Continuing Education Activity

Desmoid tumors , also known as aggressive fibromatosis, are mesenchymal neoplasms that are considered to be locally invasive but do not metastasize. Despite their lack of metastasizing, they are quite destructive locally and often require resection. This activity reviews the evaluation, and treatment of desmoid tumors, and highlights the role of the healthcare team in evaluating and treating managing patients with this condition.

Objectives:

• Review the clinical presentation of a patient with desmoid tumor.
• Review the pathological findings and imaging characteristics of desmoid tumors
• Review the treatment approaches for desmoid tumors.
• Describe how an optimally functioning interprofessional team would coordinate care to enhance outcomes for patients with desmoid tumors.

Introduction

Desmoid tumors (DT) are mesenchymal neoplasms that are considered locally invasive but non-metastasizing. [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. The management of DT is challenging and requires a discussion at a multidisciplinary tumor board (MTB). DT is primarily treated with surgery with or without radiation therapy (RT). Despite surgical resection, DT have a high rate of local recurrence, and hence, they have been labeled as intermediate locally aggressive tumors by World Health Organization (WHO).[4] According to the WHO, DT 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 chemotherapy is used in patients where surgery and RT are either not feasible or will not achieve a cure.

Etiology

The etiology of DT is unknown. Most DT occurs sporadically, and 85% have a mutation in the CTNNB1 encoding beta-catenin pathway. The three 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 was 23% for 45F, 57% for 41A, and 68% for no mutation. Desmoid tumor is seen at increased frequency in familial adenomatous polyposis (FAP), mostly abdominal FAP caused by a mutation in the APC gene. DT 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, DT is the more important cause of morbidity and mortality than colon cancer. The DT occurs with increased frequency in the female during or after pregnancy, and anecdotal evidence suggests abdominal wall trauma and high estrogen states are the possible reason. Pregnancy-associated DT have overall better outcomes.

Epidemiology

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

Histopathology

The diagnosis of DT must be reviewed by an expert soft-tissue pathologist. Histologically, DT is characterized by the proliferation of uniform spindle cells resembling myofibroblasts, in the background of abundant collagenous stroma and vascular network.[11] Other features like hyperchromasia and cellular atypia are not present usually. The tumor cells are similar to the myofibroblasts, as seen during the proliferative stage of wound healing. Cells may have nuclei containing euchromatin of heterochromatin.[12] 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, DT stains positive for nuclear beta-catenin, vimentin, cyclooxygenase-2, tyrosine kinase PDGFRb, androgen receptor, and estrogen receptor beta. DT stains negative for desmin, S-100, h-caldesmon, CD34, and c-KIT.[12] Nuclear beta-catenin positivity supports the diagnosis of DT. However, a negative stain does not exclude DT. 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 DT, extensive clinical workup should be pursued to rule out FAP syndrome. 

History and Physical

DT has a varied pattern of clinical presentation, characterized by a slow-growing tumor, that can stabilize and can even undergo spontaneous remission. DT commonly occurs in the rectus abdomins muscle, head and neck region, pelvis, and in the extremities. DT 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 can be associated with surgery or implants. One in four cases has a history of trauma or surgery at the site of desmoid. DT also has a propensity to recur in the same area causing a lot of local destruction; however, it has no capacity to metastasize. Patients with FAP are at a much higher risk of developing DT (Up to 25% higher than the general population). In patients with DT, 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 certainly mimic cancer of the respective organ (for example; a DT occurring in the breast can mimic breast cancer), hence a biopsy is mandatory to accurately diagnose a DT.

Evaluation

Imaging studies like CT scan and MRI 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. [13][14][15]MRI seems to be more useful than CT scan in helping to establish the extent of tumor and relationship to nearby organs. On T1-weighted images, desmoids are hypo- or isointense to muscle, while on T2-weighted images they are hyperintense. With gadolinium contrast, DT shows moderate enhancement with hypo-intense bands because of collagen bundles.

• 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 with vimentin, alpha-smooth muscle actin, muscle actin, and desmin are helpful in distinguishing the tumors.
• The use of NGS is recommended by most guidelines.

Treatment / Management

DTs are primarily treated through surgery, however, RT and medical therapy have a role to play as well. 

Surgical Treatment: The approach to DT is primarily surgical. The goal of surgery is to preserve the limb function and critical structures. Unlike other soft-tissue sarcomas where the goal of surgical resection is to achieve a microscopic negative margins (R0 resection), an R0 resection is only deemed 'desirable', but not a necessity in the surgery of a DT. 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, guidelines clearly prohibit a morbid surgery in an attempt to achieve an R0 resection. In combination with RT and medical therapy, the surgical treatment of DT has become more and more conservative.

Radiation therapy: RT is primarily used in the adjuvant setting when surgery leaves behind a positive margin, or when surgical resection is not possible. A dose of more than 56 Gy is associated with many complications and hence avoided. Non-randomized 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 RT is not established and currently not recommended.

Systemic Therapy: Systemic therapy is usually reserved for patients who experience rapid growth of DT or for those patients in whom the tumor is threatening a critical structure or the surgery would be extremely mutilating. 

1. Chemotherapy: DT is not a very chemosensitive tumor, however, few regimens may benefit patients.

   1. 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 DT associated with FAP, the addition of NSAID (like meloxicam) has been found to be beneficial. Liposomal doxorubicin is also an effective drug inducing long-lasting responses in many patients. 
   2. Vinca alkaloids with methotrexate (MTX): In the pediatric population, the combination of vinblastine and MTX 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 MTX.
2. Targeted therapy:

   1. Imatinib (800mg PO daily) has been successfully used in patients with DT. 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. 
   2. Sorafenib is the other drug that has shown some benefit.
3. Hormonal therapy: Considering the fact that DT can occur around the time of pregnancy, hormonal therapy like Tamoxifen has been explored and found to be useful. A higher dose of tamoxifen (120-200 mg/day, the conventional dose is 40mg/day) is advocated, however, no controlled studies exist. 
4. Non-steroidal anti-inflammatory drugs: Since COX-2 pathways are involved in the growth of DT, COX-2 inhibitors like indomethacin, sulindac, and meloxicam have been proven to induce remission in patients with Dt.

Differential Diagnosis

• Breast cancer

• Dermatological manifestations of Gardner’s syndrome

• Familiar polyposis of the colon

• Fibrosarcoma

• Gastro-Intestinal Stromal Tumor (GIST)

• Inflammatory Myofibroblastic Tumor (IMT)

• Retroperitoneal fibrosis

• Sclerosing mesenteritis

• Solitary Fibrous Tumor (SFT)

Enhancing Healthcare Team Outcomes

Desmoids may occasionally be encountered by the nurse practitioner, primary care provider or the internist. Because the diagnosis and treatment is complex, it is important to consult with an oncologist, pathologist, and a radiologist. The treatment of desmoid can be divided broadly into asymptomatic resectable, symptomatic resectable, unresectable, and recurrent desmoids. These lesions do not normally respond well to chemotherapy and radiation and surgery is the only treatment. However, recurrences are common. The prognosis for most patients is guarded.[16][17][5] (Level V)

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries [Internet]. National Cancer Institute (US); Bethesda (MD): Dec 7, 2022. Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version. [PubMed: 26389361]

2.

Wang Z, Wu J, Lv A, Tian X, Hao C. En bloc resection for intra-abdominal/retroperitoneal desmoid-type fibromatosis with adjacent organ involvement: A case series and literature review. Biosci Trends. 2018;12(6):620-626. [PubMed: 30674762]

3.

Cassidy MR, Lefkowitz RA, Long N, Qin LX, Kirane A, Sbaity E, Hameed M, Coit DG, Brennan MF, Singer S, Crago AM. Association of MRI T2 Signal Intensity With Desmoid Tumor Progression During Active Observation: A Retrospective Cohort Study. Ann Surg. 2020 Apr;271(4):748-755. [PMC free article: PMC6736761] [PubMed: 30418203]

4.

Ganeshan D, Amini B, Nikolaidis P, Assing M, Vikram R. Current Update on Desmoid Fibromatosis. J Comput Assist Tomogr. 2019 Jan-Feb;43(1):29-38. [PMC free article: PMC6331223] [PubMed: 30211798]

5.

Timbergen MJM, van de Poll-Franse LV, Grünhagen DJ, van der Graaf WT, Sleijfer S, Verhoef C, Husson O. Identification and assessment of health-related quality of life issues in patients with sporadic desmoid-type fibromatosis: a literature review and focus group study. Qual Life Res. 2018 Dec;27(12):3097-3111. [PMC free article: PMC6244798] [PubMed: 30014458]

6.

Couto Netto SD, Teixeira F, Menegozzo CAM, Leão-Filho HM, Albertini A, Ferreira FO, Akaishi EH, Utiyama EM. Sporadic Abdominal Wall Desmoid type Fibromatosis: treatment paradigm after thirty two years. BMC Surg. 2018 Jun 07;18(1):37. [PMC free article: PMC5992671] [PubMed: 29879959]

7.

Nieuwenhuis MH, Casparie M, Mathus-Vliegen LM, Dekkers OM, Hogendoorn PC, Vasen HF. A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int J Cancer. 2011 Jul 01;129(1):256-61. [PubMed: 20830713]

8.

de Camargo VP, Keohan ML, D'Adamo DR, Antonescu CR, Brennan MF, Singer S, Ahn LS, Maki RG. Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer. 2010 May 01;116(9):2258-65. [PMC free article: PMC2925106] [PubMed: 20187095]

9.

Fiore M, MacNeill A, Gronchi A, Colombo C. Desmoid-Type Fibromatosis: Evolving Treatment Standards. Surg Oncol Clin N Am. 2016 Oct;25(4):803-26. [PubMed: 27591500]

10.

Desmoid Tumor Working Group. The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020 Mar;127:96-107. [PubMed: 32004793]

11.

Muller E, Castagnaro M, Yandel DW, Wolfe HJ, Alman BA. Molecular genetic and immunohistochemical analysis of the tumor suppressor genes Rb and p53 in palmar and aggressive fibromatosis. Diagn Mol Pathol. 1996 Sep;5(3):194-200. [PubMed: 8866233]

12.

Kotiligam D, Lazar AJ, Pollock RE, Lev D. Desmoid tumor: a disease opportune for molecular insights. Histol Histopathol. 2008 Jan;23(1):117-26. [PubMed: 17952864]

13.

Guttadauro A, Maternini M, Frassani S, Guanziroli E, Lo Bianco G, Gabrielli F. Desmoid tumor of the abdominal wall A case report and literature review. Ann Ital Chir. 2017 Nov 20;6 [PubMed: 29424372]

14.

Asadoorian M, Matcuk GR, Patel DB, Tomasian A, Wassef HR, White EA. Musculoskeletal Pitfalls on Fluorodeoxyglucose F 18 PET-Computed Tomography: Pictorial Review. PET Clin. 2018 Oct;13(4):587-607. [PubMed: 30219190]

15.

Attanoos RL, Pugh MR. The Diagnosis of Pleural Tumors Other Than Mesothelioma. Arch Pathol Lab Med. 2018 Aug;142(8):902-913. [PubMed: 30040453]

16.

Bishop AJ, Zarzour MA, Ratan R, Torres KE, Feig BW, Wang WL, Lazar AJ, Moon BS, Roland CL, Guadagnolo BA. Long-Term Outcomes for Patients With Desmoid Fibromatosis Treated With Radiation Therapy: A 10-Year Update and Re-evaluation of the Role of Radiation Therapy for Younger Patients. Int J Radiat Oncol Biol Phys. 2019 Apr 01;103(5):1167-1174. [PubMed: 30552963]

17.

Turner B, Alghamdi M, Henning JW, Kurien E, Morris D, Bouchard-Fortier A, Schiller D, Puloski S, Monument M, Itani D, Mack LA. Surgical excision versus observation as initial management of desmoid tumors: A population based study. Eur J Surg Oncol. 2019 Apr;45(4):699-703. [PubMed: 30420189]