Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome. 1. Introduction Desmoid tumors (DTs), also known as aggressive fibromatosis, are fibroblastic neoplasms which are often locally aggressive but lack metastatic potential. They may occur sporadically or in association with familial adenomatous polyposis (FAP) syndrome. Among individuals with FAP, desmoids most frequently occur in intra-abdominal and abdominal wall locations with most arising from the peritoneum. These abdominal desmoids range in severity from indolent, asymptomatic lesions to highly invasive, sometimes fatal tumors. Although less common than abdominal desmoids and very rarely fatal, extra-abdominal desmoids are also a significant cause of morbidity in this population. This paper will review recent developments in the diagnosis, screening, treatment, and prognosis of FAP-associated extra-abdominal DTs. 2. Epidemiology of FAP-Associated Desmoid Tumors The overall incidence of DTs has frequently been quoted at 2–4 per million people per year [1, 2]. This estimate is derived from a 1986 Finnish study which used the pathologic records of several regional hospitals and their known catchment area populations to calculate an incidence figure [3]. Recently, the Dutch national pathology database was analyzed, and 519 total desmoid cases in patients over the age of ten were identified from 1999 to 2009. There were 480 sporadic DTs and 39 FAP-DTs. The annual incidence was 3.7 per million overall [4] consistent with the earlier Finnish study. The same nationwide study from The Netherlands identified 1400 patients over the age of ten with FAP during the 1999 to 2009 period. FAP-associated DTs (FAP-DTs) made up 7.5% of all DTs, and the relative risk of an FAP patient developing a DT was over 800-fold higher than the general population [4]. The Dutch study was limited by the use of pathologic specimens as many DTs may be identified based upon history, physical exam, and imaging but not biopsied or surgically excised especially in the FAP cohort. Additionally, some individuals with sporadic DTs may have had as yet
O. Micke and M. H. Seegenschmiedt, “Radiation therapy for aggressive fibromatosis (desmoid tumors): results of a national Patterns of Care Study,” International Journal of Radiation Oncology Biology Physics, vol. 61, no. 3, pp. 882–891, 2005.
H. S. Hosalkar, J. T. Torbert, E. J. Fox, T. F. Delaney, A. J. Aboulafia, and R. D. Lackman, “Musculoskeletal desmoid tumors,” Journal of the American Academy of Orthopaedic Surgeons, vol. 16, no. 4, pp. 188–198, 2008.
J. J. Reitamo, T. M. Scheinin, and P. Hayry, “The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor,” The American Journal of Surgery, vol. 151, no. 2, pp. 230–237, 1986.
M. H. Nieuwenhuis, M. Casparie, L. M. H. Mathus-Vliegen, O. M. Dekkers, P. C. W. Hogendoorn, and H. F. A. Vasen, “A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses,” International Journal of Cancer, vol. 129, no. 1, pp. 256–261, 2011.
T. Fallen, M. Wilson, B. Morlan, and N. M. Lindor, “Desmoid tumors—a characterization of patients seen at Mayo Clinic 1976–1999,” Familial Cancer, vol. 5, no. 2, pp. 191–194, 2006.
M. H. Nieuwenhuis, J. H. Lefevre, S. Bülow et al., “Family history, surgery, and APC mutation are risk factors for desmoid tumors in familial adenomatous polyposis: an international cohort study,” Diseases of the Colon & Rectum, vol. 54, no. 10, pp. 1229–1234, 2011.
C. D. Fletcher, K. K. Unni, and F. Mertens, World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of Soft Tissue and Bone, IARC Press, 2002.
J. A. Fletcher, R. Naeem, S. Xiao, and J. M. Corson, “Chromosome aberrations in desmoid tumors: trisomy 8 may be a predictor of recurrence,” Cancer Genetics and Cytogenetics, vol. 79, no. 2, pp. 139–143, 1995.
H. Kouho, T. Aoki, M. Hisaoka, and H. Hashimoto, “Clinicopathological and interphase cytogenetic analysis of desmoid tumours,” Histopathology, vol. 31, no. 4, pp. 336–341, 1997.
A. Leithner, M. Gapp, R. Radl et al., “Immunohistochemical analysis of desmoid tumours,” Journal of Clinical Pathology, vol. 58, no. 11, pp. 1152–1156, 2005.
A. T. Deyrup, M. Tretiakova, and A. G. Montag, “Estrogen receptor-β expression in extraabdominal fibromatoses: an analysis of 40 cases,” Cancer, vol. 106, no. 1, pp. 208–213, 2006.
I. Nishisho, Y. Nakamura, Y. Miyoshi et al., “Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients,” Science, vol. 253, no. 5020, pp. 665–669, 1991.
J. Groden, A. Thliveris, W. Samowitz et al., “Identification and characterization of the familial adenomatous polyposis coli gene,” Cell, vol. 66, no. 3, pp. 599–600, 1991.
G. Joslyn, M. Carlson, A. Thliveris et al., “Identification of deletion mutations and three new genes at the familial polyposis locus,” Cell, vol. 66, no. 3, pp. 601–613, 1991.
K. W. Kinzler, M. C. Nilbert, L. K. Su et al., “Identification of FAP locus genes from chromosome 5q21,” Science, vol. 253, no. 5020, pp. 661–665, 1991.
C. A. Hanson and J. R. Miller, “Non-traditional roles for the Adenomatous Polyposis Coli (APC) tumor suppressor protein,” Gene, vol. 361, no. 1-2, pp. 1–12, 2005.
R. T. Moon, A. D. Kohn, G. V. de Ferrari, and A. Kaykas, “WNT and β-catenin signalling: giseases and therapies,” Nature Reviews Genetics, vol. 5, no. 9, pp. 691–701, 2004.
D. J. Lips, N. Barker, H. Clevers, and A. Hennipman, “The role of APC and beta-catenin in the aetiology of aggressive fibromatosis (desmoid tumors),” European Journal of Surgical Oncology, vol. 35, no. 1, pp. 3–10, 2009.
H. Lamlum, M. Ilyas, A. Rowan et al., “The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis,” Nature Medicine, vol. 5, no. 9, pp. 1071–1075, 1999.
M. Giarola, D. Wells, P. Mondini et al., “Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours,” British Journal of Cancer, vol. 78, no. 5, pp. 582–587, 1998.
S. Tejpar, F. Nollet, C. Li et al., “Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor),” Oncogene, vol. 18, no. 47, pp. 6615–6620, 1999.
D. Kotiligam, A. J. F. Lazar, R. E. Pollock, and D. Lev, “Desmoid tumor: a disease opportune for molecular insights,” Histology and Histopathology, vol. 23, no. 1–3, pp. 117–126, 2008.
D. M. Eccles, R. van der Luijt, C. Breukel et al., “Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene,” The American Journal of Human Genetics, vol. 59, no. 6, pp. 1193–1201, 1996.
J. Couture, A. Mitri, R. Lagace 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 beta-catenin in the desmoid tumor,” Clinical Genetics, vol. 57, no. 3, pp. 205–212, 2000.
C. Albuquerque, C. Breukel, R. van der Luijt et al., “The “just-right” signaling model: APC somatic mutations are selected based on a specific level of activation of the β-catenin signaling cascade,” Human Molecular Genetics, vol. 11, no. 13, pp. 1549–1560, 2002.
A. Latchford, E. Volikos, V. Johnson et al., “APC mutations in FAP-associated desmoid tumours are non-random but not 'just right',” Human Molecular Genetics, vol. 16, no. 1, pp. 78–82, 2007.
M. Miyaki, T. Yamaguchi, T. Iijima et al., “Difference in characteristics of APC mutations between colonic and extracolonic tumors of FAP patients: variations with phenotype,” International Journal of Cancer, vol. 122, no. 11, pp. 2491–2497, 2008.
Z. Dobbie, M. Spycher, J. L. Mary et al., “Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene,” Journal of Medical Genetics, vol. 33, no. 4, pp. 274–280, 1996.
Y. L. Wallis, D. G. Morton, C. M. McKeown, and F. Macdonald, “Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition,” Journal of Medical Genetics, vol. 36, no. 1, pp. 14–20, 1999.
L. Bertario, A. Russo, P. Sala et al., “Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis,” International Journal of Cancer, vol. 95, no. 2, pp. 102–107, 2001.
M. H. Nieuwenhuis and H. F. A. Vasen, “Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature,” Critical Reviews in Oncology/Hematology, vol. 61, no. 2, pp. 153–161, 2007.
E. Elayi, E. Manilich, and J. Church, “Polishing the crystal ball: knowing genotype improves ability to predict desmoid disease in patients with familial adenomatous polyposis,” Diseases of the Colon and Rectum, vol. 52, no. 10, pp. 1762–1766, 2009.
K. M. Skubitz and A. P. N. Skubitz, “Gene expression in aggressive fibromatosis,” Journal of Laboratory and Clinical Medicine, vol. 143, no. 2, pp. 89–98, 2004.
H. Denys, A. Jadidizadeh, S. A. Nik et al., “Identification of IGFBP-6 as a significantly downregulated gene by β-catenin in desmoid tumors,” Oncogene, vol. 23, no. 3, pp. 654–664, 2004.
M. Bacac, E. Migliavacca, J. C. Stehle et al., “A gene expression signature that distinguishes desmoid tumours from nodular fasciitis,” Journal of Pathology, vol. 208, no. 4, pp. 543–553, 2006.
C. Gebert, J. Hardes, C. Kersting et al., “Expression of β-catenin and p53 are prognostic factors in deep aggressive fibromatosis,” Histopathology, vol. 50, no. 4, pp. 491–497, 2007.
S. Salas, F. Chibon, T. Noguchi et al., “Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors,” Genes Chromosomes and Cancer, vol. 49, no. 6, pp. 560–568, 2010.
E. Robanus-Maandag, C. Bosch, S. Amini-Nik, et al., “Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids,” PLoS ONE, vol. 6, Article ID e24354, 2011.
D. E. Joyner, S. H. Trang, A. J. Aboulafia, T. A. Damron, and R. L. Randall, “FAP-associated desmoid invasiveness correlates with in vitro resistance to doxorubicin,” Familial Cancer, vol. 8, no. 4, pp. 569–580, 2009.
S. B. Middleton, I. M. Frayling, and R. K. S. Phillips, “Desmoids in familial adenomatous polyposis are monoclonal proliferations,” British Journal of Cancer, vol. 82, no. 4, pp. 827–832, 2000.
C. Wu, S. Nik-Amini, P. Nadesan, W. L. Stanford, and B. A. Alman, “Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells,” Cancer Research, vol. 70, no. 19, pp. 7690–7698, 2010.
A. M. Carothers, H. Rizvi, R. M. Hasson et al., “Mesenchymal stromal cell mutations and wound healing contribute to the etiology of desmoid tumors,” Cancer Research, vol. 72, no. 1, pp. 346–355, 2012.
J. H. Lefevre, Y. Parc, S. Kernéis et al., “Risk factors for development of desmoid tumours in familial adenomatous polyposis,” British Journal of Surgery, vol. 95, no. 9, pp. 1136–1139, 2008.
A. Sinha, D. C. Gibbons, R. K. Phillips, and S. Clark, “Surgical prophylaxis in familial adenomatous polyposis: do pre-existing desmoids outside the abdominal cavity matter?” Familial Cancer, vol. 9, no. 3, pp. 407–411, 2010.
T. Iwama, K. Kuwabara, M. Ushiama, T. Yoshida, K. Sugano, and H. Ishida, “Identification of somatic APC mutations in recurrent desmoid tumors in a patient with familial adenomatous polyposis to determine actual recurrence of the original tumor or de novo occurrence,” Familial Cancer, vol. 8, no. 1, pp. 51–54, 2009.
A. Sinha, P. P. Tekkis, D. C. Gibbons, R. K. Phillips, and S. K. Clark, “Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta analysis,” Colorectal Disease, vol. 13, pp. 1222–1229, 2011.
S. Klemmer, L. Pascoe, and J. DeCosse, “Occurrence of desmoids in patients with familial adenomatous polyposis of the colon,” American Journal of Medical Genetics, vol. 28, no. 2, pp. 385–392, 1987.
P. Rozen and F. Macrae, “Familial adenomatous polyposis: the practical applications of clinical and molecular screening,” Familial Cancer, vol. 5, no. 3, pp. 227–235, 2006.
L. K. Bianchi, C. A. Burke, A. E. Bennett, R. Lopez, H. Hasson, and J. M. Church, “Fundic gland polyp dysplasia is common in familial adenomatous polyposis,” Clinical Gastroenterology and Hepatology, vol. 6, no. 2, pp. 180–185, 2008.
C. Cordero-Fernández, M. Garzón-Benavides, A. Pizarro-Moreno et al., “Gastroduodenal involvement in patients with familial adenomatous polyposis. Prospective study of the nature and evolution of polyps: evaluation of the treatment and surveillance methods applied,” European Journal of Gastroenterology and Hepatology, vol. 21, no. 10, pp. 1161–1167, 2009.
H. F. A. Vasen, G. M？slein, A. Alonso et al., “Guidelines for the clinical management of familial adenomatous polyposis (FAP),” Gut, vol. 57, no. 5, pp. 704–713, 2008.
E. J. Groen, A. Roos, F. L. Muntinghe et al., “Extra-intestinal manifestations of familial adenomatous polyposis,” Annals of Surgical Oncology, vol. 15, no. 9, pp. 2439–2450, 2008.
M. C. Posner, M. H. Shiu, J. L. Newsome, S. I. Hajdu, J. J. Gaynor, and M. F. Brennan, “The desmoid tumor. Not a benign disease,” Archives of Surgery, vol. 124, no. 2, pp. 191–196, 1989.
D. J. Pritchard, A. G. Nascimento, and I. A. Petersen, “Local control of extra-abdominal desmoid tumors,” Journal of Bone and Joint Surgery A, vol. 78, no. 6, pp. 848–854, 1996.
N. B. Merchant, J. J. Lewis, J. M. Woodruff, D. H. Leung, and M. F. Brennan, “Extremity and trunk desmoid tumors: a multifactorial analysis of outcome,” Cancer, vol. 86, pp. 2045–2052, 1999.
A. Gronchi, P. G. Casali, L. Mariani et al., “Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution,” Journal of Clinical Oncology, vol. 21, no. 7, pp. 1390–1397, 2003.
A. R. Latchford, N. J. H. Sturt, K. Neale, P. A. Rogers, and R. K. S. Phillips, “A 10-year review of surgery for desmoid disease associated with familial adenomatous polyposis,” British Journal of Surgery, vol. 93, no. 10, pp. 1258–1264, 2006.
S. Bonvalot, H. Eldweny, V. Haddad et al., “Extra-abdominal primary fibromatosis: aggressive management could be avoided in a subgroup of patients,” European Journal of Surgical Oncology, vol. 34, no. 4, pp. 462–468, 2008.
E. Stoeckle, J. M. Coindre, M. Longy et al., “A critical analysis of treatment strategies in desmoid tumours: a review of a series of 106 cases,” European Journal of Surgical Oncology, vol. 35, no. 2, pp. 129–134, 2009.
M. Fiore, F. Rimareix, L. Mariani et al., “Desmoid-type fibromatosis: a front-line conservative approach to select patients for surgical treatment,” Annals of Surgical Oncology, vol. 16, no. 9, pp. 2587–2593, 2009.
M. H. Nieuwenhuis and H. F. A. Vasen, “evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients,” British Journal of Cancer, vol. 104, pp. 37–42, 2011.
S. Salas, A. Dufresne, B. Bui, 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,” Journal of Clinical Oncology, vol. 29, pp. 3553–3558, 2011.
M. Melis, J. S. Zager, and V. K. Sondak, “Multimodality management of desmoid tumors: how important is a negative surgical margin?” Journal of Surgical Oncology, vol. 98, no. 8, pp. 594–602, 2008.
D. Bocale, M. T. Rotelli, A. Cavallini, and D. F. Altomare, “Anti-oestrogen therapy in the treatment of desmoid tumours: a systematic review,” Colorectal Disease, vol. 13, pp. e388–e395, 2011.
J. Janinis, M. Patriki, L. Vini, G. Aravantinos, and J. S. Whelan, “The pharmacological treatment of aggressive fibromatosis: a systematic review,” Annals of Oncology, vol. 14, no. 2, pp. 181–190, 2003.
R. Poon, R. Smits, C. Li et al., “Cyclooxygenase-two (COX-2) modulates proliferation in aggressive fibromatosis (desmoid tumor),” Oncogene, vol. 20, no. 4, pp. 451–460, 2001.
D. Garbay, A. Le Cesne, and N. Penel, “Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG),” Annals of Oncology, vol. 23, pp. 182–186, 2012.
N. Penel, A. Le Cesne, B. N. Bui 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,” Annals of Oncology, vol. 22, no. 2, pp. 452–457, 2011.
R. Chugh, J. K. Wathen, S. R. Patel et al., “Efficacy of imatinib in aggressive fibromatosis: results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial,” Clinical Cancer Research, vol. 16, no. 19, pp. 4884–4891, 2010.
B. Liegl, A. Leithner, T. Bauernhofer et al., “Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours?” Histopathology, vol. 49, no. 6, pp. 576–581, 2006.
M. M. Gounder, R. A. Lefkowitz, M. L. Keohan et al., “Activity of sorafenib against desmoid tumor/deep fibromatosis,” Clinical Cancer Research, vol. 17, no. 12, pp. 4082–4090, 2011.
