Fibromatosis

Wait or treat

1. Mustafa Mohamed Selim, MD Pediatric Oncology Department (NCI) Fibromatosis Wait or treat

2. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

3. local recurrence Spontaneous regression Infiltrative growth Fibromatosis Landmarks Tissue response

4. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

5. Fibromatosis L ocall y i nfiltrativ e m yofibroblasti c lesion which produce abundant extra-cellular collagen

6. Fibroblastic/myofibro b lastic tumours 1) Intermediate grade (locally aggressive) Desmoid-type fibromatosis Giant cell fibroblastoma Lipofibromatosis Palmer/plantar fibromatosis 2) Intermediate grade (rarely metastasizing) Dermatofibrosarcoma protuberans Infantile fibrosarcoma Inflammatory myofibroblastic tumour Low grade myofibroblastic sarcoma Myxoinflammatory fibroblastic sarcoma Solitary fibrous tumour 3) Malignant Adult-type fibrosarcoma Low-grade fibromyoid sarcoma Myxofibrosarcoma Sclerosing epithelioid fibrosarcoma

7. 2 Later 3 McFarlane in 1832 4 Muller 1838 WHO 2002 classification L ocally aggressive Fibromatosis History 2 Past N on-metastasising fibrosarcoma 4 5 1 L ocally infiltrative myofibroblastic lesion Aggressive Fibromatosis Desmoid Fibromatosis

8. History The term desmoid was derived from the Greek term “ desmos ” = “ tendon-like ” based on the morphologically bland myofibroblastic cells that make up desmoid tumours.

9. Stationary B iological behaviour are variable Natural history Self-limiting ( median 32 month ) R apidly progressive Recurrence

10. T ypes Extra‑abdominal ( 60 % ) Abdominal wall ( 25% ) Clinicopathologically types Intra‑abdominal ( 8‑15% ) Li Destri G , et al. 2014

11. T ypes Superficical Clinical types Sporadic Hereditary (associated with FAP) Deep

12. Smaller & non-aggressive Lacking β-catenin mutations They arise in the subcutis in the palm (more common), sole, penis, or knuckles P redomiantly affect Caucasian adults males Palmer and planter FM can occur in childhood & adolescence Associated with diabetes mellitus and epilepsy treated with drugs Key statistics Superficial Fibromatosis

13. Infilterate local tissues and locally recur , but an inability to metastasize. It represent : 0.03% of all neoplasms , 3% of all ST tumours An incidence : 2 – 4 new cases/million per-year It is most common between 10 and 60 years The peak incidence at approximately 30 years. Incidence in paediatric : ♂=♀ & extra-abdominal > abdominal P uberty - 40 years : ♂ < ♀ & more in abdominal wall Later in adulthood : ♂=♀ & abdominal = extra-abdominal Key statistics Deep Fibromatosis

14. Key statistics Deep Fibromatosis Sporadic Associated with FAP % 84-93% 10-20% Sex According age ♂ Age Older (42 years) Younger (36 years) Site Intra-abdominal Drive gene Somatic mutation CTNNB1 Germ-line mutation APC FAP: Familial Adenomatous Polyposis CTNNB1 : the gene encoding β-catenin

15. Familial adenomatous polyposis  ( FAP ) FAP is an  autosomal dominant  inherited condition. Three variants are known to exist, FAP (caused by APC gene defect on chromosome 5 ) – ( most severe ) Attenuated FAP (caused by APC gene defect on chromosome 5 ) Autosomal recessive FAP (defects in the MUTYH gene on chromosome 1 )

16. Message FAP → ↑↑↑ risk of fibromatosis 800 times Behave more aggressively C an be multifocal . Absence of Somatic mutation CTNNB1 drive you to : Search for APC mutation Referre for colonoscopy Sporadic FAP

17. Key Most of cases are sporadic E xtra- abdominal sit e is more common in pediatric A bdominal wall site is common in ♀ during p uberty - 40 years Types Superficial Deep ( sporadic or associated with FAP ) Nature Self-limiting or stationary or ra pidly progressive History L ocally infiltrative myofibroblastic lesion Sum up

18. A History, Natural history, Clinical types, Key Statistics, C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda Risk factors, Pathogenesis, Genetic features, Pathology,

19. Love For accurate work Model Learning

20. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

21. Risk P revious surgery Chromosome abnormalities (Familial A denomatous Polyposis or Gardner's syndrome) Blunt trauma Risk factors

22. β-catenin Pathogenesis It is invol v ed in cell - cell adhesion and gene transcription It is a cadherin protei n and encoded by CTNNB1 gene Dul function protein

23. Pathogenesis β -catenin acts as an intracellular signal transducer in the WNT signalling pathway β -catenin is regulated and destroyed by the β-catenin destruction complex , and in particular by the APC protein, encoded by APC gene It is a subunit of the cadherin protein complex and

24. Pathogenesis Axin brings (GSK3 enzyme) together with (β-catenin) into close physical proximity Phosphorylation of β-catenin is performed by GSK3 GSK3s are consitutively active enzymes APC is like a huge “ Christmas tree ”, it can bind multiple β-catenin molecules and 3 axin

25. Pathogenesis Ubiquitin ligase TrCP1 Phosphorylation = degradation

26. Pathogenesis Exposure of dishevelled ׳ s DIX domain and the creation of a perfct binding site for axin. Axin is then titrated away from the β-catenin destruction complex LRP proteins → inhibit activity GSK3 activity in a comptetitive manner

27. Pathogenesis No phosphorylation of β-catenin → no longer destruction→ ↑ β-catenin levels → saturate all binding sites in the cytoplasm, it will also translocates into the nucleus Pathogenesis‑associated molecules are centered on the cascade reaction of nuclear β‑catenin

28. Message In DF mutations in CTNNB1 and APC inhibit this degradation , and as a result the constitutive activation and accumulation of β-catenin occurs in cytoplasm and the nucleus of affected cells CTNNB1 and APC genes are integral components of the WNT signalling pathway which normally facilitates the T urnover and D egradation of β-catenin

29. Deep Fibromatosis Sporadic Hereditary Mutation Somatic Germ-line Drive gene CTNNB1 ( 3 p21) in codons of exon 3 T41A (59%), S45F (33%), S45P (8%) APC ( 5 q21-q22) Others Trisomy 8 (31 %), Trisomy 20 (23 %) Loss of Y chromosome AKT1 and BRAF Genetic factors Sorafenib Bad prognosis More in intra-abdominal More in extra-abdominal

30. Genetic factors

31. Genetic factors Marcel Trautmann et al., 2020 85–90% of DF harbor hotspot mutations within β-catenin gene (CTNNB1 ) 1 2 3

32. Pathology Gross picture ( deep FM ) Non-encapsulated (sometimes circumscribed) More infiltrative to surrounding tissues

33. Pathology It composed of lon g fascicles of myofibroblasts arranged in parallel with uniform spacing, in hypocellular collagenous stroma Slit-like blood vessels Small, rounded thick-walled blood vessels Normal mitosis No necrosis or Pleomorphism Microscopic picture

34. Pathology Immunohistrochemistry Cells express SMA , occasionally desmin P16 is usually positive Matrix metalloproteinases espechially ( MMP7 ) are expressed (overexpressin of MMP7 correlates with wide spread nuclear β -catenin positivity) Oestrogen receptor positivity are founded in many cases Lack h-caldesmon, CD34, S100 CD117 & PDGF alpha are rarely expressed About 80% of deep FM & lesser proportion of superficial ones show nuclear immunoreactivity for β -catenin .

35. Pathology Immunohistrochemistry Intra-nuclear staining of β-catenin has traditionally been used for the diagnosis. However , the specificity is poor ( Le Guellec S et al., 2012 ), and DF cases with no β-catenin staining in the nucleus are also occasionally observed . ( Koike H et al., 2019 ) On the other hand, several studies have reported that ∼ 85–90% of DF harbor hotspot mutations within β-catenin gene (CTNNB1).

36. Should we do mutation analysis of β-catenin for the diagnosis of desmoid -type fibromatosis ?

37. Should we do mutation analysis of β-catenin for the diagnosis of desmoid -type fibromatosis ? Tomohisa Sakai et al., 2020 The sensitivity of the CTNNB1 mutation ranged 81.1–92.4 %, and the accuracy rate was 85.1–93.1 %.

38. Should we do mutation analysis of β-catenin for the diagnosis of desmoid -type fibromatosis ? Tomohisa Sakai et al., 2020

39. Pathology Mutation analysis Intra- nuc

40. Is there is another method for detection β-catenin mutation ? Next-generation sequencing (NGS)/Sanger sequencing Activating mutations are nearly 93–95% if next generation sequencing is applied

41. Pathol-ogy Non-encapsulated & infilterative L ong fascicles in collagenous stroma Nuclear immunoreactivity for β- catenin Genetic Sporadic (somatic mutation CTNNB1 ) Associated with FAP ( Germ-line mutation APC) Pathog-enesis Risk F Trauma, surgery & FAP Sum up β-catenin CTNNB1 and APC gene

42. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

43. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda Risk factors, Pathogenesis, Genetic features, Pathology, History, Natural history, Clinical types, Key Statistics,

44. Biopsy Imaging History & examination High index of suspicion To reach Fibromatosis diagnosis

45. Intra -abdominal Anterior abdominl wall Extra -abdominal Overall DF usually presents between 15- 4 years Diagnosis History & examination

46. Diagnosis The majority of cases are sporadic The peak incidence between 25 and 30 years of age Extra-abdominal desmoid FM occur in young adults ( ♀> ♂ ) It affect any anatomical site , c ommon extra-abdominal desmoid FM: Musculature o f proximal extremitie s 50% [ especially the shoulder region(30%) and buttock (20%) ] , thigh, The trunk 43%, and Head and neck 7% ( behave more aggressively ) Extra- abdominal wal l 1 History & examination

47. Diagnosis Extra- abdominal wal l 1 The usual presentation of deep FM is as a painless lump or discrete very firm mass, sometimes with pressure symptoms resulting from direct compression: Head and neck: airway compression Limps: sever pain & contracture History & examination

48. Diagnosis Intra- abdominal wall 2 The majority of intra-abdominal cases are associated with FAP Site: mesetery , peritoneal ligaments, retroperitoneum , or pelvis Mesenteric tumours are more common in ♂ (median age 41 years) ↑ incidence in patients with FAP or gardner syndrome: Incidence is about 15% ↑ risk to 65% after abdominal surgery (especially laparotomy ) History & examination

49. Diagnosis Intra- abdominal wall 2 Patients may present with pain , a palpable mass , nausea and abdominal distension or symptoms related to the compression of adjacent intra-abdominal organs. Multiple desmoids can occur usually in patients with FAP History & examination

50. Diagnosis Anterior abdominal wal l 3 It is the most common s oft tissue neoplasm of the abdominal wall. Site: rectus sheath, rectus abdominis or internal oblique muscles Mostly in ♀ who are pregnant or within 1 year post partum and with oral contraceptive. Lesions tend to be smaller at presentation History & examination

51. Diagnosis Imaging Non-specific features It appears solid with variable, hypo-echoic with posterior acoustic enhancement It allows exclusion of other benign D.D. Ultrasonagraphy

52. Diagnosis Imaging Limited role It can help to exclude any mineralization as a cause of low signal intensity on MRI Identify periosteal reaction or erosion in advanced cases X-ray

53. Diagnosis Imaging It is less sensitive than MRI It can be used in: Intra-abdominal DF (the technique of choice) MRI can not be done or contraindicated CT

54. Diagnosis Imaging

55. Diagnosis Imaging It is the gold standard tool for diagnosis & monitoring & follow up . It is the best modality at predicting DF resectablility . It allows tumour size, infiltration and relationship to adjacent neurovascular structures. MRI

56. Fibrous tissue Low signal on T1 & T2 ↑ levels of collagen deposition ↑low signal on T1 & ↑heterogeneity signal on T2 Highly cellular, low levels of collagen deposition Low signal on T1 & high signal on T2 Early DT MRI Diagnosis Imaging Stages Evolving DT Finally DT

57. Diagnosis Imaging Extra-abdominal FM of the Rt deltoid muscle : Axial T 2 W MRI shows a hetrogeneous , predominantly hyperintense (cellular) mass with hypointense (collagenous) bands

58. Diagnosis Imaging Extra-abdominal FM of the Rt deltoid muscle : (b & c) Axial and cronal STIR MRI → cellular lesions are often better demonstrated

59. Diagnosis Imaging Extra-abdominal FM of the Rt deltoid muscle : (d-e) Axial and cronal T1 MRI provide an anatomical overview

60. Diagnosis Imaging Anterior bdominal wall FM : Axial STIR MRI showes marked hyper -intense mass (highly cellular) Anterior bdominal wall FM : Axial STIR MRI showes a large hypo -intense (collagen deposition) 2 Y observation

61. Diagnosis Imaging The converse indicates disease progression and possible requirement for 2nd line systemic therapies Converse

62. local recurrence Spontaneous regression Infiltrative growth Fibromatosis Landmarks Tissue response

63. Diagnosis Imaging It was used for assessment of response in few cases (on TKI) It can be used to differentiate FM from other benign conditions PET-CT

64. Diagnosis Biopsy Co re needle biopsy is the most the accurate method for diagnosis, for immunohistochemical , molecular analysis. Core biopsies using a 14G or 16G needle. Biopsy should be from the periphery of the tumor to maximize the chance of harvesting viable tissue US can guide superficial biopsies CT can guide deep biopsies

65. Diagnosis D.D. Nodular fasciitis Low grade myofibromatosis Low-grade fibromyxoid sarcoma Gastrointestinal stromal tumour Atypical lipomatous tumour Solitary fibrous tumour Most tumours that resemble FM lack nuclear β-catenin immunoreactivity features

66. Diagnosis Do we need confirmatory tests ? Confirmatory tests that document activating mutations in CTNNB1 are suggested . Activating mutations are relatively specific for DT and are present in up to 85% of tumors (nearly 93–95% if next generation sequencing is applied instead of Sanger sequencing).

67. 1 Prognostic factors F avorable locations versus unfavorable locations Tumor location Penel et al. 2017 Favorable Unfavorable Abdominal wall Chest wall Intra-abdominal & digestive viscera Head and neck Lower limb Upper limb Breast 2-year EFS 66% 41% Tumor location was found to be the most influential prognostic factor for local recurrence, P < . 001) Yoshihiro Nishida et al., 2020 P <.001

68. 1 2 Prognostic factors ( >4 vs >5 vs >7 vs > 10 cm ) Tumor size Larger size ( ≥ 8 cm ) was significant adverse risk factors for local recurrence-free survival ; P = .036 ) Yoshihiro Nishida et al., 2020 P .07

69. 1 2 3 Prognostic factors ( <36 vs <32 vs <26 vs < 18 years ) Patient age Young age is an indicator of bad prognosis

70. 1 2 3 4 Prognostic factors S45F showed a significant higher risk of recurrence compared with wild-type and other CTNNB1 mutations (p = 0.011) Trisomy 8 (100% 1 year recurrence rate ) Marco Fiore et al., 2021 B-CATENIN mutational status Three different CTNNB1b-catenin exon 3 point mutations—T41A, S45F, and S45P P .02

71. 1 2 3 4 5 Prognostic factors T he role of surgical margins in DT is controversial In patients treated with surgical resection alone , the risk of local recurrence was almost two fold higher for those with microscopically positive resection margins compared with those who underwent R0 resection , with a risk ratio (RR) of 1.78 (95% confidence interval [CI] 1.40–2.26). Surgical margin

72. P factors Lare size, young age, e xtremity & limp girdle, genetic ( 45F & Trisomy 8 ), and relapse D.D. Most tumours that resemble FM lack nuclear β-catenin immunoreactivity features work up MRI ( gold standard tool ) CT ( intra-abdominal ) Co re needle biopsy ( periphery ) C/O A painless lump vs Pressure symptoms Sum up

73. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

74. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

75. A C Diagnosis, Prognostic factors, B D Treatment, Assessment, Follow up Agenda History, Natural history, Clinical types, Key Statistics, Risk factors, Pathogenesis, Genetic features, Pathology,

76. Due to unpredictable natural history of the disease, establishing a therapeutic regimen for FM is challenging Treatment Treatment

77. In the past ᗔ wide local excision is the gold‑standard treatment for desmoid tumors Treatment Treatment

78. Why surgery nowadays isn’t the gold‑standard treatment for desmoid tumors ? It is considered a type of trauma , is an etiological factor for desmoid tumors and long‑term recurrence rates of surgery are quite high . Recurrence after surgery not only occurs in situ but also in adjacent areas , as it is unable to preserve connective tissues well. Fiore M, et al, 2014

79. Spont regression C Recur repeatedly D No metastasis A Local infilteration B Please choose after while Treatment

80. ↑ risk of recurrence is related to: Younger age, Chest wall, h ead & neck, and upper limb location, Association with FAP or Gardner syndrome, and The presence of an S45F mutation in the CTNNB1 gene

81. Fibromatosis Consensus 2014 2015 2017 2020 Italian and French Sarcoma Group 1 st consensus EORTC, STBSG, and SPAEN 2 nd consensus Update from EORTC, STBSG, and SPAEN 3 rd consensus Desmoid Tumor Working Group ( includes experts from Europe, North America and Japan, as well as patient Advocates ) 4 th consensus STBSG= Soft Tissue and Bone Sarcoma Group SPAEN = together with patient advocates from Sarcoma Patients EuroNet IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

82. Options Watch * wait policy ( active observation ) Surgical excision Systemic therapies Radiation therapy Alternative methods (radiofrequency ablation ) Treatment

83. Wait or treat Treatment

84. S e a r c h

85. Balance

86. W ide excision with preservation of function W atch and wait policy ( active observation ) Past Now Goal

87. Mutilating surgery should be avoided given the condition potential to resolve without intervention 03 02 An MDT approach should be adopted. 01 U nplanned excisions not preceded by appropriate MDT involvement are an ↑ risk of local recurrence Consideration

88. 1 ST Watch and wait policy MDT Should be adopted R Young age , unfavourable location , FAP , and S45F mutation 5 Options Sum up

89. First - line

90.  Sparing this cohort from treatment Identification of those patient who will remain asymptomatic with stable disease Identification of those patient who will undergo spontaneous regression 1 Benefits 2 3 Watch and wait policy 1

91. Other options are not available Extra - abdominal DF in non life threatening locations Incompletely resected or recurrent that do not pose a danger to vital organs 1 Indication 2 3 Watch and wait policy 1

92. Watch and wait policy A front-line policy of observing extra -abdominal DF in non-life threatening locations (agreement by ESNWG, NCCN, EORTC, and IFSG) Spontaneous regression was seen in 28-50% of cases of extra-abdominal FM (Colombo C et al., 2015) Regression can take significant time to occur (median 32 month ) (Bonvalot S et al., 2013) Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

93. Watch and wait policy Evidence ( Yongsung Kim et al., 2020) 1-year 2-year 3-year 25.4% 52.7% 70.9% The spontaneous stabilization rate

94. First - line When you should intervene during a period of observation? Should we use w atch and wait policy for all cases ? When I can reassure the family? What about pregnancy and active surveillance ?

95. 01 Rate of growth 02 Anatomical site 03 Risk of compression 04 Worsening of function 1. When you should intervene during a period of observation?

96. 01 Rate of growth 1. When you should intervene during a period of observation? Specifically , the indication for active treatment is reserved only in the case of persistent progression , defined as a subsequent increase in DT size or symptom burden assessed with at least two further assessments (possibly not before 1 year from diagnosis in the absence of fulfilling RECIST progressive disease). C onsider immediate intervention as opposed to active observation for progressively symptomatic tumors, or tumors with a history of rapid growth . If tumor progression would necessitate significantly more morbid interventions to manage the disease.

97. 02 Anatomical site 1. When you should intervene during a period of observation? if tumor progression would risk the patient developing significant complications (e.g. in the head and neck or mesentery )

98. 2. Should we use w atch and wait policy for all cases? Intra -abdominal sporadic fibromatosis provided low morbidity, complete resection without mutilating surgery, if not so systemic therapy can be used Extremity and limp girdle FM→ higher recurrence ( 39 - 79% ) Abdominal wall and sporadic intra-abdominal have limited risk of recurrence ( 8% and 13% , respectively).

99. 3 . When I can reassure the family? The potential of progression of DF seems to be limited after 3 years. Bonvalot S et al., 2008 ; Fiore M , et al., 2009 ; Barbier O et al., 2010

100. 4. What about pregnancy and active surveillance ? Active surveillance should be continued T he risk of progression during pregnancy is as high as 40–50% F ollowed with serial ultrasound The majority of patients experience tumor regression postpartum Fiore M, et al, 2014

101. 2 nd Systemic therapies or surgery Indi was seen in 28-50% of cases of extra-abdominal FM Spo Extra - abdominal DF in non life threatening locations Incompletely resected or recurrent that do not pose a danger to vital organs Ben Sparing a cohort from treatment Sum up of 1 st line

102. Second - line

103. Surgery Systemic 2 nd -line

104. Tumor location ( Favorable vs unfavorable site ) 1 Considerations Surgical excision 2

105. Tumor location 2-year EFS Favorable Unfavorable Observation 63% 52% Surgery 70% 25% P value 0.413 0.0013 Tumor site influence the outcome, Strongly for a non-operative approach , particularly in unfavorable sites Penel et al . 2017

106.  Symptomatic or not Tumor location ( Favorable vs unfavorable site ) Fibromatosis type ( sporadic or hereditary ) 1 Considerations 2 3 Surgical excision 2  Feasibility of surgery 4

107. Surgical margin Function preserving resection Goal Surgical excision 2 The St. Jude Children's Research Hospital reported no correlation between surgical margin and risk of recurrence (as local recurrence may follow a complete (R0) resection and incomplete resection don’t always result in recurrence ) R1 can be accepted to preserve function or cosmosis . (R ) wide microscopic margins (R 1 ) positive microscopic margins If surgery is necessary, surgical margins are less important than keeping function for the patient.

108. Operable extremity tumours that fail to respond to a trial of observation and hormonal therapy Intra- abdominal sporadic FM provided low morbidity, complete resection without mutilating surgery Abdominal wall FM in patients who progress to symptomatic disease 1 Indication 2 3 2 Surgical excision Operable head & neck, limp girdle and trunk that progress despite, observation , hormonal therapy and chemotherapy 4 IFSG guidelines local recurrence rate is 8‑31% after surgery with a clear margin

109. Indi Location (fav vs unfav ), FM type (sporadic vs hereditary), Symptomatic or not, and Feasibility Cons Intra- abdominal sporadic FM provided Symptomatic abdominal wall FM Operable extremity tumours and head & neck, limp girdle and trunk that fail to respond to a trial of observation, hormonal therapy and may be chemotherapy Goal Function preserving resection Sum up of 2 nd line ( surgery )

110. Surgery Systemic 2 nd -line

111. Third- line ?

112. Indications Systemic therapies 2 Aims Types To slow or stop growth of FM Improve disease-related symptoms as pain T hose cases (primary and recurrent) that fail a front-line trial of observation (patient becomes symptomatic or progressive) H ormonal therapies, C ytotoxic ch emotherapy, and B iological therapies (TKI)

113. History 2 Initially in 1980 when a sternal desmoid tumour unexpectedly regressed after indomtacin was commenced for a co-existing condition. Subsequent, WNT/oncogene pathway alterations in DF is responsible for cyclooxygenase-2 ( COX-2 ) mediated activation of platelet-derived growth factor receptors A. Hormonal therapies

114. Types A. Hormonal therapies 2 NSAIDs ( meloxicam, indomethacin, sulindac and celecoxib ) , T amoxifen ( anti- oestrogen agents ) , GnRH agonists ( inhibit gondadotropin secretion→ ↓ LH & FSH ) , P rogesterone , A romatas inhibitors ( block conversion of androgens to estrogens ) , M edroxyprogesterone acetate ( inhibit gondadotropin secretion ) , and T estolactone (brand name Teslac ) a non-selective, irreversible, steroidal aromatase inhibitor (no longer available for medical use)

115. Types 2 The most common combination T amoxifen ( 40-80 mg daily ) + Sulindac ( 400mg daily in divided doses ) A. Hormonal therapies

116. Hormonal therapies Although no randomised controlled trials exist to support combining NSAIDs and hormonal therapies, there is some evidence that the treatments are most effective when given together. ESNWG , EORTC and IFSG implement hormone therapy, combined with NSAIDs as 2nd line treatment in those cases (primary and recurrent) that fail a front-line trial of observation. Two of series reviewed by Janinis et al. reported a partial response to therapy in male patients (24-54 months after treatment initiation)→ providing a rational for hormone therapy in male. Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

117. Role is controversial Indications: f or unresectable or recurrent tumours Benefits : The duration of response to chemotherapy in Pain relief is usually short , while L onger in radiological tumor shrinkage or stabilization , which may continue for months before an expectant response B. Chemotherapy 2/3

118. Chemotherapy ESNWG used chemotherapy in symptomatic , inoperable DF and progressive cases. NCCN provide ambiguous guidance by suggesting that systemic therapy ( chemotherapy, hormonal therapy, NSAIDs and TKIs ) may be used for inoperable FM or following an R2 surgical resection IFSG considered chemotherapy as a 3rd line treatment in symptomatic cases that fail to respond to observation and hormonal therapy, excluding selected extremity and abdominal wall tumours would result in acceptable function (in which they considered surgery) Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

119. Combination of methotrexate with vinblastine Combination of methotrexate with vinorelbine Single agent doxorubicin Doxorubicin & dacarbazine Doxorubicin, dacarbazine , and vinorelbine with cyclophosphmide , vincristine and actinomycin Hydroxyurea . B. Chemotherapy Regimes 2/3

120. MTX & vinblastine Experience in inoperable cases of DF: Subjective improvment in symptoms (60%), Partial response and none progressing (40%) ` Azzarelli et al., 2001 Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

121. Anthracyclin A retrospective review of 62 patiens was performed by French Sarcoma Group in 2012 showed that regimens containing an anthracyclin result in significantly higher response rates than regimes without one ( 54 % vs 12 %, p= 0.001 ) Pegylated liposomal doxorubicin (Caelyx) (to avoid cardiac toxicity) also offers single agent therapy with acceptable toxicity in unresectable aggressive FM & response rate of 36% Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

122. Ifosfamide Seven patients who had previously failed to respond to either tamoxifeb or NSAID therapy Following a combination of ifosfamide & etoposide (+/- mitomycin): Six patients benefited from treatment ( 86% ) One patient stable (14%) Okuno SH., 2003 Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

123. Based on the identification c-kit and PDGFR in few cases However, imatinib , sunitinib , pazopanib , and sorafenib have emerged as promising medical therapeutic options. S unitinib ( multikinase inhibitor including VEGF & PDF receptors) → in case of imatinib resistance C. Biological therapies Clinical trials

124. TKI (imatinib) The French Sarcoma Group evaluated 41 patients → reported 3 month PFS rates → 90% 6 month PFS rates → 80% 1 year PFS rates → 65% 2 year PFS rates → 55% Penel N et al.,2011 Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer

125. S orafenib has been effective in some cases ( multikinase inhibitor including VEGF & PDGF receptors ) Desmoids harboring the S45F mutation may respond well to sorafenib and hydroxychloroquine ( Braggio D, et al, 2019 ) The gamma secretase inhibitor PF-03084014→ partial response C. Biological therapies Clinical trials

126. Sorafenib A group of 26 patients who received sorafenib : 70% (symptomatic benefit), 25% (objective partial response) and 70% remained stable at a median follow up of 4 months . Gounder MM et al., 2011 Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer Evidence

127. Sorafenib has been evaluated in a randomized phase III trial (NCT02066181 ), Two year PFS rate→ 81 % The objective response rate was 33% in the sorafenib group Frequently reported adverse effects for sorafenib were ( rash 73%, fatigue 67%, hypertension 55 %, and diarrhea 51 %) Gounder MM , et al., 2018 Evidence Sorafenib

128. Response % 1-Y PFS 2-Y PFS 3-Y PFS 10-Y PFS Side effects Imatinib <10% 66% 58% 55% Neutropenia, rash, abdominal pain, diarrhea, myalgia Sunitinib 26% 74% Neutropenia, diarrhea, hand-foot syndrome Sorafenib 33% 81% Hand-foot syndrome, rash, fatigue, hypertension, trichodynia Velbi /MTX 31 – 52% 67% Neutropenia, anemia, nausea, vomiting, elevated liver enzymes Vinorelabine /MTX Better toxicity profile than Velbi /MTX VAC Sterility, carcinogenesis, neutropenia Tamoxifen/ Sulindac 57%

129. Fourth- line

130. Historically : isolated RTH for unresectable tumors or who declined surgery . Indication : only in cases where medical and surgical options have been exhausted , and where disease is at risk of causing life-threatening problems or severely disabling outcomes ) Take care : due to risk of radiation-induced morbidity and 2nd malignancies (especially in young patients) Time : primary (uncertain role) or adjuvant (less clear role) Dose : 50-60Gy Radiation therapy (RTH) 4

131. Treatment duration is short (6 weeks), No surgical risks, Accepted % who could be controlled by RTH Primary RTH Benefits 4 Inferior response in younger patients (<18 years) Risk of 2 nd malignancy Fibrosis, joint contracture and neuropathy Drawbacks

132. Primary RTH Nuyttens et al., 2000 reviewed 22 studies, and concluded that isolated RTH can control DF in 78% of cases: 83% in primary disease 73% for recurrent tumours Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer Evidence

133. Primary RTH NCCN , EORTC and BSG adopt RTH as 1st line therapy in symptomatic and inoperable cases ESNWG recommend RTH for inoperable cases when progression occur after initial observation IFSG recommend RTH only in inoperable cases after failed trial of observation, hormonal therapy and chemotherapy (excluding abdominal wall tumours) Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer Evidence

134. Adjuvant RTH Nuyttens et al., also reported on the outcome of RTH following surgery and concluded that its use improves local control regardless of whether negative (94% vs 72%) or positive (75% vs 41) histological margins are obtained. Three large series contradict no benefit from adjvant RTH NCCN , EORTC and IFSG offer adjvant RTH in cases of recurrent disease managed surgically Evidence BSG =British Sarcoma Group ESNWG =European Sarcoma Network Working Group NCCN =National Comprehensive Cancer Network IFSG = Italian and French Sarcoma Group EORTC =European Organisation for Research and Treatment of Cancer Evidence

135. Adjuvant RTH A fter R0 surgery had no detectable benefit on recurrence. After R1/R2 resection was associated with improved recurrence rates, both in patients with primary tumors ( RR 1.54 , 95% CI 1.05–2.27) and those with recurrent DTs ( RR 1.60 , 95% CI 1.12–2.28 ). Marco Fiore et al., 2021 Evidence

136. Fifth- line

137. High intensity focused ultrasound (HIFU) treatment , C ryoablation , R adiofrequency ablation Indication : Small and moderately sized extra-abdominal tumours Doubtful benefit in larger tumours or lesions at critical sites Outcome : remain in early stages of evaluation I solated limb perfusion ( ILP) and chemoembolization ( TNF-TNF‑ α & melphalan ) Loco-regional treatments 5

138. A novel method, Minimally invasive’ Indication : Often served as a salvage for recurrent DT (palliative treatment) Side effects : acroparaesthesia of lower limb, thrombocytopenia, 1 st degree skin burn, mild pain, and low-grade fever. HIFU 5

139. Method: delivers room temperature argon gas through a sealed, segmentally insulated probe to cause rapid cooling locally due to the Joule‑Thomson effect (100 ). A promising modality & less invasive At 1 year: complete response ( 36%), partial response ( 36%) and stable disease ( 28%) Indication : to cure extra‑abdominal desmoid tumors. Side effects : injury to skin and nerves Cryoablation 5

140. Method: exploits high‑frequencies (375‑500 kHz) that are delivered by a special electrode to cause local heating effect of tumors, which would result in protein denaturation and coagulation necrosis in order to decrease or exterminate tumors (100). Indication : to treat unresectable DT (can be used in abdominal wall DT) and some benign lesions Side effects : cellulitis, soft tissue necrosis, pain, bleeding, infection, and may stimulate tumor growth Radiofrequency ablation 5

141. 1,25‑(OH)2‑vitamin D3 treatment, I nterferon‑ α, R etinoic acid, T ranilast , P redinisolone Clinical trials 6

142. Sum up Investigational treatments, ... Sx *: Surgery is an option if morbidity is limited; MTx : Medical treatment; RTx :Radiotheraphy ; ILP :Isolated limb perfusion Marco Fiore, et al . 2021

143. Assessment & follow up Following treatment close radiological follow up should be adhered to. MRI should be done after baseline MRI 2 months later, followed by serial scans 3-6 monthly depending on treatment and tumour location. Response assessment following radiotherapy is best performed at least 3 months after RTH. Tumors responding to systemic therapy may not decrease in size, but ‘ tissue response ’ may be observed, mainly defined by MRI signal changes ( e.g. decreased intensity on T2 sequences reflecting tumor fibrosis ).

144. S e a r c h Age cut off? Tumour size? The most effective systemic therapy? Role of adjuvant radiotherapy? ? ? ?

145. local recurrence Spontaneous regression Infiltrative growth Fibromatosis Landmarks Tissue response

146. Thank y u