Continuing Education Activity

Desmoid tumor, a rare malignancy of mesenchymal origin, affects a small proportion of the population with an incidence of 2 to 4 patients per million. Also known as "aggressive fibromatosis" or "desmoid-type fibromatosis," these tumors primarily impact the younger age group. Despite the absence of metastasis, desmoid tumors exhibit local invasion, leading to severe morbidity. The association with the APC gene mutation can result in multifocal DTs, occasionally leading to mortality.

The management of desmoid tumors poses a significant challenge due to the lack of a standard treatment approach. Although watchful observation is recommended for asymptomatic desmoid tumors (20% can regress spontaneously), surgical resection has fallen out of favor due to high rates of recurrence. Systemic treatment options have increased with the recent approval of gamma-secretase inhibitor nirogacestat. This activity describes the epidemiology, genetics, clinical presentation, and management of desmoid tumors, providing healthcare professionals with the knowledge and tools necessary to improve patient care for this rare yet complex tumor.

Objectives:

• Identify the signs and symptoms of desmoid tumors and interpret the radiologic and pathologic findings. 

• Screen for associated genetic mutations and identify hereditary syndromes. 

• Select appropriate systemic treatment for patients with desmoid tumors.

• Collaborate with all interprofessional team members, including specialists such as surgical oncologists, orthopedic oncologists, sarcoma pathologists, radiologists, and pharmacists, to provide efficient, comprehensive, and coordinated care to patients diagnosed with desmoid tumors.

Introduction

Desmoid tumors are mesenchymal neoplasms that are considered locally invasive but nonmetastasizing.[1][2][3] They are also known as aggressive fibromatosis, deep fibromatosis, and musculoaponeurotic fibromatosis. Even though they do not metastasize, they are locally invasive and cause significant morbidity and mortality. There is no standard approach to treating desmoid tumors; managing them is challenging and requires discussion at a multidisciplinary tumor board. 

Despite surgical resection, desmoid tumors have a high rate of local recurrence; accordingly, they have been labeled as intermediate locally aggressive tumors by the World Health Organization (WHO).[4] According to WHO, desmoid tumor is a "clonal fibroblastic proliferation that arises in the deep soft tissues and is characterized by infiltrative growth and a tendency toward local recurrence but an inability to metastasize," even though it may be multifocal in the same limb or body part. Systemic treatment is used in patients where surgery and radiation therapy are either not feasible or will not achieve a cure. Recently, several new drugs have been licensed by the United States Food and Drug Administration (FDA) to treat patients with DT.

Etiology

The etiology of desmoid tumor is unknown. Most desmoid tumors occur sporadically, and 85% have a mutation in the CTNNB1 encoding ß-catenin pathway. The 3 distinct mutations identified are 41A, 45F, and 45. Mutation 45F is associated with a high risk of recurrence.[4][5][6] The 5-year recurrence-free survival rate has been reported to be 23% for patients with a 45F mutation, 57% for patients with a 41A mutation, and 65% for those with no mutations.

Desmoid tumor is seen at increased frequency in familial adenomatous polyposis (FAP), mostly abdominal FAP caused by a mutation in the APC gene. Desmoid tumor arising in FAP has a predilection for the prior surgical site, and previous surgery is a risk factor. In patients who are treated with prophylactic colectomy, desmoid tumor is the more important cause of morbidity and mortality than colon cancer. Desmoid tumor occurs with increased frequency in females during or after pregnancy, and anecdotal evidence suggests abdominal wall trauma and high estrogen states are the possible reasons. Pregnancy-associated desmoid tumor has overall better outcomes.

Epidemiology

Desmoid tumor is a rare tumor, with a reported incidence of 2 to 4 patients per million, and accounts for 0.03% of all neoplasms.[7] The peak age of occurrence is 30 to 40 years. It occurs more commonly in women compared with men and most often between the ages of 15 and 60 years.[8][9] DT may occur at abdominal, intra-abdominal, and extra-abdominal locations.[9] Approximately 5% to 10% arise in the context of FAP.[10]

Pathophysiology

The pathophysiology of desmoid tumor lies in the dysregulation of the Wnt pathway. Mutation in the ß-catenin gene or germline mutation in the adenomatous polyposis coli (APC) gene leads to the accumulation of the β-catenin protein; in turn, β-catenin is translocated to the nucleus and activates the expression of the Wnt gene. Subsequently, several proteins, including cyclo-oxygenase 1 (COX-2) and vascular endothelial growth factor, are produced, leading to tumor growth. These proteins are also the target of some medicines used in treating desmoid tumor.[11]

Histopathology

The diagnosis of desmoid tumor must be reviewed by an expert soft-tissue pathologist. Histologically, desmoid tumor is characterized by the proliferation of uniform spindle cells resembling myofibroblasts in the background of abundant collagenous stroma and the vascular network.[12] Other features like hyperchromasia and cellular atypia are not usually present. The tumor cells are similar to the myofibroblasts, as seen during the proliferative stage of wound healing, and may have nuclei containing euchromatin or heterochromatin.[13] Large amounts of the myxoid stroma may be seen in some tumors, especially those that develop in the mesentery. On microscopy, the tumor may appear like a low-grade fibrosarcoma, but the cells lack the nuclear atypia and typical cytoplasmic features of malignancy.

On immunohistochemistry, desmoid tumor stains positive for nuclear ß-catenin, vimentin, COX-2, tyrosine kinase PDGFRB, androgen receptor, and estrogen receptor beta. Desmoid tumor stains negative for desmin, S-100, h-caldesmon, CD34, and c-KIT.[13] Nuclear ß-catenin positivity supports the diagnosis of desmoid tunmor. However, a negative stain does not exclude desmoid tumor.

Next-generation sequencing must be done to evaluate for CTNNB1 mutations. The CTNNB1 and APC mutations are mutually exclusive. Hence, the detection of one can virtually exclude the other. In patients that are CTNNB1 wild-type, especially for intra-abdominal desmoid tumor, extensive clinical workup should be pursued to rule out FAP syndrome (also known as Gardner's syndrome). 

History and Physical

Desmoid tumor has a varied pattern of clinical presentation, characterized by a slow-growing tumor that can stabilize and even undergo spontaneous remission. Desmoid tumor commonly occurs in the rectus abdomens muscle, head and neck region, pelvis, and extremities. Desmoid tumor is also known to occur in association with pregnancy and with the use of oral contraceptive pills, and it is known to regress with menopause, indicating a potential influence of the female sex hormonal environment. Breast desmoid tumors can be associated with surgery or implants. One in 4 cases has a history of trauma or surgery at the site of the desmoid tumor. Desmoid tumor also tends to recur in the same area, causing local destruction; however, it cannot metastasize.

In patients with multiple desmoid tumors, it is considered to be a "multifocal" disease rather than a metastatic disease. Patients with FAP are at a much higher risk of developing desmoid tumors (up to 25% higher than the general population). In patients with desmoid tumors, FAP can be diagnosed in up to 5% of patients. The peak incidence is in the late second decade of life, although it can occur at any age. The physical exam is usually benign unless the tumor causes pressure symptoms. They can undoubtedly mimic cancer of the respective organ (for example, a desmoid tumor occurring in the breast can mimic breast cancer); hence, a biopsy is mandatory to accurately diagnose a desmoid tumor.

Evaluation

Imaging Studies

Imaging studies like CT scans and MRIs can be done during diagnosis and follow-up. Imaging can determine the extent of the tumor, which organs are infiltrated, and a surgical resection plan.[14][15][16] An MRI seems more useful than a CT scan in helping to establish the extent of the tumor and its relationship to nearby organs. On T1-weighted images, desmoids are hypo- or isointense to muscle, whereas T2-weighted images are hyperintense. With gadolinium contrast, DT shows moderate enhancement with hypo-intense bands because of collagen bundles.

Histological Evaluation

Histological evaluation is needed to confirm the diagnosis. An incisional biopsy is preferred, but a careful biopsy may be sufficient. Histological features are as previously described in histopathology.

Immunostaining

Immunostaining with vimentin, alpha-smooth muscle actin, muscle actin, and desmin helps distinguish the tumors.

Next-Generation Sequencing

Most guidelines recommend the use of next-generation sequencing to identify druggable targets. 

Colonoscopy and Genetic Assessment

Desmoid tumor is more common in adolescents and young adults. Its association with FAP syndrome needs a thorough evaluation with colonoscopy and genetic assessment in patients who first present with desmoid tumors. 

Treatment / Management

There is no standard approach to managing desmoid tumor. Most experts recommend watchful observation in asymptomatic patients. In symptomatic patients, several treatment approaches have been proposed. Surgical resection has taken a backseat in the management of desmoid tumor due to high recurrence rates and morbid resections. Medical management has advanced significantly in the last 2 decades.[10] 

Surgical Treatment

Surgery aims to preserve the limb function and critical structures. Unlike other soft-tissue sarcomas, where surgical resection aims to achieve microscopic negative margins (R0 resection), an R0 resection is only deemed "desirable" but not a necessity in the surgery of a desmoid tumor. The significance of a positive margin (R1 or R2 resection) is highly debated. Positive margins after surgery have been reported as an independent prognostic factor in determining the risk of recurrence. However, a morbid surgery in an attempt to achieve an R0 resection is not indicated. In combination with radiation and medical therapies, the treatment of desmoid tumor has become more conservative.

Radiation Therapy

Radiation therapy is primarily used in the adjuvant setting when surgery leaves behind a positive margin, or surgical resection is impossible. A dose of more than 56 Gy is associated with many complications and hence avoided. Nonrandomized and retrospective data have shown a lower local recurrence rate with the addition of adjuvant RT in patients with a positive margin. The role of neoadjuvant radiation therapy has not been established and is currently not recommended.

Systemic Therapy

Systemic therapy is usually reserved for patients who experience rapid growth of a desmoid tumor, or for those patients in whom the tumor is threatening a critical structure (otherwise the surgery would be highly mutilating). 

Chemotherapy

Desmoid tumor is not a chemosensitive tumor; however, few regimens may benefit patients.

Doxorubicin-based Regimens

Doxorubicin-based regimens have had the best success rates. The combination of doxorubicin and dacarbazine has been shown to induce a partial response. Typically, the response in the tumor is slow and may occur for months after chemotherapy has been stopped. In patients with desmoid tumor associated with FAP, the addition of nonsteroidal antiinflammatory drugs (like meloxicam) is beneficial. Liposomal doxorubicin is also an effective drug, inducing long-lasting responses in many patients. 

Vinca Alkaloids With Methotrexate 

In the pediatric population, the combination of vinblastine and methotrexate has been found beneficial; however, this combination is very toxic for adults. Hence, in adults, vinblastine is substituted for vinorelbine and is given along with methotrexate.

Targeted Therapy

Imatinib

Imatinib (800 mg daily) has been successfully used in patients with desmoid tumor. However, no definite mechanism or pathway of action is known. Even those patients without any mutation in the KIT, PDGRA, or PDGFRB regions showed a response. 

Sorafenib 

Sorafenib (400 mg daily) was explored in a phase III randomized, double-blinded trial against a placebo and was found to significantly prolong progression-free survival (hazard ratio for progression or death, 0.13; 95% CI, 0.05-0.31; P<0.001). The objective response rate was 33% in the sorafenib group compared with 20% in the placebo group. Rash, hypertension, diarrhea, and fatigue were the most common grade 3 or higher adverse events.[17] 

Nirogacestat 

Nirogacestat (150 mg twice a day) is the first gamma-secretase inhibitor granted full USFDA approval for patients with DT whose tumors are progressing. Nirogacestat was studied in a phase III, double-blinded randomized control trial against a placebo. The drug was approved based on the significant benefit of the progression-free survival (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15-0.55; P<0.001), response rate (41% versus 8%, P<0.001) and a significant reduction in pain, symptoms burden, physical and functional role. Diarrhea, nausea, fatigue, and rash were amongst the significant grade 3 or higher adverse events.[18] 

Hormonal Therapy

Hormonal therapy is usually prescribed in combination with nonsteroidal anti-inflammatory drugs (COX-2 inhibitors). However, this approach to the treatment of desmoid tumor has fallen out of favor and is no longer recommended. 

Differential Diagnosis

Differential diagnoses for desmoid tumor include:

• Breast cancer

• Dermatological manifestations of Gardner’s syndrome

• Familiar polyposis of the colon

• Fibrosarcoma

• Gastrointestinal stromal tumor 

• Inflammatory myofibroblastic tumor 

• Retroperitoneal fibrosis

• Sclerosing mesenteritis

• Solitary fibrous tumor 

Prognosis

Desmoid tumors do not cause mortality except when associated with FAP syndrome; however, they are associated with high morbidity due to local destruction. Additionally, up to 20% of patients can experience spontaneous remission of the tumors. Hence, it is essential to consider each patient on a case-by-case basis. Surgical resection is now avoided due to morbid resections, which are often futile due to high recurrence rates. 

Complications

Most complications from desmoid tumor arise due to local compression of the neurovascular structures or invasion of the neighboring viscera or bones. Symptoms occur depending on which part of the body is involved. Slow-growing desmoid tumors (<10% growth in 3 months by imaging) can be observed, especially if asymptomatic. Patients presenting with significant symptoms of pain, deformity, or neurovascular compromise may need to be initiated on treatment sooner rather than later. 

Deterrence and Patient Education

Patients and healthcare professionals must appreciate the rarity of desmoid tumors. The diagnosis and treatment pose a particular challenge to the clinician due to the lack of a standard approach. Although the word "tumor" creates a general sense of alarm among patients, healthcare professionals must emphasize the peculiar nature of desmoid tumor and the low mortality associated with this type of tumor. The need for genetic counseling and screening colonoscopy, especially in adolescents and young adults, must be discussed. Finally, all patients should receive encouragement to participate in clinical trials.

Pearls and Other Issues

Pearls for healthcare professionals:

• Desmoid tumors do not metastasize (although they can be multifocal).
• Eighty-five percent of desmoid tumor cases are sporadic.
• DT is associated with low mortality but high morbidity.
• Observation is recommended in all patients with slow-growing desmoid tumors (<10% growth in 3 months on imaging). Up to 20% of patients will experience spontaneous remission.
• Surgical resection is no longer the preferred treatment due to high recurrence rates despite a morbid resection. 
• Systemic treatment with chemotherapy is not preferred due to the demonstrated efficacy of targeted therapy. 
• Sorafenib is a multikinase tyrosine kinase inhibitor with demonstrated progression-free survival benefit in patients with desmoid tumor requiring systemic therapy (typical dose: 400 mg daily). 
• Nirogacestat is the first gamma-secretase inhibitor to receive approval from the FDA for patients with desmoid tumor requiring systemic therapy (typical dose: 150 mg twice a day). 

Enhancing Healthcare Team Outcomes

Desmoid tumors are usually detected as a solitary mass in a patient presenting to the emergency room with symptoms of pain or in the office of a primary care physician. Because the diagnosis and treatment are complex, consulting with an oncologist, pathologist, and radiologist is important. The treatment of desmoid tumor can be divided broadly into asymptomatic resectable, symptomatic resectable, unresectable, and recurrent desmoids. A multidisciplinary discussion is essential to guide the treatment and prevent morbidity. Surgical resections are avoided due to high morbidity and high recurrence rates. Pharmacists and nurses play a critical role in managing the toxicities of the various systemic treatments. DT is associated with low mortality and high morbidity. The genetics team needs to be involved in the care of young patients.[19][20][5]