Department of Medicine, University of Minnesota Medical School, Minneapolis
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      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 (β-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.

      Abbreviations and Acronyms:

      APC (adenomatous polyposis coli gene), CK1 (casein kinase 1), DTF (desmoid-type fibromatosis), ECM (extracellular matrix), FAP (familial adenomatous polyposis), Fap-1α (fibroblast activation protein 1α), GSK3 (glycogen synthase kinase 3), MRI (magnetic resonance imaging), PDGF (platelet-derived growth factor), PDGFR-α (platelet-derived growth factor receptor-α), PLD (pegylated-liposomal doxorubicin), TGF (transforming growth factor)
      Article Highlights
      • The clinical course of desmoid-type fibromatosis (DTF), an uncommon locally invasive tumor, can vary greatly among patients, complicating the determination of the optimal treatment approach.
      • The Wnt (β-catenin) pathway appears to play a key role in DTF pathogenesis.
      • 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.
      • 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 term fibromatosis encompasses 2 general groups of tumors: superficial and deep fibromatoses. The superficial fibromatoses include palmar fibromatosis or Dupuytren contracture, plantar fibromatosis, and penile fibromatosis or Peyronie disease. Deep or aggressive fibromatosis, also known as desmoid-type fibromatosis (DTF) or desmoid tumor, is a clonal locally invasive tumor that does not metastasize.
      • Alman B.A.
      • Goldberg M.J.
      • Naber S.P.
      • Galanopoulous T.
      • Antoniades H.N.
      • Wolfe H.J.
      Aggressive fibromatosis.
      • Alman B.A.
      • Li C.
      • Pajerski M.E.
      • Diaz-Cano S.
      • Wolfe H.J.
      Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
      • Bertario L.
      • Russo A.
      • Sala P.
      • et al.
      Hereditary Colorectal Tumours Registry
      Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
      • Goldblum J.R.
      • Fletcher J.A.
      Desmoid-type fibromatosis.
      • Hoos A.
      • Lewis J.J.
      • Antonescu C.R.
      • et al.
      Characterization of molecular abnormalities in human fibroblastic neoplasms: a model for genotype-phenotype association in soft tissue tumors.
      • Li M.
      • Cordon-Cardo C.
      • Gerald W.L.
      • Rosai J.
      Desmoid fibromatosis is a clonal process.
      • Lucas D.R.
      • Shroyer K.R.
      • McCarthy P.J.
      • Markham N.E.
      • Fujita M.
      • Enomoto T.E.
      Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation.
      • Middleton S.B.
      • Frayling I.M.
      • Phillips R.K.
      Desmoids in familial adenomatous polyposis are monoclonal proliferations.
      However, although uncommon, DTF may be multifocal. The word desmoid derives from the Greek desmos meaning “bandlike, bond, or fastening.”
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • Muller J.
      About the fine structure and types of pathological tumors.
      Desmoid-type fibromatosis was originally described by McFarlane in 1832
      • MacFarlane J.
      Clinical Report on the Surgical Practice of Glasgow Royal Infirmary.
      and termed “desmoid tumor” by Mueller in 1838. By 1904, about 400 cases had been reported.
      • Muller J.
      About the fine structure and types of pathological tumors.
      • MacFarlane J.
      Clinical Report on the Surgical Practice of Glasgow Royal Infirmary.
      • Ledderhose G.
      Desmoide Geschwulste der Bauchdecken.
      • Pfeiffer C.
      Die Desmoide der Bauchdecken und ihre Prognose.
      The term fibromatosis was later introduced by Stout.
      • Stout A.P.
      Fibrosarcoma the malignant tumor of fibroblasts.
      This review used a PubMed search from January 1, 1980, through October 31, 2016, using the terms fibromatosis and desmoid.
      Histologically, DTF shows a poorly circumscribed proliferation of myofibroblast-like cells with variable collagen deposition. These myofibroblastic cells are histologically similar to the proliferative phase of wound healing, and DTF has been associated with trauma, pregnancy, and oral contraceptive use.
      • Bertario L.
      • Russo A.
      • Sala P.
      • et al.
      Hereditary Colorectal Tumours Registry
      Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
      Trauma is a common inciting agent for the development of DTF,
      • Bertario L.
      • Russo A.
      • Sala P.
      • et al.
      Hereditary Colorectal Tumours Registry
      Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
      • Clark S.K.
      • Neale K.F.
      • Landgrebe J.C.
      • Phillips R.K.
      Desmoid tumours complicating familial adenomatous polyposis.
      • Enzinger F.M.
      • Shiraki M.
      Musculo-aponeurotic fibromatosis of the shoulder girdle (extra-abdominal desmoid): analysis of thirty cases followed up for ten or more years.
      • Urist M.R.
      Trauma and neoplasm: report of a case of desmoid tumor following simple fracture of the radius and ulna.
      and surgery may sometimes promote growth of DTF. The natural history of DTF is highly variable. This review 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.

      Epidemiology of DTF

      Desmoid-type fibromatosis most commonly arises between the ages of 15 and 60 years, with a female predominance of 2- to 3-fold.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Lev D.
      • Kotilingam D.
      • Wei C.
      • et al.
      Optimizing treatment of desmoid tumors.
      The incidence of DTF is about 2 to 4 per million per year in the general population.
      • Fallen T.
      • Wilson M.
      • Morlan B.
      • Lindor N.M.
      Desmoid tumors—a characterization of patients seen at Mayo Clinic 1976-1999.
      • Nieuwenhuis M.H.
      • Casparie M.
      • Mathus-Vliegen L.M.
      • Dekkers O.M.
      • Hogendoorn P.C.
      • Vasen H.F.
      A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses.
      • Reitamo J.J.
      • Häyry P.
      • Nykyri E.
      • Saxén E.
      The desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population.
      • Shields C.J.
      • Winter D.C.
      • Kirwan W.O.
      • Redmond H.P.
      Desmoid tumours.
      In contrast, the incidence of DTF has been reported to be about 1000-fold higher in patients with familial adenomatous polyposis (FAP), in which the adenomatous polyposis coli gene (APC) is mutated.
      • Giardiello F.M.
      • Petersen G.M.
      • Piantadosi S.
      • et al.
      APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.
      • Gurbuz A.K.
      • Giardiello F.M.
      • Petersen G.M.
      • et al.
      Desmoid tumours in familial adenomatous polyposis.
      • Hizawa K.
      • Iida M.
      • Mibu R.
      • Aoyagi K.
      • Yao T.
      • Fujishima M.
      Desmoid tumors in familial adenomatous polyposis/Gardner's syndrome.
      Familial adenomatous polyposis–associated DTF is more frequently abdominal, especially in the Gardner variant of FAP, which is characterized by intestinal polyposis, osteomas, fibromas, and epidermal inclusion (“sebaceous”) cysts.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • Gardner E.J.
      A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum.
      • Nichols R.W.
      Desmoid tumors: a report of thirty-one cases.
      • Smith W.G.
      Multiple polyposis, Gardner's syndrome and desmoid tumors.
      Desmoid-type fibromatosis develops in approximately 5% to 30% of patients with FAP, usually in the mesentery.
      • Fallen T.
      • Wilson M.
      • Morlan B.
      • Lindor N.M.
      Desmoid tumors—a characterization of patients seen at Mayo Clinic 1976-1999.
      • Nieuwenhuis M.H.
      • Casparie M.
      • Mathus-Vliegen L.M.
      • Dekkers O.M.
      • Hogendoorn P.C.
      • Vasen H.F.
      A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses.
      • Gurbuz A.K.
      • Giardiello F.M.
      • Petersen G.M.
      • et al.
      Desmoid tumours in familial adenomatous polyposis.
      • Clark S.K.
      • Phillips R.K.
      Desmoids in familial adenomatous polyposis.
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Klemmer S.
      • Pascoe L.
      • DeCosse J.
      Occurrence of desmoids in patients with familial adenomatous polyposis of the colon.
      In some studies, FAP-associated DTF represents about 2% of DTF cases
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      ; in 1 Dutch study, nearly 10% of patients with DTF have or will develop FAP.
      • Nieuwenhuis M.H.
      • Casparie M.
      • Mathus-Vliegen L.M.
      • Dekkers O.M.
      • Hogendoorn P.C.
      • Vasen H.F.
      A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses.
      • Nieuwenhuis M.H.
      • Mathus-Vliegen E.M.
      • Baeten C.G.
      • et al.
      Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients.
      With aggressive follow-up of patients with FAP and in those receiving prophylactic colectomy, DTF has been reported to be the most common cause of death.
      • Klemmer S.
      • Pascoe L.
      • DeCosse J.
      Occurrence of desmoids in patients with familial adenomatous polyposis of the colon.
      • Arvanitis M.L.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • McGannon E.
      Mortality in patients with familial adenomatous polyposis.
      • Caspari R.
      • Olschwang S.
      • Friedl W.
      • et al.
      Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444.
      Kindreds of familial DTF without the colonic features of FAP have also been reported in which mutations occur in a different region of APC.
      • Eccles D.M.
      • van der Luijt R.
      • Breukel C.
      • et al.
      Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.
      • Scott R.J.
      • Froggatt N.J.
      • Trembath R.C.
      • Evans D.G.
      • Hodgson S.V.
      • Maher E.R.
      Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3′ APC gene mutation.
      Genetic predisposition to DTF in patients with FAP independent of germ line APC mutation has also been described, suggesting the existence of genes independent of APC that influence DTF formation in FAP.
      • Sturt N.J.
      • Gallagher M.C.
      • Bassett P.
      • et al.
      Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation.
      Although common in patients with FAP, most cases occur sporadically in young adults
      • Clark S.K.
      • Neale K.F.
      • Landgrebe J.C.
      • Phillips R.K.
      Desmoid tumours complicating familial adenomatous polyposis.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      and are associated with a mutation in β-catenin (CTNNB1).
      • Lev D.
      • Kotilingam D.
      • Wei C.
      • et al.
      Optimizing treatment of desmoid tumors.
      • Amary M.F.
      • Pauwels P.
      • Meulemans E.
      • et al.
      Detection of β-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme digestion (MSRED): an ancillary diagnostic tool.
      • Dômont J.
      • Salas S.
      • Lacroix L.
      • et al.
      High frequency of β-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      • Tejpar S.
      • Nollet F.
      • Li C.
      • et al.
      Predominance of β-catenin mutations and β-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor).
      Desmoid-type fibromatosis and a related disease, infantile aggressive fibromatosis, may also differ between children and adults.
      • Bo N.
      • Wang D.
      • Wu B.
      • Chen L.
      • Ruixue M.
      Analysis of β-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis.
      • Meazza C.
      • Bisogno G.
      • Gronchi A.
      • et al.
      Aggressive fibromatosis in children and adolescents: the Italian experience.
      Infantile fibromatosis (so-called diffuse or mesenchymal type of fibromatosis) is not discussed here and usually occurs before the age of 2, most commonly in the first few months of life; it may recur locally, but does not metastasize.

      Histology of DTF

      Histologically, DTF appears as a poorly circumscribed proliferation of myofibroblastic cells with variable collagen deposition. Typically, the margins of the tumor are difficult to assess at the time of surgery, and the final margins are often positive. Desmoid-type fibromatosis tumors are morphologically heterogeneous and may exhibit striking morphological intra- and intertumoral heterogeneity (Figure 1, A). In some areas tumors may resemble fibroblasts of inactive fibrous tissue, whereas other areas resemble the active fibroblasts of wound healing. This morphological heterogeneity covers a spectrum ranging from areas in which cells have oval nuclei containing pale-staining vesicular euchromatin and small nucleoli to areas in which cells have elongated nuclei that stain darkly with hematoxylin, reflecting heterochromatin.
      • Francastel C.
      • Schübeler D.
      • Martin D.I.
      • Groudine M.
      Nuclear compartmentalization and gene activity.
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      Cells with more euchromatin are presumably more “transcriptionally active,” whereas cells with more heterochromatin are felt to be more “transcriptionally inactive.”
      • Francastel C.
      • Schübeler D.
      • Martin D.I.
      • Groudine M.
      Nuclear compartmentalization and gene activity.
      Figure 1, B, shows an area that appears inactive, with sparse cells with narrow, darker-staining nuclei and few mitoses, in which in general there is more collagen deposition, imparting a more pink (collagenous) coloration to these inactive areas. Typically the areas with more “transcriptionally inactive” cells are often separated by extensive collagen.
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      Figure 1, C, from the same tumor shows an area that appears histologically active, characterized by cells with plump, light-staining oval nuclei, greater cell density, increased mitotic activity, and less collagen. Digital assessment of chromatin density and average nuclear size and pathological assessment of tumor activity were strongly correlated in 1 study,
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      and there was a spatial correlation of protein expression of genes overexpressed in DTF and nuclear morphology.
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      Figure thumbnail gr1
      Figure 1Hematoxylin 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.

      Genetic Changes in DTF

      The Wnt (β-catenin) pathway appears to play a key role in DTF pathogenesis,
      • Alman B.A.
      • Li C.
      • Pajerski M.E.
      • Diaz-Cano S.
      • Wolfe H.J.
      Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      • Colombo C.
      • Miceli R.
      • Lazar A.J.
      • et al.
      CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.
      • Lacroix-Triki M.
      • Geyer F.C.
      • Lambros M.B.
      • et al.
      β-Catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast.
      • Skubitz K.M.
      • Skubitz A.P.
      Gene expression in aggressive fibromatosis.
      with a mutation in the β-catenin gene in most sporadic cases,
      • Amary M.F.
      • Pauwels P.
      • Meulemans E.
      • et al.
      Detection of β-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme digestion (MSRED): an ancillary diagnostic tool.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Bo N.
      • Wang D.
      • Wu B.
      • Chen L.
      • Ruixue M.
      Analysis of β-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis.
      • Colombo C.
      • Miceli R.
      • Lazar A.J.
      • et al.
      CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.
      • Lacroix-Triki M.
      • Geyer F.C.
      • Lambros M.B.
      • et al.
      β-Catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast.
      • Miyoshi Y.
      • Iwao K.
      • Nawa G.
      • Yoshikawa H.
      • Ochi T.
      • Nakamura Y.
      Frequent mutations in the β-catenin gene in desmoid tumors from patients without familial adenomatous polyposis.
      • Mullen J.T.
      • DeLaney T.F.
      • Rosenberg A.E.
      • et al.
      β-Catenin mutation status and outcomes in sporadic desmoid tumors.
      • Saito T.
      • Oda Y.
      • Kawaguchi K.
      • et al.
      Possible association between higher β-catenin mRNA expression and mutated β-catenin in sporadic desmoid tumors: real-time semiquantitative assay by TaqMan polymerase chain reaction.
      • Shitoh K.
      • Konishi F.
      • Iijima T.
      • et al.
      A novel case of a sporadic desmoid tumour with mutation of the β catenin gene.
      • van Broekhoven D.L.
      • Verhoef C.
      • Grünhagen D.J.
      • et al.
      Prognostic value of CTNNB1 gene mutation in primary sporadic aggressive fibromatosis.
      or a mutation in APC, which regulates β-catenin degradation, in cases associated with FAP.
      • Alman B.A.
      • Li C.
      • Pajerski M.E.
      • Diaz-Cano S.
      • Wolfe H.J.
      Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
      • Clark S.K.
      • Neale K.F.
      • Landgrebe J.C.
      • Phillips R.K.
      Desmoid tumours complicating familial adenomatous polyposis.
      • Giardiello F.M.
      • Petersen G.M.
      • Piantadosi S.
      • et al.
      APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.
      • Gurbuz A.K.
      • Giardiello F.M.
      • Petersen G.M.
      • et al.
      Desmoid tumours in familial adenomatous polyposis.
      • Clark S.K.
      • Phillips R.K.
      Desmoids in familial adenomatous polyposis.
      • Klemmer S.
      • Pascoe L.
      • DeCosse J.
      Occurrence of desmoids in patients with familial adenomatous polyposis of the colon.
      • Eccles D.M.
      • van der Luijt R.
      • Breukel C.
      • et al.
      Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.
      • Scott R.J.
      • Froggatt N.J.
      • Trembath R.C.
      • Evans D.G.
      • Hodgson S.V.
      • Maher E.R.
      Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3′ APC gene mutation.
      • Couture J.
      • Mitri A.
      • Lagace R.
      • et al.
      A germline mutation at the extreme 3′ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of β-catenin in the desmoid tumor.
      • Harvey J.C.
      • Quan S.H.
      • Fortner J.G.
      Gardner's syndrome complicated by mesenteric desmoid tumors.
      • Rodriguez-Bigas M.A.
      • Mahoney M.C.
      • Karakousis C.P.
      • Petrelli N.J.
      Desmoid tumors in patients with familial adenomatous polyposis.
      In 1 study a CTNNB1 mutation was found in 223 of 254 sporadic DTF cases (88%),
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      with only 3 mutations reported: S45P, S45F, and T41A. S45F and T41A were the most common, with S45P seen in less than 10% of cases. Several cases of APC mutations have also been found in sporadic cases of DTF.
      • Alman B.A.
      • Li C.
      • Pajerski M.E.
      • Diaz-Cano S.
      • Wolfe H.J.
      Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      Clonal chromosomal changes have been reported in about 45% of cases of deep DTF and approximately 10% of superficial fibromatosis cases,
      • De Wever I.
      • Dal Cin P.
      • Fletcher C.D.
      • et al.
      Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology.
      with several recurrent chromosomal changes reported.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      • De Wever I.
      • Dal Cin P.
      • Fletcher C.D.
      • et al.
      Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology.
      In a study of 17 FAP-associated DTF and 38 sporadic DTF cases using comparative genomic hybridization and multiple ligation-dependent probe amplification, a limited number of genetic changes was observed in 44% of tumors.
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      • Robanus-Maandag E.
      • Bosch C.
      • Amini-Nik S.
      • et al.
      Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids.
      A higher frequency of copy number abnormalities was seen in FAP-associated DTF (59%) as compared with sporadic DTF (37%).
      • Robanus-Maandag E.
      • Bosch C.
      • Amini-Nik S.
      • et al.
      Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids.
      The incidence and severity of DTF in FAP is related to the site of APC mutation.
      • Church J.
      • Xhaja X.
      • LaGuardia L.
      • O'Malley M.
      • Burke C.
      • Kalady M.
      Desmoids and genotype in familial adenomatous polyposis.

      Molecular Biology of DTF

      Desmoid-type fibromatosis exhibits a monoclonal proliferation of myofibroblasts, presenting a true neoplastic process,
      • Li M.
      • Cordon-Cardo C.
      • Gerald W.L.
      • Rosai J.
      Desmoid fibromatosis is a clonal process.
      • Lucas D.R.
      • Shroyer K.R.
      • McCarthy P.J.
      • Markham N.E.
      • Fujita M.
      • Enomoto T.E.
      Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation.
      • Middleton S.B.
      • Frayling I.M.
      • Phillips R.K.
      Desmoids in familial adenomatous polyposis are monoclonal proliferations.
      and as described above, the Wnt or β-catenin pathway has been strongly implicated in DTF pathogenesis.
      • Alman B.A.
      • Li C.
      • Pajerski M.E.
      • Diaz-Cano S.
      • Wolfe H.J.
      Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
      • Bertario L.
      • Russo A.
      • Sala P.
      • et al.
      Hereditary Colorectal Tumours Registry
      Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Salas S.
      • Chibon F.
      • Noguchi T.
      • et al.
      Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors.
      • Tejpar S.
      • Nollet F.
      • Li C.
      • et al.
      Predominance of β-catenin mutations and β-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor).
      • Colombo C.
      • Miceli R.
      • Lazar A.J.
      • et al.
      CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.
      • Lacroix-Triki M.
      • Geyer F.C.
      • Lambros M.B.
      • et al.
      β-Catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast.
      • Skubitz K.M.
      • Skubitz A.P.
      Gene expression in aggressive fibromatosis.
      • Saito T.
      • Oda Y.
      • Kawaguchi K.
      • et al.
      Possible association between higher β-catenin mRNA expression and mutated β-catenin in sporadic desmoid tumors: real-time semiquantitative assay by TaqMan polymerase chain reaction.
      • Couture J.
      • Mitri A.
      • Lagace R.
      • et al.
      A germline mutation at the extreme 3′ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of β-catenin in the desmoid tumor.
      • Cheon S.S.
      • Cheah A.Y.
      • Turley S.
      • et al.
      β-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds.
      • Heinrich M.C.
      • McArthur G.A.
      • Demetri G.D.
      • et al.
      Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).
      In addition, induction of stabilized β-catenin in a transgenic mouse model leads to hyperplastic cutaneous wounds and the development of DTF, providing further evidence that β-catenin plays a role in these fibroproliferative diseases.
      • Cheon S.S.
      • Cheah A.Y.
      • Turley S.
      • et al.
      β-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds.
      Similarly, mice with germ line mutations in APC have a high incidence of DTF.
      • Smits R.
      • van der Houven van Oordt W.
      • Luz A.
      • et al.
      Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts.
      Abnormal growth factor production (including transforming growth factor [TGF] and platelet-derived growth factor [PDGF]) has been associated with hereditary gingival fibromatosis and plantar fibromatosis
      • Alman B.A.
      • Greel D.A.
      • Ruby L.K.
      • Goldberg M.J.
      • Wolfe H.J.
      Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain.
      • de Andrade C.R.
      • Cotrin P.
      • Graner E.
      • Almeida O.P.
      • Sauk J.J.
      • Coletta R.D.
      Transforming growth factor-β1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis.
      • Magro G.
      • Lanteri E.
      • Micali G.
      • Paravizzini G.
      • Travali S.
      • Lanzafame S.
      Myofibroblasts of palmar fibromatosis co-express transforming growth factor-α and epidermal growth factor receptor.
      and may play a role in DTF as well. Murine studies suggest that DTF can originate in mesenchymal stem cells, in some cases derived from pericytes.
      • Carothers A.M.
      • Rizvi H.
      • Hasson R.M.
      • et al.
      Mesenchymal stromal cell mutations and wound healing contribute to the etiology of desmoid tumors.
      • Sato S.
      • Tang Y.J.
      • Wei Q.
      • et al.
      Mesenchymal tumors can derive from Ng2/Cspg4-expressing pericytes with β-catenin modulating the neoplastic phenotype.
      β-Catenin, encoded by the CTNNB1 gene, is also mutated or overexpressed in various cancers
      • Morin P.J.
      β-Catenin signaling and cancer.
      and has 2 recognized functions. It is part of the cadherin complex involved in cell-cell adhesion, in which it binds the cytoplasmic domain of cadherin,
      • McCrea P.D.
      • Turck C.W.
      • Gumbiner B.
      A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin.
      and also, as part of the Wnt signaling pathway, can translocate to the nucleus in which it regulates gene transcription.
      • Minde D.P.
      • Anvarian Z.
      • Rüdiger S.G.
      • Maurice M.M.
      Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?.
      • Willert K.
      • Jones K.A.
      Wnt signaling: is the party in the nucleus?.
      β-Catenin is regulated by a destruction complex (Figure 2) including APC, which has multiple β-catenin binding sites, axin, β-catenin, casein kinase 1 (CK1), glycogen synthase kinase 3β (GSK3), and protein phosphatase 2A. β-Catenin is phosphorylated in this complex by GSK3 after a “priming” phosphorylation by CK1, which leads to ubiquitination and subsequent degradation in the proteasome.
      • Willert K.
      • Jones K.A.
      Wnt signaling: is the party in the nucleus?.
      Wnt signaling from the cell surface leads to disruption of the APC/axin/GSK3 complex and thus inhibits β-catenin phosphorylation by the complex, leading to increased nuclear β-catenin.
      • Willert K.
      • Jones K.A.
      Wnt signaling: is the party in the nucleus?.
      Nuclear β-catenin can act as a transcriptional activator when bound to a member of the T-cell factor/lymphocyte enhancer family, leading to the formation of nuclear β-catenin/T-cell factor/lymphocyte enhancer complexes, changing the way they bind promotor regions of DNA and altering gene transcription.
      • Minde D.P.
      • Anvarian Z.
      • Rüdiger S.G.
      • Maurice M.M.
      Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?.
      • Willert K.
      • Jones K.A.
      Wnt signaling: is the party in the nucleus?.
      The hedgehog signaling pathway and β-catenin signaling pathways regulate each other's activity, and 1 study found that hedgehog signaling is activated in human and murine desmoid tumors.
      • Ghanbari-Azarnier R.
      • Sato S.
      • Wei Q.
      • Al-Jazrawe M.
      • Alman B.A.
      Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling.
      Figure thumbnail gr2
      Figure 2β-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, β-catenin can also translocate to the nucleus, in which it regulates gene transcription. β-Catenin is regulated by a destruction complex including adenomatous polyposis coli gene (APC), axin, β-catenin, casein kinase 1 (CK1), glycogen synthase kinase 3β (GSK3), and protein phosphatase 2A (PP2A). β-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 β-catenin phosphorylation by the complex, leading to increased nuclear β-catenin. Nuclear β-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.
      Four genes—a disintegrin and metalloproteinase gene 12 (ADAM12), fibroblast activation protein 1α (Fap-1α), Wnt 1 inducible signaling pathway protein-1 (WISP1), and SRY-box 11 (SOX11)—have been reported to be overexpressed in DTF compared with 16 nonneoplastic tissues,
      • Skubitz K.M.
      • Skubitz A.P.
      Gene expression in aggressive fibromatosis.
      and immumohistochemistry studies have exhibited protein expression of ADAM12, Fap-1α, WISP1, and SOX11 in DTF.
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      Fap-1α is a serine protease localized to the cell surface and cytoplasm. Fap-1α has been found in tumor stroma and several fibrotic diseases including idiopathic pulmonary fibrosis.
      • Acharya P.S.
      • Zukas A.
      • Chandan V.
      • Katzenstein A.L.
      • Puré E.
      Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis.
      ADAM12 plays a role in cell-cell and cell-matrix interactions and regulates integrin signaling
      • Lafuste P.
      • Sonnet C.
      • Chazaud B.
      • et al.
      ADAM12 and α9β1 integrin are instrumental in human myogenic cell differentiation.
      • Thodeti C.K.
      • Fröhlich C.
      • Nielsen C.K.
      • et al.
      ADAM12-mediated focal adhesion formation is differently regulated by β1 and β3 integrins.
      ; ADAM12 expression has also been found in Dupuytren disease
      • Shih B.
      • Brown J.J.
      • Armstrong D.J.
      • Lindau T.
      • Bayat A.
      Differential gene expression analysis of subcutaneous fat, fascia, and skin overlying a Dupuytren's disease nodule in comparison to control tissue.
      and idiopathic pulmonary fibrosis (reviewed in reference
      • Dulauroy S.
      • Di Carlo S.E.
      • Langa F.
      • Eberl G.
      • Peduto L.
      Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.
      ). ADAM12 identifies a proinflammatory subset of PDGF receptor-α (PDGFR-α)–positive stromal cells residing in the perivascular space that can be activated by acute injury and can differentiate into myofibroblasts and act as progenitors for a large fraction of the collagen-producing cells generated in scarring; these cells are progressively eliminated during normal wound healing.
      • Dulauroy S.
      • Di Carlo S.E.
      • Langa F.
      • Eberl G.
      • Peduto L.
      Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.
      WISP1 is a secreted protein that can act as a growth factor and regulate various cellular functions.
      • Niehrs C.
      The complex world of WNT receptor signalling.
      WISP1 has been detected in a number of tumors, including the desmoplastic tumor stroma of carcinomas
      • Bauer M.
      • Su G.
      • Casper C.
      • He R.
      • Rehrauer W.
      • Friedl A.
      Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast.
      and DTF.
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      • Skubitz K.M.
      • Skubitz A.P.
      Gene expression in aggressive fibromatosis.
      • Bacac M.
      • Migliavacca E.
      • Stehle J.C.
      • et al.
      A gene expression signature that distinguishes desmoid tumours from nodular fasciitis.
      • West R.B.
      • Nuyten D.S.
      • Subramanian S.
      • et al.
      Determination of stromal signatures in breast carcinoma.
      WISP1 is up-regulated in idiopathic pulmonary fibrosis and stimulates extracellular matrix (ECM) deposition by fibroblasts.
      • Königshoff M.
      • Kramer M.
      • Balsara N.
      • et al.
      WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis.
      SOX11 is a nuclear transcription factor that is temporally regulated in development and not expressed in most adult tissues. SOX11 is deregulated in various tumors
      • Brennan D.J.
      • Ek S.
      • Doyle E.
      • et al.
      The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer.
      and overexpressed in liposarcomas.
      • Skubitz K.M.
      • Cheng E.Y.
      • Clohisy D.R.
      • Thompson R.C.
      • Skubitz A.P.
      Differential gene expression in liposarcoma, lipoma, and adipose tissue.
      SOX11 is more highly expressed in mesenchymal stem cell lines than in fibroblasts and may aid mesenchymal stem cell proliferation and pluripotent potential retention.
      • Kubo H.
      • Shimizu M.
      • Taya Y.
      • et al.
      Identification of mesenchymal stem cell (MSC)-transcription factors by microarray and knockdown analyses, and signature molecule-marked MSC in bone marrow by immunohistochemistry.
      Thus, the available data suggest a possible model of DTF pathogenesis, in which an activating stimulus, such as trauma with associated inflammation and growth factor production, in the setting of deregulation of β-catenin, leads to up-regulation of β-catenin
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
       (Figure 3, right side). Reactive oxygen species produced by neutrophils have been shown to have the potential to induce mutations in DNA. In rare cases the inciting event may stimulate a progenitor cell that does not have baseline β-catenin dysregulation (left-hand-side of the figure). β-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 β-catenin nuclear translocation,
      • Venkatesan B.
      • Prabhu S.D.
      • Venkatachalam K.
      • et al.
      WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death.
      resulting in a prosurvival signal, and further stimulate WISP1 production, and production of ECM proteins including collagen, leading to fibrosis. WISP1 binding to the tumor cells can then further stimulate tumor growth. Myofibroblasts are functionally heterogeneous and can be generated from multiple cell types.
      • Dulauroy S.
      • Di Carlo S.E.
      • Langa F.
      • Eberl G.
      • Peduto L.
      Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.
      WISP1, by binding to its receptor on other cells, may also recruit nonclonal (normal) profibrotic ADAM12-positive cells from a PDGFR-positive precursor pool,
      • Dulauroy S.
      • Di Carlo S.E.
      • Langa F.
      • Eberl G.
      • Peduto L.
      Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.
      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, including collagen, leading to fibrosis. Although the role of SOX11 is not clear, studies have reported that SOX11 assists mesenchymal stem cell proliferation and retention of pluripotent potential.
      • Kubo H.
      • Shimizu M.
      • Taya Y.
      • et al.
      Identification of mesenchymal stem cell (MSC)-transcription factors by microarray and knockdown analyses, and signature molecule-marked MSC in bone marrow by immunohistochemistry.
      In some cases DTF tumors, and their constituent cells, may stabilize or regress, with a decrease in expression of ADAM12, FAP-1α, WISP1, and SOX11 (Figure 4). In most cases of DTF, different areas of the tumor show either active or inactive areas,
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      indicating that the balance of these factors leading to progression or regression operate differently in different parts of the tumor. The mechanisms regulating these factors are unknown.
      Figure thumbnail gr3
      Figure 3A 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 β-catenin, leads to up-regulation of β-catenin. β-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 β-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-α-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 β-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.
      Figure thumbnail gr4
      Figure 4Variable progression of desmoid-type fibromatosis (DTF). In some cases of DTF, a stimulus, such as trauma with associated inflammation, in the setting of β-catenin dysregulation 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-1α, WISP1, and SOX11.

      Evidence for Clinical Treatments of DTF

      The natural clinical course of DTF can vary greatly among patients, complicating the determination of the optimal treatment approach. Clinical trials exhibiting the best approach in a particular patient are lacking. 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 course of the disease and the potential morbidity of treatment with the result that some cases of DTF may do better without treatment, Lewis et al,
      • Lewis J.J.
      • Boland P.J.
      • Leung D.H.
      • Woodruff J.M.
      • Brennan M.F.
      The enigma of desmoid tumors.
      Mitchell et al,
      • Mitchell G.
      • Thomas J.M.
      • Harmer C.L.
      Aggressive fibromatosis: evidence for a stable phase.
      and Rock et al
      • Rock M.G.
      • Pritchard D.J.
      • Reiman H.M.
      • Soule E.H.
      • Brewster R.C.
      Extra-abdominal desmoid tumors.
      were among the first to suggest that simple observation may often be the best initial approach, and this recommendation has become more common.
      • Bonvalot S.
      • Desai A.
      • Coppola S.
      • et al.
      The treatment of desmoid tumors: a stepwise clinical approach.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      • Bonvalot S.
      • Ternes N.
      • Fiore M.
      • et al.
      Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought.
      • Colombo C.
      • Miceli R.
      • Le Péchoux C.
      • et al.
      Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients.
      • Eastley N.
      • McCulloch T.
      • Esler C.
      • et al.
      Extra-abdominal desmoid fibromatosis: a review of management, current guidance and unanswered questions.
      • Garbay D.
      • Le Cesne A.
      • Penel N.
      • et al.
      Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG).
      • Gronchi A.
      • Colombo C.
      • Le Péchoux C.
      • et al.
      Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group.
      • Nakayama T.
      • Tsuboyama T.
      • Toguchida J.
      • Hosaka T.
      • Nakamura T.
      Natural course of desmoid-type fibromatosis.
      • Roussin S.
      • Mazouni C.
      • Rimareix F.
      • et al.
      Toward a new strategy in desmoid of the breast?.
      • Salas S.
      • Dufresne A.
      • Bui B.
      • et al.
      Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.
      • Joglekar S.B.
      • Rose P.S.
      • Sim F.
      • Okuno S.
      • Petersen I.
      Current perspectives on desmoid tumors: the Mayo Clinic approach.
      Some studies suggest that approximately 50% of cases will have an indolent course
      • Bonvalot S.
      • Desai A.
      • Coppola S.
      • et al.
      The treatment of desmoid tumors: a stepwise clinical approach.
      and that patients with DTF who have stable disease for more than 1 year are unlikely to require active treatment.
      • Colombo C.
      • Miceli R.
      • Le Péchoux C.
      • et al.
      Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients.
      • Briand S.
      • Barbier O.
      • Biau D.
      • et al.
      Wait-and-see policy as a first-line management for extra-abdominal desmoid tumors.
      The therapeutic approach of adults with DTF and children with either DTF or infantile aggressive fibromatosis may also differ.
      • Bo N.
      • Wang D.
      • Wu B.
      • Chen L.
      • Ruixue M.
      Analysis of β-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis.
      • Meazza C.
      • Bisogno G.
      • Gronchi A.
      • et al.
      Aggressive fibromatosis in children and adolescents: the Italian experience.
      Abdominal wall desmoids are most commonly associated with pregnancy and could relate to “trauma” of stretching the abdominal wall musculature or possibly hormonal changes or both.
      • Stout A.P.
      Fibrosarcoma the malignant tumor of fibroblasts.
      However, pregnancy is also associated with changes in circulating growth factors and immune modulators, including vascular endothelial growth factor, TGF-β, and insulin-like growth factor 1; these all could also be involved.
      • Boyne M.S.
      • Thame M.
      • Bennett F.I.
      • Osmond C.
      • Miell J.P.
      • Forrester T.E.
      The relationship among circulating insulin-like growth factor (IGF)-I, IGF-binding proteins-1 and -2, and birth anthropometry: a prospective study.
      • Forbes K.
      • Westwood M.
      Maternal growth factor regulation of human placental development and fetal growth.
      • Singh M.
      • Orazulike N.C.
      • Ashmore J.
      • Konje J.C.
      Changes in maternal serum transforming growth factor β-1 during pregnancy: a cross-sectional study.
      • Vonnahme K.A.
      • Wilson M.E.
      • Li Y.
      • et al.
      Circulating levels of nitric oxide and vascular endothelial growth factor throughout ovine pregnancy.
      Spontaneous regression of cases of abdominal wall DTF occurred in about 30% of patients in 1 series of 122 patients not treated with surgery for DTF.
      • Colombo C.
      • Miceli R.
      • Le Péchoux C.
      • et al.
      Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients.
      In another study of 147 patients, 97% of whom were young women with abdominal wall DTF, 102 underwent initial observation; of these, 29 had spontaneous regression and only 16% went to surgery by 3 years.
      • Bonvalot S.
      • Ternes N.
      • Fiore M.
      • et al.
      Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought.
      Although the rate of progression of DTF diagnosed during pregnancy is high, its prognosis is generally good,
      • Fiore M.
      • Coppola S.
      • Cannell A.J.
      • et al.
      Desmoid-type fibromatosis and pregnancy: a multi-institutional analysis of recurrence and obstetric risk.
      and is not necessarily, a contraindication for further pregnancies.
      • Cates J.M.
      Pregnancy does not increase the local recurrence rate after surgical resection of desmoid-type fibromatosis.
      Trauma, as from surgery, may worsen DTF, and DTF has a high risk of local recurrence after surgery ranging from about 25% to 60% at 5 years.
      • Lev D.
      • Kotilingam D.
      • Wei C.
      • et al.
      Optimizing treatment of desmoid tumors.
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Rodriguez-Bigas M.A.
      • Mahoney M.C.
      • Karakousis C.P.
      • Petrelli N.J.
      Desmoid tumors in patients with familial adenomatous polyposis.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      • Anthony T.
      • Rodriguez-Bigas M.A.
      • Weber T.K.
      • Petrelli N.J.
      Desmoid tumors.
      • Ballo M.T.
      • Zagars G.K.
      • Pollack A.
      • Pisters P.W.
      • Pollack R.A.
      Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy.
      • Dong-Heup K.
      • Kim D.H.
      • Goldsmith H.S.
      • Quan S.H.
      • Huvos A.G.
      Intra-abdominal desmoid tumor.
      • Gronchi A.
      • Casali P.G.
      • Mariani L.
      • et al.
      Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.
      • Johnson J.G.
      • Gilbert E.
      • Zimmermann B.
      • Watne A.L.
      Gardner's syndrome, colon cancer, and sarcoma.
      • Leibel S.A.
      • Wara W.M.
      • Hill D.R.
      • et al.
      Desmoid tumors: local control and patterns of relapse following radiation therapy.
      • Pignatti G.
      • Barbanti-Bròdano G.
      • Ferrari D.
      • et al.
      Extraabdominal desmoid tumor: a study of 83 cases.
      • Posner M.C.
      • Shiu M.H.
      • Newsome J.L.
      • Hajdu S.I.
      • Gaynor J.J.
      • Brennan M.F.
      The desmoid tumor. Not a benign disease.
      • Reitamo J.J.
      The desmoid tumor. IV. Choice of treatment, results, and complications.
      • Sørensen A.
      • Keller J.
      • Nielsen O.S.
      • Jensen O.M.
      Treatment of aggressive fibromatosis: a retrospective study of 72 patients followed for 1-27 years.
      Inflammation from other types of trauma also may augment or stimulate recurrence; however, DTF does not metastasize. Although a marginal resection is associated with a worse outcome than a complete resection, the nature of the surgical procedure is strongly influenced by tumor location and associated anatomical and functional consequences.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      In a retrospective study of a subgroup of patients, the 3-year event-free survival with a nonsurgical approach was similar to that after a complete resection.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      A multivariate analysis of 495 patients undergoing gross resection found that only age, tumor size, and tumor location site were associated with recurrence, with younger age having a worse prognosis.
      • Crago A.M.
      • Denton B.
      • Salas S.
      • et al.
      A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.
      In another multivariate analysis of 426 cases of sporadic DTF, 87% of cases were treated surgically, and about 50% of cases recurred; only age, tumor size, and tumor site were independent prognostic factors of recurrence.
      • Salas S.
      • Dufresne A.
      • Bui B.
      • et al.
      Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.
      Tumors of the extremity recurred more frequently and microscopic assessment of the surgical margin had no influence on recurrence.
      • Salas S.
      • Dufresne A.
      • Bui B.
      • et al.
      Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.
      • Crago A.M.
      • Denton B.
      • Salas S.
      • et al.
      A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.
      The high recurrence rate after surgery suggests that a clinical trial of an adjuvant tolerable chemotherapy or other treatment shortly after surgery might be worthy of study in some cases.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      Adjuvant chemotherapy after surgery might be particularly useful after abdominal surgery in patients at high risk of DTF, such as patients with Gardner syndrome, although it has not been well studied.
      In some cases radiation therapy can be useful
      • Eastley N.
      • McCulloch T.
      • Esler C.
      • et al.
      Extra-abdominal desmoid fibromatosis: a review of management, current guidance and unanswered questions.
      • Joglekar S.B.
      • Rose P.S.
      • Sim F.
      • Okuno S.
      • Petersen I.
      Current perspectives on desmoid tumors: the Mayo Clinic approach.
      • Ballo M.T.
      • Zagars G.K.
      • Pollack A.
      • Pisters P.W.
      • Pollack R.A.
      Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy.
      • Jelinek J.A.
      • Stelzer K.J.
      • Conrad E.
      • et al.
      The efficacy of radiotherapy as postoperative treatment for desmoid tumors.
      • Kiel K.D.
      • Suit H.D.
      Radiation therapy in the treatment of aggressive fibromatoses (desmoid tumors).
      • Kriz J.
      • Eich H.T.
      • Haverkamp U.
      • et al.
      Radiotherapy is effective for desmoid tumors (aggressive fibromatosis)—long-term results of a German multicenter study.
      • McCollough W.M.
      • Parsons J.T.
      • van der Griend R.
      • Enneking W.F.
      • Heare T.
      Radiation therapy for aggressive fibromatosis: the experience at the University of Florida.
      • Mendenhall W.M.
      • Zlotecki R.A.
      • Morris C.G.
      • Hochwald S.N.
      • Scarborough M.T.
      Aggressive fibromatosis.
      • Suit H.
      • Spiro I.
      Radiation in the multidisciplinary management of desmoid tumors.
      ; although radiation therapy has been reported to decrease local recurrence after marginal surgery in several uncontrolled studies, other retrospective studies have found no benefit.
      • Ma D.
      • Li S.
      • Fu R.
      • et al.
      Long-term outcomes of 47 patients with aggressive fibromatosis of the chest treated with surgery.
      The role of radiation therapy among the various treatment options remains controversial because of long-term sequelae, including edema, pain, and second malignant neoplasm.
      • Goldblum J.R.
      • Fletcher J.A.
      Desmoid-type fibromatosis.
      • Lev D.
      • Kotilingam D.
      • Wei C.
      • et al.
      Optimizing treatment of desmoid tumors.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      • Eastley N.
      • McCulloch T.
      • Esler C.
      • et al.
      Extra-abdominal desmoid fibromatosis: a review of management, current guidance and unanswered questions.
      • Joglekar S.B.
      • Rose P.S.
      • Sim F.
      • Okuno S.
      • Petersen I.
      Current perspectives on desmoid tumors: the Mayo Clinic approach.
      • Ballo M.T.
      • Zagars G.K.
      • Pollack A.
      • Pisters P.W.
      • Pollack R.A.
      Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy.
      • Leibel S.A.
      • Wara W.M.
      • Hill D.R.
      • et al.
      Desmoid tumors: local control and patterns of relapse following radiation therapy.
      • Crago A.M.
      • Denton B.
      • Salas S.
      • et al.
      A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.
      • Kiel K.D.
      • Suit H.D.
      Radiation therapy in the treatment of aggressive fibromatoses (desmoid tumors).
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis.
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Advanced aggressive fibromatosis: effective palliation with chemotherapy.
      • Nuyttens J.J.
      • Rust P.F.
      • Thomas Jr., C.R.
      • Turrisi III, A.T.
      Surgery versus radiation therapy for patients with aggressive fibromatosis or desmoid tumors: a comparative review of 22 articles.
      In 1 study of 6 radiation-induced sarcomas in patients with DTF whose original tumor had a mutation in CTNNB1, 3 had the same CTNNB1 mutation as the original DTF, and 3 had no CTNNB1 mutation, suggesting that some cases of DTF were not derived from the original DTF tumor clone.
      • Verschoor A.J.
      • Cleton-Jansen A.M.
      • Wijers-Koster P.
      • et al.
      Radiation-induced sarcomas occurring in desmoid-type fibromatosis are not always derived from the primary tumor.
      Cryoablation has also been used in an attempt to decrease the trauma associated with more extensive surgery, although its role remains to be defined.
      • Schmitz J.J.
      • Schmit G.D.
      • Atwell T.D.
      • et al.
      Percutaneous cryoablation of extraabdominal desmoid tumors: a 10-year experience.
      Various medical therapies have been used for DTF, ranging from those with low toxicity such as nonsteroidal anti-inflammatory drugs
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Klein W.A.
      • Miller H.H.
      • Anderson M.
      • DeCosse J.J.
      The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis.
      • Waddell W.R.
      • Gerner R.E.
      Indomethacin and ascorbate inhibit desmoid tumors.
      • Waddell W.R.
      • Kirsch W.M.
      Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors.
      or hormonal therapy
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Kinzbrunner B.
      • Ritter S.
      • Domingo J.
      • Rosenthal C.J.
      Remission of rapidly growing desmoid tumors after tamoxifen therapy.
      • Lim C.L.
      • Walker M.J.
      • Mehta R.R.
      • Das Gupta T.K.
      Estrogen and antiestrogen binding sites in desmoid tumors.
      • Mukherjee A.
      • Malcolm A.
      • de la Hunt M.
      • Neal D.E.
      Pelvic fibromatosis (desmoid)—treatment with steroids and tamoxifen.
      • Wilcken N.
      • Tattersall M.H.
      Endocrine therapy for desmoid tumors.
      to aggressive combination chemotherapy.
      • Gega M.
      • Yanagi H.
      • Yoshikawa R.
      • et al.
      Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis.
      • Hutchinson R.J.
      • Norris D.G.
      • Schnaufer L.
      Chemotherapy: a successful application in abdominal fibromatosis.
      • Kasper B.
      • Ströbel P.
      • Hohenberger P.
      Desmoid tumors: clinical features and treatment options for advanced disease.
      • Lynch H.T.
      • Fitzgibbons Jr., R.
      • Chong S.
      • et al.
      Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner's syndrome.
      • Okuno S.H.
      • Edmonson J.H.
      Combination chemotherapy for desmoid tumors.
      • Patel S.R.
      • Benjamin R.S.
      Desmoid tumors respond to chemotherapy: defying the dogma in oncology.
      • Patel S.R.
      • Evans H.L.
      • Benjamin R.S.
      Combination chemotherapy in adult desmoid tumors.
      • Stein R.
      Chemotherapeutic response in fibromatosis of the neck.
      Colchicine has also been used,
      • Dominguez-Malagon H.R.
      • Alfeiran-Ruiz A.
      • Chavarria-Xicotencatl P.
      • Duran-Hernandez M.S.
      Clinical and cellular effects of colchicine in fibromatosis.
      and a case report suggests a possible response to 1,2-dihydroxyvitamin D3.
      • Ferah Y.
      • Ayse K.
      • Mustafa C.
      • Ugur S.
      • Murat G.
      • Lale A.I.
      Possible therapeutic role of vitamin D3 in aggressive fibromatosis.
      Comparative evaluation of different therapies is hindered by the fact that most case series are not randomized; the variable natural history of DTF further complicates the interpretation of these studies. In cases that respond to drug, the optimal length of treatment is unknown. Treatment approaches range from holding treatment at an arbitrary time in the setting of stable disease to prolonged treatment in responders, followed by abrupt cessation of therapy or gradually weaning treatment intervals or dose.
      Magnetic resonance imaging (MRI) is the best imaging technique for diagnosis and monitoring of DTF.
      • Ahn J.M.
      • Yoon H.K.
      • Suh Y.L.
      • et al.
      Infantile fibromatosis in childhood: findings on MR imaging and pathologic correlation.
      • Guglielmi G.
      • Cifaratti A.
      • Scalzo G.
      • Magarelli N.
      Imaging of superficial and deep fibromatosis.
      • Lee J.C.
      • Thomas J.M.
      • Phillips S.
      • Fisher C.
      • Moskovic E.
      Aggressive fibromatosis: MRI features with pathologic correlation.
      • O'Keefe F.
      • Kim E.E.
      • Wallace S.
      Magnetic resonance imaging in aggressive fibromatosis.
      In some cases MRI may reveal changes associated with increased collagen deposition and decreased cellularity, such as a loss of T2 signal, suggesting either a response to treatment or a spontaneous decrease in disease activity.
      • Gounder M.M.
      • Lefkowitz R.A.
      • Keohan M.L.
      • et al.
      Activity of Sorafenib against desmoid tumor/deep fibromatosis.
      • Martin-Liberal J.
      • Benson C.
      • McCarty H.
      • Thway K.
      • Messiou C.
      • Judson I.
      Pazopanib is an active treatment in desmoid tumour/aggressive fibromatosis.
      Changes in contrast enhancement may provide similar information.
      Expression of estrogen receptor β is often present and, along with the occasional relationship of DTF activity to pregnancy, provides some rationale for hormonal therapy.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Eastley N.
      • McCulloch T.
      • Esler C.
      • et al.
      Extra-abdominal desmoid fibromatosis: a review of management, current guidance and unanswered questions.
      • Lim C.L.
      • Walker M.J.
      • Mehta R.R.
      • Das Gupta T.K.
      Estrogen and antiestrogen binding sites in desmoid tumors.
      • Mukherjee A.
      • Malcolm A.
      • de la Hunt M.
      • Neal D.E.
      Pelvic fibromatosis (desmoid)—treatment with steroids and tamoxifen.
      • Wilcken N.
      • Tattersall M.H.
      Endocrine therapy for desmoid tumors.
      • Deyrup A.T.
      • Tretiakova M.
      • Montag A.G.
      Estrogen receptor-β expression in extraabdominal fibromatoses: an analysis of 40 cases.
      • Janinis J.
      • Patriki M.
      • Vini L.
      • Aravantinos G.
      • Whelan J.S.
      The pharmacological treatment of aggressive fibromatosis: a systematic review.
      • Waddell W.R.
      Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3′,5′-adenosine monophosphate.
      It has been reported that estrogen treatment can induce the formation of desmoid tumors that regress after discontinuing the drug or after adding progesterone.
      • Svanvik J.
      • Knutsson F.
      • Jansson R.
      • Ekman H.
      Desmoid tumor in the abdominal wall after treatment with high dose estradiol for prostatic cancer.
      In 1 study of 25 patients with DTF (8 sporadic and 17 associated with FAP), a regimen of tamoxifen (120 mg/d) and sulindac (300 mg/d) was not highly effective in preventing DTF recurrence after surgery, but was still felt to be potentially useful in other settings, in which stable disease was the most common response.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      The optimal dose of tamoxifen for DTF is not well defined, and a range of doses has been used.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      Nonsteroidal anti-inflammatory drugs, typically ibuprofen or sulindac, have also been used with some efficacy.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Klein W.A.
      • Miller H.H.
      • Anderson M.
      • DeCosse J.J.
      The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis.
      • Waddell W.R.
      • Gerner R.E.
      Indomethacin and ascorbate inhibit desmoid tumors.
      • Waddell W.R.
      • Kirsch W.M.
      Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors.
      • Janinis J.
      • Patriki M.
      • Vini L.
      • Aravantinos G.
      • Whelan J.S.
      The pharmacological treatment of aggressive fibromatosis: a systematic review.
      Desmoid-type fibromatosis also expresses androgen receptors; testosterone can stimulate DTF cell growth in vitro and DTF development in mouse models, suggesting androgen blockade as another potential hormonal approach.
      • Hong H.
      • Nadesan P.
      • Poon R.
      • Alman B.A.
      Testosterone regulates cell proliferation in aggressive fibromatosis (desmoid tumour).
      A combination of methotrexate and vinblastine was one of the first chemotherapy regimens widely used for DTF, with response rates ranging from 30% to 50%.
      • Azzarelli A.
      • Gronchi A.
      • Bertulli R.
      • et al.
      Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis.
      • Skapek S.X.
      • Hawk B.J.
      • Hoffer F.A.
      • et al.
      Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children.
      • Weiss A.J.
      • Lackman R.D.
      Low-dose chemotherapy of desmoid tumors.
      • Weiss A.J.
      • Lackman R.D.
      Therapy of desmoid tumors and related neoplasms.
      Because this regimen does have considerable toxicity, vinorelbine has largely replaced vinblastine in this regimen.
      • Weiss A.J.
      • Horowitz S.
      • Lackman R.D.
      Therapy of desmoid tumors and fibromatosis using vinorelbine.
      Methotrexate combined with vinblastine or vinorelbine is more difficult to deliver over a prolonged course in adults because of toxicity.
      • Kasper B.
      • Ströbel P.
      • Hohenberger P.
      Desmoid tumors: clinical features and treatment options for advanced disease.
      • van der Hul R.L.
      • Seynaeve C.
      • van Geel B.N.
      • Verweij J.
      Low dose methotrexate and vinblastine, given weekly to patients with desmoid tumours, is associated with major toxicity.
      Other agents include more aggressive chemotherapy such as anthracyclines, gemcitabine, and even ifosfamide in rare cases.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis.
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Advanced aggressive fibromatosis: effective palliation with chemotherapy.
      • Gega M.
      • Yanagi H.
      • Yoshikawa R.
      • et al.
      Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis.
      • Okuno S.H.
      • Edmonson J.H.
      Combination chemotherapy for desmoid tumors.
      • Patel S.R.
      • Benjamin R.S.
      Desmoid tumors respond to chemotherapy: defying the dogma in oncology.
      • Patel S.R.
      • Evans H.L.
      • Benjamin R.S.
      Combination chemotherapy in adult desmoid tumors.
      • Seiter K.
      • Kemeny N.
      Successful treatment of a desmoid tumor with doxorubicin.
      • Skubitz K.M.
      • Manivel J.C.
      • Clohisy D.R.
      • Frolich J.W.
      Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors.
      Tyrosine kinase inhibitors also have activity in some DTF cases, and meaningful responses have been described.
      • Heinrich M.C.
      • McArthur G.A.
      • Demetri G.D.
      • et al.
      Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).
      • Gounder M.M.
      • Lefkowitz R.A.
      • Keohan M.L.
      • et al.
      Activity of Sorafenib against desmoid tumor/deep fibromatosis.
      • Martin-Liberal J.
      • Benson C.
      • McCarty H.
      • Thway K.
      • Messiou C.
      • Judson I.
      Pazopanib is an active treatment in desmoid tumour/aggressive fibromatosis.
      • Skubitz K.M.
      • Manivel J.C.
      • Clohisy D.R.
      • Frolich J.W.
      Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors.
      • Chugh R.
      • Wathen J.K.
      • Patel S.R.
      • et al.
      Sarcoma Alliance for Research through Collaboration (SARC)
      Efficacy of imatinib in aggressive fibromatosis: results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial.
      • Mace J.
      • Sybil Biermann J.
      • Sondak V.
      • et al.
      Response of extraabdominal desmoid tumors to therapy with imatinib mesylate.
      • Penel N.
      • Le Cesne A.
      • Bui B.N.
      • et al.
      Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up.
      • Wcislo G.
      • Szarlej-Wcislo K.
      • Szczylik C.
      Control of aggressive fibromatosis by treatment with imatinib mesylate: a case report and review of the literature.
      • Dao A.
      • Benchakroun N.
      • Jabir H.
      • et al.
      Five years of local control of subscapularis aggressive fibromatosis managed by surgery and imatinib: a case report.
      In at least 1 case the tumor was responsive to sunitinib but not imatinib at the usual doses,
      • Skubitz K.M.
      • Manivel J.C.
      • Clohisy D.R.
      • Frolich J.W.
      Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors.
      suggesting that in some cases efficacy may be due to effects on targets other than KIT (kit proto-oncogene receptor tyrosine kinase). Trials of tyrosine kinase inhibitors in DTF are ongoing (Table). Pegylated-liposomal doxorubicin (PLD) is particularly attractive, given its efficacy and low toxicity profile and is becoming widely used.
      • de Camargo V.P.
      • Keohan M.L.
      • D'Adamo D.R.
      • et al.
      Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor).
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis.
      • Constantinidou A.
      • Jones R.L.
      • Scurr M.
      • Al-Muderis O.
      • Judson I.
      Advanced aggressive fibromatosis: effective palliation with chemotherapy.
      • Skubitz K.M.
      • Manivel J.C.
      • Clohisy D.R.
      • Frolich J.W.
      Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors.
      TableOngoing Trials for Desmoid-Type Fibromatosis
      InterventionTitlePhaseLocationClinical trial identifierStatus
      SirolimusA pilot study evaluating the use of mTor inhibitor sirolimus in children and young adults with desmoid-type fibromatosisPilot phase 1/IIMaine Medical CenterNCT01265030Recruiting
      CryotherapyEvaluation of the cryodestruction of non abdominopelvic desmoid tumors in patients progressing despite medical treatmentPhase IIUniversity Hospital, StrasbourgNCT02476305Recruiting
      PF-03084014Phase II trial of the gamma-secretase inhibitor PF-03084014 in adults with desmoid tumors/aggressive fibromatosisPhase IINational Cancer InstituteNCT01981551Closed to accrual
      PazopanibPazopanib efficacy and tolerance in desmoid tumorsRandomized phase II: pazopanib vs methotrexate-vinblastineInstitut BergoniéNCT01876082Recruiting
      ImatinibImatinib in patients with desmoid tumor and chondrosarcomaPhase IIItalian Sarcoma GroupNCT00928525Closed to accrual
      Sulindac and tamoxifenSulindac and tamoxifen in treating patients with desmoid tumorPhase IIChildren's Oncology GroupNCT00068419Closed to accrual
      SorafenibSorafenib tosylate in treating patients with desmoid tumors or aggressive fibromatosisPhase IINational Cancer InstituteNCT02066181Closed to accrual
      Observation till- progressionTailored beta-catenin mutational approach in extra-abdominal sporadic desmoids tumor patientsObservationalFondazione IRCCS Istituto Nazionale dei Tumori, MilanoNCT02547831Recruiting
      ImatinibStudy to evaluate imatinib in desmoid tumorsPhase IIHeidelberg UniversityNCT01137916Closed to accrual
      5-Aminolevulinic acid (5-ALA) and photodynamic therapySafety and efficacy study using 5-ALA oral administration as an adjuvant therapy on the rate of local tumor recurrence in patients who have desmoid tumorsPhase II adjuvantTel-Aviv Sourasky Medical CenterNCT01898416Recruiting
      ImatinibA trial of imatinib for patients with aggressive desmoid tumor (aggressive fibromatosis)Phase IIYonsei UniversityNCT02495519Closed to accrual
      Antibodies to WISP1 inhibit fibrosis in mouse models of bleomycin lung toxicity, suggesting this as a potential target for the future treatment of select cases of DTF as well. Similarly, the beneficial response of DTF to certain chemotherapy approaches suggests that a similar approach could be useful in severe cases of idiopathic pulmonary fibrosis. Altering Notch signaling with γ-secretase inhibition is also under study, and an adenosine monophosphate–activated protein kinase activator inhibits peritoneal fibrosis (a complication of peritoneal dialysis) in a mouse model.
      • Ju K.D.
      • Kim H.J.
      • Tsogbadrakh B.
      • et al.
      HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis.
      Preliminary data suggest activity of a γ-secretase inhibitor in DTF. Some ongoing trials for DTF are listed in the Table.
      In some cases DTF tumors, and their constituent cells, may stabilize or regress, with a decrease in expression of biochemical markers of disease activity (Figure 4). The observation that DTF tumors sometimes stabilize or regress implies that the tumor myofibroblasts retain sensitivity to a regulatory system, likely an autocrine or more likely paracrine signaling system, similar to that of wound healing. That DTF tumors may still subsequently become active again after stabilization or regression implies that a population of cells remains that retains the ability to respond to some proinflammatory and/or profibrotic stimuli, in some cases induced by trauma, associated inflammation, or other physiological conditions, such as pregnancy. The degree to which recruited normal myofibroblasts contribute to the mass of clonal myofibroblasts in an individual DTF tumor could potentially affect the tumor behavior.

      Predicting DTF Behavior

      Predicting which treatment is most appropriate for a particular patient, such as the observation approach, would be useful. A nomogram using tumor size, location, and patient age has been reported to be useful in predicting recurrence after surgery.
      • Crago A.M.
      • Denton B.
      • Salas S.
      • et al.
      A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.
      Some studies, but not all, have suggested that the location of the β-catenin mutation correlates with differences in clinical course of sporadic DTF. For example, tumors with S45F mutations in CTNNB1 may be at a higher risk of recurrence.
      • Dômont J.
      • Salas S.
      • Lacroix L.
      • et al.
      High frequency of β-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management.
      • Lazar A.J.
      • Tuvin D.
      • Hajibashi S.
      • et al.
      Specific mutations in the β-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.
      • Le Guellec S.
      • Soubeyran I.
      • Rochaix P.
      • et al.
      CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics.
      • Bo N.
      • Wang D.
      • Wu B.
      • Chen L.
      • Ruixue M.
      Analysis of β-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis.
      • Colombo C.
      • Miceli R.
      • Lazar A.J.
      • et al.
      CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.
      • Mullen J.T.
      • DeLaney T.F.
      • Rosenberg A.E.
      • et al.
      β-Catenin mutation status and outcomes in sporadic desmoid tumors.
      • van Broekhoven D.L.
      • Verhoef C.
      • Grünhagen D.J.
      • et al.
      Prognostic value of CTNNB1 gene mutation in primary sporadic aggressive fibromatosis.
      • Salas S.
      • Dufresne A.
      • Bui B.
      • et al.
      Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.
      One study found that DTF tumors with an S45 β-catenin mutation had a higher progression arrest rate than did wild-type tumors when treated with imatinib,
      • Kasper B.
      • Gruenwald V.
      • Reichardt P.
      • Bauer S.
      • Hohenberger P.
      • Haller F.
      Correlation of CTNNB1 mutation status with progression arrest rate in RECIST progressive desmoid-type fibromatosis treated with imatinib: translational research results from a phase 2 study of the German Interdisciplinary Sarcoma Group (GISG-01).
      and a European position paper encouraged β-catenin mutation testing in DTF.
      • Kasper B.
      • Baumgarten C.
      • Bonvalot S.
      • et al.
      Desmoid Working Group
      Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients' and professionals' expertise—a sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group initiative.
      Another study found that higher nuclear β-catenin expression (>20% of tumor cells expressing nuclear β-catenin) had a higher recurrence rate than did lower expression.
      • Gebert C.
      • Hardes J.
      • Kersting C.
      • et al.
      Expression of β-catenin and p53 are prognostic factors in deep aggressive fibromatosis.
      Trisomy 8 has also been associated with a higher risk of recurrence.
      • Fletcher J.A.
      • Naeem R.
      • Xiao S.
      • Corson J.M.
      Chromosome aberrations in desmoid tumors: trisomy 8 may be a predictor of recurrence.
      In 1 study, immunohistochemical staining for ADAM12, Fap-1α, and WISP1 correlated with nuclear chromatin density and was higher in patients with an early recurrence (<1 year after surgery compared with no recurrence at 5 years).
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      Other studies suggest that gene expression patterns may also correlate with biological behavior
      • Misemer B.S.
      • Skubitz A.P.
      • Carlos Manivel J.
      • et al.
      Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity.
      • Skubitz K.M.
      • Skubitz A.P.
      Gene expression in aggressive fibromatosis.
      • Dufresne A.
      • Paturel M.
      • Alberti L.
      • et al.
      Prediction of desmoid tumor progression using miRNA expression profiling.
      • Salas S.
      • Brulard C.
      • Terrier P.
      • et al.
      Gene expression profiling of desmoid tumors by cDNA microarrays and correlation with progression-free survival.
      and might be useful in identifying patients who would more likely benefit from therapy.

      Desmoid-Type Fibromatosis as a Model for the Role of Tumor Stroma in Other Diseases

      The tumor stroma in invasive carcinomas frequently exhibits a desmoplastic response with proliferation of myofibroblasts, and tumors have been described as “wounds that do not heal.”
      • Dvorak H.F.
      Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
      ,p1650 Fibroblasts and myofibroblasts in neoplasms can secrete various trophic, mitogenic, and proinflammatory growth factors including hepatocyte growth factor, epidermal growth factor, TGF-β, and insulin-like growth factor 1 (reviewed in reference
      • Hanahan D.
      • Coussens L.M.
      Accessories to the crime: functions of cells recruited to the tumor microenvironment.
      ), possibly influencing growth of the clonal neoplastic cells. Because of their potential contribution to tumor biology, targeting the normal stromal myofibroblasts in tumors is an interesting potential approach to cancer treatment.
      • Brennen W.N.
      • Rosen D.M.
      • Wang H.
      • Isaacs J.T.
      • Denmeade S.R.
      Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug.
      As DTF closely resembles wound healing, it may be a potentially useful model to study the role of tumor stroma. Indeed, some studies suggest that gene signatures similar to that seen in DTF correlate with clinical outcome in some malignancies.
      • West R.B.
      • Nuyten D.S.
      • Subramanian S.
      • et al.
      Determination of stromal signatures in breast carcinoma.
      • Skubitz K.M.
      • Francis P.
      • Skubitz A.P.
      • Luo X.
      • Nilbert M.
      Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas.
      • Skubitz K.M.
      • Geschwind K.
      • Xu W.W.
      • Koopmeiners J.S.
      • Skubitz A.P.
      Gene expression identifies heterogeneity of metastatic behavior among gastrointestinal stromal tumors.
      • Skubitz K.M.
      • Skubitz A.P.
      • Xu W.W.
      • et al.
      Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas.
      • Beck A.H.
      • Espinosa I.
      • Gilks C.B.
      • van de Rijn M.
      • West R.B.
      The fibromatosis signature defines a robust stromal response in breast carcinoma.
      Desmoid-type fibromatosis may also provide a model for other fibrosing diseases such as progressive pulmonary fibrosis.

      Desmoid-Type Fibromatosis Case Examples

      As described above, DTF can have a different course in different patients. Thirteen cases of DTF are summarized here (10 in Supplemental Materials, Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org) to illustrate important principles of DTF biology and treatment.

      Case 1: Slow Spontaneous Regression of an Extra-Abdominal DTF in a Man

      A 28-year-old man noted a small mass in his right chest near the sternum. He developed psoriatic arthritis 8 months later and began treatment with methotrexate. A year after initiating methotrexate, etanercept was added. At presentation 8 months after starting etanercept, he was not sure the mass had grown over the part year, but he now had occasional twinges of pain lasting a few seconds, from none to several times a day. Thus, the tumor progressed symptomatically while on methotrexate. Examination revealed a firm, fixed, nontender parasternal mass. Computed tomography revealed a mass involving the sternum growing through the chest wall (Figure 5, top panel) and a biopsy revealed DTF. Consultation at another institution recommended surgical removal of the chest wall mass; however, he was observed, and 3 months later his symptoms and imaging of the mass were unchanged. Ten months after the biopsy, the mass was slightly smaller and symptoms were unchanged. At 35 months after the biopsy, his symptoms had resolved and the mass was smaller (Figure 5, bottom panel). He remains symptom free 50 months after the biopsy and continues the observation. This case exhibits slow spontaneous regression of an extra-abdominal DTF in a man, not related to estrogen.
      Figure thumbnail gr5
      Figure 5Slow 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.

      Case 2: DTF Caused by Local Trauma/Inflammation and Stable Disease After Methotrexate and Vinblastine

      A 33-year-old man presented with a painful mass in the arm. He had an influenza shot 1.5 years before presentation, and shortly thereafter he became aware of a persistent discomfort in the region of the injection site that gradually progressed, and a painful mass developed. The size of the mass and degree of pain progressed markedly over the 2 months before presentation. Examination revealed a slightly tender warm 10 cm hard mass fixed to the underlying tissue in the proximal right arm. Magnetic resonance imaging revealed a 7×5×8.5 cm mass along the triceps muscle that was hyperintense on a fluid-sensitive image with some areas of heterogeneity (Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org). A tru-cut biopsy revealed DTF, and an open biopsy performed to exclude a low-grade sarcoma also revealed DTF. Surgical treatment was felt to require shoulder disarticulation. As surgical treatment was felt to result in significant morbidity, chemotherapy with methotrexate and vinblastine was begun. At 6 weeks of treatment, there was no clear evidence of change in tumor size or symptoms, and he moved to a different state in which chemotherapy was continued for 2 more months without change in tumor size. The tumor was then surgically excised. He was sent for consideration of postoperative radiation therapy and thereafter lost to follow-up. This case exhibits DTF development after local trauma/inflammation, potential significant morbidity of treatment (shoulder disarticulation or more limited disfiguring surgery), and disease stabilization with methotrexate and vinblastine.

      Case 3: Aggressive Multifocal DTF Controlled With PLD

      A 32-year-old man with Gardner syndrome presented with painful extra-abdominal desmoid tumors as well as large intra-abdominal desmoids requiring opiates. He also had a pulmonary embolus and venous thrombosis and was taking coumadin. He had been treated a year earlier with tamoxifen for 8 weeks, but tumors grew during this period. He began treatment with PLD and had a good response. Treatment was held after 6 cycles. Desmoid-type fibromatosis progression was noted 10 months after the last chemotherapy, and he received imatinib 400 mg/d orally, but it progressed. He began treatment with PLD and noted stabilization of pain after 1 month and some tumor shrinkage at 3 months. Three months later, imaging revealed further tumor regression, and the interval between PLD treatments was increased. Subsequent imaging revealed continued gradual tumor shrinkage and then stabilization, and PLD was discontinued 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 imaging, 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 carefully 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), β-catenin mutation and APC mutation 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 variability. 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 long to treat a responding tumor and how to quantify tumor response must be considered. RECIST (Response Evaluation Criteria In Solid Tumors) is known to be a poor measure of response in DTF, but some measure of size (optimally careful analysis of tumor volume) and tumor “activity” (possibly determined by contrast enhancement or changes in T1/T2 signal on MRI) need to be considered. Because tumor stabilization can be a beneficial outcome, a measure of symptoms experienced by the patient should be included as well, including a quality of life assessment such as QLQ-C30 or FACTG. Perhaps better than nonlinear subjective variables such as a “pain scale” are clear measures such as the following: is a pain medication required, how much pain medication is used, does the tumor interfere with sleep (yes/no), how far can the patient walk before tumor pain limits the activity (this could be objectively determined at each clinic visit for cases with serious symptoms), and what is the range of motion of the affected body part. Only with carefully controlled trials that use careful stratification based on known variables can the best treatment approaches for DTF be determined.

      Summary

      Because of the heterogeneity of the biological behavior of DTF, the optimal approach to treatment is unclear. Historically, surgery was the mainstay of treatment, but recurrence after surgery is common.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Rodriguez-Bigas M.A.
      • Mahoney M.C.
      • Karakousis C.P.
      • Petrelli N.J.
      Desmoid tumors in patients with familial adenomatous polyposis.
      • Anthony T.
      • Rodriguez-Bigas M.A.
      • Weber T.K.
      • Petrelli N.J.
      Desmoid tumors.
      • Dong-Heup K.
      • Kim D.H.
      • Goldsmith H.S.
      • Quan S.H.
      • Huvos A.G.
      Intra-abdominal desmoid tumor.
      • Johnson J.G.
      • Gilbert E.
      • Zimmermann B.
      • Watne A.L.
      Gardner's syndrome, colon cancer, and sarcoma.
      In addition, trauma can stimulate DTF growth, and surgery is a form of trauma associated with inflammation and production of various growth factors important in wound healing that may also stimulate clonal DTF cells; this is especially true in the case of FAP-associated mesenteric DTF.
      • Bertario L.
      • Russo A.
      • Sala P.
      • et al.
      Hereditary Colorectal Tumours Registry
      Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
      • Hansmann A.
      • Adolph C.
      • Vogel T.
      • Unger A.
      • Moeslein G.
      High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors.
      • Jones I.T.
      • Jagelman D.G.
      • Fazio V.W.
      • Lavery I.C.
      • Weakley F.L.
      • McGannon E.
      Desmoid tumors in familial polyposis coli.
      • Harvey J.C.
      • Quan S.H.
      • Fortner J.G.
      Gardner's syndrome complicated by mesenteric desmoid tumors.
      • Reitamo J.J.
      The desmoid tumor. IV. Choice of treatment, results, and complications.
      • Friedl W.
      • Caspari R.
      • Sengteller M.
      • et al.
      Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families.
      Although surgery remains an option for the initial treatment in which the expected morbidity is low and the chance of complete removal is high, given the usually slow progression of DTF, a regimen with low toxicity is the preferred initial approach and observation has become more standard.
      • Mitchell G.
      • Thomas J.M.
      • Harmer C.L.
      Aggressive fibromatosis: evidence for a stable phase.
      • Bonvalot S.
      • Desai A.
      • Coppola S.
      • et al.
      The treatment of desmoid tumors: a stepwise clinical approach.
      • Bonvalot S.
      • Eldweny H.
      • Haddad V.
      • et al.
      Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.
      • Bonvalot S.
      • Ternes N.
      • Fiore M.
      • et al.
      Spontaneous regression of primary abdominal wall desmoid tumors: more common than previously thought.
      • Colombo C.
      • Miceli R.
      • Le Péchoux C.
      • et al.
      Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients.
      • Eastley N.
      • McCulloch T.
      • Esler C.
      • et al.
      Extra-abdominal desmoid fibromatosis: a review of management, current guidance and unanswered questions.
      • Garbay D.
      • Le Cesne A.
      • Penel N.
      • et al.
      Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG).
      • Gronchi A.
      • Colombo C.
      • Le Péchoux C.
      • et al.
      Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group.
      • Nakayama T.
      • Tsuboyama T.
      • Toguchida J.
      • Hosaka T.
      • Nakamura T.
      Natural course of desmoid-type fibromatosis.
      • Roussin S.
      • Mazouni C.
      • Rimareix F.
      • et al.
      Toward a new strategy in desmoid of the breast?.
      • Salas S.
      • Dufresne A.
      • Bui B.
      • et al.
      Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation.
      Of course, the appropriate clinical decision depends on the particular case, and some require aggressive chemotherapy initially.

      Conclusion

      Desmoid-type fibromatosis is an uncommon locally invasive tumor. 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.

      Acknowledgments

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

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at: http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

      References

        • Alman B.A.
        • Goldberg M.J.
        • Naber S.P.
        • Galanopoulous T.
        • Antoniades H.N.
        • Wolfe H.J.
        Aggressive fibromatosis.
        J Pediatr Orthop. 1992; 12: 1-10
        • Alman B.A.
        • Li C.
        • Pajerski M.E.
        • Diaz-Cano S.
        • Wolfe H.J.
        Increased β-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
        Am J Pathol. 1997; 151: 329-334