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Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis

Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis Hindawi Publishing Corporation Sarcoma Volume 2012, Article ID 726537, 11 pages doi:10.1155/2012/726537 Review Article Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis 1, 2 1, 2 3 George T. Calvert, Michael J. Monument, Randall W. Burt, 1, 2 1, 2 Kevin B. Jones, and R. Lor Randall Department of Orthopaedics and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Sarcoma Services, Center for Children, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Department of Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Correspondence should be addressed to George T. Calvert, calvertg@gmail.com Received 2 February 2012; Accepted 30 March 2012 Academic Editor: Leslie G. Dodd Copyright © 2012 George T. Calvert et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 from a 1986 Finnish study which used the pathologic records of several regional hospitals and their known catchment area Desmoid tumors (DTs), also known as aggressive fibro- populations to calculate an incidence figure [3]. Recently, matosis, are fibroblastic neoplasms which are often locally the Dutch national pathology database was analyzed, and aggressive but lack metastatic potential. They may occur 519 total desmoid cases in patients over the age of ten sporadically or in association with familial adenomatous were identified from 1999 to 2009. There were 480 sporadic polyposis (FAP) syndrome. Among individuals with FAP, DTs and 39 FAP-DTs. The annual incidence was 3.7 per desmoids most frequently occur in intra-abdominal and million overall [4] consistent with the earlier Finnish study. abdominal wall locations with most arising from the peri- The same nationwide study from The Netherlands identified toneum. These abdominal desmoids range in severity from 1400 patients over the age of ten with FAP during the 1999 indolent, asymptomatic lesions to highly invasive, some- to 2009 period. FAP-associated DTs (FAP-DTs) made up times fatal tumors. Although less common than abdominal 7.5% of all DTs, and the relative risk of an FAP patient desmoids and very rarely fatal, extra-abdominal desmoids developing a DT was over 800-fold higher than the general are also a significant cause of morbidity in this population. population [4]. The Dutch study was limited by the use of This paper will review recent developments in the diagnosis, pathologic specimens as many DTs may be identified based screening, treatment, and prognosis of FAP-associated extra- upon history, physical exam, and imaging but not biopsied or abdominal DTs. surgically excised especially in the FAP cohort. Additionally, some individuals with sporadic DTs may have had as yet undiagnosed FAP. Therefore, FAP-DTs likely constitute more 2. Epidemiology of FAP-Associated than 7.5% of all DTs. Desmoid Tumors A 1994 study of the Johns Hopkins Polyposis Registry The overall incidence of DTs has frequently been quoted at 2– found that 10% (83/825) of FAP patients had desmoids, and 4 per million people per year [1, 2]. This estimate is derived their relative risk of DTs was 852-fold higher than the general 2 Sarcoma population [5]. A study of Mayo Clinic data from 1976 to Table 1: Demographic risk factors for desmoid development among FAP patients. 1999 identified 447 desmoid patients of whom 70 (15.7%) had FAP [6]. In all of the previously mentioned studies, intra- Risk Factor Reference abdominal and abdominal wall desmoids predominated in Younger age [4] the FAP cohorts whereas extra-abdominal desmoids were Male sex [4] most common among sporadic cases. The sites of extra- abdominal DTs (head and neck, trunk exclusive of abdom- Intra-abdominal location [4] inal wall, and extremity) do not appear to vary between the Abdominal wall Location [4] sporadic and FAP-associated desmoid cohorts. Other consis- Mutation 3 of codon 1444 [7] tent demographic findings include younger age at DT pre- Previous abdominal surgery [7] sentation among FAP patients, history of abdominal surgery in abdominal DTs, and reduced female predominance of DTs among individuals with FAP [4–7]. Although females develop DTs more frequently than males in both FAP- and Binding of WNT on the cell surface upregulates the accumu- non-FAP-associated disease, the sex predominance is less in lation of beta-catenin in the cytoplasm, and the beta-catenin the FAP cohort. Table 1 summarizes the known risk factors molecules subsequently move to the nucleus and activate for DT development in FAP patients based upon the previous WNT pathway transcription factors [18]. The APC gene pro- cited studies. duct, located in the cytoplasm, forms a molecular complex with Glycogen Synthase Kinase 3 (GSK3) and Axin which in turn binds beta-catenin leading to its subsequent degrada- 3. Desmoid Histology, Cytogenetics, and tion [19]. The APC pathway is summarized in Figure 1. Immunohistochemistry Both sporadic and FAP-DTs have been analyzed for APC and beta-catenin mutations. As expected, most FAP-DTs Desmoids usually present grossly as firm, white tumors with show a second somatic mutation of the APC gene [20]. How- a coarse, trabeculated surface. They may appear to be scar- ever, the secondary somatic mutations of the FAP-DTs have like and encapsulated which belies their infiltrative behavior been shown to differ consistently from the secondary somatic at the microscopic level. Histologic analysis reveals bland mutations in the colonic polyps from the same individuals spindle-shaped cells in a collagenous stroma containing [21]. APC mutations are infrequently found in sporadic blood vessels [8]. The cells lack atypia, but the mitotic rate is DTs [22] which more frequently demonstrate beta-catenin variable [8]. Sporadic and FAP-DTs are indistinguishable at mutations [23, 24]. the gross and microscopic levels. Cytogenetic analyses of DTs (both sporadic and FAP-associated) have shown trisomies of chromosomes 8 and 20 to be recurrent abnormalities [9]. 5. Genotype Phenotype Correlations in Trisomy 8 was found to correlate with recurrence in two FAP-Associated Desmoids separate studies [9, 10]. Immunohistological staining of DTs is positive for vimentin and variably positive for muscle and The correlation of genotype with phenotype in FAP-DTs may permit more efficient screening strategies, improved treat- smooth muscle markers [8]. A study of 116 DT samples ment regimens, and ultimately targeted therapy of the dis- (both sporadic and FAP specimens) found only 7 estrogen ease. A variant of FAP, termed hereditary desmoid disease receptor-beta-positive tumors, one C-KIT-positive tumor, was first described by Eccles et al. in 1996 [25]. They reported and no HER2 or estrogen receptor-alpha-positive tumors 100% penetrance of desmoid tumors in a three-generation [11]. A subsequent study of 40 desmoids using different kindred with a mutation in the extreme 3 end of the APC immunohistological techniques found some degree of estro- gene [25]. DTs in this kindred had both extra- and gen receptor beta expression in all samples whereas estrogen intra-abdominal involvement. Subsequently, Couture et al. receptor alpha expression was absent in all samples [12]. reported a large French-Canadian kindred with a similar phenotype and extreme 3 mutation of the APC gene [26]. 4. Desmoids and the APC Gene Pathway This kindred had extensive desmoid disease and attenuated colonic polyp formation in contrast to classic FAP. These Mutation of the tumor suppressor Adenomatous Polyposis authors further demonstrated that desmoid tissue from a Coli (APC) gene was identified as the cause of FAP in 1991 member of the kindred had elevated beta-catenin levels [26]. by two different groups working independently [13–16]. The Prior studies of the secondary somatic mutations which APC gene is located on the long arm of chromosome 5 occur in FAP colon polyps revealed that the type and loca- (5q21); its product has been implicated in a wide variety tion of the somatic mutation were nonrandom and at least of cellular processes including cell migration, cell adhesion, partially determined by the location of the germ-line muta- chromosome segregation, spindle assembly, apoptosis, and tion [21, 27]. The APC gene product contains seven 20 amino neuronal differentiation [17]. Despite these many roles, the acid beta-catenin degradation repeats (AARs). These repeat classical function of APC in neopalsia is inhibition of the segments permit binding of beta-catenin leading to its WNT signaling pathway. WNTs are a family of secreted gly- ultimate degradation. The “just right” model of FAP tumori- coproteins which act as short range ligands in cell signaling. genesis proposes that there is an ideal level of beta-catenin Sarcoma 3 WNT sFRP WNT Frizzled Frizzled DKK LRP5/6 β-catenin LRP5/6 DSH AXIN DSH β-catenin β-catenin CK1 GBP AXIN β-catenin GSK3 GSK3 APC Ubiquitin- β-catenin β-catenin mediated Activated APC β-catenin proteolysis CBP β-catenin Target genes Target genes TCF TCF Nucleus Nucleus Figure 1: Model of the WNT/APC/beta-catenin pathway (Adapted from Moon et al. [18].) binding suitable for polyp progression to colon cancer, and risk factors considered [34]. The authors utilized the risks selective pressure results in nonrandom selection of somatic identified using this system to guide surgical management. mutations with the appropriate number of AARs [27]. They advocated use of antiadhesion material, sulindac pro- Analysis of FAP-DTs by Latchford et al. revealed that 87% phylaxis, and minimally invasive techniques in patients at (26/30) of tumors had one allele with no AARs and increased risk of desmoid formation [34]. preferentially retained a total of two AARs 57% (17/30) [28]. These authors suggested that specific levels of beta-catenin 6. Gene Expression Profiles of activity are required by the different tumor types with desmoids preferentially requiring two AAR segments. A FAP-Associated Desmoids large Japanese study (86 colorectal tumors, 40 extracolonic tumors) identified similar associations between AARs and APC is a large protein with numerous binding sites and phenotype. With respect to FAP-DTs, 5 of 6 were found to multiple putative functions. Gene expression profiling is one have two AARs in the Japanese study [29]. strategy which has been used to better understand the com- Development of desmoids among individuals with FAP plex downstream effects of APC mutations. A critical factor has been correlated with specific mutations. Early studies in gene expression profiling is determination of which tissues with small numbers of FAP-DTs suggested that mutations should be compared because genes can only be up- or down- in these patients tended to occur at the 3 end of the gene regulated with respect to a reference specimen. With ref- [30, 31]. A 2001 study from Hereditary Colorectal Tumor erence to DTs, numerous tissue samples have been studied Registry in Milan analyzed 809 FAP patients of which 107 including FAP-DTs, sporadic DTs, banked reference fibrous (11.9%) developed DTs including 59 extraabdominal cases tissue, fibrous tissue from the same patient, adenomatous [32]. These authors found a 12-fold increased risk of DT tissue from the same FAP patient, and many other banked when the APC mutation occurred beyond codon 1444 as histologic specimens. The technical aspects of each study are compared with upstream mutations [32]. In a multivariate beyond the scope of this paper, but some notable findings analysis, these authors determined that genotype was the merit discussion. The first desmoid gene expression profile strongest predictor of desmoid development [32]. A 2007 study (2004) compared 12 sporadic DTs with banked normal review of the world literature on APC genotype/phenotype fibrous tissue. Notably, the study identified two distinct correlation identified ten articles with data on FAP-DTs. groups within the 12 patients based upon gene expression, The reviewers concluded that patients with APC mutations but no obvious clinical correlations were evident [35]. A 2006 downstream of codon 1400 were at increased risk of desmoid study analyzed four tumors (2 with APC mutations, 2 with development [33]. More recently, genotype data have been beta-catenin mutations) using normal fibrous tissue from the incorporated into a desmoid risk scoring system for FAP same patients as control. Sixty-nine differentially expressed patients. Female sex, presence of other extracolonic man- genes were identified, of which 33 were upregulated and ifestations, a relative with a DT, and genotype were the 36 were downregulated [36]. Interestingly, no differences in 4 Sarcoma the profiles of the APC and beta-catenin tissues were identi- Although it is now generally agreed that desmoids, both fied. The authors additionally confirmed consistent down- sporadic and FAP associated, are neoplastic, the cell of origin regulation of insulin-like growth factor-binding protein 6 has yet to be identified. Recent animal studies suggest that using reverse transcriptase PCR and Northern blot assays mesenchymal stem cells (MSCs) are likely candidates and [36]. at minimum contribute to tumor development. Wu et al. A study comparing desmoid samples (both sporadic recently demonstrated that MSCs and desmoids had similar and FAP associated) with nodular fasciitis was performed gene expression profiles, and mice deficient in MSCs but using 33 DTs and 11 nodular fasciitis specimens. Hierar- prone to desmoids (mice with an APC mutation and def- chical clustering revealed distinct gene expression signatures icient MSC production) developed fewer desmoid tumors between the two groups [37]. The authors concluded that while colonic tumor rates were uneffected [43]. In fact, this technology may be useful in diagnostically challenging desmoid development was directly proportional to the num- cases. Gene expression profiling may also be of prognostic ber of MSCs present. Additionally, MSCs with the APC wt/1638N value as demonstrated by a 2007 study which found that ele- mutation from heterozygote APC mice produced DTs vated beta-catenin and p53 expression correlated with local when transplanted to immunodeficient mice, but MSCs recurrence in a retrospective analysis of 37 DTs (sporadic without the mutation did not. Furthermore, they found that versus FAP not specified) [38]. A recent study reported the MSCs from mice with inducible expression of beta-catenin tm2kem results of array comparative genomic hybridization analysis (Catnb mice) could also induce desmoid-like tumors of 196 DTs (only 5% were FAP-DTs) [39]. Four recurrent when transplanted to immunodeficient mice. Finally, they chromosomal abnormalities were identified: loss of 6q, loss showed that these tumors were clonally derived from the of 5q, gain of 20q, and gain of chromosome 8 [39]. Loss of donor MSCs with use of a green florescent protein tag [43]. 5q is likely explained by APC localization to this region. The A 2012 study has further defined the role of mesenchymal other gains and losses suggest avenues of future investigation. stem cells in FAP-DTs using human tissue. Carothers et al. A 2011 study compared sporadic and FAP-DTs using analyzed 16 human desmoid specimens and using immuno- array comparative genomic hybridization analysis [40]. The histochemistry found that desmoid tissue expressed MSC authors analyzed 17 FAP-DTs and 38 sporadic DTs. They markers but surrounding normal tissue did not [44]. They found more copy number abnormalities among the FAP- next developed a primary desmoid cell line from the human DTs than the sporadic DTs. Loss of 6q was common to both desmoid tissue. These cells had an immunohistochemical sporadic and FAP-DTs, and the authors believed that further profile consistent with MSC, and the cells were able to dif- study of genes in this region may help elucidate desmoid ferentiate into chondrocytes, osteocytes, and adipocytes con- tumorigenesis [40]. They noted that several known or puta- firming that they are MSCs [44]. These human desmoids- tive tumors suppressor genes including ANKRD6, BACH2, derived MSCs were found to have elevated beta-catenin in MAP3K7/TAK1, EPHA7,and NLBP/KIAA0776 reside in this their nuclei (similar to desmoid tissue) and demonstrated region. As yet, none of these putative tumor suppressors have upregulation of the Notch and Hedgehog pathways [44]. been correlated with the downregulated genes identified in The aforementioned studies do not definitively prove the previously discussed gene expression profile studies. that MSCs are the cell of origin in FAP-DTs, but they at a Another application of gene expression profiling is minimum demonstrate the importance of MSCs in desmoid analysis of treatment response. A 2010 report compared a development. The association between desmoid develop- FAP-DT human cell line with a sporadic DT human cell line ment and surgical wound healing in patients with FAP has using microarray analysis [41]. Doxorubicin-treated cells long been established [45]. Presence of extra-abdominal and from each line were compared with each other and their abdominal wall DTs increases the risk of intra-abdominal DT untreated controls. Separate in vitro assays had already development at the time of prophylactic colon resection [46]. shown that the FAP-DT cell line demonstrated greater doxo- A recent case report analyzed the individual tumor mutations rubicin resistance than the sporadic DT cell line [41]. The of a FAP patient with multiple recurrences at the same sur- gene expression profiles of the treated cells differed in that the gical site. Interestingly, different APC mutations were identi- pro-survival genes netrin 1 and tumor necrosis factor receptor fied in the “recurrent” tumors suggesting that these were in superfamily member 10c were upregulated in the treated fact new clonal populations and not true recurrences [47]. FAP-DT line and the proapoptotic gene forkhead box L2 was Based upon the previously noted findings, one can postulate upregulated in the treated sporadic DT line [41]. Although a model in which secondary somatic mutations develop in this study was preliminary and in vitro, gene expression pro- the MSC rich wound healing environment of FAP patients. filing may ultimately be applicable to prediction of response This model fits well with the known development of des- to treatment in humans. moids after surgical or incidental trauma in the FAP pop- ulation. 7. DesmoidCellofOrigin As recently as 2000, debate existed as to whether desmoids 8. FAP Screening and Treatment Guidelines in were neoplastic or reactive. A 2000 study by Middleton et al. relation to Desmoid Treatment demonstrated that FAP-DTs were monoclonal [42]. The authors derived a clonality ratio by assessing X chromosome Physicians specializing in the treatment of sarcomas will inactivation in desmoid samples from 12 female patients. rarely be the first to diagnose FAP because desmoids in these Sarcoma 5 patients most frequently occur after gastrointestinal man- Table 2: Extracolonic FAP manifestation (Neiuwenhuis [33]and Groen [54]). ifestations of the disease are evident. Additionally, many kindreds have been extensively tested, and affected family Prevalence in FAP Extracolonic manifestation members are frequently diagnosed early in childhood. How- patients ever, de novo mutations may occur, and individuals with FAP CHRPE 70–75% may still initially present with extracolonic manifestations Osteomas and dental abnormalities 70–90% such as desmoids. A meta-analysis of desmoid risk among Upper GI tumors 50–90% FAP patients identified family history of DT, APC mutation 3 to codon1399, previous abdominal surgery, and female sex Epidermoid cysts and lipomas 25–50% to be significant risk factors for DTs [48]. Thesameanalysis Desmoid tumors 15–20% found that 80% of FAP-DTs occur before age 40 [48]. Two Adrenal tumors 7–13% other studies have noted that FAP-DTs present at a younger Papillary thyroid cancer 1-2% age in females than males [45, 49]. Practitioners should Hepatoblastoma 1-2% therefore suspect FAP in patients with a family history of Brain Tumors (Medulloblastoma and others) 1-2% desmoids and in young patients presenting with desmoids. Pancreatic Cancer 1% Referral to gastroenterologists, geneticists, and colon and rectal surgeons experienced in FAP care is critical if the diagnosis is suspected. Many cancer centers have well estab- lished multidisciplinary groups and polyposis registries. A 2006 review of screening guidelines recommended careful centers. In 1989, a large series (131 patients, both sporadic postcolectomy follow-up to asses for desmoids as early inter- and FAP-DT) from Memorial Sloane-Kettering was pub- vention has anecdotally improved outcome for some [50]. lished detailing desmoid cases at the institution from 1965 to Practical surveillance measures for all FAP patients include 1984. Adequacy of surgical margin was found to be the single asking them about new masses and examining their body most important factor in successful treatment of desmoids surface for tumors at each visit. [55]. The authors concluded that “aggressive resection in an effort to obtain as wide a margin as possible is clearly the sin- Other extracolonic manifestations of FAP should be gle most important determinant of successful outcome” [55]. considered by the clinician treating FAP-DTs. Gastric polyps A Mayo Clinic series reporting extra-abdominal desmoid were found in 88% of FAP in a 2008 study of 75 consecutive cases from 1981 to 1989 similarly found a high local recur- FAP patients, and gastric cancer rates are increased in this rence rate (9/19) in patients with microscopic residual dis- population [51]. Duodenal and papillary adenomas occur in ease [56]. In 1999, another report (105 patients with primary 50–90% of FAP patients, and there is an overall 5% lifetime desmoid disease, both sporadic and FAP-DT) from Memo- risk of duodenal cancer in FAP patients [52, 53]. Routine rial Sloan-Kettering covering the years 1982–1997 did not surveillance of the upper gastrointestinal tract with endo- find positive microscopic margin to be predictive of local scopy is therefore recommended [53]. APC is a tumor sup- recurrence [57]. These later authors recommended against pressor gene and is associated with other cancers including excessively morbid resections in an effort to obtain wide papillary thyroid carcinoma, hepatoblastoma, medulloblas- margins. In 2003, Gronchi et al. reported a series of 203 toma and other brain tumors, and pancreatic cancer [54]. consecutive desmoid patients treated over 35 years at a single The associated cancer risks are low (1-2% for each diagnosis) institution. They found that microscopic positive margins compared with the 100% risk of colon cancer in untreated did not adversely affect recurrence rates for primary disease FAP [33, 54]. However, these associated tumors (except [58]. They recommended function sparing surgery and pancreatic cancer) tend to occur at a young age, often before resection of all macroscopic disease but avoidance of heroic gastrointestinal manifestations develop. This fact further attempts at obtaining negative microscopic margins. A emphasizes the importance of genetic testing of at-risk smaller series from the United Kingdom reported the results individuals. Nonmalignant FAP associations include adrenal of surgery for 32 FAP-DTs including 16 intra-abdominal, tumors, osteomas, congenital hypertrophy of the retinal 12 abdominal, and 4 extra-abdominal tumors treated from pigment epithelium (CHRPE), and dental abnormalities [33, 1994 to 2004. In contrast to some prior reports of abdominal 54]. Most of these nonmalignant entities do not cause signi- desmoids in FAP patients, they had no desmoids-related ficant morbidity, and as previously noted DTs are the most mortalities and only one patient required long-term par- clinically significant nonmalignant extracolonic manifesta- enteral nutrition [59]. These authors noted that they had a tion of the disease. Table 2 summarizes the extra-colonic high threshold for surgery, and that most intra-abdominal manifestations of FAP. desmoids at their institution were treated conservatively. Even more recently, several authors have begun advocat- 9. Evolving Trends in the ing a wait and see approach to DTs as it has been recognized Surgical Management of FAP-DTs that many DTs undergo a prolonged stable phase or even spontaneous regression. A 1998 article from this journal The surgical treatment paradigm for DTs in general has reported a series of 17 patients treated nonoperatively, all of changed substantially over the past decade. Overall, a less whom had an interval of at least six months without disease aggressive surgical approach has been adopted by many progression [60]. Subsequently, a French report identified 6 Sarcoma Table 3: Surgical and nonoperative outcomes from selected studies. References Subjects Anatomic site Presentation Intervention Surgical margins Follow-up Outcomes 36% LR Retrospective review Median F/U Median time to LR: 15 months Posner et al. [55] Extra-abdominal Primary (n = 131) Surgery (n = 131) Not reported (n = 131) 88 months Negative microscopic margins predictive of EFS Observation (n = 3) Negative Observation/XRT: 1/6 no progression XRT (n = 3) Retrospective review (n = 15) Minimum F/U Negative margins: 2/15 LR; 13/15 no LR Pritchard et al. [56] Extra-abdominal Primary (n = 50) Surgery (n = 34) (n = 50) Positive/marginal 48 months Positive/marginal margins: 12/29 LR; Surgery + XRT (n = 29) 17/29 no LR (n = 10) Negative Surgery (n = 105) Negative margin: 14/58 LR (24%) Prospective cohort (n = 58/105) Mean F/U Merchant et al. [57] Extra-abdominal Primary (n = 105) Adjuvant XRT Positive margin: 12/47 LR (26%) (n = 105) Positive 49 months (n = 31) No difference in LR with adjuvant XRT (n = 47/105) Negative margin De novo DT: 76% LR Retrospective review Primary (n = 128) (n = 146) Median F/U Recurrent DT: 59% LR Gronchi et al. [58] Extra-abdominal Surgery (n = 203) (n = 203) Recurrent (n = 75) Positive margin 135 months Positive margins not predictive of (n = 56) recurrence for de novo DT FAP associated 42% LR in macroscopically complete Retrospective review Primary (n = 20) Surgery (n = 20) Median F/U Latchford et al. [59] Extra-abdominal Not reported resections (n = 20) (32 tumors) Medication (n = 19) 60 months and abdominal No desmoid-related mortalities Sarcoma 7 Table 3: Continued. References Subjects Anatomic site Presentation Intervention Surgical margins Follow-up Outcomes Nonoperative group: 14/23 stable Nonoperative (n = 23) disease Observation (n = 11) Negative Surgical resection: 57/89 LR (64%) Retrospective review Medication (n = 12) (n = 19/89) Median F/U Similar EFS with nonoperative Bonvalot et al. [61] Extra-abdominal Primary (n = 112) (n = 112) Surgery (n = 89) Positive 76 months treatment and negative margin Medication (n = 9) (n = 70/89) surgical resection Adjuvant XRT (n = 13) Tumor location and negative margin predictive of EFS Increased LR with recurrent disease Medication (n = 11) Functional impairment correlates Retrospective review Extra-abdominal Primary (n = 69) Negative (n = 22) Median F/U Stoeckle et al. [62] XRT (n = 23) with number of surgeries (n = 106) and abdominal Recurrent (n = 37) Positive (n = 70) 129 months Surgery (n = 92) Time to stable disease increased with number of surgeries Extra-abdominal Retrospective review Primary (n = 74) Observation (n = 83) Median F/U Observation: 5 year PFS: 50% Fiore et al. [63] and N/A (n = 142) Recurrent (n = 68) Medication (n = 59) 33 months Medical therapy: 5 year PFS: 59% intra-abdominal Abdominal DT: similar PFS with FAP associated operative and non-operative Retrospective review Surgery (n = 49) Median F/U Nieuwenhuis Vase [64] Extra-abdominal Primary (n = 78) Not reported therapy (n = 78) Non-operative (n = 29) 96 months and abdominal Extra-abdominal DT: PFS favors surgical resection Negative margin Observation only: 78% Observation (n = 27) Retrospective review (n = 111) stable/remission Medication (n = 23) (n = 426) Extra-abdominal Positive margin Median F/U Negative margins: 44% LR; 64% no Salas et al. [65] Primary (n = 426) XRT (n = 6) multicenter and abdominal (n = 147) 54 months LR Surgery (n = 370) database Unknown Positive margins: 67% progression; Surgery + XRT (n = 37) (n = 112) 33% no progression EFS: event free survival; PFS: progression free survival; LR: local recurrence; F/U: follow-up; DT: Desmoid tumor; XRT: radiation therapy. 8 Sarcoma a subgroup of patients who did well with a wait and see of cyclooxygenase-2, and mice treated with a cyclooxygenase- approach. Only 23 patients were included in the nonoper- 2 inhibitor had decreased desmoid tumor size [69]. There are ative group, and there were no strict inclusion criteria [61]. little human data corroborating the effects of prostaglandins A subsequent, larger study analyzed the results of a routine and prostaglandin inhibition on DTs. front-line conservative approach used to treat both primary Multiple chemotherapeutic agents have shown efficacy and recurrent desmoids at two institutions [63]. Seventy- against desmoids including doxorubicin, methotrexate plus four primary and 68 recurrent tumors were studied. Eighty- vinblastine, cyclophosphamide plus doxorubicin, and VAC three received no intervention, and 59 received medical (vincristine, actinomycin-D, cyclophosphamide) [68, 70]. therapy. Overall progression-free survival was 64% at 3 years Interferon alpha has also been used singly and in combina- and 53% at 5 years. There was not a statistically significant tion with some of the aforementioned cytotoxic agents [68]. difference in progression free survival between the no inter- More recently, targeted biologic agents have been added to vention and the medically treated groups [63]. The authors the desmoid treatment armamentarium. Two phase 2 trials did not believe that subsequent surgery was compromised by have reported efficacy of imatinib, a tyrosine kinase inhibitor, delay in the patients who progressed. More recently, a study in the treatment of desmoids [71, 72]. As previously men- was performed to identify factors associated with progression tioned, C-KIT expression is lacking in most DTs. Analysis free survival. In a multivariate analysis of 426 sporadic of 124 DTs from 85 patients found that PDGF alpha and desmoid tumors, age less than 37, extremity location, and PDGF receptor alpha were expressed in all tumors, but PDGF size greater than 7 cm were associated with progression [65]. beta and PDGF receptor beta were not expressed [73]. The Notably, the authors could not determine how to use this same authors failed to identify PDGF receptor mutations in information with respect to surgery versus wait and see.One 14 analyzed specimens [73]. These data suggest that ima- could argue that DTs at high risk of progression should be tinib’s efficacy against desmoids results from a mechanism resected early because conservative treatment is more likely other than direct inhibition of these known tyrosine kin- to fail. On the contrary, perhaps the high-risk group should ase protooncogenes. Another tyrosine kinase inhibitor, so- be observed because they may be more biologically aggressive rafenib, has also shown efficacy against desmoids in a and therefore more likely to recur after surgery. This cannot smaller single-institution trial [74]. Finally, a clinical trial be answered without prospective data. (NCT01265030) of the mammalian target of rapamycin Most of the aforementioned studies included few if (mTOR) inhibitor, sirolimus, for the treatment of desmoids any FAP-DTs. There are no studies which show that FAP in children and young adults was opened in 2010. The large associated extra-abdominal desmoids behave differently than number of agents used for DTs clearly indicates that presently their sporadic counterparts with respect to surgical man- there is lack of consensus with respect to medical manage- agement of primary disease. As previously discussed, FAP- ment of this condition. DTs may occur after surgery and trauma. This phenomenon is presumably related to the wound healing environment 11. Conclusion in the setting of germ-line APC mutations. A conservative approach to intra-abdominal desmoids has long been recom- Understanding of the epidemiology, genetics, molecular and mended due to the high morbidity and even mortality noted cellular biology, pathophysiology, and treatment of FAP in many early studies [64, 66]. Modern studies of FAP-DTs related desmoid tumors has improved substantially over the have shown that resection is surgically safe but recurrence past decade. Despite these improvements, DTs remain a rates remain high. Consensus for first-line conservative major cause of morbidity in the FAP population. A more management is growing [63–65]. Thestudiesreferencedin conservative surgical approach is presently advocated by this section are summarized in Table 3. many oncologic surgeons. Medical management is attempted first for most abdominal DTs, and a wait and see approach is undertaken for many extra-abdominal DTs. Surgical goals 10. Medical Treatment of FAP-Associated and techniques are now often less aggressive than in the past. Recent studies have implicated mesenchymal stem cells as Extra-Abdominal Desmoids critical components of desmoid development. Gene expres- Current first-line medical management includes antihor- sion profiling has shown promise in elucidating downstream monal therapy (specifically tamoxifen) and nonsteroidal elements of the WNT/APC/beta catenin pathway. Future anti-inflammatory drugs (NSAIDs, specifically sulindac, progress in treatment will likely depend upon continued indomethacin, and more recently celecoxib) [62]. A recent advances in understanding of basic desmoid biology and review of antiestrogen therapy for DTs found that approx- the development of additional targeted therapies for the imately half of patients respond, and response does not treatment of refractory cases. appear to correlate with estrogen receptor status [67]. Fur- thermore, the desmoid location and FAP status of the patient References do not appear to influence the response [67]. NSAIDs have shown efficacy against desmoids in numerous studies, but [1] O. Micke and M. H. Seegenschmiedt, “Radiation therapy for the mechanism of action of these agents is even less clear than aggressive fibromatosis (desmoid tumors): results of a national that of antidestrogen therapies [68]. A mouse model of APC- Patterns of Care Study,” International Journal of Radiation associated desmoid tumors was found to have elevated levels Oncology Biology Physics, vol. 61, no. 3, pp. 882–891, 2005. Sarcoma 9 [2] H. S. Hosalkar, J. T. Torbert, E. J. 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Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis

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Copyright © 2012 George T. Calvert et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Sarcoma Volume 2012, Article ID 726537, 11 pages doi:10.1155/2012/726537 Review Article Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis 1, 2 1, 2 3 George T. Calvert, Michael J. Monument, Randall W. Burt, 1, 2 1, 2 Kevin B. Jones, and R. Lor Randall Department of Orthopaedics and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Sarcoma Services, Center for Children, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Department of Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112, USA Correspondence should be addressed to George T. Calvert, calvertg@gmail.com Received 2 February 2012; Accepted 30 March 2012 Academic Editor: Leslie G. Dodd Copyright © 2012 George T. Calvert et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 from a 1986 Finnish study which used the pathologic records of several regional hospitals and their known catchment area Desmoid tumors (DTs), also known as aggressive fibro- populations to calculate an incidence figure [3]. Recently, matosis, are fibroblastic neoplasms which are often locally the Dutch national pathology database was analyzed, and aggressive but lack metastatic potential. They may occur 519 total desmoid cases in patients over the age of ten sporadically or in association with familial adenomatous were identified from 1999 to 2009. There were 480 sporadic polyposis (FAP) syndrome. Among individuals with FAP, DTs and 39 FAP-DTs. The annual incidence was 3.7 per desmoids most frequently occur in intra-abdominal and million overall [4] consistent with the earlier Finnish study. abdominal wall locations with most arising from the peri- The same nationwide study from The Netherlands identified toneum. These abdominal desmoids range in severity from 1400 patients over the age of ten with FAP during the 1999 indolent, asymptomatic lesions to highly invasive, some- to 2009 period. FAP-associated DTs (FAP-DTs) made up times fatal tumors. Although less common than abdominal 7.5% of all DTs, and the relative risk of an FAP patient desmoids and very rarely fatal, extra-abdominal desmoids developing a DT was over 800-fold higher than the general are also a significant cause of morbidity in this population. population [4]. The Dutch study was limited by the use of This paper will review recent developments in the diagnosis, pathologic specimens as many DTs may be identified based screening, treatment, and prognosis of FAP-associated extra- upon history, physical exam, and imaging but not biopsied or abdominal DTs. surgically excised especially in the FAP cohort. Additionally, some individuals with sporadic DTs may have had as yet undiagnosed FAP. Therefore, FAP-DTs likely constitute more 2. Epidemiology of FAP-Associated than 7.5% of all DTs. Desmoid Tumors A 1994 study of the Johns Hopkins Polyposis Registry The overall incidence of DTs has frequently been quoted at 2– found that 10% (83/825) of FAP patients had desmoids, and 4 per million people per year [1, 2]. This estimate is derived their relative risk of DTs was 852-fold higher than the general 2 Sarcoma population [5]. A study of Mayo Clinic data from 1976 to Table 1: Demographic risk factors for desmoid development among FAP patients. 1999 identified 447 desmoid patients of whom 70 (15.7%) had FAP [6]. In all of the previously mentioned studies, intra- Risk Factor Reference abdominal and abdominal wall desmoids predominated in Younger age [4] the FAP cohorts whereas extra-abdominal desmoids were Male sex [4] most common among sporadic cases. The sites of extra- abdominal DTs (head and neck, trunk exclusive of abdom- Intra-abdominal location [4] inal wall, and extremity) do not appear to vary between the Abdominal wall Location [4] sporadic and FAP-associated desmoid cohorts. Other consis- Mutation 3 of codon 1444 [7] tent demographic findings include younger age at DT pre- Previous abdominal surgery [7] sentation among FAP patients, history of abdominal surgery in abdominal DTs, and reduced female predominance of DTs among individuals with FAP [4–7]. Although females develop DTs more frequently than males in both FAP- and Binding of WNT on the cell surface upregulates the accumu- non-FAP-associated disease, the sex predominance is less in lation of beta-catenin in the cytoplasm, and the beta-catenin the FAP cohort. Table 1 summarizes the known risk factors molecules subsequently move to the nucleus and activate for DT development in FAP patients based upon the previous WNT pathway transcription factors [18]. The APC gene pro- cited studies. duct, located in the cytoplasm, forms a molecular complex with Glycogen Synthase Kinase 3 (GSK3) and Axin which in turn binds beta-catenin leading to its subsequent degrada- 3. Desmoid Histology, Cytogenetics, and tion [19]. The APC pathway is summarized in Figure 1. Immunohistochemistry Both sporadic and FAP-DTs have been analyzed for APC and beta-catenin mutations. As expected, most FAP-DTs Desmoids usually present grossly as firm, white tumors with show a second somatic mutation of the APC gene [20]. How- a coarse, trabeculated surface. They may appear to be scar- ever, the secondary somatic mutations of the FAP-DTs have like and encapsulated which belies their infiltrative behavior been shown to differ consistently from the secondary somatic at the microscopic level. Histologic analysis reveals bland mutations in the colonic polyps from the same individuals spindle-shaped cells in a collagenous stroma containing [21]. APC mutations are infrequently found in sporadic blood vessels [8]. The cells lack atypia, but the mitotic rate is DTs [22] which more frequently demonstrate beta-catenin variable [8]. Sporadic and FAP-DTs are indistinguishable at mutations [23, 24]. the gross and microscopic levels. Cytogenetic analyses of DTs (both sporadic and FAP-associated) have shown trisomies of chromosomes 8 and 20 to be recurrent abnormalities [9]. 5. Genotype Phenotype Correlations in Trisomy 8 was found to correlate with recurrence in two FAP-Associated Desmoids separate studies [9, 10]. Immunohistological staining of DTs is positive for vimentin and variably positive for muscle and The correlation of genotype with phenotype in FAP-DTs may permit more efficient screening strategies, improved treat- smooth muscle markers [8]. A study of 116 DT samples ment regimens, and ultimately targeted therapy of the dis- (both sporadic and FAP specimens) found only 7 estrogen ease. A variant of FAP, termed hereditary desmoid disease receptor-beta-positive tumors, one C-KIT-positive tumor, was first described by Eccles et al. in 1996 [25]. They reported and no HER2 or estrogen receptor-alpha-positive tumors 100% penetrance of desmoid tumors in a three-generation [11]. A subsequent study of 40 desmoids using different kindred with a mutation in the extreme 3 end of the APC immunohistological techniques found some degree of estro- gene [25]. DTs in this kindred had both extra- and gen receptor beta expression in all samples whereas estrogen intra-abdominal involvement. Subsequently, Couture et al. receptor alpha expression was absent in all samples [12]. reported a large French-Canadian kindred with a similar phenotype and extreme 3 mutation of the APC gene [26]. 4. Desmoids and the APC Gene Pathway This kindred had extensive desmoid disease and attenuated colonic polyp formation in contrast to classic FAP. These Mutation of the tumor suppressor Adenomatous Polyposis authors further demonstrated that desmoid tissue from a Coli (APC) gene was identified as the cause of FAP in 1991 member of the kindred had elevated beta-catenin levels [26]. by two different groups working independently [13–16]. The Prior studies of the secondary somatic mutations which APC gene is located on the long arm of chromosome 5 occur in FAP colon polyps revealed that the type and loca- (5q21); its product has been implicated in a wide variety tion of the somatic mutation were nonrandom and at least of cellular processes including cell migration, cell adhesion, partially determined by the location of the germ-line muta- chromosome segregation, spindle assembly, apoptosis, and tion [21, 27]. The APC gene product contains seven 20 amino neuronal differentiation [17]. Despite these many roles, the acid beta-catenin degradation repeats (AARs). These repeat classical function of APC in neopalsia is inhibition of the segments permit binding of beta-catenin leading to its WNT signaling pathway. WNTs are a family of secreted gly- ultimate degradation. The “just right” model of FAP tumori- coproteins which act as short range ligands in cell signaling. genesis proposes that there is an ideal level of beta-catenin Sarcoma 3 WNT sFRP WNT Frizzled Frizzled DKK LRP5/6 β-catenin LRP5/6 DSH AXIN DSH β-catenin β-catenin CK1 GBP AXIN β-catenin GSK3 GSK3 APC Ubiquitin- β-catenin β-catenin mediated Activated APC β-catenin proteolysis CBP β-catenin Target genes Target genes TCF TCF Nucleus Nucleus Figure 1: Model of the WNT/APC/beta-catenin pathway (Adapted from Moon et al. [18].) binding suitable for polyp progression to colon cancer, and risk factors considered [34]. The authors utilized the risks selective pressure results in nonrandom selection of somatic identified using this system to guide surgical management. mutations with the appropriate number of AARs [27]. They advocated use of antiadhesion material, sulindac pro- Analysis of FAP-DTs by Latchford et al. revealed that 87% phylaxis, and minimally invasive techniques in patients at (26/30) of tumors had one allele with no AARs and increased risk of desmoid formation [34]. preferentially retained a total of two AARs 57% (17/30) [28]. These authors suggested that specific levels of beta-catenin 6. Gene Expression Profiles of activity are required by the different tumor types with desmoids preferentially requiring two AAR segments. A FAP-Associated Desmoids large Japanese study (86 colorectal tumors, 40 extracolonic tumors) identified similar associations between AARs and APC is a large protein with numerous binding sites and phenotype. With respect to FAP-DTs, 5 of 6 were found to multiple putative functions. Gene expression profiling is one have two AARs in the Japanese study [29]. strategy which has been used to better understand the com- Development of desmoids among individuals with FAP plex downstream effects of APC mutations. A critical factor has been correlated with specific mutations. Early studies in gene expression profiling is determination of which tissues with small numbers of FAP-DTs suggested that mutations should be compared because genes can only be up- or down- in these patients tended to occur at the 3 end of the gene regulated with respect to a reference specimen. With ref- [30, 31]. A 2001 study from Hereditary Colorectal Tumor erence to DTs, numerous tissue samples have been studied Registry in Milan analyzed 809 FAP patients of which 107 including FAP-DTs, sporadic DTs, banked reference fibrous (11.9%) developed DTs including 59 extraabdominal cases tissue, fibrous tissue from the same patient, adenomatous [32]. These authors found a 12-fold increased risk of DT tissue from the same FAP patient, and many other banked when the APC mutation occurred beyond codon 1444 as histologic specimens. The technical aspects of each study are compared with upstream mutations [32]. In a multivariate beyond the scope of this paper, but some notable findings analysis, these authors determined that genotype was the merit discussion. The first desmoid gene expression profile strongest predictor of desmoid development [32]. A 2007 study (2004) compared 12 sporadic DTs with banked normal review of the world literature on APC genotype/phenotype fibrous tissue. Notably, the study identified two distinct correlation identified ten articles with data on FAP-DTs. groups within the 12 patients based upon gene expression, The reviewers concluded that patients with APC mutations but no obvious clinical correlations were evident [35]. A 2006 downstream of codon 1400 were at increased risk of desmoid study analyzed four tumors (2 with APC mutations, 2 with development [33]. More recently, genotype data have been beta-catenin mutations) using normal fibrous tissue from the incorporated into a desmoid risk scoring system for FAP same patients as control. Sixty-nine differentially expressed patients. Female sex, presence of other extracolonic man- genes were identified, of which 33 were upregulated and ifestations, a relative with a DT, and genotype were the 36 were downregulated [36]. Interestingly, no differences in 4 Sarcoma the profiles of the APC and beta-catenin tissues were identi- Although it is now generally agreed that desmoids, both fied. The authors additionally confirmed consistent down- sporadic and FAP associated, are neoplastic, the cell of origin regulation of insulin-like growth factor-binding protein 6 has yet to be identified. Recent animal studies suggest that using reverse transcriptase PCR and Northern blot assays mesenchymal stem cells (MSCs) are likely candidates and [36]. at minimum contribute to tumor development. Wu et al. A study comparing desmoid samples (both sporadic recently demonstrated that MSCs and desmoids had similar and FAP associated) with nodular fasciitis was performed gene expression profiles, and mice deficient in MSCs but using 33 DTs and 11 nodular fasciitis specimens. Hierar- prone to desmoids (mice with an APC mutation and def- chical clustering revealed distinct gene expression signatures icient MSC production) developed fewer desmoid tumors between the two groups [37]. The authors concluded that while colonic tumor rates were uneffected [43]. In fact, this technology may be useful in diagnostically challenging desmoid development was directly proportional to the num- cases. Gene expression profiling may also be of prognostic ber of MSCs present. Additionally, MSCs with the APC wt/1638N value as demonstrated by a 2007 study which found that ele- mutation from heterozygote APC mice produced DTs vated beta-catenin and p53 expression correlated with local when transplanted to immunodeficient mice, but MSCs recurrence in a retrospective analysis of 37 DTs (sporadic without the mutation did not. Furthermore, they found that versus FAP not specified) [38]. A recent study reported the MSCs from mice with inducible expression of beta-catenin tm2kem results of array comparative genomic hybridization analysis (Catnb mice) could also induce desmoid-like tumors of 196 DTs (only 5% were FAP-DTs) [39]. Four recurrent when transplanted to immunodeficient mice. Finally, they chromosomal abnormalities were identified: loss of 6q, loss showed that these tumors were clonally derived from the of 5q, gain of 20q, and gain of chromosome 8 [39]. Loss of donor MSCs with use of a green florescent protein tag [43]. 5q is likely explained by APC localization to this region. The A 2012 study has further defined the role of mesenchymal other gains and losses suggest avenues of future investigation. stem cells in FAP-DTs using human tissue. Carothers et al. A 2011 study compared sporadic and FAP-DTs using analyzed 16 human desmoid specimens and using immuno- array comparative genomic hybridization analysis [40]. The histochemistry found that desmoid tissue expressed MSC authors analyzed 17 FAP-DTs and 38 sporadic DTs. They markers but surrounding normal tissue did not [44]. They found more copy number abnormalities among the FAP- next developed a primary desmoid cell line from the human DTs than the sporadic DTs. Loss of 6q was common to both desmoid tissue. These cells had an immunohistochemical sporadic and FAP-DTs, and the authors believed that further profile consistent with MSC, and the cells were able to dif- study of genes in this region may help elucidate desmoid ferentiate into chondrocytes, osteocytes, and adipocytes con- tumorigenesis [40]. They noted that several known or puta- firming that they are MSCs [44]. These human desmoids- tive tumors suppressor genes including ANKRD6, BACH2, derived MSCs were found to have elevated beta-catenin in MAP3K7/TAK1, EPHA7,and NLBP/KIAA0776 reside in this their nuclei (similar to desmoid tissue) and demonstrated region. As yet, none of these putative tumor suppressors have upregulation of the Notch and Hedgehog pathways [44]. been correlated with the downregulated genes identified in The aforementioned studies do not definitively prove the previously discussed gene expression profile studies. that MSCs are the cell of origin in FAP-DTs, but they at a Another application of gene expression profiling is minimum demonstrate the importance of MSCs in desmoid analysis of treatment response. A 2010 report compared a development. The association between desmoid develop- FAP-DT human cell line with a sporadic DT human cell line ment and surgical wound healing in patients with FAP has using microarray analysis [41]. Doxorubicin-treated cells long been established [45]. Presence of extra-abdominal and from each line were compared with each other and their abdominal wall DTs increases the risk of intra-abdominal DT untreated controls. Separate in vitro assays had already development at the time of prophylactic colon resection [46]. shown that the FAP-DT cell line demonstrated greater doxo- A recent case report analyzed the individual tumor mutations rubicin resistance than the sporadic DT cell line [41]. The of a FAP patient with multiple recurrences at the same sur- gene expression profiles of the treated cells differed in that the gical site. Interestingly, different APC mutations were identi- pro-survival genes netrin 1 and tumor necrosis factor receptor fied in the “recurrent” tumors suggesting that these were in superfamily member 10c were upregulated in the treated fact new clonal populations and not true recurrences [47]. FAP-DT line and the proapoptotic gene forkhead box L2 was Based upon the previously noted findings, one can postulate upregulated in the treated sporadic DT line [41]. Although a model in which secondary somatic mutations develop in this study was preliminary and in vitro, gene expression pro- the MSC rich wound healing environment of FAP patients. filing may ultimately be applicable to prediction of response This model fits well with the known development of des- to treatment in humans. moids after surgical or incidental trauma in the FAP pop- ulation. 7. DesmoidCellofOrigin As recently as 2000, debate existed as to whether desmoids 8. FAP Screening and Treatment Guidelines in were neoplastic or reactive. A 2000 study by Middleton et al. relation to Desmoid Treatment demonstrated that FAP-DTs were monoclonal [42]. The authors derived a clonality ratio by assessing X chromosome Physicians specializing in the treatment of sarcomas will inactivation in desmoid samples from 12 female patients. rarely be the first to diagnose FAP because desmoids in these Sarcoma 5 patients most frequently occur after gastrointestinal man- Table 2: Extracolonic FAP manifestation (Neiuwenhuis [33]and Groen [54]). ifestations of the disease are evident. Additionally, many kindreds have been extensively tested, and affected family Prevalence in FAP Extracolonic manifestation members are frequently diagnosed early in childhood. How- patients ever, de novo mutations may occur, and individuals with FAP CHRPE 70–75% may still initially present with extracolonic manifestations Osteomas and dental abnormalities 70–90% such as desmoids. A meta-analysis of desmoid risk among Upper GI tumors 50–90% FAP patients identified family history of DT, APC mutation 3 to codon1399, previous abdominal surgery, and female sex Epidermoid cysts and lipomas 25–50% to be significant risk factors for DTs [48]. Thesameanalysis Desmoid tumors 15–20% found that 80% of FAP-DTs occur before age 40 [48]. Two Adrenal tumors 7–13% other studies have noted that FAP-DTs present at a younger Papillary thyroid cancer 1-2% age in females than males [45, 49]. Practitioners should Hepatoblastoma 1-2% therefore suspect FAP in patients with a family history of Brain Tumors (Medulloblastoma and others) 1-2% desmoids and in young patients presenting with desmoids. Pancreatic Cancer 1% Referral to gastroenterologists, geneticists, and colon and rectal surgeons experienced in FAP care is critical if the diagnosis is suspected. Many cancer centers have well estab- lished multidisciplinary groups and polyposis registries. A 2006 review of screening guidelines recommended careful centers. In 1989, a large series (131 patients, both sporadic postcolectomy follow-up to asses for desmoids as early inter- and FAP-DT) from Memorial Sloane-Kettering was pub- vention has anecdotally improved outcome for some [50]. lished detailing desmoid cases at the institution from 1965 to Practical surveillance measures for all FAP patients include 1984. Adequacy of surgical margin was found to be the single asking them about new masses and examining their body most important factor in successful treatment of desmoids surface for tumors at each visit. [55]. The authors concluded that “aggressive resection in an effort to obtain as wide a margin as possible is clearly the sin- Other extracolonic manifestations of FAP should be gle most important determinant of successful outcome” [55]. considered by the clinician treating FAP-DTs. Gastric polyps A Mayo Clinic series reporting extra-abdominal desmoid were found in 88% of FAP in a 2008 study of 75 consecutive cases from 1981 to 1989 similarly found a high local recur- FAP patients, and gastric cancer rates are increased in this rence rate (9/19) in patients with microscopic residual dis- population [51]. Duodenal and papillary adenomas occur in ease [56]. In 1999, another report (105 patients with primary 50–90% of FAP patients, and there is an overall 5% lifetime desmoid disease, both sporadic and FAP-DT) from Memo- risk of duodenal cancer in FAP patients [52, 53]. Routine rial Sloan-Kettering covering the years 1982–1997 did not surveillance of the upper gastrointestinal tract with endo- find positive microscopic margin to be predictive of local scopy is therefore recommended [53]. APC is a tumor sup- recurrence [57]. These later authors recommended against pressor gene and is associated with other cancers including excessively morbid resections in an effort to obtain wide papillary thyroid carcinoma, hepatoblastoma, medulloblas- margins. In 2003, Gronchi et al. reported a series of 203 toma and other brain tumors, and pancreatic cancer [54]. consecutive desmoid patients treated over 35 years at a single The associated cancer risks are low (1-2% for each diagnosis) institution. They found that microscopic positive margins compared with the 100% risk of colon cancer in untreated did not adversely affect recurrence rates for primary disease FAP [33, 54]. However, these associated tumors (except [58]. They recommended function sparing surgery and pancreatic cancer) tend to occur at a young age, often before resection of all macroscopic disease but avoidance of heroic gastrointestinal manifestations develop. This fact further attempts at obtaining negative microscopic margins. A emphasizes the importance of genetic testing of at-risk smaller series from the United Kingdom reported the results individuals. Nonmalignant FAP associations include adrenal of surgery for 32 FAP-DTs including 16 intra-abdominal, tumors, osteomas, congenital hypertrophy of the retinal 12 abdominal, and 4 extra-abdominal tumors treated from pigment epithelium (CHRPE), and dental abnormalities [33, 1994 to 2004. In contrast to some prior reports of abdominal 54]. Most of these nonmalignant entities do not cause signi- desmoids in FAP patients, they had no desmoids-related ficant morbidity, and as previously noted DTs are the most mortalities and only one patient required long-term par- clinically significant nonmalignant extracolonic manifesta- enteral nutrition [59]. These authors noted that they had a tion of the disease. Table 2 summarizes the extra-colonic high threshold for surgery, and that most intra-abdominal manifestations of FAP. desmoids at their institution were treated conservatively. Even more recently, several authors have begun advocat- 9. Evolving Trends in the ing a wait and see approach to DTs as it has been recognized Surgical Management of FAP-DTs that many DTs undergo a prolonged stable phase or even spontaneous regression. A 1998 article from this journal The surgical treatment paradigm for DTs in general has reported a series of 17 patients treated nonoperatively, all of changed substantially over the past decade. Overall, a less whom had an interval of at least six months without disease aggressive surgical approach has been adopted by many progression [60]. Subsequently, a French report identified 6 Sarcoma Table 3: Surgical and nonoperative outcomes from selected studies. References Subjects Anatomic site Presentation Intervention Surgical margins Follow-up Outcomes 36% LR Retrospective review Median F/U Median time to LR: 15 months Posner et al. [55] Extra-abdominal Primary (n = 131) Surgery (n = 131) Not reported (n = 131) 88 months Negative microscopic margins predictive of EFS Observation (n = 3) Negative Observation/XRT: 1/6 no progression XRT (n = 3) Retrospective review (n = 15) Minimum F/U Negative margins: 2/15 LR; 13/15 no LR Pritchard et al. [56] Extra-abdominal Primary (n = 50) Surgery (n = 34) (n = 50) Positive/marginal 48 months Positive/marginal margins: 12/29 LR; Surgery + XRT (n = 29) 17/29 no LR (n = 10) Negative Surgery (n = 105) Negative margin: 14/58 LR (24%) Prospective cohort (n = 58/105) Mean F/U Merchant et al. [57] Extra-abdominal Primary (n = 105) Adjuvant XRT Positive margin: 12/47 LR (26%) (n = 105) Positive 49 months (n = 31) No difference in LR with adjuvant XRT (n = 47/105) Negative margin De novo DT: 76% LR Retrospective review Primary (n = 128) (n = 146) Median F/U Recurrent DT: 59% LR Gronchi et al. [58] Extra-abdominal Surgery (n = 203) (n = 203) Recurrent (n = 75) Positive margin 135 months Positive margins not predictive of (n = 56) recurrence for de novo DT FAP associated 42% LR in macroscopically complete Retrospective review Primary (n = 20) Surgery (n = 20) Median F/U Latchford et al. [59] Extra-abdominal Not reported resections (n = 20) (32 tumors) Medication (n = 19) 60 months and abdominal No desmoid-related mortalities Sarcoma 7 Table 3: Continued. References Subjects Anatomic site Presentation Intervention Surgical margins Follow-up Outcomes Nonoperative group: 14/23 stable Nonoperative (n = 23) disease Observation (n = 11) Negative Surgical resection: 57/89 LR (64%) Retrospective review Medication (n = 12) (n = 19/89) Median F/U Similar EFS with nonoperative Bonvalot et al. [61] Extra-abdominal Primary (n = 112) (n = 112) Surgery (n = 89) Positive 76 months treatment and negative margin Medication (n = 9) (n = 70/89) surgical resection Adjuvant XRT (n = 13) Tumor location and negative margin predictive of EFS Increased LR with recurrent disease Medication (n = 11) Functional impairment correlates Retrospective review Extra-abdominal Primary (n = 69) Negative (n = 22) Median F/U Stoeckle et al. [62] XRT (n = 23) with number of surgeries (n = 106) and abdominal Recurrent (n = 37) Positive (n = 70) 129 months Surgery (n = 92) Time to stable disease increased with number of surgeries Extra-abdominal Retrospective review Primary (n = 74) Observation (n = 83) Median F/U Observation: 5 year PFS: 50% Fiore et al. [63] and N/A (n = 142) Recurrent (n = 68) Medication (n = 59) 33 months Medical therapy: 5 year PFS: 59% intra-abdominal Abdominal DT: similar PFS with FAP associated operative and non-operative Retrospective review Surgery (n = 49) Median F/U Nieuwenhuis Vase [64] Extra-abdominal Primary (n = 78) Not reported therapy (n = 78) Non-operative (n = 29) 96 months and abdominal Extra-abdominal DT: PFS favors surgical resection Negative margin Observation only: 78% Observation (n = 27) Retrospective review (n = 111) stable/remission Medication (n = 23) (n = 426) Extra-abdominal Positive margin Median F/U Negative margins: 44% LR; 64% no Salas et al. [65] Primary (n = 426) XRT (n = 6) multicenter and abdominal (n = 147) 54 months LR Surgery (n = 370) database Unknown Positive margins: 67% progression; Surgery + XRT (n = 37) (n = 112) 33% no progression EFS: event free survival; PFS: progression free survival; LR: local recurrence; F/U: follow-up; DT: Desmoid tumor; XRT: radiation therapy. 8 Sarcoma a subgroup of patients who did well with a wait and see of cyclooxygenase-2, and mice treated with a cyclooxygenase- approach. Only 23 patients were included in the nonoper- 2 inhibitor had decreased desmoid tumor size [69]. There are ative group, and there were no strict inclusion criteria [61]. little human data corroborating the effects of prostaglandins A subsequent, larger study analyzed the results of a routine and prostaglandin inhibition on DTs. front-line conservative approach used to treat both primary Multiple chemotherapeutic agents have shown efficacy and recurrent desmoids at two institutions [63]. Seventy- against desmoids including doxorubicin, methotrexate plus four primary and 68 recurrent tumors were studied. Eighty- vinblastine, cyclophosphamide plus doxorubicin, and VAC three received no intervention, and 59 received medical (vincristine, actinomycin-D, cyclophosphamide) [68, 70]. therapy. Overall progression-free survival was 64% at 3 years Interferon alpha has also been used singly and in combina- and 53% at 5 years. There was not a statistically significant tion with some of the aforementioned cytotoxic agents [68]. difference in progression free survival between the no inter- More recently, targeted biologic agents have been added to vention and the medically treated groups [63]. The authors the desmoid treatment armamentarium. Two phase 2 trials did not believe that subsequent surgery was compromised by have reported efficacy of imatinib, a tyrosine kinase inhibitor, delay in the patients who progressed. More recently, a study in the treatment of desmoids [71, 72]. As previously men- was performed to identify factors associated with progression tioned, C-KIT expression is lacking in most DTs. Analysis free survival. In a multivariate analysis of 426 sporadic of 124 DTs from 85 patients found that PDGF alpha and desmoid tumors, age less than 37, extremity location, and PDGF receptor alpha were expressed in all tumors, but PDGF size greater than 7 cm were associated with progression [65]. beta and PDGF receptor beta were not expressed [73]. The Notably, the authors could not determine how to use this same authors failed to identify PDGF receptor mutations in information with respect to surgery versus wait and see.One 14 analyzed specimens [73]. These data suggest that ima- could argue that DTs at high risk of progression should be tinib’s efficacy against desmoids results from a mechanism resected early because conservative treatment is more likely other than direct inhibition of these known tyrosine kin- to fail. On the contrary, perhaps the high-risk group should ase protooncogenes. Another tyrosine kinase inhibitor, so- be observed because they may be more biologically aggressive rafenib, has also shown efficacy against desmoids in a and therefore more likely to recur after surgery. This cannot smaller single-institution trial [74]. Finally, a clinical trial be answered without prospective data. (NCT01265030) of the mammalian target of rapamycin Most of the aforementioned studies included few if (mTOR) inhibitor, sirolimus, for the treatment of desmoids any FAP-DTs. There are no studies which show that FAP in children and young adults was opened in 2010. The large associated extra-abdominal desmoids behave differently than number of agents used for DTs clearly indicates that presently their sporadic counterparts with respect to surgical man- there is lack of consensus with respect to medical manage- agement of primary disease. As previously discussed, FAP- ment of this condition. DTs may occur after surgery and trauma. This phenomenon is presumably related to the wound healing environment 11. Conclusion in the setting of germ-line APC mutations. A conservative approach to intra-abdominal desmoids has long been recom- Understanding of the epidemiology, genetics, molecular and mended due to the high morbidity and even mortality noted cellular biology, pathophysiology, and treatment of FAP in many early studies [64, 66]. Modern studies of FAP-DTs related desmoid tumors has improved substantially over the have shown that resection is surgically safe but recurrence past decade. Despite these improvements, DTs remain a rates remain high. Consensus for first-line conservative major cause of morbidity in the FAP population. A more management is growing [63–65]. Thestudiesreferencedin conservative surgical approach is presently advocated by this section are summarized in Table 3. many oncologic surgeons. Medical management is attempted first for most abdominal DTs, and a wait and see approach is undertaken for many extra-abdominal DTs. Surgical goals 10. Medical Treatment of FAP-Associated and techniques are now often less aggressive than in the past. Recent studies have implicated mesenchymal stem cells as Extra-Abdominal Desmoids critical components of desmoid development. Gene expres- Current first-line medical management includes antihor- sion profiling has shown promise in elucidating downstream monal therapy (specifically tamoxifen) and nonsteroidal elements of the WNT/APC/beta catenin pathway. Future anti-inflammatory drugs (NSAIDs, specifically sulindac, progress in treatment will likely depend upon continued indomethacin, and more recently celecoxib) [62]. 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