Fibromatosis is a group of fibroblastic or myofibroblastic tissues that can be locally aggressive but do not metastasize . The incidence of desmoids tumor has been reported as 2–4 cases per 1 million population, and deep fibromatosis, such as those arising in the abdominal cavity, are often referred to as IAF , which accounts for 8% of fibromatosis . Although rare, IAF is the most common primary mesenteric tumor with spindle cell morphology . Its causes and underlying mechanisms are unknown. Although most cases are sporadic, about 20% cases are associated with familial adenomatous polyposis (FAP) in a syndrome known as Gardner syndrome , about 10% cases with abdominal surgery or trauma experiences for various reasons [17, 21–24], and rare cases with prior radiation therapy [25, 26]. The two cases reported here were associated with previous abdominal surgery for GIST.
Of the above-mentioned situations, IAF developed after surgical resection for other tumors has special clinical significance. IAF has been observed in the sites of previous abdominal surgery for tumors [23, 24]. Its diagnosis often is difficult to establish preoperatively, and it is usually misdiagnosed as recurrence at first clinical impression [2, 22, 23, 27]. Surgical excision of the lesion is a difficult decision owing to the suspicion of metastasis mainly due to the following reasons. 1) The appearance of IAF on contrast enhanced imaging is not specific, therefore, the imaging diagnosis of IAF developed after abdominal surgery for other tumors is very difficult except in patients with familial adenomatous polyposis [20, 28]. 2) The time interval between surgery and development of fibromatosis ranges from 2 months to several years (2.6 years on average) , which overlaps with recurrent disease.
Recently, there have been prior several case reports describing IAF arising on the site of a previously excised GIST. In these cases, IAF was first misdiagnosed as GIST recurrence [2, 3]. Very recently, a non-random association between GIST and IAF was described. However, it’s different from a non-random association between GIST and myeloid leukemia , since an accurate diagnosis could only be established after surgical removal and pathological examination, as there are no typical imaging findings to suggest a IAF. Although it is a very rare event, IAF developed synchronously or metachronously with GIST could occur in most medical centers, for example, 28 IAF patients were collected from 10 medical centers .
Introduction of imatinib has greatly changed the clinical approach to intra-abdominal stromal spindle cell tumors. GIST is the most common mesenchymal tumor in gastrointestinal tract. Oncogenic mutations in KIT or PDGFRA have been identified as central tumor-initiating events in many GISTs . Treatments with imatinib and sunitinib, two small-molecule inhibitors of the mutant KIT and PDGFRA receptor tyrosine kinases, significantly prolong survival of patients with GIST . The median time for disease progression is 18–24 months in imatinib-treated patients with unresectable GIST. The clinical decision has been changed in patients with recurrent GIST.
In this study, the first patient had the disease in the era before imatinib. Since GIST is resistant to conventional cytotoxic chemotherapy , surgical resection was the first option for the patients. The second patient had the disease in the imatinib era, therefore, imatinib therapy was the first recommendation. However, the patient was not benefited from imatinib treatment: the tumor continued to grow rapidly after six months of imatinib therapy. After referred to our hospital, pathological re-evaluation suggested that the primary GIST was of borderline nature and the opportunity for recurrence was very low based on our previous experiences [31, 32]. Furthermore, mutations in KIT and PDGFRA were not found in GIST. Since imatinib is less effective against GIST without KIT or PDGFRA mutation , and initial studies suggest that sunitinib treatment rarely results in objective responses in GIST [34, 35], debulking surgery remains a recognized standard practice in the case of local progression because such procedure could prolong survival of patients who are resistant or insensitive to imatinib treatment . Therefore, the decision of surgical resection was made for cure and definite diagnosis after MDT discussion.
Surgical intervention for IAF is generally considered to be the treatment of choice and is curative in many cases. Some studies have reported better prognosis for IAF patients with non-Gardner’s-associated IAF than for those complicated by Gardner’s syndrome [8, 10, 17, 37]. In the study, both patients had no family history of FAP and uneventful prognosis. Complete surgical resection remains the cornerstone of management of IAF, while unresectable or residual disease can be treated with multiple choices. Nonsurgical treatment protocols mainly rely on sulindac , toremifene , cytotoxic chemotherapy , or in some circumstances, radiotherapy . Each of them has variable and unpredictable efficacy . Therefore. new treatment protocols for IAF are gradually being recommended, such as imatinib , sunitinib , bevacizumab , or sorafenib . However, the two cases reported had been treated with imatinib at a dose of 400 mg for liver metastatic GIST. One achieved four years of long-term stable control  and the other achieved 11 months of disease control , but both developed IAF in primary GIST bed. The second patient was not benefit from imatinib therapy at this dosage.
Mace et al. recommended imatinib treatment at dose of 400 mg giving twice per day as a new therapeutic approach for desmoids tumor . In Dumont’s cases, a patient who received imatinib at 400 mg/day for gastric GIST developed IAF on the posterior wall of the gastric antrum 35 months after initial diagnosis. After increasing imatinib dose to 800 mg/day, patient partially responded to both tumors , suggesting that patients with IAF might benefit from high dosage of imatinib.
Nevertheless, surgical trauma at the GIST excision site may predispose to the development of the IAF. This situation broads differential diagnosis and elicits a range of potential treatment options ranging from imatinib therapy to aggressive surgical re-excision for IAF. An accurate diagnosis is possible only after surgical removal and pathological examination, as there are no typical imaging findings to suggest IAF. Excluding diagnosis of recurrence of GIST is crucial for further management of our patients due to the increasing use of imatinib in the treatment of advanced GIST. In rare instances as illustrated in our cases, co-existence of another disease should be considered. The current two cases highlight the need for careful consideration of IAF when a rapidly growing spindle cell tumor is encountered in a post-GIST patient.
Written informed consents were obtained from patients and their family members for publication of this report.