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LC is a 59-year-old male with history of pre-diabetes and GERD who presented to his primary care physician in Durango for his annual exam. At that visit, he complained of intermittent constipation, but had an otherwise negative review of systems. His was referred for a colonoscopy. He had no prior screening colonoscopies. His colonoscopy was remarkable for multiple polyps and a rectosigmoid mass. The polyps were found to be tubular adenomas and the rectosigmoid mass biopsy showed “submucosal spindle cell proliferation.” A CT scan showed circumferential wall thickening of a six-centimeter long segment of the rectosigmoid junction. He was admitted for an exploratory laparotomy. The surgeons found no tumor in the rectosigmoid colon, but when creating a rectal-sacral space, they encountered “more than a golf ball sized mass.” It was biopsied, but further resection was aborted due to disease extent. The biopsy was consistent with a spindle cell tumor and his care was transferred to UC Health.
His case was presented at the multidisciplinary conference and was suspected to be a desmoid tumor. Since the patient was largely asymptomatic, his care plan involved serial MRI imaging to monitor tumor progression. Over the course of the next few months, his constipation gradually worsened and his appetite started to decrease. He was started on sorafenib chemotherapy, but had significant nausea and vomiting, which became intolerable. Seven months after his initial diagnosis, the patient presented to his primary care provider in severe distress with intractable abdominal pain and no bowel movement for the previous week. He was sent to the ED and found to have a partial bowel obstruction with left hydronephrosis. He was transferred back to UC Health and admitted for colonic diversion and ureteral decompression.
Upon admission, the patient was prescribed oxycodone 5 mg q4 PRN and cyclobenzaprine for his abdominal pain. Anesthetic assessment classified the patient as ASA 2, based on his BMI of 37. Opening of the patients mouth allowed visualization of the entire soft palate, so he scored a Mallampati 1. The patient had previously required a video glidescope and rapid sequence intubation. The patients first operation for ureteral decompression was done under general anesthesia. He was given midazolam and fentanyl prior to induction. Lidocaine was injected for local anesthesia, then propofol and rocuronium. He was pre-oxygenated for two minutes and intubated using direct laryngoscopy with MAC. Sevoflurane was used for maintenance. Total anesthetic time was 86 minutes. His second operation for colonic diversion was also done under general anesthesia. The patient received metronidazole and cefazolin 20 minutes prior to the procedure. He was given midazolam and fentanyl, induced with propofol, relaxed with rocuronium, and intubated using a C-MAC. During the case he required blood pressure support with phenylephrine. Both desflurane and sevoflurane were used for anesthetic maintenance. 20mL of 0.25% bupivacaine was injected around the surgical incision prior to extubation. Total anesthetic time was 368 minutes.
On his second day of admission, the patient was taken to the OR for a cystoscopy, left retrograde pyelogram, and left ureteral stent placement. First, the bladder and ureters were evaluated for evidence of tumors and none were noted. Then, the left ureteral orifice was cannulated and a retrograde pyelogram was performed. He had a narrow-caliber distal ureter indicative of longstanding obstruction. A wire was advanced with a ureteral catheter under fluoroscopic guidance to the left renal pelvis and a pyelogram was performed to identify the renal anatomy, which was tortuous. A 5-French stent was placed along the wire and deployed. The stent position was verified and the cystoscope withdrawn.
On hospital day five, the patient returned to the operating room for the Hartmann procedure with end descending colostomy creation and debulking of his pelvic tumor. The descending and sigmoid colon were dissected and mobilized. The sigmoid colon was stapled and divided. The tumor extended from the sacrum into the mesorectum and left ureter. It was dissected using scissors and electrocautery. There was gross tumor left behind, classifying this dissection as R2. Curative resection was not attempted because of the local invasion into sacral nerves and vasculature, and the risks were felt to outweigh the benefits. The left ureter was re-implanted into the bladder. A descending colostomy was created using interrupted 3-0 chromic sutures. A 10mm JP drain was placed into the area of anastomosis between the ureter and the bladder. The fascia was closed with #1 PDS and the skin closed with stables. A 24-French Malecot drain was inserted into the rectal stump and sutured with 0 vicryl.
The patient recovered as an inpatient over the following two weeks. His post-operative course was complicated by fevers, which were attributed to a UTI and positive blood cultures. The infectious disease team managed his antibiotic regimen. A pelvic fluid collection was drained by interventional radiology. He was discharged 18 days after admission on oral antibiotics with strict return precautions. His final pathology report was still pending at the time of discharge.
1. How is the diagnosis of aggressive fibromatosis (desmoid tumor) made?
Given the breadth of possibilities of soft tissue tumors and the overlap in morphology, the diagnosis of a desmoid tumor can be challenging. Many of the soft tissue tumors of the abdominal wall have similar clinical presentations, but the distinct subtype should be carefully considered to optimize clinical management and outcomes. Desmoid tumors are often locally aggressive, but are not capable of metastasis. In one review of 320 surgical specimens initially diagnosed as desmoid fibromatosis, 29% were later identified as other reactive and neoplastic soft tissue tumors. Most commonly, the misclassified tumors were actually Gardner fibromas, scar tissue, superficial fibromatosis, nodular fasciitis, and myofibromas. The most reliable method for investigating the type of mesenchymal tumor is immunohistochemistry staining. Positive staining for β-catenin is present in most desmoids and they typically are negative for KIT, DOG1, S100 protein, ALK, and STAT6.
2. What is the pathogenesis of a desmoid tumor?
Desmoid tumors develop from spindle or stellate cells. Gene mutation of the APC/Wnt/β-catenin signaling pathway is the cause of unrestricted tumor growth. This pathway functions to make and degrade β-catenin, which has dual roles in the cell: cell adhesion at adherens junctions and gene transcription in the nucleus.[3-4] In normal physiology, the APC complex tightly regulates the levels of β-catenin by phosphorylating the protein, tagging it for proteasome degradation. The Wnt signaling cascade functions to inhibit that phosphorylation and allow β-catenin to be translocated to the nucleus as an activating transcription factor. Desmoid tumors commonly have a mutation in exon 3 of the β-catenin gene, CTNNB1, which is the protein responsible for phosphorylation. This mutation limits degradation and allows unbridled production of β-catenin. The β-catenin protein accumulates in the nucleus and induces abnormally high DNA transcription. Increased transcription leads to fibroproliferation of the spindle cells.[3-4] Rarely, in tumors associated with familial adenomatous polyposis, one non-functional copy of APC results in similarly unregulated transcription.
3. What is the epidemiology and risk factors of desmoid tumors?
Desmoid tumors are extremely rare with an incidence between two and four per million people per year. They arise from the walls of organs and muscles with between 37-50% occurring in the abdominal region.[6-7] The uterus is the most commonly involved organ. They may also present extra-abdominally in the extremities, pelvis, or chest wall. These tumors most often occur between the ages of 15 and 60, with a median age at diagnosis of 34. There is a three-fold increased incidence in women compared to men, but there is no association with race.[1, 10]
Most desmoid tumors develop from sporadic mutations, however there is a significant association between desmoid tumors and patients with familial adenomatous polyposis (FAP). In contrast to the prevalence of the tumor in the general population of 0.03%, the prevalence in FAP patients is reported as high as 32%.[7-8] When a patient has inherited colonic adenomatosis together with extra-colonic growths such as osteomas, epidermal cysts, fibromas, dental abnormalities, or desmoid tumors, it is referred to as Gardner’s syndrome (GS). FAP and GS are believed to be variants of the same disorder which may be related to gene penetrance, since they arise from the same genetic mutation.
There is an association between desmoid tumors and high estrogen states such the perinatal period. There is some evidence that desmoid fibromatosis is modulated by estrogen, which is corroborated by the tumors clinical response to hormonal therapies, but the exact mechanism is poorly understood. Nearly 50% of desmoid tumors diagnosed in women occur perinatally.
Another possible contributing etiology is preceding trauma to the tumor site. In one study, surgical or penetrating trauma was identified in 28% of patients. This risk factor likely represents a connection between physiologic wound healing and pathophysiologic fibroproliferative disorders.
4. What treatment options are available for desmoid tumors?
Desmoid tumors are characterized by a widely variable disease course. Since the tumors are locally aggressive rather than metastatic, the location of the primary tumor and the symptoms of the patient play a large role in treatment planning.
For patients with tumors that are asymptomatic and non-life-threatening, careful observation with serial imaging is an acceptable treatment.[12-16] Retrospective studies have shown that a conservative approach is both safe and effective. High rates of stable disease without progression make observation the best way to spare patients from the potential morbidities associated with other more aggressive treatment options.
Intervention is indicated for patients if the tumor is causing symptoms, rapidly enlarging, or encroaching on nearby vital anatomical structures. Local treatment options for desmoid tumors include surgical removal or targeted radiotherapy Historically, surgical resection with negative margins was considered the gold standard of care, but the ability to completely remove the tumor is often complicated by anatomic limitations and the infiltrative pattern of the tumor. A positive surgical margin, R1 or R2, is associated with a higher rate of recurrence. Surgery is a therapeutic mainstay, except in cases which the location would result in considerable loss of function or comorbidities. Notably, the benefit of surgery with radiotherapy or radiotherapy alone has actually been shown in retrospective studies to result in superior local control than surgery alone, even when the surgical margins are clear.[12, 18]
When local treatment fails to stop disease progression, systemic treatment may be indicated. Options for systemic treatment include cytotoxic chemotherapy, molecular targeted therapies, NSAIDs, and hormonal therapies. Cytotoxic therapies are typically reserved for rapidly growing or advanced disease because the regimens used have significant side effects and toxicity, leading to neuropathy, pneumonitis, and hepatitis. Anthracycline based chemotherapy has been shown to have the highest response rate.[19-20] Hormonal treatments of desmoid tumors are primarily reported in retrospective studies and case reports and lack data from randomized controlled trials.[12, 21-22] Case reports show cessation of tumor growth on high dose tamoxifen, but without more patient data, it is not considered a first-line therapy. There are case reports demonstrating tumor regression with the use of NSAIDs alone as first line therapy.[23-24] Targeted molecular therapies that have been studied are the tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib. Small retrospective and prospective studies each with between 19-79 patients have reported between 11-26% partial tumor response, 21-80% stable disease, and 36-80% progression-free survival at 6 months.[25-30]
Desmoid tumors are exceptionally rare, and the presentation of an extra-abdominal desmoid tumor in an older male with no past surgical history and no family history of colon cancer is truly an anomaly. His disease course vividly illustrates the often aggressive and locally invasive nature of the tumors; exemplifying that these tumors become problematic by encroaching on nearby anatomy, the ureters and rectum in his case, rather than by metastasizing. The watchful waiting approach to his treatment is common and was appropriate given his initial clinical presentation. Surgical tumor debulking was the necessary next step to manage his tumor-related obstruction. Ultimately, more data is needed to elucidate the most effective treatment regimens for these patients. Unfortunately, these types of studies will be challenging if not impossible since this patient population is so small.
- Stojadinovic A, Hoos A, Karpoff HM, et al. Soft Tissue Tumors of the Abdominal Wall: Analysis of Disease Patterns and Treatment. Arch Surg. 2001;136(1):70–79. doi:10.1001/archsurg.136.1.70
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- Hirota S. Differential diagnosis of gastrointestinal stromal tumor by histopathology and immunohistochemistry. Transl Gastroenterol Hepatol. 2018;3:27. Published 2018 May 12. doi:10.21037/tgh.2018.04.01
- Lazar, AlexanderJF, Shohrae Hajibashi, and Dina Lev. “Desmoid Tumor: From Surgical Extirpation to Molecular Dissection.” Current Opinion in Oncology 21.4 (2009): 352-59. Print.
- Jyrki J. Reitamo, Pekka Häyry, Erkki Nykyri, Erkki Saxen; The Desmoid Tumor. I.: Incidence, Sex-, Age- and Anatomical Distribution in the Finnish Population, American Journal of Clinical Pathology, Volume 77, Issue 6, 1 June 1982, Pages 665–673, https://doi-org.proxy.hsl.ucdenver.edu/10.1093/ajcp/77.6.665
- Mankin, Henry J, Francis J Hornicek, and Dempsey S Springfield. “Extra-abdominal Desmoid Tumors: A Report of 234 Cases.” Journal of Surgical Oncology. 102.5 (2010): 380-84. Web.
- Fallen, Taya, Marcia Wilson, Bruce Morlan, and Noralane M Lindor. “Desmoid Tumors — a Characterization of Patients Seen at Mayo Clinic 1976-1999.” Familial Cancer. 5.2 (2006): 191-94. Web.
- Nieuwenhuis, Marry H, Mariel Casparie, Lisbeth M H Mathus-Vliegen, Olaf M Dekkers, Pancras C W Hogendoorn, and Hans F A Vasen. “A Nation-wide Study Comparing Sporadic and Familial Adenomatous Polyposis-related Desmoid-type Fibromatoses.” International Journal of Cancer. 129.1: 256-61. Web.
- Fotiadis C, Tsekouras D, Antonakis P, Sfiniadakis J, Genetzakis M, Zografos G. Gardner’s syndrome: A case report and review of the literature. World J Gastroenterol 2005; 11(34): 5408-5411
- Fiore, Marco, et al. “Desmoid-Type Fibromatosis and Pregnancy.” Annals of Surgery 259.5 (2014): 973-78. Print.
- Lopez, R., et al. “Problems in Diagnosis and Management of Desmoid Tumors.” Am J Surg 159.5 (1990): 450-3. Print.
- Martínez Trufero, J., Pajares Bernad, I., Torres Ramón, I. et al. Curr. Treat. Options in Oncol. (2017) 18: 29. https://doi-org.proxy.hsl.ucdenver.edu/10.1007/s11864-017-0474-0
- Penel, N., et al. “Surgical Versus Non-Surgical Approach in Primary Desmoid-Type Fibromatosis Patients: A Nationwide Prospective Cohort from the French Sarcoma Group.” Eur J Cancer 83 (2017): 125-31. Print.
- Briand, S., et al. “Wait-and-See Policy as a First-Line Management for Extra-Abdominal Desmoid Tumors.” J Bone Joint Surg Am 96.8 (2014): 631-8. Print.
- Park, J. S., et al. “Conservative Management of Desmoid Tumors Is Safe and Effective.” J Surg Res 205.1 (2016): 115-20. Print.
- Al-Jazrawe, M., M. Au, and B. Alman. “Optimal Therapy for Desmoid Tumors: Current Options and Challenges for the Future.” Expert Rev Anticancer Ther 15.12 (2015): 1443-58. Print.
- Kasper, B., P. Strobel, and P. Hohenberger. “Desmoid Tumors: Clinical Features and Treatment Options for Advanced Disease.” Oncologist 16.5 (2011): 682-93. Print.
- Nuyttens, J. J., et al. “Surgery Versus Radiation Therapy for Patients with Aggressive Fibromatosis or Desmoid Tumors: A Comparative Review of 22 Articles.” Cancer 88.7 (2000): 1517-23. Print.
- Garbay, D., et al. “Chemotherapy in Patients with Desmoid Tumors: A Study from the French Sarcoma Group (Fsg).” Ann Oncol 23.1 (2012): 182-6. Print.
- de Camargo, V. P., et al. “Clinical Outcomes of Systemic Therapy for Patients with Deep Fibromatosis (Desmoid Tumor).” Cancer 116.9 (2010): 2258-65. Print.
- Janinis, J., et al. “The Pharmacological Treatment of Aggressive Fibromatosis: A Systematic Review.” Ann Oncol 14.2 (2003): 181-90. Print.
- Hansmann, A., et al. “High-Dose Tamoxifen and Sulindac as First-Line Treatment for Desmoid Tumors.” Cancer 100.3 (2004): 612-20. Print.
- Tanaka, Keita, et al. “Regression of sporadic intra-abdominal desmoid tumour following administration of non-steroidal anti-inflammatory drug.” World Journal of Surgical Oncology 6.1 (2008): 17.
- Waddell, W. R., and R. E. Gerner. “Indomethacin and Ascorbate Inhibit Desmoid Tumors.” J Surg Oncol 15.1 (1980): 85-90. Print.
- Heinrich, Michael C., et al. “Clinical and Molecular Studies of the Effect of Imatinib on Advanced Aggressive Fibromatosis (Desmoid Tumor).” Journal of Clinical Oncology 24.7 (2006): 1195-203. Print.
- Penel, N., et al. “Imatinib for Progressive and Recurrent Aggressive Fibromatosis (Desmoid Tumors): An Fnclcc/French Sarcoma Group Phase Ii Trial with a Long-Term Follow-Up.” Ann Oncol 22.2 (2011): 452-7. Print.
- Kasper, B., et al. “Correlation of Ctnnb1 Mutation Status with Progression Arrest Rate in Recist Progressive Desmoid-Type Fibromatosis Treated with Imatinib: Translational Research Results from a Phase 2 Study of the German Interdisciplinary Sarcoma Group (Gisg-01).” Ann Surg Oncol 23.6 (2016): 1924-7. Print.
- Gounder, M. M., et al. “Activity of Sorafenib against Desmoid Tumor/Deep Fibromatosis.” Clin Cancer Res 17.12 (2011): 4082-90. Print.
- Munhoz, Rodrigo Ramella, et al. “Efficacy of Sorafenib in Patients with Desmoid-Type Fibromatosis.” Journal of Clinical Oncology 34.15_suppl (2016): 11065-65. Print.
- Jo, JC., Hong, Y.S., Kim, KP. et al. Invest New Drugs (2014) 32: 369. https://doi.org/10.1007/s10637-013-0059-0
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