Abdominal desmoid in familial adenomatous polyposis presenting as a pancreatic cystic lesion

A 17-year-old male with familial adenomatous polyposis (FAP) presented with chest pain and significant weight loss. An abdominal CT scan detected a cystic pancreatic lesion of unknown etiology. The patient therefore underwent surgical resection of the distal pancreas, which included the lesion, because of the known association of pancreatic cancer with FAP. Histopathological examination of the resected specimen showed a benign pancreatic cyst and fibrous plaque with desmoid fibromatosis adherent to the surface of the pancreas, serosa of the stomach, and colon. The fibrous plaque was histologically identical to the fibrous mesenteric plaque known to occur in FAP and associated mesenteric fibromatosis. We present pathologic evidence that the pancreatic cyst formation was induced by FAP-associated desmoid invasion. Desmoid growth should be considered in the differential diagnosis of a pancreatic cystic mass lesion in patients with FAP or its Gardner syndrome variant. This case report provides the first pathologic evidence for benign epithelial cyst formation in the pancreas caused by fibromatosis invasion of that organ as a part of FAP.     

The enigma of desmoid tumors

Opinion statement Desmoid tumors (aggressive fibromatosis) are rare neoplastic tumors that may occur sporadically or in association with familial adenomatous polyposis (FAP). The etiology of these tumors is unknown, but hormonal, genetic, and physical factors play a role in their development and growth. A distinction is often made between desmoids in patients with FAP and those in patients without FAP, but clinically these tumors are treated the same; the only difference is the preferential intra-abdominal location of FAP desmoids. The goal of desmoid treatment is local control. Choosing the appropriate method for achieving local control may be complex as the functional and cosmetic outcomes of each method must be considered. In addition, because desmoids spontaneously regress, any claim of successful intervention must be viewed skeptically. Local control is mainly achieved by surgical intervention and may be improved with the addition of radiation therapy (RT). For patients who cannot undergo surgery, the options for local control include RT and systemic therapies such as hormones, nonsteroidal anti-inflammatory drugs (NSAIDs), interferon, and chemotherapy. Patients with symptomatic, progressive disease who can tolerate chemotherapy should be presented with the option of low-dose or standard antisarcoma chemotherapy. Although it is unclear which regimen is better, patients appear to have quicker responses to the standard antisarcoma therapy. Hormone therapy, NSAIDs, and interferon are used often, with varying success, and should be reserved for minimally symptomatic patients or for patients who do not want or are not candidates for chemotherapy. The treatment of desmoid tumors remains an enigma. As more options become available, selecting the correct therapy becomes more nuanced. Further clinical trials are needed to help the clinician navigate his or her way through the morass of desmoid tumor therapies.     

Urological sequelae of desmoids associated with familial adenomatous polyposis

The aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n?=?118, group A) were compared to those that developed ureteric obstruction (n?=?40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diagnosis was 31 years and desmoids typically occurred 3.6 years after colectomy for familial adenomatous polyposis. Ureteric obstruction secondary to tumour growth occurred in 25% of cases. There was no significant difference in gender distribution or overall age at desmoid diagnosis between the two groups. In group B, the median age at desmoid diagnosis was significantly younger in women compared to men (25 and 43 years, respectively) (p?=?0.01). Thirty-eight percent of patients already had ureteric obstruction at desmoid diagnosis, the remainder occurred after 48.6 months, but 20 years in two cases. Seventy-three percent (29/40) had ureteric stenting, a long-term requirement for most. Permanent renal injury occurred in six cases but survival between the two groups was not significantly different. Ureteric obstruction occurs frequently in patients with familial adenomatous polyposis and an intra-abdominal desmoid tumour. Those most at risk are the young following colectomy. Clinicians should actively survey the renal tract at regular intervals after a diagnosis of an intra-abdominal desmoid tumour as complications can arise insidiously, at any stage.     

<Emphasis Type="Italic">APC</Emphasis> mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.     

The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis

Seven familial polyposis patients with desmoid tumors were treated with indomethacin, sulindac, or tamoxifen either as single agents or in combination. Serial computed tomographic (CT) scan examination was employed for objective measurement of tumor size since physical examination alone was an inaccurate means to evaluate intraabdominal and retroperitoneal desmoids. Only one patient with minimal tumor burden demonstrated a favorable response with complete resolution of an abdominal wall desmoid.     

Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients

Background:

The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients.

Methods:

Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids.

Results:

Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy.

Conclusion:

For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.     

Phenotypic variation in hereditary nonpolyposis colon cancer syndrome. Association with infiltrative fibromatosis (desmoid tumor).

Familial infiltrative fibromatosis (desmoid tumor) is a recognized complication of familial adenomatous polyposis (FAP) but has not been described in families without colonic polyposis. The authors describe a unique family in which a predisposition to infiltrative fibromatosis and nonpolyposis colon cancer was inherited dominantly through four generations. This report expands the range of phenotypic variation described for the hereditary nonpolyposis colon cancer (HNPCC) syndrome and adds to the extracolonic complications that are common with FAP and HNPCC.     

Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis.

PURPOSE: To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor). EXPERIMENTAL DESIGN: Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (beta-catenin) mutations, were further investigated for beta-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor alpha (PDGFRA)/PDGF receptor beta (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach. RESULTS: No CTNNB1 (beta-catenin) mutations were found in the familial adenomatous polyposis patients, but previously reported activating mutations were found in six of the eight sporadic patients. All of the cases carrying an altered WNT pathway showed nuclear and cytoplasmic immunoreactivity for beta-catenin, whereas beta-catenin expression was restricted to the cytoplasm in the sporadic patients lacking CTNNB1 mutations. COX-2 protein and mRNA overexpression was detected in all 14 cases, together with the expression and phosphorylation of PDGFRA and PDGFRB, which in turn paralleled the presence of their cognate ligands. No PDGFRB mutations were found. The results are consistent with PDGFRA and PDGFRB activation sustained by an autocrine/paracrine loop. CONCLUSIONS: Aggressive fibromatosis is characterized by WNT/oncogene pathway alterations triggering COX-2-mediated constitutive coactivation of PDGFRA and PDGFRB, and may therefore benefit from combined nonsteroidal anti-inflammatory drug + tyrosine kinase inhibitor treatment.     

Combination chemotherapy for desmoid tumors

BACKGROUND: Desmoid tumor (aggressive fibromatosis) is an aggressive fibroblastic proliferation of well circumscribed, locally invasive, differentiated fibrous tissue. For patients with desmoid tumors that are not amenable to surgery or radiation therapy, the use of hormonal agents and nonsteroidal antiinflammatory drugs (NSAIDs) have been attempted, with some success. The use of chemotherapy also has been reported to have activity. METHODS: Seven patients (5 males and 2 females) with a median age of 40 years (range, 17-66 years) who received cytotoxic chemotherapy (combinations of cyclophosphamide and doxorubicin; mitomycin, doxorubicin, and cisplatin; and ifosfamide and etoposide) for desmoid tumor were reviewed retrospectively. Five patients were found to have recurrent tumors. Four patients had familial adenomatous polyposis. Four patients had failed tamoxifen and six had failed NSAIDs prior to receiving cytotoxic chemotherapy. In six patients the desmoid tumor was intraabdominal and one tumor had occurred on the buttock. RESULTS: Patients received a median number of six cycles of chemotherapy (range, two to eight cycles). Objective disease regression occurred in 3 patients. There was an apparent clinical benefit in six patients with the duration of benefit ranging from 3 months to 15 years. The chemotherapy was well tolerated and no treatment-related mortality was reported. CONCLUSIONS: The results of the current study indicate that the use of combination chemotherapy for desmoid tumors may provide long-term clinical benefits.     

Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours.

Desmoids are locally aggressive, non-metastasizing soft-tissue tumours, whose aetiology is still unclear. In patients affected with familial adenomatous polyposis (FAP), the incidence of desmoids is much higher than in the general population. The APC gene, which is responsible for FAP, is involved in the development of desmoids associated with this syndrome. In this study 16 sporadic and four FAP-related desmoids were analysed in order to investigate the possible involvement of APC in non-syndromic cases also. The 5'' end (exons 1-11) and the coding portion of exon 15 of APC were screened using the in vitro synthesized-protein assay (IVSP). Exons 5, 6, 8-14, and a region of exon 15 spanning codons 1036-1634 were investigated by single-strand conformation polymorphism (SSCP) analysis. APC germline mutations were identified in all FAP patients, but not in sporadic cases. Somatic mutations were found in three FAP-associated desmoids (75%) and two sporadic tumours (12.5%). In one of the latter cases, both alleles were affected. These findings indicate a limited role of the gene in the development of desmoid tumours outside FAP.     

An unusual case of familial adenomatous polyposis with very early symptom occurrence

We report the clinical case of a patient who showed an “accelerated” form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family—already described in 2001—featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient.     

Chemoprevention of carcinogenesis in familial tumors

Among familial cancers, chemoprevention has been studied for familial adenomatous polyposis, hereditary nonpolyposis colorectal cancers, and familial breast cancers. This report reviews the studies on chemoprevention in familial adenomatous polyposis. A large number of clinical trials have been performed using sulindac, a non-steroidal anti-inflammatory drug (NSAID). Sulindac reduces the size and number of large-bowel polyps. However, as yet, it cannot be used for this indication in the clinical setting, because of the frequent occurrence of serious gastrointestinal side effects, and there are a number of patients in whom aggressive tumors developed despite a reduction in the size of polyps. Studies of cyclooxygenase-2 (COX-2) selective inhibitors, with minimal side effects on the digestive tract, are showing promising results. In addition to NSAIDs, clinical trials have been performed using vitamins and dietary components. These show minimal side effects, but their efficacy is still insufficient for clinical use, and further studies are anticipated.     

Dacarbazine-Doxorubicin therapy ameliorated an extremely aggressive mesenteric desmoid tumor associated with familial adenomatous polyposis: report of a case

A 30-year-old man with familial adenomatous polyposis (FAP)underwent prophylactic proctocolectomy by laparoscopy-assistedsurgery. After 10 months, we found an intra-abdominal tumor,which grew rapidly to 25 cm in diameter. We performed an emergencyoperation, which revealed that it was a desmoid tumor derivedmainly from colorectal mesenterium. The tumor was removed withthree short segments of intestine and the left ureter. A computedtomography (CT) scan done 3 months later showed a 10 cm mesentericdesmoid tumor at the beginning of jejunum, approaching the rootof the superior mesenteric artery (SMA). Fortunately, we wereable to remove the tumor without injuring the SMA. To our distress,however, another recurrent mesenteric desmoid tumor was discoveredin the pelvis one month later, which grew rapidly from 5 cmto 16 cm within 4 months. During this period, we gave the patientseveral regimens, including antiestrogen (tamoxifen), a nonsteroidalanti-inflammtory drug and imatinib mesylate (Gleevec), whichhad little or no effect. Finally, when the desmoid occupiedthe pelvic space, we gave the patient dacarbazine (DTIC) anddoxorubicin (DOX). After seven courses, the mesenteric tumorshowed an almost complete response (CR). The chemotherapy causedgrade 3 to 4 leukocytopenia, but without any hazardous events.No evidence of further recurrence of mesenteric desmoid hasbeen seen for 4 years. This combination chemotherapy is a promisingstrategy, even against an extremely aggressive, life-threateningmesenteric desmoid associated with FAP.     

Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.     

Case report: metachronous central nervous system desmoid tumours and thyroid carcinoma in a young familial adenomatous polyposis patient

We report a familial adenomatous polyposis patient with a known truncating mutation on exon 15 of the APC gene who developed an invasive follicular thyroid cancer in addition to multiple intra-cranial and spinal desmoids. This combination of manifestations has not previously been recorded in the literature.     

Gene Expression Profiling in Familial Adenomatous Polyposis Adenomas and Desmoid Disease

Gene expression profiling is a powerful method by which alterations in gene expression can be interrogated in a single experiment. The disease familial adenomatous polyposis (FAP) is associated with germline mutations in the APC gene, which result in aberrant β-catenin control. The molecular mechanisms underlying colorectal cancer development in FAP are being characterised but limited information is available about other symptoms that occur in this disorder. Although extremely rare in the general population, desmoid tumours in approximately 10% of FAP patients. The aim of this study was to determine the similarities and differences in gene expression profiles in adenomas and compare them to those observed in desmoid tumours. Illumina whole genome gene expression BeadChips were used to measure gene expression in FAP adenomas and desmoid tumours. Similarities between gene expression profiles and mechanisms important in regulating formation of FAP adenomas and desmoid tumours were identified. This study furthers our understanding of the mechanisms underlying FAP and desmoid tumour formation.     

Endocrine therapy for desmoid tumors.

Two female patients with desmoid tumors (aggressive fibromatosis) showed tumor regression after endocrine therapy. In one patient, tumor response to tamoxifen has been maintained over several years of treatment. In the second patient, who had inoperable mesenteric fibromatosis, the tumor progressed on tamoxifen but regressed after treatment with Zoladex (goserelin acetate, ICI, Melbourne, Australia) and medroxyprogesterone acetate (MPA). To the authors' knowledge this is the first report of the use of Zoladex in the treatment of desmoid tumors. This review of the literature reveals that the biology of this disease is related to the endogenous hormonal environment and that estrogen receptors have been documented in desmoid tumors. Thirty-five cases are identified where endocrine agents have been employed, with a response rate of 51%. Furthermore, tumors may respond to second-line hormonal therapy after failing to respond to initial endocrine treatment. Endocrine treatments have also been used in other disorders of fibroblastic origin. The authors recommend that endocrine treatment be employed in inoperable desmoid tumors or where there has been postsurgical recurrence. In addition, the role for endocrine therapy in other soft tissue neoplasms should be determined.