HCI Sarcoma Services
Desmoid Tumors: The Nonmalignant Malignancy
R. Lor Randall MD, FACS The L.B. and Olive S. Young Presidential Chair for Cancer Research
Director, Sarcoma Services & SARC Fellowship, Lab Medical Director, HCH Surgical Services
Co-Leader Sarcoma Disease Oriented Research Team Co-Director, Huntsman-Intermountain Adolescent & Young Adult Cancer Care Program
Huntsman Cancer Institute & Primary Children’s Hospital University of Utah
Sara Shaw, BS
John Groundland, MD
DTRF Annual Meeting
September 23, 2017
Philadelphia, PA
HCI Sarcoma Services
Disclosures • Zimmer Biomet • Daiichi Sankyo • Chair, Orthopaedics, Children’s Oncology Group • Vice Chair, Bone Cmte, Children’s Oncology Group • Steering Cmte, Soft Tissue Sarcoma, COG • Sarcoma Foundation of America, Medical Advisory Board • Past President, Connective Tissue Oncology Society • President-Elect, Musculoskeletal Tumor Society • President-Elect, ABJS • Co-Chair NCCN ST Sarcoma Cmte • The University of Utah is MTF Institution • Past recipient DTRF • Editor, various journals
Desmoid Tumor – What Is It?
• Benign soft tissue tumor
– Derived from mesenchymal (connective) tissue
– Driven most commonly by a genetic aberration
involving the beta–catenin or APC gene
• No metastatic potential
• Can be locally aggressive, painful, and
potentially morbid.
– Locally “malignant”
– Can malign one’s life
Tumors Derived from Fibrous Tissue
• Fibromas
• Fibromatosis – dupytren / lederhosen
• Nodular Fasciitis
• Desmoid Tumors
• Dermatofibrosarcoma Protuberans
• Fibrosarcoma
Desmoid Tumor – Classification
Tumor = mass (in this case from a neoplasm)
Benign
(does not metastasize)
Indolent
Active
Aggressive
Pre-Cancerous
Malignant
(cancer)
Low Grade
Intermediate
High Grade Desmoid Tumors
Desmoid Tumors – What Do They Do?
Concise, accurate description of behavior
is difficult to make, due to their:
• Low incidence
• Variable anatomic locations
• Wide spectrum of locally aggressive
behavior
Desmoid Tumor
Two Clinical Entities 1. Sporadic
85% of desmoid cases
More commonly occur in the extremities
Beta-Catenin gene mutation
2. Familial Adenomatous Polyposis (FAP)
15% of desmoid cases
FAP desmoids are usually in the abdomen
APC gene mutation
People with FAP have 1000x higher incidence of
desmoid than the general population
Desmoid Tumor – Presentation
Highly variable because of the highly
variable nature of the tumor itself:
– Size
– Location
– Rate of growth and/or infiltration
Desmoid Tumor – Presentation
• A Bump
• Growth may be slow or rapid
• Pain may occur, from local nerve compression or rapid
growth causing swelling
• Depending on location of tumor, neighboring anatomic
structures may become compressed
– Neck airway or vascular obstruction shortness
of breath or lightheadedness
– Extremity nerve compression numbness,
tingling, weakness
– Abdominal nausea, bowel obstruction
Desmoid Tumor – The Numbers
• New Cases diagnosed/year in the US: 900
• Age – Range: any
– Most common: 30-50 years
• Gender – 2:1 female:male
– Hormone sensitivity? • Higher prevalence in females
• Growth often changes with pregnancy, menopause and oral contraceptive
Desmoid Tumor – Anatomic Locations
• Extra-Abdominal – Usually Sporadic Cases
– 50% Limbs
– 43% Trunk
– 7% Head and Neck
– 10% have multi-focal presentation
• Intra-abdominal – Usually associated with FAP
– Patients with an intra-abdominal desmoid
should be screened with colonoscopy
Merchant et al, Cancer 1999
Desmoid Tumor – Evaluation
• History and Physical
• Imaging
• Biopsy
• Team Approach
Goal:
Establish the diagnosis
and develop a comprehensive plan of care
NCCN Clinical Practice Guidelines in Oncology, 2017
Desmoid Tumor – Evaluation
• History and Physical
– History of the mass • First appearance
• Rate of growth
– Local symptoms
– Systemic symptoms
– Physical nature of the mass: mobile, firm …
• Imaging
• Biopsy
• Team Approach
Desmoid Tumor – Evaluation
• History and Physical
• Imaging
– Ultrasound
– Radiographs
– MRI
– CT
• Biopsy
• Team Approach
Examples MRI of a 26 year old female with a
desmoid tumor in the gluteal musculature
Examples MRI of a 40 year old female with a
superficial desmoid tumor of the flank
Examples MRI of a 27 year old female with desmoid
tumor of the left leg
Radiograph Ultrasound MRI
Examples MRI of a 46 year old female with
desmoid tumor of the right arm
Desmoid Tumor – Evaluation
• History and Physical
• Imaging
• Biopsy
– Image-guided
– Open
• Team Approach
Desmoid Tumor – Evaluation
• History and Physical
• Imaging
• Biopsy
• Team Approach
– Orthopedic and General Oncologic Surgeons
– Medical Oncologist
– Radiation Oncologist
– Musculoskeletal Radiologist
– Pathologist
Desmoid Tumor
What Should We Do?
• Watch
• Medication
• Surgery
• Radiation
Desmoid Tumor – Treatment
• Watching ≠ Doing nothing
• Spontaneous Regression vs Disease stabilization vs
Progression
• Spontaneous regression occurs in up to 50% of cases
• If regression occurs, average time to regression is 32
months
• Conversion to active treatment occurs in up to 50% of
cases; as long as surveillance is adequate, no “bridges
are burnt.”
Watch Medicine Surgery Radiation
Kasper et al, European Journal of Cancer, 21015
Park et al, Journal of Surgical Research, 2016
• Will a Desmoid Progress?
– Studies are contradictory
– No single factor or genetic aberration has been identified to
clearly predict behavior
• Potential Predictors of Progression
– Female gender
– Younger age at presentation (under 30-35)
– Larger tumor size (>5-10 cm)
– Anatomic location (extremity desmoids, particularly in
hands / feet)
Watch Medicine Surgery Radiation
Desmoid Tumor – Treatment
Many Medicine Options:
•NSAIDs
•Anti-estrogens &
aromatase inhibitors
•Chemotherapy
•Targeted therapy
•Combination Therapy
Watch Medicine Surgery Radiation
Cons Pros
Decrease in Pain
Possibility of Avoiding More Invasive
Treatment
Control of Tumor Growth
Progression Despite Treatment
Uncertain Length of Treatment
Side Effects of Medication
Desmoid Tumor – Treatment
Definitive and comparative response rates
between medications are not available due
to the small number of patients studied,
variable application of medications and wide
range of tumor characteristics studied.
Watch Medicine Surgery Radiation
Desmoid Tumor – Treatment
Drug Class Drug Regression Stable Disease Progression
NSAID Sulindac 48% 28% 14%
Hormonal
Therapy
Tamoxifen 58% nr nr
Targeted
Therapy
Imatinib 5-15% 60-80% 15%
Surafenib 25% 70% 5%
ChemoTherapy Methotrexate /
Vinblastine
11% 66% 22%
Pegylated
Doxorubicin
33% 67% 0%
Watch Medicine Surgery Radiation
Desmoid Tumor – Treatment
Bocale et al, Colorectal Disease 2011. Constantinidou et al Acta Oncologica, 2011
Fiore et al, European Journal of Cancer, 2015. Quast et al, Fam Onc 2016
• Once considered the cornerstone of
treatment, surgery is now reserved for a
limited subset of tumors
• Reports on the rate of relapse following
surgical resection vary
– Influenced by tumor characteristics and
ability to excise the entirety of the tumor
Watch Medicine Surgery Radiation
Desmoid Tumor – Treatment
Melis et al, JCO, 2008
Study “Clean” Surgical
Margins
Microscopic (+)
Margins
Macroscopic (+)
Margins
Spear et al 23% 44% 50%
Posner et al 15% 55%
Merchant et al 24% 22% 50%
Gronchi et al 23% 26%
Watch Medicine Surgery Radiation
Recurrence rate after surgery based on extent
of residual demonstrable disease
Desmoid Tumor – Treatment
• Radiation can be used alone or as an
adjunct to surgery
• Isolated radiation can control disease
progression in 78% of cases
• Radiation following surgery has produced
contradictory results
• Doses of 50-60 Gy are required
– Can have unwanted side effects / risks,
particularly in young patients with decades of life
remaining
Watch Medicine Surgery Radiation
Desmoid Tumor – Treatment
Miralbell et al, Int J of Rad Onc Bio Phys, 1990
MRI guided Ultrasound Ablation •MRI is used to determine the depth / width of the tumor, allowing
ultrasound to be focused on the tumor, sparing neighboring tissues.
•Ultrasound increases micromotion within the tissue, resulting in a
focused increase in energy – which manifests as heat
•Heating of the desmoid to 50-80 degrees C may cause tissue death
•Early reports (18 total patients) have demonstrated the ability of this
ablation to reduce both total tumor volume and viable tumor volume
•In the report by Ghanouni, Tumor Volume decreased 39 -100%, but
follow up was limited (5-39 months) due novelty of the technique
Watch Medicine Surgery Radiation
Desmoid Tumor - EmergingTreatment
Bucknor MD, Rieke V. J Ther Ultrasound. 2017
Ghanouni et al Eur Radiol. 2017
Diagnosis
Evaluation by a
Multi-disciplinary
team
Radiation
Alone for
unresectable
disease or
Adjuvant to surgery
Surgery
Symptomatic
and/or
resectable
disease
Medication
NSAIDs
Hormones
Targeted Rx
Chemotherapy
Watchful
Waiting
Repeat Exam
Repeat
Imaging
Desmoid Tumor
A Multi-Disciplinary Approach
Ablation
Emerging
technique for
appropriate cases
Additional References
Review Articles and General Clinical Guidelines
•Eastley N, McCulloch T, Esler C, Hennig I, Fairbairn J, Gronchi A, Ashford R. Extra-abdominal desmoid
fibromatosis: A review of management, current guidance and unanswered questions. Eur J Surg Oncol.
2016 Jul;42(7):1071-83.
•Hawkins DS, Spunt SL, Skapek SX; COG Soft Tissue Sarcoma Committee. Children's Oncology
Group's 2013 blueprint for research: Soft tissue sarcomas. Pediatr Blood Cancer. 2013 Jun;60(6):1001-
8.
•von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Conrad EU 3rd, Ganjoo KN, George S,
Gonzalez RJ, Heslin MJ, Kane JM 3rd, Koon H, Mayerson J, McCarter M, McGarry SV, Meyer C,
O'Donnell RJ, Pappo AS, Paz IB, Petersen IA, Pfeifer JD, Riedel RF, Schuetze S, Schupak KD,
Schwartz HS, Tap WD, Wayne JD, Bergman MA, Scavone J. Soft Tissue Sarcoma, Version 2.2016,
NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016 Jun;14(6):758-86.
Desmoid Tumor and Familial Adenomatous Polyposis
•Turina M, Pavlik CM, Heinimann K, Behrensmeier F, Simmen HP. Recurrent desmoids determine
outcome in patients with Gardner syndrome: a cohort study of three generations of an APC mutation-
positive family across 30 years. Int J Colorectal Dis. 2013 Jun;28(6):865-72.
•Calvert GT, Monument MJ, Burt RW, Jones KB, Randall RL. Extra-abdominal desmoid tumors
associated with familial adenomatous polyposis. Sarcoma. 2012;2012:726537
Studies Investigating Desmoid Response to Medicine •Chugh R, Wathen JK, Patel SR, Maki RG, Meyers PA, Schuetze SM, Priebat DA, Thomas DG, Jacobson JA, Samuels
BL, Benjamin RS, Baker LH; Sarcoma Alliance for Research through Collaboration (SARC). Efficacy of imatinib in
aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC)
trial. Clin Cancer Res. 2010 Oct 1;16(19):4884-9
•Dufresne A, Bertucci F, Penel N, Le Cesne A, Bui B, Tubiana-Hulin M, Ray-Coquard I, Cupissol D, Chevreau C, Perol
D, Goncalves A, Jimenez M, Bringuier PP, Blay JY. Identification of biological factors predictive of response to imatinib
mesylate in aggressive fibromatosis. Br J Cancer. 2010 Aug 10;103(4):482-5.
•Kasper B, Gruenwald V, Reichardt P, Bauer S, Rauch G, Limprecht R, Sommer M, Dimitrakopoulou-Strauss A, Pilz L,
Haller F, Hohenberger P. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final
results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017 May;76:60-67.
•Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer
Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the γ-Secretase
Inhibitor PF-03084014 in Adults With DesmoidTumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May
10;35(14):1561-1569.
•Penel N, Le Cesne A, Bui BN, Perol D, Brain EG, Ray-Coquard I, Guillemet C, Chevreau C, Cupissol D, Chabaud S,
Jimenez M, Duffaud F, Piperno-Neumann S, Mignot L, Blay JY. 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 Feb;22(2):452-7
•Skapek SX, Anderson JR, Hill DA, Henry D, Spunt SL, Meyer W, Kao S, Hoffer FA, Grier HE, Hawkins DS, Raney RB.
Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology
Group (COG) phase II study. Pediatr Blood Cancer. 2013 Jul;60(7):1108-12
Additional References
Radiation
•Keus RB, Nout RA, Blay JY, de Jong JM, Hennig I, Saran F, Hartmann JT, Sunyach MP, Gwyther SJ,
Ouali M, Kirkpatrick A, Poortmans PM, Hogendoorn PC, van der Graaf WT. Results of a phase II pilot
study of moderate dose radiotherapy for inoperable desmoid-type fibromatosis--an EORTC STBSG and
ROG study. Ann Oncol. 2013 Oct;24(10):2672-6.
Ultrasound Ablation of Desmoid Tumors
•Bucknor MD, Rieke V.. MRgFUS for desmoid tumors within the thigh: early clinical experiences. J Ther
Ultrasound. 2017 Feb 3;5:4
•Ghanouni P, Dobrotwir A, Bazzocchi A, Bucknor M, Bitton R, Rosenberg J, Telischak K, Busacca M,
Ferrari S, Albisinni U, Walters S, Gold G, Ganjoo K, Napoli A, Pauly KB, Avedian R. Magnetic resonance-
guided focused ultrasound treatment of extra-abdominal desmoidtumors: a retrospective multicenter study.
Eur Radiol. 2017 Feb;27(2):732-740
Biology of Desmoid Tumors •Trang SH, Joyner DE, Damron TA, Aboulafia AJ, Randall RL. Potential for functional redundancy in EGF and TGFalpha signaling in desmoid cells: a cDNA microarray analysis. Growth Factors. 2010 Feb;28(1):10-23.
•Joyner DE, Trang SH, Aboulafia AJ, Damron TA, Randall RL. FAP-associated desmoid invasiveness correlates with in vitro resistance to doxorubicin. Fam Cancer. 2009;8(4):569-80.
•Joyner DE, Trang SH, Damron TA, Aboulafia AJ, Cummings JE, Randall RL. Desmoid cell motility is induced in vitro by rhEGF. J Orthop Res. 2009 Sep;27(9):1258-62
Additional References
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