Sporadic Desmoid Tumors Research Articles

Pleuropulmonary Desmoid Tumors: Immunohistochemical Comparison With Solitary Fibrous Tumors and Assessment of β-Catenin and Cyclin D1 Expression

Abstract Context.—Desmoid tumors arising in the lung and pleura are extremely rare and can resemble other, more common neoplasms native to these sites. Alterations of the adenomatous polyposis coli/β-catenin pathway have been detected in sporadic desmoid tumors and have been associated with nuclear accumulation of β-catenin and overexpression of cyclin D1. Objective.—To analyze the expression of β-catenin and cyclin D1 in desmoid tumors and solitary fibrous tumors (SFTs), and to compare the utilities of these substances for distinguishing between these entities with those of other, more commonly used stains. Design.—Formalin-fixed, paraffin-embedded sections of 4 desmoid tumors (1 pulmonary, 1 pleural, 2 pleural/chest wall), and 5 benign and 6 malignant SFTs of the pleura were immunostained for β-catenin, cyclin D1, ALK1, CD34, vimentin, desmin, smooth muscle actin, muscle-specific actin, S100, and pancytokeratin. Staining intensity and the percentage of stained tumor cells were assessed semiquantitatively. Results.—Diffuse moderate or strong nuclear staining for β-catenin was found in all desmoid tumors, 4 of 5 benign SFTs, and 2 of 6 malignant SFTs. All cases except 1 benign SFT showed concurrent cytoplasmic staining. Nuclear and cytoplasmic cyclin D1 staining was increased in all groups. The best distinction between desmoid tumors and SFTs was provided by CD34 (desmoid tumors, 0/4; SFTs, 8/11) and smooth muscle actin (desmoid tumors, 4/4; SFTs, 0/11). Conclusions.—Our findings suggest that alterations in the adenomatous polyposis coli/β-catenin pathway and cyclin D1 dysregulation may contribute to the pathogenesis of pleuropulmonary desmoid tumors and SFTs. CD34 and smooth muscle actin stains are particularly useful for differentiating between pleuropulmonary desmoid tumors and SFTs.

An Unusual Presentation of Desmoid Tumor in the Ileum

Desmoid tumors are nonencapsulated, locally invasive tumors of fibrous origin. Although lacking the ability to metastasize, they are notorious for recurrence. A wide variety of locations have been documented in the literature with respect to the origin of these tumors. Intra-abdominal desmoids are commonly found in the mesentery. We present the report of a case in which a sporadic desmoid tumor originated from the wall of the ileum. The patient was successfully treated with surgery alone, and has remained recurrence free on follow-up. Modalities of treatment documented in the literature include surgery, nonsteroidal, anti-inflammatory drugs such as sulindac, and chemotherapeutic drugs such as vinblastine and methotrexate, radiotherapy, and, recently, tyrosine kinase inhibitors such as Imatinib (gleevec). Of all the options described, surgery with tumor-free margins has been defined as the best treatment modality.

Desmoid Tumors – a Characterization of Patients Seen at Mayo Clinic 1976–1999

Desmoid tumors occur with high frequency in individuals with Familial Adenomatous Polyposis (FAP). Because of this, individuals developing desmoid tumors may be referred for genetic risk assessment. Determining whether a person has a FAP-related desmoid tumor or a sporadic desmoid can be challenging. We sought to characterize the patients who were seen at our institution to determine if there were clinical differences in presentation between FAP-associated and sporadic desmoid tumors. We searched the Mayo Clinic-modified H-ICDA (Hospital adaptation of the International Classification of Diseases) diagnostic codes for all diagnoses of desmoid tumors in patients seen between 1976 and 1999. Charts were reviewed to determine accuracy of diagnosis, age when seen, gender, site of tumor, and presence of polyposis. A total of 454 patients (174 males and 280 females) met the search criterion. Of the 447 patients on whom all data was obtained, 70 had FAP and 377 had no evidence of FAP. The female/male ratio for FAP cases was 1.12 compared to female/male ratio of 1.71 for non-FAP cases. (P=0.17). Location of development of desmoid tumors was correlated with but not specific for distinguishing FAP from non-FAP desmoids. Abdominal desmoids comprised the majority of FAP desmoids and extra-abdominal desmoids comprised the majority of non-FAP desmoids (P<0.001) but age was not a discriminating factor. Using Bayesian analysis, we demonstrate how these findings can assist genetic professionals in their evaluation of patients with desmoid tumors by providing prior probabilities of FAP based upon clinical presentation.

Genetic Testing for Germline Mutations of the APC Gene in Patients With Apparently Sporadic Desmoid Tumors but a Family History of Colorectal Carcinoma

Desmoid tumors, also known as aggressive fibromatosis, occur with an incidence of 10 to 15 percent in patients affected by familial adenomatous polyposis, an autosomal inherited disease caused by germline mutations in the APC gene. However, sporadic forms with no hereditary background exist. The aim of this study was to find out whether there are APC germline mutations in apparently sporadic desmoid tumor patients without clinical or familial signs of familial adenomatous polyposis but with a family history of colorectal carcinoma in at least one family member. Genomic DNA and mRNA were isolated from peripheral blood leukocytes of index patients of eight nonrelated families. Mutation screening was performed using reverse transcriptase polymerase chain reaction-based protein truncation test for APC exons 1-14. The large APC exon 15 was scrutinized by the protein truncation test of four overlapping genomic fragments. Additionally, genomic DNA from five desmoid tumors was analyzed for loss of heterozygosity at D5S346 close to the APC locus. No translational stop mutations typical for familial adenomatous polyposis could be found in the APC gene in any of the analyzed blood samples from the desmoid tumor patients. Additionally, no loss of heterozygosity at D5S346 was found in four of five desmoids; one tumor was not informative. These results may suggest that patients with sporadic desmoids and no clinical signs of familial adenomatous polyposis detected on careful examination, esophagogastroduodenoscopy, and complete colonoscopy do not need to be tested routinely for germline mutations of the APC gene. However, as large studies dealing with this problem are absent, it might be more time and cost effective to perform an APC mutational analysis instead.

Comprehensive genetic and endoscopic evaluation may be necessary to distinguish sporadic versus familial adenomatous polyposis–associated abdominal desmoid tumors

Background There are limited data regarding how many patients with desmoid tumors actually represent cases with underlying familial adenomatous polyposis. Methods A proband presenting with desmoid tumors and several of the family members underwent a detailed family history, genetic (adenomatous polyposis coli [APC] gene sequencing), and upper and lower endoscopic evaluation. Results The proband's initial diagnosis was of a sporadic desmoid tumor. Colonoscopy was entirely normal. However, on subsequent esophagogastroduodenoscopy, several gastric polyps were found. The proband's mother subsequently underwent colonoscopy and was found to have multiple colon adenomas. On genetic analysis, a deletion of “T” was identified at codon 2645 of the APC gene in the proband. The proband's mother had a normal APC protein truncation test result. However, on full gene sequencing, the mother was found to harbor the same APC gene mutation. Conclusion A detailed family history and endoscopic and genetic evaluations for patients with desmoid tumors are vital because they may be the sentinel presentation of familial adenomatous polyposis. If confirmed in larger studies, APC full gene sequencing and upper and lower gastrointestinal tract evaluation may need to be part of standard evaluation of patients with abdominal desmoid tumors.

Possible Association Between Higher β-Catenin mRNA Expression and Mutated β-Catenin in Sporadic Desmoid Tumors: Real-Time Semiquantitative Assay by TaqMan Polymerase Chain Reaction

We screened for genetic alterations of adenomatous polyposis coli (APC) and β-catenin genes in 17 frozen specimens from 12 cases of sporadic desmoid tumors and then subdivided these cases into two groups according to the results of mutational analysis. We further examined mRNA expression of β-catenin and cyclin D1 by TaqMan PCR and compared the mRNA expression within both groups. Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed β-catenin mutation in 3 of 12 cases (6 of 17 specimens), whereas no APC missense mutations in the mutation cluster region were found. TaqMan PCR revealed extremely higher mRNA expression of β-catenin and cyclin D1 in desmoid tumors, compared with those of normal skeletal muscles. In the β-catenin mutated group, cyclin D1 mRNA expression was significantly higher than that of the β-catenin wild-type group (p = 0.0120, Mann-Whitney U test). In addition, in the β-catenin mutated group, β-catenin mRNA expression was also significantly higher than that of the β-catenin wild-type group (p = 0.0036, Mann-Whitney U test). All cases of desmoid tumors showed detectable β-catenin nuclear expression immunohistochemically. These results suggest that a continuously elevated β-catenin protein level caused by the β-catenin mutation itself may have a stronger power that can transactivate transcription in vivo. Furthermore, the results provide a possible association between higher β-catenin mRNA expression and mutated β-catenin in sporadic desmoid tumors. This may suggest that the β-catenin gene may be up-regulated by mutated or continuously elevated β-catenin protein, that is, the β-catenin gene may also be one of the targeted genes in the APC-β-catenin-Tcf pathway.

?-catenin nuclear expression correlates with cyclin D1 overexpression in sporadic desmoid tumours

The immunohistochemical expression of beta-catenin, cyclin D1, Ki-67 and PCNA was Examined in 38 cases of sporadic extra-abdominal or abdominal-wall desmoid tumours without familial adenomatous polyposis (FAP), to evaluate the hypothesis that the accumulated beta-catenin within the nuclei could affect the regulation of the cyclin D1 gene. There was a statistically significant correlation between beta-catenin accumulation and cyclin D1 overexpression (p=0.029). Each group with beta-catenin accumulation or cyclin D1 overexpression showed a higher PCNA-LI than those without, the difference being statistically significant (p=0.007, p=0.004, respectively). Differential PCR was also performed to detect amplification of the cyclin D1 gene and mutational analysis was undertaken for exon 3 of the beta-catenin gene. Amplification of the cyclin D1 gene was observed in 13 out of 22 cases (59.1%). There were nine-point mutations in 7 out of 18 cases (38.9%). The distribution of beta-catenin mutation fell within a wide range, from codon 21 to codon 67. In conclusion, beta-catenin nuclear expression correlated with cyclin D1 overexpression in sporadic desmoid tumours, which could be an in vivo model system for the APC-beta-catenin-Tcf pathway. In addition, beta-catenin mutations in desmoid tumours occurred at an unusually wide range of sites within the gene.

A novel case of a sporadic desmoid tumour with mutation of the beta catenin gene.

A 42 year old man without familial adenomatous polyposis had recurrent desmoid tumours in the left subclavicular site. Histological examination showed a typical desmoid tumour. Molecular analysis was performed in...

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.

Desmoid tumors in patients with familial adenomatous polyposis.

Sporadic desmoid tumors occur mainly in the abdominal wall and in extraabdominal sites. Desmoid tumors in patients with familial adenomatous polyposis (FAP) usually occur in the abdominal wall and in the bowel mesentery. Surgical resection of desmoids in patients with FAP has been controversial. A retrospective review of patients with FAP and desmoid tumors treated from 1950 to 1991 was performed. Patients were evaluated for gender, age, site of desmoid tumors, treatment, recurrence, and survival. Twenty-one of 24 patients underwent 60 surgical procedures related to the desmoid tumors. Seven of nine patients who underwent potentially curative surgery had recurrences; three were reresected. Major morbidity after palliative or curative surgery was 47%. Five patients were alive with no evidence of disease at a median of 198 months, 10 patients were alive with disease at a median of 102 months, and 5 patients died with disease at a median of 31 months after diagnosis. Desmoid tumors are common in patients with FAP. Unresectability and recurrence are more common than cure. Palliative and curative resections have a high morbidity. Surgery should be reserved for those patients with symptomatic mesenteric desmoids.