Desmoid tumor pathophysiology

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Case #1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Faizan Sheraz, M.D. [3]

Overview

Desmoid tumors arises from monoclonal proliferation of well-differentiated fibroblasts. They appear as firm overgrowths of fibrous tissue with marked cellularity and aggressive local infiltration. The exact etiology remains uncertain, however, they are seem to be associated with antecedent surgical or accidental trauma at the tumor site and various mutations at the molecular level including beta-catenin gene, CTNNB1 or APC gene involved in Wnt/beta-cateninsignaling pathway. Pediatric desmoids have AKT1 E17K, BRAF V600E and TP53 R273H mutations in addition to CTNNB1 mutation. Immunohistochemistry shows an elevated beta-catenin protein level in all tumors, regardless of the mutational status. Associated conditions include Turcot syndrome, Gardner syndrome, Familial adenomatous polyposis and estrogen therapy. Desmoid tumors arise from connective tissue, fasciae and aponeuroses and appear as dense scar tissuewith most common sites of abdominal involvement being abdominal wall, root of the mesentery and retroperitoneum. Histologically, desmoid tumors consist of linearly arranged elongated fibroblasts and myofibroblas surrounded and separated from each other by collagen. These tumors show a tendency to evolve over time.

Pathophysiology

• It is understood that desmoid toomurs is the result of:
  • Arise from monoclonal proliferation of well-differentiated fibroblasts
  • Can grow almost anywhere in body
  • Appear as well-differentiated, firm overgrowths of fibrous tissue
  • Marked cellularity
  • Benign tumors
  • Aggressive local infiltration
  • Superficial desmoids are less aggressive than the deep desmoids (abdominal, extra abdominal, mesenteric)
  • High local recurrence rate (25% to 85%)
  • Don't metastasize
  • Typically affects easily movable elastic tissues
• Their exact etiology remains uncertain, although they are frequently associated with previous trauma or surgical incision. On the molecular level, desmoids are characterised by mutations in the β-catenin gene, CTNNB1, or the adenomatous polyposis coli gene, APC.

Genetics

• The key factor in pathogenesis of desmoids at genetic level is beta-catenin stabilization implicated by mutations in two mediators of Wnt-APC-beta-catenin pathway.

Normal function of CTNNB1 and APC genes

• CTNNB1 gene provides instructions for making a protein called beta-catenin which is involved in cell-signaling pathway
• Beta-catenin interacts with other proteins to control the activity (expression) of particular genes, which helps promote cell proliferation and differentiation
• Protein produced by APC gene helps to regulate cellular beta-catenin levels
• When beta-catenin is no longer needed, glycogen synthase kinase 3beta (GSK3beta) binds to the APC protein
• Phosphorylation of GSK3beta (bound to APC) leads to beta-catenin binding to this APC site
• Kinase activity of APC complex leads to phosphorylation of beta-catenin at its serine and threonine sites encoded in exon 3
• This leads to ubiquitin-mediated protein degradation of beta-catenin in proteasome

Mutations in adults

• Wnt/beta-catenin signaling pathway
  • Mutational analysis shows that Wnts play an important role in controlling diverse developmental processes such as patterning of the body axis, central nervous system and limbs, and the regulation of inductive events during organogenesis.
  • Sporadic tumors occur due to somatic mutations in Beta-catenin/APC coding genes
  • Activating mutations in APC gene/Beta-catenin gene (CTNNB1) lead to dysregulation of beta-catenin (a cytosolic and nuclear protein which acts as a cellular adhesion molecule) levels in cell leading to its accumulation in nucleus which is associated with transcription activation of CYCD1 and MYC genes.
  • This leads to promotion of proliferation and enhanced survival associated with development of desmoid tumor.
  • Following is a summary of all the events that occur at molecular level secondary to activating mutations in APC gene/Beta-catenin gene (CTNNB1)/Wnt signaling pathway, eventually leading to development of desmoid tumor.

Binding of an activating external/Wnt ligand to a receptor complex (a member of a seven-transmembrane-domain receptor of the frizzled family) and a LRP5/6 co-receptor(LDL-receptor-related protein family)

Canonical Wnt (Wingless) signaling pathway activation

Inhibition of kinase activity of APC complex (which tightly binds and regulates Beta-catenin levels by its phosphorylation in proteasome at serine and threonine sites encoded in exon 3, leading to ubiquitin-mediated protein degradation)

Elevated Beta-catenin levels in cytoplasm (due to non-phosphorylation)

Beta-catenin translocates to nucleus

B-catenin together with TCF/LEF transcription factors, acts to activate transcription of genes such as CYCD1 and MYC

Promotion of proliferation and enhanced survival

• APC mutations
  • Function of normal APC protein is to prevent the accumulation of beta-catenin by mediating its phosphorylation and resultant degradation
  • Familial cases of desmoid (aka hereditary desmoid disease) are associated with germline mutations in the APC gene.
  • APC gene mutation on chromosome 5q is responsible for FAP
  • Generally, desmoid tumors occur more frequently when mutations are in the 3' end of the APC gene, specifically between codons 1445 and 1580
  • More than 300 mutations have been described leading to frame shifts or premature stop codons, resulting in a premature truncated APC gene product which causes loss of the beta-catenin regulatory domain
  • This leads to accumulation of beta catenin which binds to, and activate the transcription factor tcf-4
  • Sex hormones seem to play a role in activation of these mutations and signaling pathways leading to desmoids
• Mutations in CTNNB1 (Beta-catenin gene) (85%)
  • Associated with sporadic desmoids
  • Following are the three particular sites for CTNNB1 mutations:
    • T41A (59%)
    • S45F (33%)(associated with a higher recurrence rate after surgical resection of a primary desmoid tumor)
    • S45P (8%)
• Other sporadic tumors
  • Benign fibrous bone lesions arising in both soft tissue and bone tumors such as:
    • Dupuytren's contracture
    • Plantar fibrosis
    • Peyronie's disease
    • Carpal tunnel syndrome
    • Infantile fibrosarcoma
    • Fibrous dysplasia
• Trisomy 8 (frequent finding in hematologic malignancies)
• Trisomy 20

Additional mutations in pediatric desmoids

• In addition to CTNNB1 mutations, following mutations contribute to pediatric desmoids:
  • AKT1 E17K mutation (31%)
  • BRAF V600E mutation (19%)
  • TP53 R273H mutation (9%)

Immunohistochemistry

• Immunohistochemistry shows an elevated beta-catenin protein level in all tumors, regardless of the mutational status

Associated Diseases

• Some cases have been associated with estrogen therapy
• Turcot syndrome
• Gardner syndrome
• Familial adenomatous polyposis
  • In the case of mesenteric desmoid they are seen either sporadically or in association with familial polyposis coli syndrome (FAP)

Gross Pathology

• Desmoid tumors look like dense scar tissue.
• Adhere tenaciously to surrounding structures and organs just like a scar tissue hence, difficult to remove.
• Desmoid tumors arise from:
  • Connective tissue
  • Fasciae
  • Aponeuroses
• Abdominal wall desmoid tumors arise from:

• Musculoaponeurotic structures of the abdominal wall (especially the rectus and internal oblique muscles and their fascial coverings).
• External oblique muscle and the transversalis muscle or fascia
• Mostly measure 5 cm by 15 cm in diameter
• Firm and gritty texture
• Appears as glistening white and coarsely trabeculated, resembling scar tissue on cut surface
• No distinct capsule
• Ill defined margins
• Well circumscribed on imaging

Location

Frequent locations in the abdomen are:

• Abdominal wall
• Root of the mesentery
• Retroperitoneum

Patient presenting a large desmoid tumor on the posterior thoracic wall.Source: Abrao FC. et al, Thoracic Surgery Department, Instituto do Corao InCor, Hospital das Clnicas da Faculdade de Medicina da Universidade de Sã Paulo HCFMUSP, Sã Paulo, Brazil.

Rapid progression of a pregnancy-associated intra-abdominal desmoid tumor in the post-partum period: A case report. (A) Intra-operative view of intra-abdominal desmoid tumor with adherent portion of small bowel. (B) Desmoid tumor after surgical resection.Source: Hanna D. et al, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, United States

Breast Desmoid Tumor after Ductal Carcinoma Treatment: Salvaging a DIEP Flap Reconstruction. Chest wall defect after desmoid tumor resection (A) and resected desmoid tumor (B). Source: Zavlin D. et al, *Institute for Reconstructive Surgery, Houston Methodist Hospital, Weill Cornell Medicine, Houston, Tex.; and †College of Medicine, Texas A&M University College of Medicine, Houston, Tex.

Extra-Abdominal Fibromatosis (Desmoid Tumor): A Rare Tumor of the Lower Extremity Arising from the Popliteal Fossa. Gross cross-sectional view of pathologyic resected specimen. The gross lesion is poorly circumscribed and usually measures between 5 and 15 cm. On cut section, it is hard and tan-white. The lesion is poorly circumscribed and is centered in skeletal muscle and the adjacent fascia. There often are infiltration and obliteration of adjacent structures. Source: Ali Kaygain M. et al, Department of Cardiovascular Surgery, Erzurum Regional Training and Research Hospital, 25020 Erzurum, Turkey

Microscopic Pathology

On microscopic histopathological analysis, the characteristic findings of desmoid tumors inclde:

• Elongated fibroblasts and myofibroblasts
• Myofibroblasts are characterized by elongated, tapered cytoplasm; elongated, vesicular, typical-appearing nuclei; and multiple small nucleoli
• Cells are linearly arranged
• Cells are surrounded and separated from each other by collagen
• These tumors show a tendency to evolve over time

Stages of evolution of desmoid tumors

Vandevenne et al described three stages of evolution of desmoid tumors as follows:

Stages of evolution of desmoid tumors

Stage	Histological features
First stage	More cellular lesions Fewer areas of hyalinized collagen
Second stage	Increased amount of collagen deposition in central and peripheral tumor areas
Third stage	Increased fibrous composition Decreased cellularity Decreased water content

Histological features of desmoid tumors in the proximal part of the left thigh of a 29-year-old woman (arrows) (a–d). (a) Desmoid tumors invaded into the skeletal striated muscle aggressively. Degeneration of skeletal muscle cells could be seen (HE × 100). (b) Budding-like protrusion of the lesions invading into the muscles could be seen on the juncture of tumors and muscles (HE × 40). (c) Isolated small lesions in muscles were found away from the main part of the tumor (HE × 40). (d) Microscopically, desmoid tumors were poorly circumscribed on tumor-ligament boundary (HE × 40).Source: Wang YF. et al, Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044 P.R. China

Histological features of postoperative recurrent desmoid tumors in the right forearm of a 15-year-old man (arrows) (a–d). (a) Lesions with adipose tissue involvement (HE × 40). (b) Desmoid tumors around vessels could not invade into the vessel wall to form tumor thrombus (HE × 40). (c) Desmoid tumors invaded into the connective tissue and perineurium around nerve tissue (HE × 40). (d) Desmoid tumors with bone involvement penetrated into the periosteum and cortical bone and invaded into the bone marrow cavity along the bone trabecula (HE × 40).Source: Wang YF. et al, Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044 P.R. China

Immunological features of desmoid tumors in the middle section of the left thigh of a 35-year-old woman with femur involvement (a–d). (a) β-catenin staining of desmoid tumors (EnVision × 200). (b) Vimentin staining of desmoid tumors (EnVision × 200). (c) Desmin staining of desmoid tumors (EnVision × 200). (d) Ki-67 staining of desmoid tumors (EnVision × 200).Source: Wang YF. et al, Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, 100044 P.R. China

Extra-Abdominal Fibromatosis (Desmoid Tumor): A Rare Tumor of the Lower Extremity Arising from the Popliteal Fossa. Desmoid fibromatosis showing fascicular arrangement of bland fibroblasts, which are interrupted by thin-walled, compressed vascular channels resulting in an appearance akin to a hypocellular scar. Note entrapped muscle fibers. No mitotic activity or nuclear pleomorphism is present (H&E, original magnification, 40x). Source: Ali Kaygain M. et al, Department of Cardiovascular Surgery, Erzurum Regional Training and Research Hospital, 25020 Erzurum, Turkey