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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