Desmoid tumor overview

Desmoid tumor Microchapters
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Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Desmoid tumor from other Diseases
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1

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

Overview

Desmoid tumors are the benign tumors that arise from monoclonal proliferation of well-differentiated fibroblasts (which are found throughout the body). Main function of fibroblasts is in wound healing and to provide structural support and protection to the vital organs such as lung, liver, blood vessels, heart, kidneys, skin, intestines. Depending upon the underlying etiology, desmoid tumors can be classified as abdominal, intra-abdominal, extra-abdominal, multiple familial, associated with Gardner syndrome and associated with Turcot syndrome. Desmoids can arise in virtually any part of the body. Desmoids appear as well-differentiated, firm overgrowths of fibrous tissue with marked cellularity and aggressive local infiltration. Histologically, desmoid tumors consist of linearly arranged elongated fibroblasts and myofibroblasts surrounded and separated from each other by collagen. Most common frequent causes of desmoid tumors at molecular level include mutations in the β-catenin gene, CTNNB1, or the adenomatous polyposis coli gene, APC, all involved in Wnt/beta-catenin signaling pathway. Pediatric desmoid tumors have AKT1 E17K, BRAF V600E and TP53 R273H mutations also in addition to CTNNB1 mutations. Desmoid tumors account for approximately 0.03 percent of all neoplasm and less than 3% of all the soft tissue tumors.They are more common in women (of fertile age) than men, and mostly occur in age of 30's to 40's. These tumors can be slow growing or extremely aggressive, musculoaponeurotic tumors without any metastatic potential. When they are aggressive they can cause life threatening problems or even death due to compression of vital organs such as the intestines, kidneys, lungs, blood vessels, and nerves. Common risk factors for desmoid tumors include personal or family history of FAP, Gardner syndrome, Turcot syndrome, female gender, pregnancy, estrogen therapy, history of antecedent surgical or accidental trauma or irradiation at the tumor site, history of breast cancer and androgens.

Desmoids may be diagnosed on an imaging test done for another reason in asymptomatic patients. In symptomatic patients, it can present as a painless or painful mass/lump, insomnia, difficulty moving, nausea, vomiting, anxiety depending upon size and location of tumor. Gold standard for diagnosis is histological examination of a biopsy specimen followed by immunohistochemistry for nuclear beta-catenin. Various imaging studies like CT, MRI, ultrasonography, color doppler, plain radiograph and angiography may aid in further diagnosis and deciding treatment strategy especially for highly recurrent tumors. Wait and watch therapy is applied for treatment of asymptomatic patients. For symptomatic patients various therapeutic options are available such as surgery, radiation therapy, tumor ablation and medical therapy with chemotherapeutic agents, anti-hormonal agents, NSAIDs and tyrosine kinase inhibitors.

Historical Perspective

Muller first coined the term desmoid in 1858 to describe tumors with tendon-like consistency. It origniates from a Greek word "desmos" meaning band or tendon-like. Gradner first described the development of desmoid tumors in FAP patients in 1951.

Classification

Depending upon the underlying etiology, desmoid tumors can be classified as abdominal, intra-abdominal, extra-abdominal, multiple familial, associated with Gardner syndrome and associated with Turcot syndrome.

Pathophysiology

Desmoid tumors are benign tumors arising 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-catenin signaling 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 tissue with 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.

Causes

The exact etiology of desmoid tumors is unknown. However, Wnt/beta-catenin signaling pathway, APC mutations, CTNNB1 (beta-catenin) gene mutations, sporadic tumors and trisomy 8 and trisomy 20 seem to play a role in development of sporadic desmoids in adults. Familial desmoids in FAP patients are associated with germline APC mutations. Pediatric desmoids have AKT1 E17K, BRAF V600E and TP53 R273H mutations in addition to CTNNB1 mutations.

Differentiating Desmoid tumor from other Diseases

Extra-abdominal desmoid tumor must be differentiated from fibrosarcoma, low-grade fibromyxoid sarcoma and Gardner fibroma. Intra-abdominal desmoid tumor must be differentiated from gastrointestinal stromal tumor (GIST), benign fibrous tumor/solitary fibrous tumor (SFT), inflammatory myofibroblastic tumor (IMT), sclerosing mesenteritis and retroperitoneal fibrosis. Furthermore, generally all desmoid tumors must be differentiated from acute hematoma, lymphoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, neurofibroma, nodular fasciitis, hypertrophic scars,keloids and primitive neuroectodermal tumor.

Epidemiology and Demographics

Desmoid tumor accounts for 0.03% of all tumors and less than 3% of all the soft tissue tumors. It affects 1 to 2 per 500,000 people worldwide. Incidence of desmoid tumor is approximately two to four per million population per year in general population. Familial desmoids are present in 10% to 25% of FAP patients. Gender ratio is 2:1 for females to males and commonly affects individuals between 20 to 60 years of age.

Risk Factors

Common risk factors for the development of desmoid tumor include personal or family history of familial adenomatous polyposis (FAP), Gardner syndrome, Turcot syndrome, specific location of APC (adenomatous polyposis coli) gene mutation i.e. 3' of codon 1444, family history of desmoid tumor, estrogen therapy, oral contraceptive pills, pregnancy, history of antecedent surgical or accidental trauma or repeated irradiation at the tumor site, female gender and androgens.

Natural History, Complications and Prognosis

Desmoids can develop virtually at any site of body causing wide range of clinical symptoms depending on size and tumor location or they can cause no symptoms at all. They may be accidentally picked up on a scan or a routine physical examination done for other medical reasons. They might grow aggressively or slowly or remian stable, hence, exhibiting wide range of behaviors in different individuals. Common complications of desmoid tumor include progression to agressive fibromatosis, involvement of intra-abdominal viscera that may lead to rupture of intestines, compression of the kidneys or ureters, rectal bleeding, compression of critical blood vessels such as the mesenteric vessels and the vena cava, amputation and loss of significant portions of foregut post-surgery. Five-year progression-free survival rate is 50% in patients with a primary or recurrent desmoid who are not treated initially with surgery, radiotherapy (RT), or systemic therapy. Massive and inoperable desmoids have become an important cause of morbidity and mortality in FAP patients post-colectomy. Desmoid tumor associated with FAP has the least favorable prognosis due to high recurrence rate. Whereas, non-FAP-associated intra-abdominal fibromatosis has a low recurrence rate after surgical resection.

Diagnostic study of choice

Definitive diagnosis of a desmoid tumor can only be established by histological examination of a biopsy specimen. Electron microscopy can be done which shows spindle cells of desmoids appearing as myofibroblasts.

History and Symptoms

Depending on size, location and spread of tumor, patients may remain asymptomatic for long time period or may show symptoms like painless/painful lump appearning as a swelling in affected area, nausea, vomiting, anxiety, loss of sleep, pain or soreness caused by compressed nerves or muscles, limping and decreased movement or range of motion or other difficulty using the legs, feet, arms or hands or other affected part of the body. Intra-abdominal desmoids can present with abdominal pain, abdominal mass, constipation due to intestinal obstruction, bowel ischemia, functional deterioration in an ileoanal anastomosis (especially in post-colectomy FAP patient), bloating, rupture of intestine, compression of the kidneys or ureters, rectal bleeding, and compression of critical blood vessels such as the mesenteric vessels and the vena cava.

Physical Examination

Common physical examination findings of desmoid tumor include lump or swelling in the affected area, abdominal tenderness, pallor, and elevated temperature.

Laboratory findings

Immunohistochemical staining of spindle cells of desmoid tumors are positive for nuclear beta-catenin, vimentin, alpha smooth muscle actin, muscle actin and negative for desmin, cytokeratins, and S-100. Antibodies like smooth muscle actin, desmin and KIT may be helpful in distinguishing desmoid tumors from other tumors. In addition, APC germline mutations may be performed in patients with sporadic desmoid tumors with no clinical or famililal signs of FAP but having a family history of colorectal carcinoma in at least one family member.

CT

CT scan can be done in order to define the relationship of desmoid tumor to adjacent structures, assess resectibility and find out the need for treatment. On CT scan, desmoid tumor is characterized by a homogeneously or focally hyperattenuating well circumscribed mass which may demonstrate enhancement following administration of intravenous contrast.

MRI

MRI is preferred over CT, especially for truncal and extremity desmoid tumors. On MRI, desmoid tumor has variable characteristics depending on their cellularity and fibrous content with loss of signal following fat saturation. They appear isointense/hypointense on T1 and hyperintense on T2.

Other Imaging Findings

Other imaging studies for the diagnosis of desmoid tumor include ultrasonography, which demonstrates tumor size and location. On ultrasonography, desmoid tumors appear as well-defined lesions with variable echogenicity, and ill defined/irregular borders. On color Doppler, desmoids appear like muscles, may be lobulated and may show vascularity. Plain radiographs and angiography may be of diagnostic help in some cases.

Medical Therapy

Wait and watch strategy is applied to desmoid tumors which are asymptomatic, unresectable, non-life threatening, not causing any significant impairment, and resectable tumors with increased morbidity associated with surgery.Different drugs including chemotherapeutic agents, NSAIDs, anti-hormonal agents and tyrosine kinase inhibitors can be used to shrink or stabilize the tumor size and to improve the symptoms. Radiation therapy and tumor ablation with heat, cold, microwave and/or high-frequency ultrasound waves can also be of therapeutic use as required.

Surgery

The goals of surgery include tumor removal and functional restoration at the tumor site. Standard surgical goal is wide local excision with a grossly negative microscopic margin followed by reconstruction of defect with skin graft, rotational muscle flap or free muscle flap. Abdominal wall resection may be required to close the defect and minimize the risk of hernias. Incomplete tumor removal or involved excision margins may lead to local recurrence in 25% to 40% of patients. Hence, because of high recurrence risk post-surgery, imaging of the tumor site with ultrasound or MRI scans may be recommended to closely monitor patient’s health on follow up visits after surgery.

Future or investigational therapies

Angiogenesis inhibitors and different chemotherapy agents are under investigation nowadays which might prove fruitful for treatment of desmoid tumors in future. Furthermore, mutational analysis for beta-catenin gene may soon be used to predict the recurrence risk and to aid in designing the individual therapies.