Desmoid-type fibromatosis/Desmoid tumor

-Locally aggressive, recurring, non-metastasizing tumor of connective tissue -Localization: extremities (30-40%) abdominal wall (20%) chest wall (10-15%) retroperitoneum (15%) head and neck, paraspinal -Presentation as a usually initially painless mass, possible role of trauma -Many cases in the abdominal wall occur after pregnancy Molecular features of desmoids

• The majority (90-95%) of desmoids are sporadic and have a mutation in the beta-Catenin gene which appears necessary for a desmoid to develop*

*important contribution by Dr. Aimee Crago Molecular features of desmoids

• The majority (90-95%) of desmoids are sporadic and have a mutation in the beta-Catenin gene which appears necessary for a desmoid to develop • A smaller number of desmoids occurs as part of the Gardner syndrome (APC gene), an inheritable disorder that is characterized by numerous polyps polyps in the colon, with an increased risk for colon cancer Molecular features of desmoids

• The majority (90-95%) of desmoids are sporadic and have a mutation in the beta-Catenin gene which appears necessary for a desmoid to develop • A smaller number of desmoids occurs as part of the Gardner syndrome (APC gene), an inheritable disorder that is characterized by numerous polyps polyps in the colon, with an increased risk for colon cancer • In both types of desmoids, beta-Catenin protein is overexpressed in the nucleus and this leads to increased cell proliferation and survival

D. Aggarwal et al. Lung India 2012

Other features of desmoid

• Rare: less than 4 new patients per million per year • Patients tend to be young and women are affected twice as often as men • Diagnosing desmoids is not always easy Sarcomas

• Tumors that originates from connective tissue cells: muscle, fibroblasts, fat, cartilage, bone, smooth muscle, etc. • Soft tissue sarcoma: 11,000 new cases/yr • Bone sarcoma: 2,900 new case/yr • (breast carcinoma 227,000/yr)

http://www.seer.cancer.gov/ Sarcomas

• Given the rarity of sarcomas only few pathologists see most subtypes on a regular basis • Role for specialized sarcoma centers (diagnosis AND treatment)

Sarcomas, 1% of new cancer diagnoses in adults but 50 (!) subtypes

Demicco and Lazar Sem in Onc 2011, S3-18 Sarcoma

• Over 50 types of sarcoma are recognized (and even more benign soft tissue lesions) • Subdivided in groups by (presumed) tissue of origin Tools available to Pathologists

• Histology – Training, experience, consult w colleagues • Immunohistochemistry • Molecular studies (DNA) Rhabdomyosarcoma with cross-striations

Normal muscle with cross-striations Normal fat tissue

Liposarcoma Diagnosis of desmoid tumors

• Histology: bland spindle cell lesion invading muscle and other normal tissues • Problem: can look like scar and other fibroblastic tumors • Immunohistochemistry: mutations in either beta- Catenin or APC gene lead to increased nuclear beta-Catenin • Problem: same staining can be seen in other tumor and the stain is often difficult to read • Molecular studies: finding beta-Catenin or APC gene mutations is very good support desmoid Difficult to tell desmoid from scar by histology

scar scar desmoid There are other fibroblastic lesions too

Palmar fibromatosis

Fibromatosis Elastofibroma Fibr Tendon Sheath Sol Fibrous tumor

collagenous fibroma (6) elastofibroma (4) infantile digital fibromatosis (3) palmar fibromatosis (8) nasopharyngeal angiofibroma (6) fibroma of tendon sheath (4) nodular fasciitis (6) dermatofibrosarcoma protuberans (4) desmoid type fibromatosis (7) solitary fibrous tumor (5) nuclear stain for beta-Catenin helps in many but not all cases Diagnosis of desmoid tumors

• Histology: bland spindle cell lesion invading muscle and other normal tissues • Problem: can look like scar and other fibroblastic tumors • Immunohistochemistry: mutations in either beta- Catenin or APC gene lead to increased nuclear beta-Catenin • Problem: same staining can be seen in other tumor and the stain is often difficult to read • Molecular studies: finding beta-Catenin or APC gene mutations is very good support Complexity of desmoid tumors

 Despite their histologically bland appearance, a significant subset of these tumors recurs aggressively and requires often debilitating surgery  Currently there are no molecular markers that predict the behavior of desmoid tumors  Previous work of Aimee Crago and Mushriq Al- Jazrawe/Ben Alman indicated:  variability in frequency of CTNNB1 mutations in desmoid tumors  heterogeneity in composition of desmoid tumors (tumor cells + normal fibroblasts)  Confirmed and further detailed by work of Joanna Przybyl  Desmoid tumors may be more complex than previously assumed Problem: When a desmoid comes back, it is difficult to tell recurring desmoid from the scar of the previous surgery

Preliminary studies already identify possible markers

Plan: Extend these studies and validate findings Major questions in desmoids

• How to distinguish desmoids that need immediate surgery from those where one can “watch and wait” • How to distinguish desmoids that will recur from those that won’t • Develop better diagnostic markers for desmoids – Evaluate completeness of resection – Distinguish scar from recurrent desmoid Thank you!

Stanford University, School of Medicine

 Matt van de Rijn

 Shirley Zhu

 Sushama Varma

 Sujay Vennam

 Kristen Ganjoo

 Joanna Przybyl

The Desmoid Tumor Research Foundation