Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. ␤-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding ␤-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%) , 45F (33%) , and 45P (8% , excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23% , P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear ␤-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches. (Am J Pathol

Unlike melanoma, clear cell sarcoma harbors either a t(12;22)(q13;q12) recurrent translocation, resulting in an EWSR1/ATF1 chimeric gene, or less commonly a t(2;22)(q34;q12) translocation fusing EWSR1 and CREB1. Few studies have examined the prevalence of all chimeric types and variants to assess the usage of ancillary genetic testing in routine diagnosis. We investigated rearrangement prevalence in 17 clear cell sarcomas, two positive control cell lines, and two melanomas (negative controls). Fluorescence in situ hybridization (FISH) analysis using the LSI EWSR1 break-apart probe and a reverse transcription polymerase chain reaction (RT-PCR) assay optimized for formalin-fixed paraffin-embedded tissue to detect all four reported EWSR1/ATF1 clear cell sarcoma chimeric types and the EWSR1/CREB1 variant was performed. All 15 cases available for testing by FISH were positive for EWSR1 rearrangement including two cases with insufficient RNA for RT-PCR. Thirteen of 15 cases successfully tested by RT-PCR harbored a type 1 chimeric transcript (EWSR1 exon 8/ATF1 exon 4), of which five tumors simultaneously carried a type 2 chimeric transcript (EWSR1 exon 7/ATF1 exon 5). One case carried a type 2 transcript alone and one case contained an EWSR1/CREB1 transcript. Both control cases were positive by both techniques with one case carrying both types 1 and 2 chimeric transcripts and the other types 2 and 3 (EWSR1 exon 10/ATF1 exon 5). Consequently, both techniques are equally effective in assessing for an EWSR1 rearrangement and are useful ancillary diagnostic tests for clear cell sarcoma. They also reinforce the prevalence of this translocation in these tumors. In addition, EWSR1-CREB1 was identified in a clear cell sarcoma of soft tissue providing further evidence that this chimeric variant is not exclusive to gastrointestinal clear cell sarcomas and should be included in RT-PCR assays of soft tissue clear cell sarcomas.

The biological behaviors of well-differentiated and dedifferentiated liposarcomas differ significantly. This article presents outcomes of two different surgical approaches that were implemented at the UTMDACC, treating these tumors as different disease entities.

Tumor size and grade in the AJCC STS staging system need revision; moreover, primary site, histologic subtype, margin status, and recurrence offer additional relevant prognostic insight. Incorporation of these factors may enhance the AJCC staging system, thereby further facilitating individualized therapeutic strategies for STS patients.

Purpose:We examined a cohort of patients with alveolar soft part sarcoma (ASPS) treated at our institution and showed the characteristic ASPSCR1-TFE3 fusion transcript in their tumors. Investigation of potential angiogenesis-modulating molecular determinants provided mechanistic and potentially therapeutically relevant insight into the enhanced vascularity characteristic of this unusual tumor. Experimental Design: Medical records of 71patients with ASPS presenting at the University of Texas M.D. Anderson Cancer Center (1986-2005 were reviewed to isolate 33 patients with formalin-fixed paraffin-embedded material available for study. RNA extracted from available fresh-frozen and formalin-fixed paraffin-embedded human ASPS tumors were analyzed for ASPSCR1-TFE3 fusion transcript expression using reverse transcription-PCR and by angiogenesis oligomicroarrays with immunohistochemical confirmation. Results: Similar to previous studies, actuarial 5-and 10-year survival rates were 74% and 51%, respectively, despite frequent metastasis. ASPSCR1-TFE3 fusion transcripts were identified in 16 of 18 ASPS samples. In the three frozen samples subjected to an angiogenesis oligoarray, 18 angiogenesis-related genes were up-regulated in tumor over adjacent normal tissue. Immunohistochemistry for jag-1, midkine, and angiogenin in 33 human ASPS samples confirmed these results. Comparison with other sarcomas indicates that the ASPS angiogenic signature is unique. Conclusion: ASPS is a highly vascular and metastatic tumor with a surprisingly favorable outcome; therapeutically resistant metastases drive mortality. Future molecular therapies targeting overexpressed angiogenesis-promoting proteins (such as those identified here) could benefit patients with ASPS. Alveolar soft part sarcoma (ASPS) is a malignancy of uncertain histogenesis, first described in 1952 (1). A rare soft tissue sarcoma (STS) subtype, it has a uniquely indolent growth pattern combined with unexpectedly high metastatic (particularly pulmonary) activity. Unlike other STS, ASPS also metastasizes to the brain (2 -7). Interestingly, whereas the metastatic rates in this disease are high, prior large series indicate prolonged survival with metastatic disease. Surgery is the therapeutic mainstay for localized and metastatic disease; chemoresistance frequently precludes meaningful systemic intervention. A characteristic translocation in ASPS results in a novel fusion of the ASPSCR1 (previously designated ASPL) and TFE3 genes (chromosomes 17q25 and Xp11.2, respectively), resulting in a functional transcription factor with altered target gene activation (8). This creates a novel ASPSCR1-TFE3 fusion protein that seems to acts as an aberrant transcription factor that induces unregulated transcription of TFE3-regulated genes.Histologically, ASPS has a distinctive appearance, usually consisting of nests of epithelioid to polygonal cells arranged in nests or bundles, sometimes with a central lack of cohesion that is reminiscent of pulmonary alveolar structures. Intracellul...