High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors

BACKGROUND: Desmoid tumors are mesenchymal nonmetastasizing neoplasms. Although rare in the general population, they are a common extracolonic manifestation of familial adenomatous polyposis (FAP). Because of high tumor recurrence rates, surgery has been less than satisfactory in the treatment of desmoid tumors. In the current study, high doses of tamoxifen in combination with sulindac were used to treat severe desmoid tumors to avoid surgery. METHODS: Since 1992, 25 patients at Heinrich Heine University (Dusseldorf, Germany) were treated with a combination of tamoxifen and sulindac. In the current study, 17 patients with FAP-associated and 8 patients with sporadic desmoid tumors received 120 mg of tamoxifen and 300 mg of sulindac daily. Every 6 months, the protracted course of desmoid growth was measured by computed tomography and/or magnetic resonance imaging scans. Tumor responses were characterized as progressive disease, stable disease (SD), partial regression (PR), and complete regression (CR). RESULTS: Of the group of patients who received tamoxifen and sulindac as a primary treatment, all three patients with sporadic desmoid tumors demonstrated cessation of growth, and 10 of the 13 patients with FAP-associated tumors achieved either a PR or CR. In the sporadic desmoid tumor group, eight of nine patients developed tumor recurrences after undergoing surgery at other institutions. Of these, two patients had SD and two patients had a PR to CR. CONCLUSIONS: The patients with desmoid tumors who were managed conservatively with high-dose tamoxifen and sulindac had the best outcome. Desmoid tumor recurrence after surgery was high and in the FAP-associated tumor group, therapy with tamoxifen and sulindac was found to be less successful. Based on this experience, the authors recommended high-dose tamoxifen and sulindac as the primary treatment for patients with FAP-associated desmoid tumors. However, to our knowledge, the best approach after surgical intervention for patients with sporadic desmoid tumors remains to be determined.     

Giant desmoid tumor of the abdominal wall associated with familial adenomatous polyposis

In this paper a case of vast desmoid tumor of the abdominal wall associated with familial adenomatous polyposis is reported. Desmoid tumors represent a particular type of fibrous neoplasms with a higher prevalence in females. They are extremely rare in the sporadic form, while they are found in about 10% of patients affected by familial adenomatous polyposis. Despite their benign histology and the absence of metastatic potential, they can be considered as fibrosarcomas with a low level of malignancy because of their locally invasive nature. The treatment of choice is surgical excision, as wide as possible, aimed at preventing recurrences, which are frequent in this tumor type. The usefulness of complementary therapies such as radiotherapy, hormone or chemotherapy, is not entirely clear.     

Chromosome changes in desmoid tumors developed in patients with familial adenomatous polyposis.

Chromosome analyses were performed on benign desmoid tumors obtained from two female patients with familial adenomatous polyposis (FAP), one of whom was diagnosed as having Gardner syndrome (GS). The modal chromosome number was 46 in both specimens, and detailed Q-banding analysis in Case 1 (GS) revealed a clonal abnormality of an interstitial deletion of the long arm of chromosome 5, del(5)(q21q31). The deleted region included an assigned locus for an FAP major gene (5q21-q22). All of the metaphases analyzed in this case showed an extra segment of bright fluorescence on the short arm of chromosome 15, but this unusual chromosome (15p+) was observed in both peripheral lymphocyte and skin fibroblast cultures from the patient, indicating that the 15p+ was constitutional in nature. In Case 2, no clonal rearrangements were identified and most cells had a normal karyotype. However, two cells showed rearrangements involving a 17q with non-identical breakpoints, one of which was observed as a solitary chromosome change. Based on the present findings in Case 1 and those reported so far, the chromosomal defect on 5q might be one of the causal genetic events primarily associated with the development of both benign desmoid tumors and colorectal adenomas and carcinomas in FAP patients.     

Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis

Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4-3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66-13.51), osteomas (OR = 2.9; 95% CI 1.8-4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1-3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5-15.8), family history of desmoids (OR = 5.8; 95% CI 3.1-10.6), female gender (OR = 2.1; 95% CI 1.1-3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1-3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs.     

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.     

The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J- Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti- inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.      

Frequent mutations in the beta-catenin gene in desmoid tumors from patients without familial adenomatous polyposis.

Mutations in the APC gene contribute to development of sporadic desmoid tumors as well as to the hereditary tumors that usually accompany familial adenomatous polyposis (FAP). Adenomatous polyposis coli (APC) mutations cause an intracellular accumulation of beta-catenin that results in abnormal signaling in the wnt/wingless pathway. Mutations of the beta-catenin gene itself have also been noted in several types of tumors. In this study we screened the beta-catenin gene in 13 sporadic desmoid tumors for alterations in exon 3, which encodes several serine/threonine residues that are targets for phosphorylation by GSK-3beta. Somatic substitutions at codons 41 (threonine) and 45 (serine) were identified in seven independent tumors, respectively. Although no APC mutations were detected among the remaining six tumors, we found accumulation of beta-catenin by Western blotting analysis in one such tumor for which frozen tissues were available. Our results have suggested that possible involvement of beta-catenin activation by beta-catenin gene mutation or alteration of other factor(s) can contribute to desmoid tumorigenesis.     

Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach

The results of treatment of desmoid tumor patients with nonsteroid antiinflammatory drugs alone or in combination with tamoxifen are described. Tumor growth was inhibited in six of seven patients. Nonsteroid antiinflammatory drugs administered along with 5-fluorouracil and cyclophosphamide and other inhibitors of T-suppressor cells were used to treat nine patients with metastatic carcinoma of the stomach. Survival of these patients was extended so that after 12 months minimal follow-up the majority are well. A prospective controlled clinical trial is indicated.     

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.     

Gynecological malignancies, brain tumors, and familial adenomatous polyposis.

The syndrome of familial adenomatous polyposis has a wide spectrum of clinical manifestations including adenomatous polyps of the colon and small bowel, adenocarcinoma of ampulla of Vater, tumors of the central nervous system, bone lesions, and various soft tissue tumors. The one common denominator is colonic polyposis. It is not known whether this phenotypic heterogeneity is due to various genotypes, or if the entire clinical spectrum is due to one genetic defect. We are reporting the association of gynecologic malignancies with familial adenomatous polyposis as an additional variant of this disease. This report is on two sisters from a family with familial polyposis coli who developed adenomatous polyposis of the colon, central nervous system tumors, and cancers of the ovary and uterus. The gynecological malignancies add another variant to this clinical syndrome.     

Assessment of endostatin gene therapy for familial adenomatous polyposis-related desmoid tumors

Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)-related desmoid tumors. Endostatin is a well-known antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease.     

Hepatocellular and gastric carcinoma associated with familial polyposis coli

A case of familial polyposis coli in association with hepatocellular and gastric carcinoma is reported. No similar case has ever been documented in the world literature. This may be surprising as it is well known that familial polyposis has a potent oncogenicity not only in the colon but also in extracolonic organs.     

The efficacy of radiotherapy as postoperative treatment for desmoid tumors

PURPOSE: The purpose of this study was to determine if radiotherapy is a beneficial adjuvant treatment after desmoid tumor resection. METHODS AND MATERIALS: A retrospective analysis was performed on 54 patients who underwent surgery without prior radiation at our institution between 1982 and 1998 to remove a desmoid tumor. Thirty-five patients had adjuvant radiation therapy after surgery, and 19 patients had surgery alone without immediate postoperative radiation. Sixteen of the 35 patients who underwent immediate postoperative radiation treatment had at least one prior resection before reoperation at our institution. Recurrence was defined as radiographic increase in tumor size after treatment. Follow-up interval (mean 39 months) and duration of local control were measured from the date of surgery at our institution. Potential prognostic factors for time to tumor progression were analyzed. RESULTS: Adjuvant treatment with radiation was the only significant prognostic factor for local control. The five-year actuarial local control rate was 81% for the 35 patients who underwent radiation in addition to surgery, compared to 53% for the 19 patients who underwent surgery alone (p = 0.018). For the patients who did not receive adjuvant radiation, only younger age at the time of surgery was associated with increased risk of failure (p = 0.035). Gross or microscopic margin status and number of prior operations were not detected as prognostic for local failure. For patients who did receive postoperative radiation, only abdominal location was associated with increased risk of failure (p = 0.0097). CONCLUSION: Radiation treatment as an adjuvant to surgery improved local control over surgery alone. Multiple operations before adjuvant radiation did not decrease the probability of subsequent tumor control. Radiation should be considered as adjuvant therapy to surgery if repeated surgery for a recurrent tumor would be complicated by a significant risk of morbidity.     

Percutaneous cryoablation for the treatment of extra-abdominal desmoid tumors

Background

Desmoid tumors are rare locally invasive, benign neoplasms that develop along aponeurotic structures. Current treatment is complicated by associated morbidity and high recurrence rates.

Methods

A retrospective, single-institution review identified 23 patients (age: 16-77) with extra-abdominal desmoid tumors who received CT-guided percutaneous cryoablation as either a first-line (61%) or salvage (39%) treatment in 30 sessions between 2014 and 2018. Median maximal lesion diameter was 69 mm (range: 11-209). Intent was curative in 52% and palliative in 48%. Contrast-enhanced cross-sectional imaging was obtained before and after treatment in addition to routine clinical follow-up.

Results

Technical success was achieved in all patients. The median follow-up was 15.4 months (3.5-43.4). Symptomatic improvement was demonstrated in 89% of patients. At 12 months, the average change in viable volume was −80% (range −100% to + 10%) and response by modified response evaluation criteria in solid tumors (mRECIST) was CR 36%, PR 36%, and SD 28% No rapid postablation growth or track seeding was observed. Four patients underwent repeat cryoablation for either residual or recurrent disease. Two patients sustained a major procedural complication consisting of significant neuropraxia.

Conclusion

Cryoablation for desmoid tumors demonstrates a high degree of symptom improvement and local tumor control on early follow-up imaging with relatively low morbidity.     

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.     

Torre's syndrome in association with premalignant and malignant tumors and suspected familial polyposis

Torre's syndrome was diagnosed in a patient with the clinical characteristics of familial polyposis coli, an association, that to our knowledge, has not been reported previously.     

Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis

Loss of heterozygosity (LOH) and K-ras mutation were analyzed in 111 colorectal polyps and 26 invasive carcinomas from 40 patients with familial adenomatous polyposis of distinct histopathological types. LOH, being less than 2% in moderate adenomas, was detected on chromosome 5q (20%) in severe adenomas, on 5q (26%) and 17p (38%) in intramucosal carcinomas, and on 5q (52%), 17p (56%), 18 (46%), and 22q (33%) in invasive carcinomas. LOH on chromosome 5q occurred most frequently in the region close to the APC gene both in adenomas and carcinomas, and a loss of the normal allele of the APC gene was demonstrated in 3 cases. K-ras mutation markedly increased in the step of development from moderate (11%) to severe (36%) adenomas. These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.     

Therapeutic potential of replication-selective oncolytic adenoviruses on cells from familial and sporadic desmoid tumors

PURPOSE: Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers and has been associated with familial and sporadic desmoid tumors. The aim of the present study is to assess the therapeutic potential of oncolytic adenoviruses selectively replicating in cells in which the Wnt signaling pathway is active on primary cells from desmoid tumors. EXPERIMENTAL DESIGN: Primary cells extracted from familial (n = 3) or sporadic (n = 3) desmoid tumors were cultured short term. Cancer cell survival and viral replication were measured in vitro upon infection with two different oncolytic adenoviruses targeting a constitutive activation of the Wnt signaling pathway. Adenoviral infectivity was also assessed. RESULTS: Although cells extracted from one sporadic desmoid tumor responded very well to the oncolytic action of the adenoviruses (<20% of viable cells upon infection at a multiplicity of infection of 10), cells from two tumor samples were totally resistant to the viral action. Cells from the remaining samples showed intermediate sensitivity to the oncolytic viruses. These effects were correlated to the level of infectivity of the cells. Finally, in responder cells, evidences of viral replication was observed. CONCLUSIONS: Our experimental data suggest that the response of desmoid tumor cells to oncolytic adenovirus is neither correlated to the type of mutation activating the Wnt signaling pathway nor to the familial or sporadic nature of the tumor. In addition, they highlight the variability of infectivity of individual tumors and predict a great variability in the response to oncolytic adenoviruses.