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Desmoid tumours
EJSO 2001; 27: 701–706 doi:10.1053/ejso.2001.1169, available online at http://www.idealibrary.com on
REVIEW
Desmoid tumours C. J. Shields, D. C. Winter, W. O. Kirwan and H. P. Redmond Department of Academic Surgery, National University of Ireland (Cork), Cork University Hospital, Wilton, Cork, Ireland
Desmoid tumours exhibit fibroblastic proliferation and arise from fascial or musculoaponeurotic structures. Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment. 2001 Harcourt Publishers Ltd Key words: desmoid tumour; fibromatosis; Gardner’s syndrome; familial adenomatous polyposis; tamoxifen.
INTRODUCTION
INCIDENCE
Desmoid tumours are benign tumours exhibiting fibroblastic proliferation that arise from fascial or musculoaponeurotic structures. Initially described by MacFarlane in 1832,1 the term desmoid (derived from the Greek desmos meaning tendon-like) was first employed by Mu¨ller in 1838.2 These connective tissue hyperplasias infiltrate locally, but do not metastasise, and they tend to recur following excision.3–5 The term aggressive fibromatosis is sometimes employed to better describe the marked cellularity and aggressive local behaviour of these lesions.6 Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment.
Though described over a century ago, there is a relative paucity of data concerning desmoids. In the general population, they are rare, accounting for 0.03% of all neoplasms,7,8 and have an estimated incidence of 2–4 per million per year,9 though this figure may reflect a lack of reporting of these tumours. An association with familial adenomatous polyposis of the colon (FAP) has been well documented,10,11 as has a more pronounced association with the subgroup, Gardner’s syndrome.12 Both abdominal and extraabdominal desmoids occur more commonly in FAP patients, exhibiting an incidence of 3.5–32%.12–16 In the original Gardner kindred the incidence was 29%.12
Correspondence to: Prof. H. P. Redmond, Department of Surgery, Cork University Hospital, Wilton, Cork, Ireland. Fax: +353 21 490 1240; E-mail: [email protected] 0748–7983/01/080701+06 $35.00/0
AETIOLOGY Although the aetiology of desmoids is poorly defined, numerous factors are acknowledged to be strongly associated with their development. An antecedent history of trauma to the site of the tumour, often surgical in nature, may be elicited in approximately 25% of cases.17,18 Within the FAP population, there is a strong correlation between prophylactic proctocolectomy and the subsequent development of desmoid tumours.13,19–21 Family history has been postulated as 2001 Harcourt Publishers Ltd
702 a predisposing factor among FAP patients,13,19 Gurbuz et al. noting an increased risk of 2.5 times in first degree relatives.19 The close association of this neoplasm with FAP and Gardner’s syndrome, coupled with the putative importance of family history, may implicate an intrinsic genetic defect in the development of desmoid tumours. The adenomatous polyposis coli (APC) gene on chromosome 5, responsible for the development of FAP, has been studied for specific mutations which may relate to desmoid development. A link with the 3′ region of this gene was described by Caspari et al.,22 though others have subsequently failed to demonstrate a genetic subset of FAP patients prone to these tumours.19 Reports of familial desmoids arising without evidence of FAP, or with variable expression of the disease, suggest the existence of a distinct genetic defect predisposing to the development of these tumours, or a FAP mutation displaying a penetrant desmoid phenotype, with attenuated colonic disease.23,24 A compelling association of desmoids with the endogenous hormonal environment and exogenous sex hormones has been described. A preponderance of cases afflicting women of reproductive age has been noted in many series.6,7,17 In a study by Reitamo et al., 80% of the desmoid tumours were described in females, 50% of which occurred in those between the ages of 20 and 40.7 Others have noted a significant, though less pronounced predominance of desmoid tumours in the female population, with a female/male ratio ranging from 1.4 to 1.8.6,16,17,25 The influence of femal gender in the FAP population is more disputed, with some studies failing to show a significant preponderance of desmoid tumours amongst females.19,20 However, one large study by Jones et al. of FAP patients in Cleveland reported a female/male ratio of 3.0.13 The predominance of cases affecting young women, frequently during or after pregnancy, is particularly apparent.13,26 Anecdotal reports of tumour regression during menopause,9,26 the development of desmoids in patients following exposure to oral contraceptives,13,27 and reports of tumour regression with tamoxifen treatment,28 serve to underline the putative endocrine basis for these tumours. The induction of fibrous tumours in animal models following administration of exogenous oestrogen provides further anecdotal evidence.9 Oestrogen exerts a mitogenic influence on many cell types, including fibroblasts.29 Therefore, it is proposed that oestrogen plays a key role in the multifactorial pathogenesis of desmoids.
REVIEW transilluminable, and are typically smooth, with normal skin overlying them. The presence of a desmoid tumour (and indeed any soft tissue tumour) should alert the physician to taking a thorough family history for colonic carcinoma, polyps or both. Thus examination of the fundi for characteristic black spots, and colonoscopy should be performed to diagnose or outrule Gardner’s syndrome. Conversely, desmoid tumours should be susptected in patients with FAP or Gardner’s syndrome who present with evidence of swellings. Since they infiltrate locally, they may demonstrate (in the same fashion as adenocarcinoma of the urachal remnant of the bladder) an ‘iceberg phenomenon’, with only a small proportion clinically manifest.30 Radiological investigations should be employed to better define the extent of the tumour, and the relevant anatomy, before embarking upon what may result in a more radical and technically difficult resection than anticipated clinically. Lymphadenopathy is not seen in the drainage area of the tumour unless a concomitant disease process is extant, enabling differentiation from the more malignant sarcomas, such as dermatofibrosarcoma protuberans, which exhibits lymphadenopathy in 10–20% of cases at presentation.31 Intra-abdominal desmoids can remain asymptomatic for a considerable period, while relentlessly enlarging and infiltrating into adjacent structures.32 The intraabdominal compression of viscera may occasion the initial presentation of the patient, with symptoms of intestinal, vascular, and ureteric obstruction, or neural involvement.33 Weiss et al. reported the case of one patient who exhibited quadriceps paralysis and neurogenic bladder due to local invasion of her lumbosacral plexus.34 Desmoids may occur at the site of any fascia, but particularly that of muscle, hence the descriptive term musculo-aponeurotic fibromatosis. Many studies have shown that between 37% and 50% of desmoids arise in the abdominal region.6,17,35,36 The most common extra-abdominal sites include the shoulder girdle, chest wall and inguinal regions.5 McKinnon et al., in a series of 36 patients, found the chest wall to be the commonest site.18 There is evidence, though, that age may play a role in determining the site of the tumour. Desmoids may occur at any age, and have been documented from 3 years to 67 years of age.10,11 Reitamo et al. found that in a group of desmoid patients under 15 years of age, the tumours occurred predominantly in females, in an extra-abdominal distribution, whereas abdominal tumours were significantly commoner in an older age group (18–36 years), with a female preponderance of only 1.8:1.7
CLINICAL CONSIDERATIONS Peripheral desmoids present as tumours which are intimately associated with contiguous structures. They are firm, may be mobile, are neither fluctuant nor
HISTOLOGY The macroscopic appearance is of a hard fibrous lump, typically infiltrating and adherent to the local tissue.
REVIEW They have a relatively poor vascularization with a pale tan colour, allowing differentiation from neighbouring tissue.37 Examination of the transected desmoid reveals a fibrous consistency with no areas of haemorrhage or necrosis. The appearance of a capsule is misleading because the infiltration may be extending beyond an apparently well-circumscribed mass. Microscopically, there is dense collagenous material with interspersed spindle cells and fibroblasts, which have an abundant eosinophilic cytoplasm.38 The nuclei of the large fibroblasts show considerable pleomorphism, with notable mitotic activity. Despite these appearance, this type of lesion should not be mistaken for a fibrosarcoma, which is more obviously malignant with a higher mitotic activity, greater nucleocytoplasmic ratio, and a higher vascularity, with little evidence of collagen formation.31 In desmoids macrophages, multinucleated giant cells and widespread lymphocytes are manifest, particularly at the periphery.39 In contrast, malignant fibrosarcomas generally have a relative paucity of these cells.
IMAGING The principal role of imaging in the investigation of desmoid tumours is to define the degree of extension to local structures and complications such as hydronephrosis and small bowel obstruction.36,40 Desmoids tend to have a similar attenuation to muscle on contrast-enhanced computed tomography (CT) scans.36 However, CT cannot distinguish a desmoid from similar soft tissue tumours, rendering histological diagnosis necessary. Magnetic resonance imaging (MRI) features of malignant neoplasms, such as inhomogenous signal, poor margination, and neurovascular involvement, can also be demonstrated in desmoids. Disappointingly, MRI has little value in assessing margin, even with contrast,41 though extent and tumour relationship to neurovascular structures are better visualized than with CT, and MRI is an accurate predictor or resectability.42 While scintigraphic evaluation has been shown to be effective in determining extent prior to surgery, extent in these cases refers to the macroscopically demonstrable margin, which correlates poorly with microscopic invasion.43
TREATMENT The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Surgical excision remains the principle therapeutic manoeuvre, however the scope of the resection and the influence of involved margins on local recurrence remain controversial.
703 There are conflicting reports on the importance of adequate excision, with some authors espousing a conservative resection.3,44,45 However, aggressive resection with uninvolved margins appears to be an important determinant of a successful outcome.46,47 Uncompromising attempts at resection are warranted, not solely for the initial lesion, but also for recurrent lesions. Disappointingly, clean margins are no guarantee of a lower risk of recurrence, although these patients may enjoy a prolonged disease-free interval.6 Overall recurrence with surgery alone is 40%. The incidence of recurrent lesions in children is significantly higher, though this may reflect a less aggressive approach initially. The scope of the resection is largely determined by the location of the tumour. A desmoid lesion situated on an extremity facilitates a radical excision with limb salvage. However, an adequate margin of resection cannot always be obtained, due to the importance of preservation of vital anatomic structures. Indeed, a radical resection of mesenteric desmoids is often unfeasible.48 In these cases, adjuvant therapy may prove to be of benefit. Radiotherapy has an important adjuvant role in the treatment of sarcomas,49 however, its role in the management of desmoids is less clearly defined.50 It has been employed in attempts to control residual disease, as an adjunct to excision, and as an alternative to mutilating resection.51 Its efficacy is disputed, with some reports of partial and complete resection following adjuvant radiotherapy.52 However, using multivariate regression analysis, Posner et al. failed to demonstrate a decrease in recurrence.6 As some authors maintain that desmoids are insensitive to radiation, the inconsistent nature of the results of radiotherapy may possibly be attributed to ovarian ablation, and its subsequent effect on female hormone production. Treatment with chemotherapy is frequently unsatisfactory. It has been employed only sporadically, and with inconclusive results.53,54 There have been no convincing results from conventional antineoplastic drugs, possibly due to the low mitotic index exhibited by these tumours, although antisarcoma therapy (doxorubicin and dicarbazine) has shown some promising initial results in a small series, as has combination therapy with vinblastine and methotrexate in children.55,56 Dramatic responses of desmoid tumours to tamoxifen have been reported, with response rates of 50% quoted.57,58 Lim et al. found that 33% of desmoids expressed oestrogen receptors,59 although oestrogen receptor negativity does not necessarily imply an unresponsiveness to oestrogen. Successful hormonal manipulation may obviate the need for extensive or mutilating resection of recurrent disease. Extra-abdominal desmoids have exhibited some
704 propensity for responding to immunotherapy. Interferon alpha therapy may prolong the disease-free interval when coupled with surgery,60 and isolated limb perfusion with tumour necrosis factor alpha (TNF) and melphalan may preclude the need for disfiguring surgery in patients with recurrent peripheral desmoids.61 The role of prostaglandin manipulation of desmoids, specifically the use of non-steroidal anti-inflammatory compounds such as sulindac, is ill defined, with conflicting reports of efficacy.13,55
THE FUTURE Future attempts to devise effective treatment regimes for this frustrating disease are likely to focus on the molecular basis of fibroblast mitogenesis.62,63 Regulators of cellular proliferation, such as the insulin-like growth factors (e.g. IGF-1), and other mitogenic peptides, have recently been implicated in the regulation of apoptosis,64 thereby providing a potential pharmacological target for suppressing unchecked and unrestrained cell proliferation. The inhibition of cyclo-oxygenase activity by non-steroidal anti-inflammatory drugs results in a striking reduction in colorectal tumour multiplicity.65 A putative effect on the stromal constituents of polyps may possibly be extrapolated to desmoid tumours. More than one type of oestrogen receptor has been identified, with at least two intracellular isoforms (denoted alpha and beta),66 and one putative membrane domain.67 This may account for the unpredictable responses of desmoids to tamoxifen in the clinical setting. Concern over certain side-effects of tamoxifen, including the risk of endometrial carcinoma and osteoporosis, and the potential for more specific anti-oestrogen effects may lead to a trial of selective oestrogen receptor modulators (SERMs) in these situations. However, it should be noted that the growth inhibitory effects of tamoxifen may be observed in cells that lack demonstrable oestrogen receptors.68,69 This may be due to perturbation of cell signalling cascades required for function and growth independent of oestrogen receptor coupling by tamoxifen.70,71 Therefore, it does not necessarily follow that the growth inhibitory effects of tamoxifen are related to its anti-oestrogen activity and this has implications for the proposed use of SERMs.
CONCLUSION The development of evidence-based clinical guidelines for the management of this tumour is confounded by the rarity of the disease. With an incidence of 0.03%,7,8 many surgeons will encounter a negligible number during a career. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. Underestimation of desmoids may be attributed to dispute over pathological
REVIEW classification, and misconceptions regarding their behaviour, with the result that an indolent nature is often inadvisably ascribed to these non-metastasising though relentlessly invasive tumours. Radical resection with clear margins remains the principal determinant of outcome, however, lamentably, clear margins do not necessarily correlate with lower recurrence rates. Where surgery is precluded because of its mutilating nature or inherent dangers, other modalities may be employed, such as radiotherapy, as an adjunct to inadequate excision. In recurrence, aggressive resection may be obviated by the use of anti-oestrogens. The reclassification of the desmoid tumour as a lowgrade sarcoma, and the establishment of a tumour registry would greatly advance the collation of data on this rare and frustrating disease. Management of these patients in a regional centre, facilitating multidisciplinary care, may expedite the elucidation of ‘best practice’, specifically the clarification of the relation between clear margins and long-term outcome, and the application of hormonal therapy. Future innovations in the management of desmoid tumours may owe as much to serendipity as biological insight.
REFERENCES 1. MacFarlane J. Clinical reports on the surgical practice of Glasgow Royal Infirmary. Glasgow: D. Robertson, 1832: 63. 2. Mu¨ller J. Ueber den feinern Bau und die Formen der krankhaftlichen Geschwulste. Berlin: G. Reimer, 1838: 80. 3. Lewis JJ, Boland PJ, Leuny DH, Woodruff JM, Brennan MF. The enigma of desmoid tumours. Ann Surg 1999; 299: 6, 866–72. 4. Wara WM, Phillips TL, Hill DR, Bovill E Jr, Luk KH, Lichter AS, Leibel SA. Desmoid tumours: treatment and prognosis. Radiology 1977; 124: 225–6. 5. Khorsand J, Karakousis CP. Desmoid tumours and their management. Am J Surg 1985; 149: 215–8. 6. Posner MC, Shiu MH, Newsome JL, Hafdu SI, Gaynor JL, Brennan MF. The desmoid tumor. Not a benign disease. Arch Surg 1989; 124: 191–6. 7. Reitamo JJ, Hayry P, Nykyri E, Saxen E. The desmoid tumour. I. Incidence, sex, age, and anatomical distribution in the Finnish population. Am J Clin Pathol 1982; 77: 665–73. 8. Pack GT, Ehrlich HE. Neoplasms of the abdominal wall with special consideration of desmoid tumours. Int Abstr Surg 1944; 79: 177–98. 9. Dahn I, Jonsson N, Lundh G. Desmoid tumours. A series of 33 cases. Acta Chir Scand 1963; 126: 305–14. 10. Brodsky JT, Gordan MS, Hajdu SI, Burt M. Desmoid tumors of the chest wall. A locally recurrent problem. J Thorac Cardiovasc Surg 1992; 104: 900–3. 11. Halata MS, Miller J, Stone RK. Gardner syndrome. Early presentation with a desmoid tumor. Discovery of multiple colonic polyps. Clin Pediatr 1989; 28: 538–40. 12. Naylor EW, Gardner EJ, Richards RC. Desmoid tumours and mesenteric fibromatosis in Gardner’s syndrome. Arch Surg 1979; 114: 1181–5. 13. Jones IT, Jagelman DG, Fazio VW, Lavery IC, Weakley FL, McGannon E. Desmoid tumors in familial polyposis coli. Ann Surg 1986; 204: 94–7. 14. Bussey HI. Extracolonic lesions associated with polyposis coli. Proc R Soc Med 1972; 65: 294. 15. Richards RC, Rogers SW, Gardner EJ. Spontaneous mesenteric fibromatosis in Gardner’s syndrome. Cancer 1981; 47: 597–601. 16. Jarviren HJ. Desmoid disease as part of familial adenomatous polyposis coli. Acta Chir Scand 1987; 153: 374–83. 17. Lopez R, Kemalyan N, Moseley HS, Dennis D, Vetto RM. Problems
REVIEW
18.
19. 20. 21.
22.
23. 24.
25.
26.
27.
28. 29. 30. 31.
32.
33.
34. 35.
36. 37. 38.
39. 40.
41.
42. 43.
44.
in diagnosis and management of desmoid tumors. Am J Surg 1990; 159: 450–3. McKinnon JG, Neifeld JP, Kay S, Parker GA, Foster WC, Lawrence W. Management of desmoid tumors. Surg Gynecol Obstet 1989; 169: 104–6. Gurbuz AK, Giardiello FM, Petersen GM, et al. Desmoid tumours in familial adenomatous polyposis. Gut 1994; 35: 377–81. McAdam WA, Goligher JC. The occurrence of desmoids in patients with familial polyposis coli. Br J Surg 1970; 57: 618–31. Lynch HT, Fitzgibbons R. Surgery, desmoid tumors, and familial adenomatous polyposis: case report and literature review. Am J Gastroenterol 1996; 91: 2598–601. 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. Hum Mol Genet 1995; 4: 337–40. Zayit I, Dihmis C. Familial multicentric fibromatosis – desmoids. Cancer 1989; 24: 786–96. Ozuner G, Hull TL. Familial desmoids in association with adrenal and ovarian masses and leiomyomas: report of three cases. Dis Colon Rectum 1999; 42: 529–32. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet 1987; 28: 385–92. Lotfi AM, Dozois RR, Gordon H, Hruska LS, Weiland LH, Carryer PW, Hurt RD. Mesenteric fibromatosis complicating familial adenomatous polyposis: predisposing factors and results of treatment. Int J Colorectal Dis 1989; 4: 30–6. Waddell WR. Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3′,5′-adenosine monophosphate. Ann Surg 1975; 181: 299–302. Wilcken N, Tattersall MH. Endocrine therapy for desmoid tumors. Cancer 1991; 68: 1384–8. Dhingra K. Antiestrogens – tamoxifen, SERMs and beyond. Invest New Drugs 1999; 17: 285–311. Sarno RC, Klauber G, Carter BL. Computer assisted tomography of urachal abnormalities. J Comput Assist Tomogr 1983; 7: 674–6. Pritchard DJ, Soule EH, Taylor WF, Ivins JC. Fibrosarcoma – a clinicopathologic and statistical study of 199 tumors of the soft tissues of the extremities and trunk. Cancer 1974; 33: 888–97. Easter DW, Halasz NA. Recent trends in the management of desmoid tumors. Summary of 19 cases and review of the literature. Ann Surg 1989; 210: 765–9. Corbel L, Souissi M, Chretien Y, Dufour B. Desmoid tumor of the mesentery. An uncommon cause of ureteral obstruction. J Radiol 1992; 73: 669–72. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer 1989; 64: 1192–4. Reitamo JJ, Scheinin TM, Hayry P. The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg 1986; 151: 230–7. Einstein DM, Tagliabue JR, Desai RK. Abdominal desmoids: CT findings in 25 patients. Am J Roentgenol 1991; 157: 275–9. Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease (6th edn). Philadelphia: Saunders, 1998: 1476. Salloum H, Kanitakis J, Chouvet B, Grimand P, Claudy A. Extraabdominal desmoid tumor. Microscopic aspects and histogenesis. Ann Dermatol Venereol 1993; 120: 685–8. Torres D. Multiple sebaceous tumours. Arch Dermatol 1968; 98: 549. Doi K, Iida M, Kohrogi N, Mibu R, Onitsuka H, Yao T, Fujishima M. Large intra-abdominal desmoid tumors in a patient with familial adenomatosis coli: their rapid growth detected by computerized tomography. Am J Gastroenterol 1993; 88: 595–8. Quinn SF, Erickson SJ, Dee PM, Walling A, Hackbarth DA, Knudson GJ, Moseley HS. MR imaging in fibromatosis: results in 26 patients with pathologic correlation. Am J Roentgenol 1991; 156: 539–42. O’Keefe F, Kim EE, Wallace S. Magnetic resonance imaging in aggressive fibromatosis. Clin Radiol 1990; 42: 170–3. Ohta H, Endo K, Konishi J, Iwasaki R, Kotoura Y, Yamamuro T, Kotoura H. Scintigraphic evaluation of aggressive fibromatosis. J Nucl Med 1990; 31: 1632–4. Rock MG, Pritchard DJ, Reiman HM, Soule EH, Brewster RC.
705
45. 46.
47.
48.
49. 50. 51. 52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65. 66. 67.
68.
Extra-abdominal desmoid tumors. J Bone Joint Surg Am 1984; 66: 1369–74. Reitamo JJ. The desmoid tumour. IV. Choice of treatment, results and complications. Arch Surg 1983; 118: 1318–22. Ballo MT, Zagars GK, Pollack A, Pisters PW, Pollack RA. Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. J Clin Oncol 1999; 17: 158–67. Kulaylat MN, Karakousis CP, Keaney CM, McCorvey D, Bem J, Ambrus Sr JL. Desmoid tumour: a pleomorphic lesion. Eur J Surg Oncol 1999; 25: 487–97. Clark SK, Neale KF, Landgrebe JC, Phillips RK. Desmoid tumours complicating familial adenomatous polyposis. Br J Surg 1999; 86: 1185–9. O’Sullivan B, Wylie J, Catton C, et al. The local management of soft tissue sarcoma. Semin Radiat Oncol 1999; 9: 328–48. De Vita VT, Hellman S, Rosenberg SA. Principles and Practice of Oncology (5th edn). Philadelphia: JB Lippincot, 1987: 1444. Keus R, Bartelink H. The role of radiotherapy in the treatment of desmoid tumours. Radiother Oncol 1986; 7: 1–5. Zelefsky MJ, Harrison LB, Shiu MH, Armstrong JG, Hajdu SI, Brennan MF. Combined surgical resection and iridium 192 implantation for locally advanced and recurrent desmoid tumors. Cancer 1991; 67: 380–4. Kitamura A, Kanagawa T, Yamada S, Kawai T. Effective chemotherapy for abdominal desmoid tumor in a patient with Gardner’s syndrome. Report of a case. Dis Colon Rectum 1991; 34: 822–6. Tsukada K, Church JM, Jagelman DG, Fazio VW, Lavery IC. Systemic cytotoxic chemotherapy and radiation therapy for desmoid in familial adenomatous polyposis. Dis Colon Rectum 1991; 34: 1090–2. Lynch HT, Fitzgibbons R, Chong S, Cavalieri J, Lynch J, Wallace F, Patel S. Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner’s syndrome. Dis Colon Rectum 1994; 37: 260–7. Skapek SX, Hawk BJ, Hoffer FA, et al. Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol 1998; 16: 3021–7. Waddell WR, Gerner RE, Reich MP. Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach. J Surg Oncol 1983; 22: 197–211. Kinzbrunner B, Ritter S, Domingo J, Rosenthal CJ. Remission of rapidly growing desmoid tumors after tamoxifen therapy. Cancer 1983; 52: 2201–4. Lim CL, Walker MJ, Mehta RR, Das Gupta TK. Estrogen and antiestrogen binding sites in desmoid tumors. Eur J Cancer Clin Oncol 1986; 22: 583–7. Leithner A, Schnack B, Katterschafka T, et al. Treatment of extraabdominal desmoid tumors with interferon-alpha with or without tretinoin. J Surg Oncol 2000; 73: 21–5. Lev-Chelouche D, Abu-Abeid S, Nakache R, et al. Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Surgery 1999; 126: 963–7. Pouyssegur J, Chambard JC, Franchi A, Paris S, Van ObberghenSchilling E. Growth factor activation of an amiloride-sensitive Na+/H+ exchange system in quiescent fibroblasts: coupling to ribosomal protein S6 phosphorylation. Proc Natl Acad Sci USA 1982; 79: 3935–9. Yamagata M, Tannock IF. The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. Br J Cancer 1996; 73: 1328–34. Morales MP, Galvez A, Eltit JM, Ocaranza P, Diaz-Araya G, Lavandero S. IGF-1 regulates apoptosis of cardiac myocyte induced by osmotic-stress. Biochem Biophys Res Commun 2000; 270: 3, 1029–35. Gupta RA, DuBois RN. Combinations for cancer prevention. Nat Med 2000; 6: 974–5. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–9. Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labeling and impededligand binding. FASEB J 1995; 9: 404–10. Ziv Y, Gupta MK, Milsom JW, Vladisavljevic A, Kitago K, Fazio VW.
706 The effect of tamoxifen on established human colorectal cancer cell lines in vitro. Anticancer Res 1996; 16: 3767–71. 69. Picariello L, Fiorelli G, Benvenuti S, et al. In vitro bioeffects of the antiestrogen LY117018 on desmoid tumor and colon cancer cells. Anticancer Res 1997; 17: 2099–104. 70. Weiss DJ, Gurpide E. Non-genomic effects of estrogens and antiestrogens. J Steroid Biochem 1988; 31: 671–6.
REVIEW 71. Valverde MA, Mintenig GM, Sepulveda FV. Differential effects of tamoxifen and I- on three distinguishable chloride currents activated in T84 intestinal cells. Pflugers Arch 1993; 425: 552–4.
Accepted for publication 21 May 2001
REVIEW
Desmoid tumours C. J. Shields, D. C. Winter, W. O. Kirwan and H. P. Redmond Department of Academic Surgery, National University of Ireland (Cork), Cork University Hospital, Wilton, Cork, Ireland
Desmoid tumours exhibit fibroblastic proliferation and arise from fascial or musculoaponeurotic structures. Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment. 2001 Harcourt Publishers Ltd Key words: desmoid tumour; fibromatosis; Gardner’s syndrome; familial adenomatous polyposis; tamoxifen.
INTRODUCTION
INCIDENCE
Desmoid tumours are benign tumours exhibiting fibroblastic proliferation that arise from fascial or musculoaponeurotic structures. Initially described by MacFarlane in 1832,1 the term desmoid (derived from the Greek desmos meaning tendon-like) was first employed by Mu¨ller in 1838.2 These connective tissue hyperplasias infiltrate locally, but do not metastasise, and they tend to recur following excision.3–5 The term aggressive fibromatosis is sometimes employed to better describe the marked cellularity and aggressive local behaviour of these lesions.6 Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment.
Though described over a century ago, there is a relative paucity of data concerning desmoids. In the general population, they are rare, accounting for 0.03% of all neoplasms,7,8 and have an estimated incidence of 2–4 per million per year,9 though this figure may reflect a lack of reporting of these tumours. An association with familial adenomatous polyposis of the colon (FAP) has been well documented,10,11 as has a more pronounced association with the subgroup, Gardner’s syndrome.12 Both abdominal and extraabdominal desmoids occur more commonly in FAP patients, exhibiting an incidence of 3.5–32%.12–16 In the original Gardner kindred the incidence was 29%.12
Correspondence to: Prof. H. P. Redmond, Department of Surgery, Cork University Hospital, Wilton, Cork, Ireland. Fax: +353 21 490 1240; E-mail: [email protected] 0748–7983/01/080701+06 $35.00/0
AETIOLOGY Although the aetiology of desmoids is poorly defined, numerous factors are acknowledged to be strongly associated with their development. An antecedent history of trauma to the site of the tumour, often surgical in nature, may be elicited in approximately 25% of cases.17,18 Within the FAP population, there is a strong correlation between prophylactic proctocolectomy and the subsequent development of desmoid tumours.13,19–21 Family history has been postulated as 2001 Harcourt Publishers Ltd
702 a predisposing factor among FAP patients,13,19 Gurbuz et al. noting an increased risk of 2.5 times in first degree relatives.19 The close association of this neoplasm with FAP and Gardner’s syndrome, coupled with the putative importance of family history, may implicate an intrinsic genetic defect in the development of desmoid tumours. The adenomatous polyposis coli (APC) gene on chromosome 5, responsible for the development of FAP, has been studied for specific mutations which may relate to desmoid development. A link with the 3′ region of this gene was described by Caspari et al.,22 though others have subsequently failed to demonstrate a genetic subset of FAP patients prone to these tumours.19 Reports of familial desmoids arising without evidence of FAP, or with variable expression of the disease, suggest the existence of a distinct genetic defect predisposing to the development of these tumours, or a FAP mutation displaying a penetrant desmoid phenotype, with attenuated colonic disease.23,24 A compelling association of desmoids with the endogenous hormonal environment and exogenous sex hormones has been described. A preponderance of cases afflicting women of reproductive age has been noted in many series.6,7,17 In a study by Reitamo et al., 80% of the desmoid tumours were described in females, 50% of which occurred in those between the ages of 20 and 40.7 Others have noted a significant, though less pronounced predominance of desmoid tumours in the female population, with a female/male ratio ranging from 1.4 to 1.8.6,16,17,25 The influence of femal gender in the FAP population is more disputed, with some studies failing to show a significant preponderance of desmoid tumours amongst females.19,20 However, one large study by Jones et al. of FAP patients in Cleveland reported a female/male ratio of 3.0.13 The predominance of cases affecting young women, frequently during or after pregnancy, is particularly apparent.13,26 Anecdotal reports of tumour regression during menopause,9,26 the development of desmoids in patients following exposure to oral contraceptives,13,27 and reports of tumour regression with tamoxifen treatment,28 serve to underline the putative endocrine basis for these tumours. The induction of fibrous tumours in animal models following administration of exogenous oestrogen provides further anecdotal evidence.9 Oestrogen exerts a mitogenic influence on many cell types, including fibroblasts.29 Therefore, it is proposed that oestrogen plays a key role in the multifactorial pathogenesis of desmoids.
REVIEW transilluminable, and are typically smooth, with normal skin overlying them. The presence of a desmoid tumour (and indeed any soft tissue tumour) should alert the physician to taking a thorough family history for colonic carcinoma, polyps or both. Thus examination of the fundi for characteristic black spots, and colonoscopy should be performed to diagnose or outrule Gardner’s syndrome. Conversely, desmoid tumours should be susptected in patients with FAP or Gardner’s syndrome who present with evidence of swellings. Since they infiltrate locally, they may demonstrate (in the same fashion as adenocarcinoma of the urachal remnant of the bladder) an ‘iceberg phenomenon’, with only a small proportion clinically manifest.30 Radiological investigations should be employed to better define the extent of the tumour, and the relevant anatomy, before embarking upon what may result in a more radical and technically difficult resection than anticipated clinically. Lymphadenopathy is not seen in the drainage area of the tumour unless a concomitant disease process is extant, enabling differentiation from the more malignant sarcomas, such as dermatofibrosarcoma protuberans, which exhibits lymphadenopathy in 10–20% of cases at presentation.31 Intra-abdominal desmoids can remain asymptomatic for a considerable period, while relentlessly enlarging and infiltrating into adjacent structures.32 The intraabdominal compression of viscera may occasion the initial presentation of the patient, with symptoms of intestinal, vascular, and ureteric obstruction, or neural involvement.33 Weiss et al. reported the case of one patient who exhibited quadriceps paralysis and neurogenic bladder due to local invasion of her lumbosacral plexus.34 Desmoids may occur at the site of any fascia, but particularly that of muscle, hence the descriptive term musculo-aponeurotic fibromatosis. Many studies have shown that between 37% and 50% of desmoids arise in the abdominal region.6,17,35,36 The most common extra-abdominal sites include the shoulder girdle, chest wall and inguinal regions.5 McKinnon et al., in a series of 36 patients, found the chest wall to be the commonest site.18 There is evidence, though, that age may play a role in determining the site of the tumour. Desmoids may occur at any age, and have been documented from 3 years to 67 years of age.10,11 Reitamo et al. found that in a group of desmoid patients under 15 years of age, the tumours occurred predominantly in females, in an extra-abdominal distribution, whereas abdominal tumours were significantly commoner in an older age group (18–36 years), with a female preponderance of only 1.8:1.7
CLINICAL CONSIDERATIONS Peripheral desmoids present as tumours which are intimately associated with contiguous structures. They are firm, may be mobile, are neither fluctuant nor
HISTOLOGY The macroscopic appearance is of a hard fibrous lump, typically infiltrating and adherent to the local tissue.
REVIEW They have a relatively poor vascularization with a pale tan colour, allowing differentiation from neighbouring tissue.37 Examination of the transected desmoid reveals a fibrous consistency with no areas of haemorrhage or necrosis. The appearance of a capsule is misleading because the infiltration may be extending beyond an apparently well-circumscribed mass. Microscopically, there is dense collagenous material with interspersed spindle cells and fibroblasts, which have an abundant eosinophilic cytoplasm.38 The nuclei of the large fibroblasts show considerable pleomorphism, with notable mitotic activity. Despite these appearance, this type of lesion should not be mistaken for a fibrosarcoma, which is more obviously malignant with a higher mitotic activity, greater nucleocytoplasmic ratio, and a higher vascularity, with little evidence of collagen formation.31 In desmoids macrophages, multinucleated giant cells and widespread lymphocytes are manifest, particularly at the periphery.39 In contrast, malignant fibrosarcomas generally have a relative paucity of these cells.
IMAGING The principal role of imaging in the investigation of desmoid tumours is to define the degree of extension to local structures and complications such as hydronephrosis and small bowel obstruction.36,40 Desmoids tend to have a similar attenuation to muscle on contrast-enhanced computed tomography (CT) scans.36 However, CT cannot distinguish a desmoid from similar soft tissue tumours, rendering histological diagnosis necessary. Magnetic resonance imaging (MRI) features of malignant neoplasms, such as inhomogenous signal, poor margination, and neurovascular involvement, can also be demonstrated in desmoids. Disappointingly, MRI has little value in assessing margin, even with contrast,41 though extent and tumour relationship to neurovascular structures are better visualized than with CT, and MRI is an accurate predictor or resectability.42 While scintigraphic evaluation has been shown to be effective in determining extent prior to surgery, extent in these cases refers to the macroscopically demonstrable margin, which correlates poorly with microscopic invasion.43
TREATMENT The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Surgical excision remains the principle therapeutic manoeuvre, however the scope of the resection and the influence of involved margins on local recurrence remain controversial.
703 There are conflicting reports on the importance of adequate excision, with some authors espousing a conservative resection.3,44,45 However, aggressive resection with uninvolved margins appears to be an important determinant of a successful outcome.46,47 Uncompromising attempts at resection are warranted, not solely for the initial lesion, but also for recurrent lesions. Disappointingly, clean margins are no guarantee of a lower risk of recurrence, although these patients may enjoy a prolonged disease-free interval.6 Overall recurrence with surgery alone is 40%. The incidence of recurrent lesions in children is significantly higher, though this may reflect a less aggressive approach initially. The scope of the resection is largely determined by the location of the tumour. A desmoid lesion situated on an extremity facilitates a radical excision with limb salvage. However, an adequate margin of resection cannot always be obtained, due to the importance of preservation of vital anatomic structures. Indeed, a radical resection of mesenteric desmoids is often unfeasible.48 In these cases, adjuvant therapy may prove to be of benefit. Radiotherapy has an important adjuvant role in the treatment of sarcomas,49 however, its role in the management of desmoids is less clearly defined.50 It has been employed in attempts to control residual disease, as an adjunct to excision, and as an alternative to mutilating resection.51 Its efficacy is disputed, with some reports of partial and complete resection following adjuvant radiotherapy.52 However, using multivariate regression analysis, Posner et al. failed to demonstrate a decrease in recurrence.6 As some authors maintain that desmoids are insensitive to radiation, the inconsistent nature of the results of radiotherapy may possibly be attributed to ovarian ablation, and its subsequent effect on female hormone production. Treatment with chemotherapy is frequently unsatisfactory. It has been employed only sporadically, and with inconclusive results.53,54 There have been no convincing results from conventional antineoplastic drugs, possibly due to the low mitotic index exhibited by these tumours, although antisarcoma therapy (doxorubicin and dicarbazine) has shown some promising initial results in a small series, as has combination therapy with vinblastine and methotrexate in children.55,56 Dramatic responses of desmoid tumours to tamoxifen have been reported, with response rates of 50% quoted.57,58 Lim et al. found that 33% of desmoids expressed oestrogen receptors,59 although oestrogen receptor negativity does not necessarily imply an unresponsiveness to oestrogen. Successful hormonal manipulation may obviate the need for extensive or mutilating resection of recurrent disease. Extra-abdominal desmoids have exhibited some
704 propensity for responding to immunotherapy. Interferon alpha therapy may prolong the disease-free interval when coupled with surgery,60 and isolated limb perfusion with tumour necrosis factor alpha (TNF) and melphalan may preclude the need for disfiguring surgery in patients with recurrent peripheral desmoids.61 The role of prostaglandin manipulation of desmoids, specifically the use of non-steroidal anti-inflammatory compounds such as sulindac, is ill defined, with conflicting reports of efficacy.13,55
THE FUTURE Future attempts to devise effective treatment regimes for this frustrating disease are likely to focus on the molecular basis of fibroblast mitogenesis.62,63 Regulators of cellular proliferation, such as the insulin-like growth factors (e.g. IGF-1), and other mitogenic peptides, have recently been implicated in the regulation of apoptosis,64 thereby providing a potential pharmacological target for suppressing unchecked and unrestrained cell proliferation. The inhibition of cyclo-oxygenase activity by non-steroidal anti-inflammatory drugs results in a striking reduction in colorectal tumour multiplicity.65 A putative effect on the stromal constituents of polyps may possibly be extrapolated to desmoid tumours. More than one type of oestrogen receptor has been identified, with at least two intracellular isoforms (denoted alpha and beta),66 and one putative membrane domain.67 This may account for the unpredictable responses of desmoids to tamoxifen in the clinical setting. Concern over certain side-effects of tamoxifen, including the risk of endometrial carcinoma and osteoporosis, and the potential for more specific anti-oestrogen effects may lead to a trial of selective oestrogen receptor modulators (SERMs) in these situations. However, it should be noted that the growth inhibitory effects of tamoxifen may be observed in cells that lack demonstrable oestrogen receptors.68,69 This may be due to perturbation of cell signalling cascades required for function and growth independent of oestrogen receptor coupling by tamoxifen.70,71 Therefore, it does not necessarily follow that the growth inhibitory effects of tamoxifen are related to its anti-oestrogen activity and this has implications for the proposed use of SERMs.
CONCLUSION The development of evidence-based clinical guidelines for the management of this tumour is confounded by the rarity of the disease. With an incidence of 0.03%,7,8 many surgeons will encounter a negligible number during a career. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. Underestimation of desmoids may be attributed to dispute over pathological
REVIEW classification, and misconceptions regarding their behaviour, with the result that an indolent nature is often inadvisably ascribed to these non-metastasising though relentlessly invasive tumours. Radical resection with clear margins remains the principal determinant of outcome, however, lamentably, clear margins do not necessarily correlate with lower recurrence rates. Where surgery is precluded because of its mutilating nature or inherent dangers, other modalities may be employed, such as radiotherapy, as an adjunct to inadequate excision. In recurrence, aggressive resection may be obviated by the use of anti-oestrogens. The reclassification of the desmoid tumour as a lowgrade sarcoma, and the establishment of a tumour registry would greatly advance the collation of data on this rare and frustrating disease. Management of these patients in a regional centre, facilitating multidisciplinary care, may expedite the elucidation of ‘best practice’, specifically the clarification of the relation between clear margins and long-term outcome, and the application of hormonal therapy. Future innovations in the management of desmoid tumours may owe as much to serendipity as biological insight.
REFERENCES 1. MacFarlane J. Clinical reports on the surgical practice of Glasgow Royal Infirmary. Glasgow: D. Robertson, 1832: 63. 2. Mu¨ller J. Ueber den feinern Bau und die Formen der krankhaftlichen Geschwulste. Berlin: G. Reimer, 1838: 80. 3. Lewis JJ, Boland PJ, Leuny DH, Woodruff JM, Brennan MF. The enigma of desmoid tumours. Ann Surg 1999; 299: 6, 866–72. 4. Wara WM, Phillips TL, Hill DR, Bovill E Jr, Luk KH, Lichter AS, Leibel SA. Desmoid tumours: treatment and prognosis. Radiology 1977; 124: 225–6. 5. Khorsand J, Karakousis CP. Desmoid tumours and their management. Am J Surg 1985; 149: 215–8. 6. Posner MC, Shiu MH, Newsome JL, Hafdu SI, Gaynor JL, Brennan MF. The desmoid tumor. Not a benign disease. Arch Surg 1989; 124: 191–6. 7. Reitamo JJ, Hayry P, Nykyri E, Saxen E. The desmoid tumour. I. Incidence, sex, age, and anatomical distribution in the Finnish population. Am J Clin Pathol 1982; 77: 665–73. 8. Pack GT, Ehrlich HE. Neoplasms of the abdominal wall with special consideration of desmoid tumours. Int Abstr Surg 1944; 79: 177–98. 9. Dahn I, Jonsson N, Lundh G. Desmoid tumours. A series of 33 cases. Acta Chir Scand 1963; 126: 305–14. 10. Brodsky JT, Gordan MS, Hajdu SI, Burt M. Desmoid tumors of the chest wall. A locally recurrent problem. J Thorac Cardiovasc Surg 1992; 104: 900–3. 11. Halata MS, Miller J, Stone RK. Gardner syndrome. Early presentation with a desmoid tumor. Discovery of multiple colonic polyps. Clin Pediatr 1989; 28: 538–40. 12. Naylor EW, Gardner EJ, Richards RC. Desmoid tumours and mesenteric fibromatosis in Gardner’s syndrome. Arch Surg 1979; 114: 1181–5. 13. Jones IT, Jagelman DG, Fazio VW, Lavery IC, Weakley FL, McGannon E. Desmoid tumors in familial polyposis coli. Ann Surg 1986; 204: 94–7. 14. Bussey HI. Extracolonic lesions associated with polyposis coli. Proc R Soc Med 1972; 65: 294. 15. Richards RC, Rogers SW, Gardner EJ. Spontaneous mesenteric fibromatosis in Gardner’s syndrome. Cancer 1981; 47: 597–601. 16. Jarviren HJ. Desmoid disease as part of familial adenomatous polyposis coli. Acta Chir Scand 1987; 153: 374–83. 17. Lopez R, Kemalyan N, Moseley HS, Dennis D, Vetto RM. Problems
REVIEW
18.
19. 20. 21.
22.
23. 24.
25.
26.
27.
28. 29. 30. 31.
32.
33.
34. 35.
36. 37. 38.
39. 40.
41.
42. 43.
44.
in diagnosis and management of desmoid tumors. Am J Surg 1990; 159: 450–3. McKinnon JG, Neifeld JP, Kay S, Parker GA, Foster WC, Lawrence W. Management of desmoid tumors. Surg Gynecol Obstet 1989; 169: 104–6. Gurbuz AK, Giardiello FM, Petersen GM, et al. Desmoid tumours in familial adenomatous polyposis. Gut 1994; 35: 377–81. McAdam WA, Goligher JC. The occurrence of desmoids in patients with familial polyposis coli. Br J Surg 1970; 57: 618–31. Lynch HT, Fitzgibbons R. Surgery, desmoid tumors, and familial adenomatous polyposis: case report and literature review. Am J Gastroenterol 1996; 91: 2598–601. 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. Hum Mol Genet 1995; 4: 337–40. Zayit I, Dihmis C. Familial multicentric fibromatosis – desmoids. Cancer 1989; 24: 786–96. Ozuner G, Hull TL. Familial desmoids in association with adrenal and ovarian masses and leiomyomas: report of three cases. Dis Colon Rectum 1999; 42: 529–32. Klemmer S, Pascoe L, DeCosse J. Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet 1987; 28: 385–92. Lotfi AM, Dozois RR, Gordon H, Hruska LS, Weiland LH, Carryer PW, Hurt RD. Mesenteric fibromatosis complicating familial adenomatous polyposis: predisposing factors and results of treatment. Int J Colorectal Dis 1989; 4: 30–6. Waddell WR. Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3′,5′-adenosine monophosphate. Ann Surg 1975; 181: 299–302. Wilcken N, Tattersall MH. Endocrine therapy for desmoid tumors. Cancer 1991; 68: 1384–8. Dhingra K. Antiestrogens – tamoxifen, SERMs and beyond. Invest New Drugs 1999; 17: 285–311. Sarno RC, Klauber G, Carter BL. Computer assisted tomography of urachal abnormalities. J Comput Assist Tomogr 1983; 7: 674–6. Pritchard DJ, Soule EH, Taylor WF, Ivins JC. Fibrosarcoma – a clinicopathologic and statistical study of 199 tumors of the soft tissues of the extremities and trunk. Cancer 1974; 33: 888–97. Easter DW, Halasz NA. Recent trends in the management of desmoid tumors. Summary of 19 cases and review of the literature. Ann Surg 1989; 210: 765–9. Corbel L, Souissi M, Chretien Y, Dufour B. Desmoid tumor of the mesentery. An uncommon cause of ureteral obstruction. J Radiol 1992; 73: 669–72. Weiss AJ, Lackman RD. Low-dose chemotherapy of desmoid tumors. Cancer 1989; 64: 1192–4. Reitamo JJ, Scheinin TM, Hayry P. The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg 1986; 151: 230–7. Einstein DM, Tagliabue JR, Desai RK. Abdominal desmoids: CT findings in 25 patients. Am J Roentgenol 1991; 157: 275–9. Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease (6th edn). Philadelphia: Saunders, 1998: 1476. Salloum H, Kanitakis J, Chouvet B, Grimand P, Claudy A. Extraabdominal desmoid tumor. Microscopic aspects and histogenesis. Ann Dermatol Venereol 1993; 120: 685–8. Torres D. Multiple sebaceous tumours. Arch Dermatol 1968; 98: 549. Doi K, Iida M, Kohrogi N, Mibu R, Onitsuka H, Yao T, Fujishima M. Large intra-abdominal desmoid tumors in a patient with familial adenomatosis coli: their rapid growth detected by computerized tomography. Am J Gastroenterol 1993; 88: 595–8. Quinn SF, Erickson SJ, Dee PM, Walling A, Hackbarth DA, Knudson GJ, Moseley HS. MR imaging in fibromatosis: results in 26 patients with pathologic correlation. Am J Roentgenol 1991; 156: 539–42. O’Keefe F, Kim EE, Wallace S. Magnetic resonance imaging in aggressive fibromatosis. Clin Radiol 1990; 42: 170–3. Ohta H, Endo K, Konishi J, Iwasaki R, Kotoura Y, Yamamuro T, Kotoura H. Scintigraphic evaluation of aggressive fibromatosis. J Nucl Med 1990; 31: 1632–4. Rock MG, Pritchard DJ, Reiman HM, Soule EH, Brewster RC.
705
45. 46.
47.
48.
49. 50. 51. 52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65. 66. 67.
68.
Extra-abdominal desmoid tumors. J Bone Joint Surg Am 1984; 66: 1369–74. Reitamo JJ. The desmoid tumour. IV. Choice of treatment, results and complications. Arch Surg 1983; 118: 1318–22. Ballo MT, Zagars GK, Pollack A, Pisters PW, Pollack RA. Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy. J Clin Oncol 1999; 17: 158–67. Kulaylat MN, Karakousis CP, Keaney CM, McCorvey D, Bem J, Ambrus Sr JL. Desmoid tumour: a pleomorphic lesion. Eur J Surg Oncol 1999; 25: 487–97. Clark SK, Neale KF, Landgrebe JC, Phillips RK. Desmoid tumours complicating familial adenomatous polyposis. Br J Surg 1999; 86: 1185–9. O’Sullivan B, Wylie J, Catton C, et al. The local management of soft tissue sarcoma. Semin Radiat Oncol 1999; 9: 328–48. De Vita VT, Hellman S, Rosenberg SA. Principles and Practice of Oncology (5th edn). Philadelphia: JB Lippincot, 1987: 1444. Keus R, Bartelink H. The role of radiotherapy in the treatment of desmoid tumours. Radiother Oncol 1986; 7: 1–5. Zelefsky MJ, Harrison LB, Shiu MH, Armstrong JG, Hajdu SI, Brennan MF. Combined surgical resection and iridium 192 implantation for locally advanced and recurrent desmoid tumors. Cancer 1991; 67: 380–4. Kitamura A, Kanagawa T, Yamada S, Kawai T. Effective chemotherapy for abdominal desmoid tumor in a patient with Gardner’s syndrome. Report of a case. Dis Colon Rectum 1991; 34: 822–6. Tsukada K, Church JM, Jagelman DG, Fazio VW, Lavery IC. Systemic cytotoxic chemotherapy and radiation therapy for desmoid in familial adenomatous polyposis. Dis Colon Rectum 1991; 34: 1090–2. Lynch HT, Fitzgibbons R, Chong S, Cavalieri J, Lynch J, Wallace F, Patel S. Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner’s syndrome. Dis Colon Rectum 1994; 37: 260–7. Skapek SX, Hawk BJ, Hoffer FA, et al. Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children. J Clin Oncol 1998; 16: 3021–7. Waddell WR, Gerner RE, Reich MP. Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach. J Surg Oncol 1983; 22: 197–211. Kinzbrunner B, Ritter S, Domingo J, Rosenthal CJ. Remission of rapidly growing desmoid tumors after tamoxifen therapy. Cancer 1983; 52: 2201–4. Lim CL, Walker MJ, Mehta RR, Das Gupta TK. Estrogen and antiestrogen binding sites in desmoid tumors. Eur J Cancer Clin Oncol 1986; 22: 583–7. Leithner A, Schnack B, Katterschafka T, et al. Treatment of extraabdominal desmoid tumors with interferon-alpha with or without tretinoin. J Surg Oncol 2000; 73: 21–5. Lev-Chelouche D, Abu-Abeid S, Nakache R, et al. Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Surgery 1999; 126: 963–7. Pouyssegur J, Chambard JC, Franchi A, Paris S, Van ObberghenSchilling E. Growth factor activation of an amiloride-sensitive Na+/H+ exchange system in quiescent fibroblasts: coupling to ribosomal protein S6 phosphorylation. Proc Natl Acad Sci USA 1982; 79: 3935–9. Yamagata M, Tannock IF. The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. Br J Cancer 1996; 73: 1328–34. Morales MP, Galvez A, Eltit JM, Ocaranza P, Diaz-Araya G, Lavandero S. IGF-1 regulates apoptosis of cardiac myocyte induced by osmotic-stress. Biochem Biophys Res Commun 2000; 270: 3, 1029–35. Gupta RA, DuBois RN. Combinations for cancer prevention. Nat Med 2000; 6: 974–5. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–9. Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labeling and impededligand binding. FASEB J 1995; 9: 404–10. Ziv Y, Gupta MK, Milsom JW, Vladisavljevic A, Kitago K, Fazio VW.
706 The effect of tamoxifen on established human colorectal cancer cell lines in vitro. Anticancer Res 1996; 16: 3767–71. 69. Picariello L, Fiorelli G, Benvenuti S, et al. In vitro bioeffects of the antiestrogen LY117018 on desmoid tumor and colon cancer cells. Anticancer Res 1997; 17: 2099–104. 70. Weiss DJ, Gurpide E. Non-genomic effects of estrogens and antiestrogens. J Steroid Biochem 1988; 31: 671–6.
REVIEW 71. Valverde MA, Mintenig GM, Sepulveda FV. Differential effects of tamoxifen and I- on three distinguishable chloride currents activated in T84 intestinal cells. Pflugers Arch 1993; 425: 552–4.
Accepted for publication 21 May 2001