- Email: [email protected]
Aggressive fibromatosis
Pathology (February 2014) 46(2), pp. 135–140
SOFT TISSUE PATHOLOGY
Aggressive fibromatosis CYRIL FISHER
AND
KHIN THWAY
Royal Marsden Hospital, London, United Kingdom
Summary Aggressive (deep or desmoid-type) fibromatoses are locally infiltrative collagen-forming tumours with potential for recurrence but not metastasis. They exert their clinical effects primarily in relation to location and have variable biological behaviour. In sporadic cases there are somatic mutations in the b-catenin (CTNNB1) gene on 3p21, resulting in immunohistochemically demonstrable overexpression in nuclei. Fibromatosis in patients with familial adenomatous polyposis (FAP) harbours inactivating germline mutations in the desmoid region of the adenomatous polyposis coli (APC) gene on 5q21-q22. The differential diagnosis includes other myofibroblastic lesions, perineurioma, low grade fibromyxoid sarcoma and, in the abdomen, gastrointestinal stromal tumour and liposarcoma with ‘low-grade’ dedifferentiation. The primary management is surgical, though some desmoids cease to grow and can be watched. Other therapies have a role in stabilising growth or shrinking tumours. Although no single therapy is effective in all cases, available modalities including irradiation, hormonal therapy, chemotherapy, and receptor tyrosine kinase inhibition can be of value in appropriate clinicopathological subgroups. Key words: Fibromatosis, myofibroblast, sarcoma, soft tissue tumour. Received 8 August, revised 17 November, accepted 19 November 2013
INTRODUCTION Although termed ‘non-metastasising fibrosarcoma’ in the first Armed Forces Institute of Pathology fascicle,1 fibromatosis was acknowledged in the second series fascicle of 19672 as a benign fibroblastic proliferation. Subsequently, electron microscopy showed the lesional cells to be fibroblasts and myofibroblasts, often with abundant dilated rough endoplasmic reticulum. Fibromatoses are now recognised as locally infiltrative myofibroblastic lesions which produce abundant extracellular collagen. In the WHO 2002 classification they became categorised as intermediate (locally aggressive) neoplasms.3 They are classified4 into superficial and deep (aggressive, musculo-aponeurotic or desmoid) types, the latter being extra-abdominal or intra-abdominal. Unrelated soft tissue lesions with similar terminology include gingival fibromatosis (hereditary gingival hyperplasia), infantile digital fibromatosis, inclusion-body fibromatosis, fibromatosis colli and juvenile hyaline fibromatosis.
CLINICAL FEATURES Superficial fibromatoses differ clinically from deep fibromatoses in being smaller and non-aggressive, and in lacking somatic b-catenin mutations and displaying less frequent Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000045
#
immunoreactivity for b-catenin in nuclei.5 They arise in the subcutis in the palm, sole, penis, or over knuckles and predominantly affect Caucasian adult males, although palmar and (more commonly) plantar fibromatoses can occur in childhood and adolescence.6 Associated factors include types 1 and 2 diabetes mellitus, epilepsy treated with drugs, and alcoholic liver disease.7 Deep (desmoid-type) fibromatoses can arise in any anatomical site, with distinct subsets in the abdominal wall and the abdomen (mesentery or retroperitoneum). Extra-abdominal desmoid fibromatoses occur in young adults, more frequently in females, in the musculature of proximal extremities (especially the shoulder region and buttock), the large muscles of the thigh, and also in chest wall and head and neck. Less commonly, they occur in infancy or childhood, though desmoid fibromatoses account for up to 60% of fibrous tumours in childhood. They can rarely arise in a field of therapeutic irradiation, for example for Hodgkin’s disease8 or germ cell tumour.9 Multiple desmoids can occur, usually in patients with familial adenomatous polyposis (FAP).10 Fibromatoses of the anterior abdominal wall arise in the rectus sheath, rectus abdominis or internal oblique muscles, and most often in women who are pregnant or within 1 year postpartum. Intra-abdominal fibromatosis arises in the mesentery, peritoneal ligaments, retroperitoneum, or pelvis and can become very large. Mesenteric tumours are more common in males (mean age 41 years) and have an increased incidence in patients with FAP or Gardner syndrome, in whom intra-abdominal fibromatosis develops in up to 15%.11 In one series, such patients were found to have a 65% chance of developing mesenteric fibromatosis after abdominal surgery.12 Fibromatosis can also develop in surgical scars, especially of laparotomy. The usual presentation of deep fibromatosis is as a painless plaque or discrete very firm mass, sometimes with local mass or pressure symptoms. There is generally a relatively long history of slow growth, but exceptionally there is rapid enlargement. In a recent series, desmoids typically grew over a median period of 3 years, then stabilised, and recurrences or progression most commonly occurred between 14 and 17 months.13
PATHOLOGICAL FEATURES Deep fibromatoses are non-encapsulated and sometimes circumscribed but more frequently infiltrate surrounding tissues including skeletal muscle or intestinal wall. The lesion is composed of long fascicles of myofibroblasts arranged in parallel with uniform spacing, in a hypocellular collagenous stroma (Fig. 1). Myofibroblasts have oval, pale-staining or vesicular nuclei with one or two small, punctate nucleoli, variable amounts of cytoplasm, and ill-defined cell membranes (Fig. 2). Pleomorphism and necrosis are not seen, but normal
2014 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
136
FISHER and THWAY
Fig. 1 This core needle biopsy of typical desmoid fibromatosis illustrates sweeping fascicles of slender spindle cells evenly arranged within a uniform collagenous stroma.
Pathology (2014), 46(2), February
Fig. 3 Typically there are thin, slit-like vessels, and others that in cross section display thicker walls and increased numbers of nuclei. Mast cells are present in perivascular spaces.
mitoses up to about 5 per 10 high power fields are acceptable. Blood vessels are characteristically slit-like or small-calibre and rounded with thick walls (Fig. 3). Ectatic or haemangiopericytoma-like vascular channels are an infrequent feature in mesenteric fibromatoses (Fig. 4). The stroma contains mast cells which often lie in perivascular spaces, and peripheral lymphoid aggregates. A loose storiform pattern with oedematous stroma, resembling nodular fasciitis, can be seen focally in rapidly growing lesions, especially in mesenteric fibromatoses (Fig. 5), and thick, parallel, keloid-like collagen fibres (Fig. 6) are sometimes present, especially in intra-abdominal tumours. Metaplastic ossification can also occur. Skeletal muscle infiltrated by fibromatosis can display damaged and regenerating muscle fibres with multiple hyperchromatic nuclei (Fig. 7); these are desmin positive (Fig. 8) and can be misinterpreted as rhabdomyoblasts.
IMMUNOHISTOCHEMICAL FEATURES The lesional cells express SMA and occasionally (and very focally) desmin but lack h-caldesmon, CD34, and (usually) S100 protein.14 CD11715,16 and platelet derived growth factor
Fig. 2 The cells have small ovoid nuclei with punctuate nucleoli and indistinct cell boundaries.
Fig. 4 Angiectatic vascular channels are seen in some examples of intraabdominal fibromatosis.
Fig. 5 Focal myxoid change can occur in rapidly growing lesions. There is also extravasation of red cells, increasing the resemblance to nodular fasciitis.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
AGGRESSIVE FIBROMATOSIS
137
Fig. 6 Keloid fibres are sometimes a feature, especially in mesenteric fibromatoses.
Fig. 8 The damaged muscle fibres are immunoreactive for desmin, unlike the surrounding lesional cells of fibromatosis.
alpha (and receptor)17 are rarely expressed. P16 is usually positive.18 Matrix metalloproteinases, and especially MMP7, a target of the WNT/b-catenin signalling pathway, are expressed, and overexpression of MMP7 correlates with widespread nuclear b-catenin positivity.19 Many cases display oestrogen receptor positivity,20 which might be relevant when anti-oestrogen therapy is under consideration. About 80% of deep fibromatoses, and a lesser proportion of superficial ones, show nuclear immunoreactivity for b-catenin in a variable number of cells (Fig. 9).21,22 There is a granular pattern of staining. This can be very useful in diagnosis, since other microscopically similar fibroblastic-myofibroblastic lesions lack nuclear b-catenin immunoreactivity.23,24 Care must be taken in interpretation, however, because in some myofibroblastic lesions the cytoplasm can stain in a paranuclear distribution, somewhat resembling a nucleus in shape (Fig. 9); this is not diagnostic of fibromatosis.
20, and loss of Y chromosome. In deep fibromatosis, b-catenin positivity relates to somatic mutations in codons 41 or 45 of exon 3 of the b-catenin gene (CTNNB1) on 3p21, whereas fibromatosis in patients with FAP has inactivating germline mutations in the desmoid region of the adenomatous polyposis coli (APC) gene on 5q21-q22.30,31 The mutations are highly specific and this can be useful for diagnosis32 and for prediction of recurrence.33 Mutations in the APC and b-catenin genes are not detected in superficial fibromatoses.5 These genes form part of the Wnt signalling pathway, and mutations in either result in stabilisation of the b-catenin protein and binding of b-catenin to the TCF/Lef family of transcription factors.34 A gene signature has been identified that distinguishes desmoid fibromatosis from nodular fasciitis.35
GENETIC FEATURES Fibromatosis is now understood to be a clonal process.25–29 Cytogenetic changes in fibromatosis include trisomy 8, trisomy
Fig. 7 Fibromatosis infiltrating skeletal muscle can result in damaged and regenerating muscle fibres with multiple hyperchromatic nuclei.
DIFFERENTIAL DIAGNOSIS Most tumours that resemble fibromatosis have specific diagnostic features and also lack nuclear b-catenin immunoreactivity. Other myofibroblastic lesions that are cytologically similar to fibromatosis can be distinguished by their clinical
Fig. 9 Immunoreactivity for b-catenin is seen in nuclei of tumour cells. The number of positive cells is very variable within a given tumour and can be very small. Cytoplasmic positivity for b-catenin, also present in some cells here, can be seen in various myofibroblastic lesions and is not diagnostic of fibromatosis.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
138
Pathology (2014), 46(2), February
FISHER and THWAY
and morphological features and by ancillary investigations. For example, nodular fasciitis has a short history of rapid growth, and variable cellularity and fibrosis according to the age of the lesion, as well as a genetic rearrangement, t(17;22)(p13;q13.1) with USP6-MYH9 fusion.36 Low grade myofibrosarcoma is a cellular, infiltrative lesion which, unlike fibromatosis, has focal nuclear atypia and sometimes necrosis.37 Among fibroblastic lesions, reactive nodular fibrous pseudotumour can be a late complication of abdominal surgery, especially in males, and arises in mesentery or on the intestinal surface as solitary or multiple hypocellular nodules comprising spindled or stellate fibroblasts dispersed in a densely collagenous stroma.38 Solitary fibrous tumour has variable fibrosis with random orientation of short spindle cells, is CD34 positive, can undergo dedifferentiation,39,40 and many cases harbour NAB2-STAT6 gene fusions.41,42 Low-grade fibromyxoid sarcoma lacks myofibroblastic nuclear features, has whorled fibromyxoid areas, and cellular myxoid foci, and is immunoreactive for MUC4.43 In addition, it has diagnostic translocations with fusion genes FUS-CREB3L2, FUS-CREB3L1,44 or rarely EWSR1-CREB3L1.45 Perineurial cell tumours have elongated spindle cells with variable collagen; the spindle cells can express CD34, EMA and claudin-1.46 Among intra-abdominal tumours, gastrointestinal stromal tumour can, like fibromatosis, involve bowel wall, mesentery or omentum but displays immunoreactivity for CD117, DOG1, CD34 and h-caldesmon as well as KIT or PDGFRA mutations.47–49 A non-random association between gastrointestinal stromal tumour and desmoid fibromatosis has been suggested.50 Atypical lipomatous tumour can have areas of ‘low grade’ dedifferentiation with a cellular spindle cell proliferation resembling fibromatosis.51 The lesional cells do not overexpress b-catenin, and can show immunoreactivity for MDM2, CDK4 and p16,52,53 and MDM2 gene amplification with FISH.54
systemic therapies including hormonal manipulations, cytotoxic chemotherapy with various agents, and biological therapies such as tyrosine kinase inhibitors. Hormonal therapies including tamoxifen, GnRH agonists, progestogens and aromatase inhibitors, have been applied, sometimes in combination with non-steroidal anti-inflammatory drugs (NSAIDs). Anti-oestrogenic agents such as tamoxifen combined with sulindac or celecoxib have had an additive effect in some patients.63,64 In an early study of treatment with NSAIDs concurrent with or following testolactone or tamoxifen, five of seven patients showed major regression and one partial regression with extensive central necrosis of an enormous intra-abdominal tumour.65 Treatment with tamoxifen and celecoxib resulted in stabilisation or reduction of tumour in half of the patients in a further small series.66 Biological therapies have been used in some cases. Desmoids are rarely positive for CD117, and lack KIT mutations. They show immunoreactivity for PDGFa and PDGRFa,67 although corresponding genetic mutations have not been demonstrated.17 However, therapy with tyrosine kinase inhibitors including imatinib68–73 and sorafenib74 has been effective in some cases. Chemotherapy with single agent or drug combinations has been employed with variable effect. Ifosfamide has been shown to be effective against fibromatosis cells in tissue culture.75 Clinical treatment regimes have included adriamycin,66 methotrexate with vinblastine,76,77 and doxorubicin with dacarbazine.78 Pegylated liposomal doxorubicin79–81 also offers single agent therapy with acceptable toxicity in unresectable aggressive fibromatoses. The response rate has been found to be higher in anthracycline-containing treatment regimens and hormone therapy, than in single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib.77,82
CONCLUSION BEHAVIOUR AND MANAGEMENT Deep fibromatoses do not metastasise, but they can infiltrate locally and recur repeatedly. In the head and neck or abdomen, lesional tissue can infiltrate adjacent structures, causing difficulty in surgical excision and sometimes resulting in death. Predictive factors for recurrence include age, site, tumour size, mutational status and incompleteness of excision.55,56 A higher risk of recurrence is related to younger age, mesenteric location, association with FAP or Gardner syndrome,12,57–59 and the presence of an S45F mutation in the CTNNB1 gene.33 The recurrence rate in extra-abdominal desmoids has been reported as 19.3%60 and 35%,55 with head and neck tumours having the highest incidence.61 Up to 23% of mesenteric lesions recur,62 especially when FAP-associated. Pregnancy-associated fibromatoses of the anterior abdominal wall can sometimes recur, including in or following subsequent pregnancies. Wide excision with preservation of function is the goal in treatment.60 However, many lesions, including those which might be unresectable, can reach a variable size then cease to grow and remain stable or even regress. Therefore, increasingly, there is a role for non-intervention with ‘watchful waiting’ in such cases. Surgery for recurrent lesions is often curative.60 For frequently recurring lesions, or those not susceptible to complete surgical excision, a variety of additional therapeutic interventions have been applied. These include local irradiation, and
Aggressive (deep) fibromatoses are locally infiltrative collagenforming tumours with potential for recurrence but not metastasis. They exert their clinical effects primarily in relation to location, and have variable biological behaviour. In sporadic cases there are somatic mutations in the b-catenin (CTNNB1) gene on 3p21, resulting in immunohistochemically demonstrable overexpression in nuclei. Fibromatosis in patients with FAP is related to inactivating germline mutations in the desmoid region of the APC gene on 5q21-q22. The primary management is non-interventional or surgical, with other therapies having a role in stabilising growth or shrinking tumours. Although no single therapy is effective in all cases, available modalities including irradiation, hormonal therapy, chemotherapy and receptor tyrosine kinase inhibition can be of value in appropriate clinicopathological subgroups. Among these options, pegylated liposomal doxorubicin and sorafenib appear to be the most active agents, especially if tumour shrinkage is desired. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. Address for correspondence: Professor C. Fisher, Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK. E-mail: [email protected]
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
AGGRESSIVE FIBROMATOSIS
References 1. Stout AP. Tumors of the Soft Tissues. Bethesda, MD: Armed Forces Institute of Pathology, 1953. 2. Stout AP, Lattes R. Tumors of the Soft Tissues. Second Series Bethesda, MD: Armed Forces Institute of Pathology, 1967. 3. Fletcher C, Unni K, Mertens F, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2002. 4. Fletcher C, Bridge JA, Hogendoorn PCW, et al. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013, 305–310. 5. Montgomery E, Lee JH, Abraham SC, et al. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol 2001; 14: 695–701. 6. Fetsch JF, Laskin WB, Miettinen M. Palmar-plantar fibromatosis in children and preadolescents: a clinicopathologic study of 56 cases with newly recognized demographics and extended follow-up information. Am J Surg Pathol 2005; 29: 1095–105. 7. Geoghegan JM, Forbes J, Clark DI, et al. Dupuytren’s disease risk factors. J Hand Surg (Br) 2004; 29: 423–6. 8. Bar-Maor JA, Shabshin U. Mesenteric fibromatosis. J Pediatr Surg 1993; 28: 1618–9. 9. Wegner HE, Fleige B, Dieckmann KP. Mesenteric desmoid tumor 19 years after radiation therapy for testicular seminoma. Urol Int 1994; 53: 48–9. 10. Berk T, Cohen Z, McLeod RS, et al. Management of mesenteric desmoid tumours in familial adenomatous polyposis. Can J Surg 1992; 35: 393–5. 11. Clark SK, Smith TG, Katz DE, et al. Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg 1998; 85: 970–3. 12. Speake D, Evans DG, Lalloo F, et al. Desmoid tumours in patients with familial adenomatous polyposis and desmoid region adenomatous polyposis coli mutations. Br J Surg 2007; 94: 1009–13. 13. Stoeckle E, Coindre JM, Longy M, et al. A critical analysis of treatment strategies in desmoid tumours: a review of a series of 106 cases. Eur J Surg Oncol 2009; 35: 129–34. 14. Leithner A, Gapp M, Radl R, et al. Immunohistochemical analysis of desmoid tumours. J Clin Pathol 2005; 58: 1152–6. 15. Hornick JL, Fletcher CD. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 2002; 117: 188–93. 16. Lucas DR, al-Abbadi M, Tabaczka P, et al. c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical evaluation of two commercial antibodies. Am J Clin Pathol 2003; 119: 339–45. 17. Liegl B, Leithner A, Bauernhofer T, et al. Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours? Histopathology 2006; 49: 576–81. 18. Stalinska L, Turant M, Tosik D, et al. Analysis of pRb, p16INK4A proteins and proliferating antigens: PCNA, Ki-67 and MCM5 expression in aggressive fibromatosis (desmoid tumor). Histol Histopathol 2009; 24: 299–308. 19. Matono H, Oda Y, Nakamori M, et al. Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Hum Pathol 2008; 39: 1802–8. 20. Deyrup AT, Tretiakova M, Montag AG. Estrogen receptor-beta expression in extraabdominal fibromatoses: an analysis of 40 cases. Cancer 2006; 106: 208–13. 21. Ng TL, Gown AM, Barry TS, et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol 2005; 18: 68–74. 22. Thway K, Gibson S, Ramsay A, et al. Beta-catenin expression in pediatric fibroblastic and myofibroblastic lesions: a study of 100 cases. Pediatr Dev Pathol 2009; 12: 292–6. 23. Montgomery E, Torbenson MS, Kaushal M, et al. Beta-catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis. Am J Surg Pathol 2002; 26: 1296–301. 24. Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, et al. Nuclear betacatenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol 2005; 29: 653–9. 25. Bridge JA, Sreekantaiah C, Mouron B, et al. Clonal chromosomal abnormalities in desmoid tumors. Implications for histopathogenesis. Cancer 1992; 69: 430–6. 26. Li M, Cordon-Cardo C, Gerald WL, et al. Desmoid fibromatosis is a clonal process. Hum Pathol 1996; 27: 939–43. 27. Lucas DR, Shroyer KR, McCarthy PJ, et al. Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol 1997; 21: 306–11. 28. De Wever I, Dal Cin P, Fletcher CD, et al. Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology. Mod Pathol 2000; 13: 1080–5.
139
29. Middleton SB, Frayling IM, Phillips RK. Desmoids in familial adenomatous polyposis are monoclonal proliferations. Br J Cancer 2000; 82: 827– 32. 30. Tejpar S, Michils G, Denys H, et al. Analysis of Wnt/Beta catenin signalling in desmoid tumors. Acta Gastroenterol Belg 2005; 68: 5–9. 31. Huss S, Nehles J, Binot E, et al. beta-Catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. Histopathology 2013; 62: 294–304. 32. Le Guellec S, Soubeyran I, Rochaix P, et al. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mod Pathol 2012; 25: 1551–8. 33. Lazar AJ, Tuvin D, Hajibashi S, et al. Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 2008; 173: 1518–27. 34. Kotiligam D, Lazar AJ, Pollock RE, et al. Desmoid tumor: a disease opportune for molecular insights. Histol Histopathol 2008; 23: 117–26. 35. Bacac M, Migliavacca E, Stehle JC, et al. A gene expression signature that distinguishes desmoid tumours from nodular fasciitis. J Pathol 2006; 208: 543–53. 36. Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest 2011; 91: 1427–33. 37. Fisher C. Myofibrosarcoma. Virchows Arch 2004; 445: 215–23. 38. Yantiss RK, Nielsen GP, Lauwers GY, et al. Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases. Am J Surg Pathol 2003; 27: 532–40. 39. Mosquera JM, Fletcher CD. Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component–is this dedifferentiated SFT? Am J Surg Pathol 2009; 33: 1314–21. 40. Thway K, Hayes A, Ieremia E, et al. Heterologous osteosarcomatous and rhabdomyosarcomatous elements in dedifferentiated solitary fibrous tumor: further support for the concept of dedifferentiation in solitary fibrous tumor. Ann Diagn Pathol 2012; 17: 457–63. 41. Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 2013; 45: 131–2. 42. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45: 180–5. 43. Doyle LA, Moller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733–41. 44. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest 2005; 85: 408–15. 45. Shah AA, LeGallo RD, van Zante A, et al. EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma. Am J Surg Pathol 2013; 37: 571–8. 46. Folpe AL, Billings SD, McKenney JK, et al. Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002; 26: 1620–6. 47. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23: 91–102. 48. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors presenting as omental masses–a clinicopathologic analysis of 95 cases. Am J Surg Pathol 2009; 33: 1267–75. 49. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med 2011; 135: 1298–310. 50. Dumont AG, Rink L, Godwin AK, et al. A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients. Ann Oncol 2012; 23: 1335–40. 51. Henricks WH, Chu YC, Goldblum JR, et al. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 1997; 21: 271–81. 52. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005; 29: 1340–7. 53. Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 2012; 36: 462–9. 54. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffinembedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 2007; 31: 1476–89.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
140
FISHER and THWAY
55. Pritchard DJ, Nascimento AG, Petersen IA. Local control of extra-abdominal desmoid tumors. J Bone Joint Surg Am 1996; 78: 848–54. 56. Salas S, Dufresne A, Bui B, et al. Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation. J Clin Oncol 2011; 29: 3553–8. 57. Soravia C, Berk T, McLeod RS, et al. Desmoid disease in patients with familial adenomatous polyposis. Dis Colon Rectum 2000; 43: 363–9. 58. Quintini C, Ward G, Shatnawei A, et al. Mortality of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis: a single center review of 154 patients. Ann Surg 2012; 255: 511–6. 59. Colombo C, Foo WC, Whiting D, et al. FAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center. Histol Histopathol 2012; 27: 641–9. 60. Phillips SR, A’Hern R, Thomas JM. Aggressive fibromatosis of the abdominal wall, limbs and limb girdles. Br J Surg 2004; 91: 1624–9. 61. Sharma A, Ngan BY, Sandor GK, et al. Pediatric aggressive fibromatosis of the head and neck: a 20-year retrospective review. J Pediatr Surg 2008; 43: 1596–604. 62. Burke AP, Sobin LH, Shekitka KM. Mesenteric fibromatosis. A follow-up study. Arch Pathol Lab Med 1990; 114: 832–5. 63. 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. 64. Hansmann A, Adolph C, Vogel T, et al. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 2004; 100: 612–20. 65. Waddell WR, Kirsch WM. Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors. Am J Surg 1991; 161: 416–21. 66. Francis WP, Zippel D, Mack LA, et al. Desmoids: a revelation in biology and treatment. Ann Surg Oncol 2009; 16: 1650–4. 67. Gibson S, Sebire NJ, Anderson J. Platelet-derived growth factor receptors and ligands are up-regulated in paediatric fibromatoses. Histopathology 2007; 51: 752–7. 68. Mace J, Sybil Biermann J, Sondak V, et al. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 2002; 95: 2373–9. 69. Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 2006; 24: 1195–203.
Pathology (2014), 46(2), February
70. Wcislo G, Szarlej-Wcislo K, Szczylik C. Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature. J Cancer Res Clin Oncol 2007; 133: 533–8. 71. Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res 2010; 16: 4884–91. 72. Kurtz JE, Asmane I, Voegeli AC, et al. A V530I mutation in c-KIT exon 10 is associated to imatinib response in extraabdominal aggressive fibromatosis. Sarcoma 2010; 2010: 458156. 73. Penel N, Le Cesne A, Bui BN, et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol 2011; 22: 452–7. 74. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011; 17: 4082–90. 75. Verrill MW, Coley HM, Judson IR, et al. Susceptibility of fibromatosis cells in short-term culture to Ifosfamide: a possible experimental treatment in clinically aggressive cases. Sarcoma 1999; 3: 79–84. 76. Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer 2001; 92: 1259–64. 77. Garbay D, Le Cesne A, Penel N, et al. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012; 23: 182–6. 78. Gega M, Yanagi H, Yoshikawa R, et al. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 2006; 24: 102–5. 79. Constantinidou A, Jones RL, Scurr M, et al. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009; 45: 2930–4. 80. Constantinidou A, Jones RL, Scurr M, et al. Advanced aggressive fibromatosis: Effective palliation with chemotherapy. Acta Oncol 2011; 50: 455–61. 81. Wehl G, Rossler J, Otten JE, et al. Response of progressive fibromatosis to therapy with liposomal doxorubicin. Onkologie 2004; 27: 552–6. 82. de Camargo VP, Keohan ML, D’Adamo DR, et al. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer 2010; 116: 2258–65.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
SOFT TISSUE PATHOLOGY
Aggressive fibromatosis CYRIL FISHER
AND
KHIN THWAY
Royal Marsden Hospital, London, United Kingdom
Summary Aggressive (deep or desmoid-type) fibromatoses are locally infiltrative collagen-forming tumours with potential for recurrence but not metastasis. They exert their clinical effects primarily in relation to location and have variable biological behaviour. In sporadic cases there are somatic mutations in the b-catenin (CTNNB1) gene on 3p21, resulting in immunohistochemically demonstrable overexpression in nuclei. Fibromatosis in patients with familial adenomatous polyposis (FAP) harbours inactivating germline mutations in the desmoid region of the adenomatous polyposis coli (APC) gene on 5q21-q22. The differential diagnosis includes other myofibroblastic lesions, perineurioma, low grade fibromyxoid sarcoma and, in the abdomen, gastrointestinal stromal tumour and liposarcoma with ‘low-grade’ dedifferentiation. The primary management is surgical, though some desmoids cease to grow and can be watched. Other therapies have a role in stabilising growth or shrinking tumours. Although no single therapy is effective in all cases, available modalities including irradiation, hormonal therapy, chemotherapy, and receptor tyrosine kinase inhibition can be of value in appropriate clinicopathological subgroups. Key words: Fibromatosis, myofibroblast, sarcoma, soft tissue tumour. Received 8 August, revised 17 November, accepted 19 November 2013
INTRODUCTION Although termed ‘non-metastasising fibrosarcoma’ in the first Armed Forces Institute of Pathology fascicle,1 fibromatosis was acknowledged in the second series fascicle of 19672 as a benign fibroblastic proliferation. Subsequently, electron microscopy showed the lesional cells to be fibroblasts and myofibroblasts, often with abundant dilated rough endoplasmic reticulum. Fibromatoses are now recognised as locally infiltrative myofibroblastic lesions which produce abundant extracellular collagen. In the WHO 2002 classification they became categorised as intermediate (locally aggressive) neoplasms.3 They are classified4 into superficial and deep (aggressive, musculo-aponeurotic or desmoid) types, the latter being extra-abdominal or intra-abdominal. Unrelated soft tissue lesions with similar terminology include gingival fibromatosis (hereditary gingival hyperplasia), infantile digital fibromatosis, inclusion-body fibromatosis, fibromatosis colli and juvenile hyaline fibromatosis.
CLINICAL FEATURES Superficial fibromatoses differ clinically from deep fibromatoses in being smaller and non-aggressive, and in lacking somatic b-catenin mutations and displaying less frequent Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000045
#
immunoreactivity for b-catenin in nuclei.5 They arise in the subcutis in the palm, sole, penis, or over knuckles and predominantly affect Caucasian adult males, although palmar and (more commonly) plantar fibromatoses can occur in childhood and adolescence.6 Associated factors include types 1 and 2 diabetes mellitus, epilepsy treated with drugs, and alcoholic liver disease.7 Deep (desmoid-type) fibromatoses can arise in any anatomical site, with distinct subsets in the abdominal wall and the abdomen (mesentery or retroperitoneum). Extra-abdominal desmoid fibromatoses occur in young adults, more frequently in females, in the musculature of proximal extremities (especially the shoulder region and buttock), the large muscles of the thigh, and also in chest wall and head and neck. Less commonly, they occur in infancy or childhood, though desmoid fibromatoses account for up to 60% of fibrous tumours in childhood. They can rarely arise in a field of therapeutic irradiation, for example for Hodgkin’s disease8 or germ cell tumour.9 Multiple desmoids can occur, usually in patients with familial adenomatous polyposis (FAP).10 Fibromatoses of the anterior abdominal wall arise in the rectus sheath, rectus abdominis or internal oblique muscles, and most often in women who are pregnant or within 1 year postpartum. Intra-abdominal fibromatosis arises in the mesentery, peritoneal ligaments, retroperitoneum, or pelvis and can become very large. Mesenteric tumours are more common in males (mean age 41 years) and have an increased incidence in patients with FAP or Gardner syndrome, in whom intra-abdominal fibromatosis develops in up to 15%.11 In one series, such patients were found to have a 65% chance of developing mesenteric fibromatosis after abdominal surgery.12 Fibromatosis can also develop in surgical scars, especially of laparotomy. The usual presentation of deep fibromatosis is as a painless plaque or discrete very firm mass, sometimes with local mass or pressure symptoms. There is generally a relatively long history of slow growth, but exceptionally there is rapid enlargement. In a recent series, desmoids typically grew over a median period of 3 years, then stabilised, and recurrences or progression most commonly occurred between 14 and 17 months.13
PATHOLOGICAL FEATURES Deep fibromatoses are non-encapsulated and sometimes circumscribed but more frequently infiltrate surrounding tissues including skeletal muscle or intestinal wall. The lesion is composed of long fascicles of myofibroblasts arranged in parallel with uniform spacing, in a hypocellular collagenous stroma (Fig. 1). Myofibroblasts have oval, pale-staining or vesicular nuclei with one or two small, punctate nucleoli, variable amounts of cytoplasm, and ill-defined cell membranes (Fig. 2). Pleomorphism and necrosis are not seen, but normal
2014 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
136
FISHER and THWAY
Fig. 1 This core needle biopsy of typical desmoid fibromatosis illustrates sweeping fascicles of slender spindle cells evenly arranged within a uniform collagenous stroma.
Pathology (2014), 46(2), February
Fig. 3 Typically there are thin, slit-like vessels, and others that in cross section display thicker walls and increased numbers of nuclei. Mast cells are present in perivascular spaces.
mitoses up to about 5 per 10 high power fields are acceptable. Blood vessels are characteristically slit-like or small-calibre and rounded with thick walls (Fig. 3). Ectatic or haemangiopericytoma-like vascular channels are an infrequent feature in mesenteric fibromatoses (Fig. 4). The stroma contains mast cells which often lie in perivascular spaces, and peripheral lymphoid aggregates. A loose storiform pattern with oedematous stroma, resembling nodular fasciitis, can be seen focally in rapidly growing lesions, especially in mesenteric fibromatoses (Fig. 5), and thick, parallel, keloid-like collagen fibres (Fig. 6) are sometimes present, especially in intra-abdominal tumours. Metaplastic ossification can also occur. Skeletal muscle infiltrated by fibromatosis can display damaged and regenerating muscle fibres with multiple hyperchromatic nuclei (Fig. 7); these are desmin positive (Fig. 8) and can be misinterpreted as rhabdomyoblasts.
IMMUNOHISTOCHEMICAL FEATURES The lesional cells express SMA and occasionally (and very focally) desmin but lack h-caldesmon, CD34, and (usually) S100 protein.14 CD11715,16 and platelet derived growth factor
Fig. 2 The cells have small ovoid nuclei with punctuate nucleoli and indistinct cell boundaries.
Fig. 4 Angiectatic vascular channels are seen in some examples of intraabdominal fibromatosis.
Fig. 5 Focal myxoid change can occur in rapidly growing lesions. There is also extravasation of red cells, increasing the resemblance to nodular fasciitis.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
AGGRESSIVE FIBROMATOSIS
137
Fig. 6 Keloid fibres are sometimes a feature, especially in mesenteric fibromatoses.
Fig. 8 The damaged muscle fibres are immunoreactive for desmin, unlike the surrounding lesional cells of fibromatosis.
alpha (and receptor)17 are rarely expressed. P16 is usually positive.18 Matrix metalloproteinases, and especially MMP7, a target of the WNT/b-catenin signalling pathway, are expressed, and overexpression of MMP7 correlates with widespread nuclear b-catenin positivity.19 Many cases display oestrogen receptor positivity,20 which might be relevant when anti-oestrogen therapy is under consideration. About 80% of deep fibromatoses, and a lesser proportion of superficial ones, show nuclear immunoreactivity for b-catenin in a variable number of cells (Fig. 9).21,22 There is a granular pattern of staining. This can be very useful in diagnosis, since other microscopically similar fibroblastic-myofibroblastic lesions lack nuclear b-catenin immunoreactivity.23,24 Care must be taken in interpretation, however, because in some myofibroblastic lesions the cytoplasm can stain in a paranuclear distribution, somewhat resembling a nucleus in shape (Fig. 9); this is not diagnostic of fibromatosis.
20, and loss of Y chromosome. In deep fibromatosis, b-catenin positivity relates to somatic mutations in codons 41 or 45 of exon 3 of the b-catenin gene (CTNNB1) on 3p21, whereas fibromatosis in patients with FAP has inactivating germline mutations in the desmoid region of the adenomatous polyposis coli (APC) gene on 5q21-q22.30,31 The mutations are highly specific and this can be useful for diagnosis32 and for prediction of recurrence.33 Mutations in the APC and b-catenin genes are not detected in superficial fibromatoses.5 These genes form part of the Wnt signalling pathway, and mutations in either result in stabilisation of the b-catenin protein and binding of b-catenin to the TCF/Lef family of transcription factors.34 A gene signature has been identified that distinguishes desmoid fibromatosis from nodular fasciitis.35
GENETIC FEATURES Fibromatosis is now understood to be a clonal process.25–29 Cytogenetic changes in fibromatosis include trisomy 8, trisomy
Fig. 7 Fibromatosis infiltrating skeletal muscle can result in damaged and regenerating muscle fibres with multiple hyperchromatic nuclei.
DIFFERENTIAL DIAGNOSIS Most tumours that resemble fibromatosis have specific diagnostic features and also lack nuclear b-catenin immunoreactivity. Other myofibroblastic lesions that are cytologically similar to fibromatosis can be distinguished by their clinical
Fig. 9 Immunoreactivity for b-catenin is seen in nuclei of tumour cells. The number of positive cells is very variable within a given tumour and can be very small. Cytoplasmic positivity for b-catenin, also present in some cells here, can be seen in various myofibroblastic lesions and is not diagnostic of fibromatosis.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
138
Pathology (2014), 46(2), February
FISHER and THWAY
and morphological features and by ancillary investigations. For example, nodular fasciitis has a short history of rapid growth, and variable cellularity and fibrosis according to the age of the lesion, as well as a genetic rearrangement, t(17;22)(p13;q13.1) with USP6-MYH9 fusion.36 Low grade myofibrosarcoma is a cellular, infiltrative lesion which, unlike fibromatosis, has focal nuclear atypia and sometimes necrosis.37 Among fibroblastic lesions, reactive nodular fibrous pseudotumour can be a late complication of abdominal surgery, especially in males, and arises in mesentery or on the intestinal surface as solitary or multiple hypocellular nodules comprising spindled or stellate fibroblasts dispersed in a densely collagenous stroma.38 Solitary fibrous tumour has variable fibrosis with random orientation of short spindle cells, is CD34 positive, can undergo dedifferentiation,39,40 and many cases harbour NAB2-STAT6 gene fusions.41,42 Low-grade fibromyxoid sarcoma lacks myofibroblastic nuclear features, has whorled fibromyxoid areas, and cellular myxoid foci, and is immunoreactive for MUC4.43 In addition, it has diagnostic translocations with fusion genes FUS-CREB3L2, FUS-CREB3L1,44 or rarely EWSR1-CREB3L1.45 Perineurial cell tumours have elongated spindle cells with variable collagen; the spindle cells can express CD34, EMA and claudin-1.46 Among intra-abdominal tumours, gastrointestinal stromal tumour can, like fibromatosis, involve bowel wall, mesentery or omentum but displays immunoreactivity for CD117, DOG1, CD34 and h-caldesmon as well as KIT or PDGFRA mutations.47–49 A non-random association between gastrointestinal stromal tumour and desmoid fibromatosis has been suggested.50 Atypical lipomatous tumour can have areas of ‘low grade’ dedifferentiation with a cellular spindle cell proliferation resembling fibromatosis.51 The lesional cells do not overexpress b-catenin, and can show immunoreactivity for MDM2, CDK4 and p16,52,53 and MDM2 gene amplification with FISH.54
systemic therapies including hormonal manipulations, cytotoxic chemotherapy with various agents, and biological therapies such as tyrosine kinase inhibitors. Hormonal therapies including tamoxifen, GnRH agonists, progestogens and aromatase inhibitors, have been applied, sometimes in combination with non-steroidal anti-inflammatory drugs (NSAIDs). Anti-oestrogenic agents such as tamoxifen combined with sulindac or celecoxib have had an additive effect in some patients.63,64 In an early study of treatment with NSAIDs concurrent with or following testolactone or tamoxifen, five of seven patients showed major regression and one partial regression with extensive central necrosis of an enormous intra-abdominal tumour.65 Treatment with tamoxifen and celecoxib resulted in stabilisation or reduction of tumour in half of the patients in a further small series.66 Biological therapies have been used in some cases. Desmoids are rarely positive for CD117, and lack KIT mutations. They show immunoreactivity for PDGFa and PDGRFa,67 although corresponding genetic mutations have not been demonstrated.17 However, therapy with tyrosine kinase inhibitors including imatinib68–73 and sorafenib74 has been effective in some cases. Chemotherapy with single agent or drug combinations has been employed with variable effect. Ifosfamide has been shown to be effective against fibromatosis cells in tissue culture.75 Clinical treatment regimes have included adriamycin,66 methotrexate with vinblastine,76,77 and doxorubicin with dacarbazine.78 Pegylated liposomal doxorubicin79–81 also offers single agent therapy with acceptable toxicity in unresectable aggressive fibromatoses. The response rate has been found to be higher in anthracycline-containing treatment regimens and hormone therapy, than in single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib.77,82
CONCLUSION BEHAVIOUR AND MANAGEMENT Deep fibromatoses do not metastasise, but they can infiltrate locally and recur repeatedly. In the head and neck or abdomen, lesional tissue can infiltrate adjacent structures, causing difficulty in surgical excision and sometimes resulting in death. Predictive factors for recurrence include age, site, tumour size, mutational status and incompleteness of excision.55,56 A higher risk of recurrence is related to younger age, mesenteric location, association with FAP or Gardner syndrome,12,57–59 and the presence of an S45F mutation in the CTNNB1 gene.33 The recurrence rate in extra-abdominal desmoids has been reported as 19.3%60 and 35%,55 with head and neck tumours having the highest incidence.61 Up to 23% of mesenteric lesions recur,62 especially when FAP-associated. Pregnancy-associated fibromatoses of the anterior abdominal wall can sometimes recur, including in or following subsequent pregnancies. Wide excision with preservation of function is the goal in treatment.60 However, many lesions, including those which might be unresectable, can reach a variable size then cease to grow and remain stable or even regress. Therefore, increasingly, there is a role for non-intervention with ‘watchful waiting’ in such cases. Surgery for recurrent lesions is often curative.60 For frequently recurring lesions, or those not susceptible to complete surgical excision, a variety of additional therapeutic interventions have been applied. These include local irradiation, and
Aggressive (deep) fibromatoses are locally infiltrative collagenforming tumours with potential for recurrence but not metastasis. They exert their clinical effects primarily in relation to location, and have variable biological behaviour. In sporadic cases there are somatic mutations in the b-catenin (CTNNB1) gene on 3p21, resulting in immunohistochemically demonstrable overexpression in nuclei. Fibromatosis in patients with FAP is related to inactivating germline mutations in the desmoid region of the APC gene on 5q21-q22. The primary management is non-interventional or surgical, with other therapies having a role in stabilising growth or shrinking tumours. Although no single therapy is effective in all cases, available modalities including irradiation, hormonal therapy, chemotherapy and receptor tyrosine kinase inhibition can be of value in appropriate clinicopathological subgroups. Among these options, pegylated liposomal doxorubicin and sorafenib appear to be the most active agents, especially if tumour shrinkage is desired. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. Address for correspondence: Professor C. Fisher, Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK. E-mail: [email protected]
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
AGGRESSIVE FIBROMATOSIS
References 1. Stout AP. Tumors of the Soft Tissues. Bethesda, MD: Armed Forces Institute of Pathology, 1953. 2. Stout AP, Lattes R. Tumors of the Soft Tissues. Second Series Bethesda, MD: Armed Forces Institute of Pathology, 1967. 3. Fletcher C, Unni K, Mertens F, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2002. 4. Fletcher C, Bridge JA, Hogendoorn PCW, et al. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013, 305–310. 5. Montgomery E, Lee JH, Abraham SC, et al. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol 2001; 14: 695–701. 6. Fetsch JF, Laskin WB, Miettinen M. Palmar-plantar fibromatosis in children and preadolescents: a clinicopathologic study of 56 cases with newly recognized demographics and extended follow-up information. Am J Surg Pathol 2005; 29: 1095–105. 7. Geoghegan JM, Forbes J, Clark DI, et al. Dupuytren’s disease risk factors. J Hand Surg (Br) 2004; 29: 423–6. 8. Bar-Maor JA, Shabshin U. Mesenteric fibromatosis. J Pediatr Surg 1993; 28: 1618–9. 9. Wegner HE, Fleige B, Dieckmann KP. Mesenteric desmoid tumor 19 years after radiation therapy for testicular seminoma. Urol Int 1994; 53: 48–9. 10. Berk T, Cohen Z, McLeod RS, et al. Management of mesenteric desmoid tumours in familial adenomatous polyposis. Can J Surg 1992; 35: 393–5. 11. Clark SK, Smith TG, Katz DE, et al. Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg 1998; 85: 970–3. 12. Speake D, Evans DG, Lalloo F, et al. Desmoid tumours in patients with familial adenomatous polyposis and desmoid region adenomatous polyposis coli mutations. Br J Surg 2007; 94: 1009–13. 13. Stoeckle E, Coindre JM, Longy M, et al. A critical analysis of treatment strategies in desmoid tumours: a review of a series of 106 cases. Eur J Surg Oncol 2009; 35: 129–34. 14. Leithner A, Gapp M, Radl R, et al. Immunohistochemical analysis of desmoid tumours. J Clin Pathol 2005; 58: 1152–6. 15. Hornick JL, Fletcher CD. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 2002; 117: 188–93. 16. Lucas DR, al-Abbadi M, Tabaczka P, et al. c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical evaluation of two commercial antibodies. Am J Clin Pathol 2003; 119: 339–45. 17. Liegl B, Leithner A, Bauernhofer T, et al. Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours? Histopathology 2006; 49: 576–81. 18. Stalinska L, Turant M, Tosik D, et al. Analysis of pRb, p16INK4A proteins and proliferating antigens: PCNA, Ki-67 and MCM5 expression in aggressive fibromatosis (desmoid tumor). Histol Histopathol 2009; 24: 299–308. 19. Matono H, Oda Y, Nakamori M, et al. Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Hum Pathol 2008; 39: 1802–8. 20. Deyrup AT, Tretiakova M, Montag AG. Estrogen receptor-beta expression in extraabdominal fibromatoses: an analysis of 40 cases. Cancer 2006; 106: 208–13. 21. Ng TL, Gown AM, Barry TS, et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol 2005; 18: 68–74. 22. Thway K, Gibson S, Ramsay A, et al. Beta-catenin expression in pediatric fibroblastic and myofibroblastic lesions: a study of 100 cases. Pediatr Dev Pathol 2009; 12: 292–6. 23. Montgomery E, Torbenson MS, Kaushal M, et al. Beta-catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis. Am J Surg Pathol 2002; 26: 1296–301. 24. Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, et al. Nuclear betacatenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol 2005; 29: 653–9. 25. Bridge JA, Sreekantaiah C, Mouron B, et al. Clonal chromosomal abnormalities in desmoid tumors. Implications for histopathogenesis. Cancer 1992; 69: 430–6. 26. Li M, Cordon-Cardo C, Gerald WL, et al. Desmoid fibromatosis is a clonal process. Hum Pathol 1996; 27: 939–43. 27. Lucas DR, Shroyer KR, McCarthy PJ, et al. Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol 1997; 21: 306–11. 28. De Wever I, Dal Cin P, Fletcher CD, et al. Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology. Mod Pathol 2000; 13: 1080–5.
139
29. Middleton SB, Frayling IM, Phillips RK. Desmoids in familial adenomatous polyposis are monoclonal proliferations. Br J Cancer 2000; 82: 827– 32. 30. Tejpar S, Michils G, Denys H, et al. Analysis of Wnt/Beta catenin signalling in desmoid tumors. Acta Gastroenterol Belg 2005; 68: 5–9. 31. Huss S, Nehles J, Binot E, et al. beta-Catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. Histopathology 2013; 62: 294–304. 32. Le Guellec S, Soubeyran I, Rochaix P, et al. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mod Pathol 2012; 25: 1551–8. 33. Lazar AJ, Tuvin D, Hajibashi S, et al. Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 2008; 173: 1518–27. 34. Kotiligam D, Lazar AJ, Pollock RE, et al. Desmoid tumor: a disease opportune for molecular insights. Histol Histopathol 2008; 23: 117–26. 35. Bacac M, Migliavacca E, Stehle JC, et al. A gene expression signature that distinguishes desmoid tumours from nodular fasciitis. J Pathol 2006; 208: 543–53. 36. Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest 2011; 91: 1427–33. 37. Fisher C. Myofibrosarcoma. Virchows Arch 2004; 445: 215–23. 38. Yantiss RK, Nielsen GP, Lauwers GY, et al. Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases. Am J Surg Pathol 2003; 27: 532–40. 39. Mosquera JM, Fletcher CD. Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component–is this dedifferentiated SFT? Am J Surg Pathol 2009; 33: 1314–21. 40. Thway K, Hayes A, Ieremia E, et al. Heterologous osteosarcomatous and rhabdomyosarcomatous elements in dedifferentiated solitary fibrous tumor: further support for the concept of dedifferentiation in solitary fibrous tumor. Ann Diagn Pathol 2012; 17: 457–63. 41. Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 2013; 45: 131–2. 42. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45: 180–5. 43. Doyle LA, Moller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733–41. 44. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest 2005; 85: 408–15. 45. Shah AA, LeGallo RD, van Zante A, et al. EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma. Am J Surg Pathol 2013; 37: 571–8. 46. Folpe AL, Billings SD, McKenney JK, et al. Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002; 26: 1620–6. 47. Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006; 23: 91–102. 48. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors presenting as omental masses–a clinicopathologic analysis of 95 cases. Am J Surg Pathol 2009; 33: 1267–75. 49. Patil DT, Rubin BP. Gastrointestinal stromal tumor: advances in diagnosis and management. Arch Pathol Lab Med 2011; 135: 1298–310. 50. Dumont AG, Rink L, Godwin AK, et al. A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients. Ann Oncol 2012; 23: 1335–40. 51. Henricks WH, Chu YC, Goldblum JR, et al. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 1997; 21: 271–81. 52. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005; 29: 1340–7. 53. Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 2012; 36: 462–9. 54. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffinembedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 2007; 31: 1476–89.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
140
FISHER and THWAY
55. Pritchard DJ, Nascimento AG, Petersen IA. Local control of extra-abdominal desmoid tumors. J Bone Joint Surg Am 1996; 78: 848–54. 56. Salas S, Dufresne A, Bui B, et al. Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation. J Clin Oncol 2011; 29: 3553–8. 57. Soravia C, Berk T, McLeod RS, et al. Desmoid disease in patients with familial adenomatous polyposis. Dis Colon Rectum 2000; 43: 363–9. 58. Quintini C, Ward G, Shatnawei A, et al. Mortality of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis: a single center review of 154 patients. Ann Surg 2012; 255: 511–6. 59. Colombo C, Foo WC, Whiting D, et al. FAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center. Histol Histopathol 2012; 27: 641–9. 60. Phillips SR, A’Hern R, Thomas JM. Aggressive fibromatosis of the abdominal wall, limbs and limb girdles. Br J Surg 2004; 91: 1624–9. 61. Sharma A, Ngan BY, Sandor GK, et al. Pediatric aggressive fibromatosis of the head and neck: a 20-year retrospective review. J Pediatr Surg 2008; 43: 1596–604. 62. Burke AP, Sobin LH, Shekitka KM. Mesenteric fibromatosis. A follow-up study. Arch Pathol Lab Med 1990; 114: 832–5. 63. 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. 64. Hansmann A, Adolph C, Vogel T, et al. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 2004; 100: 612–20. 65. Waddell WR, Kirsch WM. Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors. Am J Surg 1991; 161: 416–21. 66. Francis WP, Zippel D, Mack LA, et al. Desmoids: a revelation in biology and treatment. Ann Surg Oncol 2009; 16: 1650–4. 67. Gibson S, Sebire NJ, Anderson J. Platelet-derived growth factor receptors and ligands are up-regulated in paediatric fibromatoses. Histopathology 2007; 51: 752–7. 68. Mace J, Sybil Biermann J, Sondak V, et al. Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 2002; 95: 2373–9. 69. Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 2006; 24: 1195–203.
Pathology (2014), 46(2), February
70. Wcislo G, Szarlej-Wcislo K, Szczylik C. Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature. J Cancer Res Clin Oncol 2007; 133: 533–8. 71. Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res 2010; 16: 4884–91. 72. Kurtz JE, Asmane I, Voegeli AC, et al. A V530I mutation in c-KIT exon 10 is associated to imatinib response in extraabdominal aggressive fibromatosis. Sarcoma 2010; 2010: 458156. 73. Penel N, Le Cesne A, Bui BN, et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol 2011; 22: 452–7. 74. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011; 17: 4082–90. 75. Verrill MW, Coley HM, Judson IR, et al. Susceptibility of fibromatosis cells in short-term culture to Ifosfamide: a possible experimental treatment in clinically aggressive cases. Sarcoma 1999; 3: 79–84. 76. Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer 2001; 92: 1259–64. 77. Garbay D, Le Cesne A, Penel N, et al. Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG). Ann Oncol 2012; 23: 182–6. 78. Gega M, Yanagi H, Yoshikawa R, et al. Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 2006; 24: 102–5. 79. Constantinidou A, Jones RL, Scurr M, et al. Pegylated liposomal doxorubicin, an effective, well-tolerated treatment for refractory aggressive fibromatosis. Eur J Cancer 2009; 45: 2930–4. 80. Constantinidou A, Jones RL, Scurr M, et al. Advanced aggressive fibromatosis: Effective palliation with chemotherapy. Acta Oncol 2011; 50: 455–61. 81. Wehl G, Rossler J, Otten JE, et al. Response of progressive fibromatosis to therapy with liposomal doxorubicin. Onkologie 2004; 27: 552–6. 82. de Camargo VP, Keohan ML, D’Adamo DR, et al. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer 2010; 116: 2258–65.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.