Recent breakthroughs regarding gastrointestinal stromal tumors (GIST) and their pathogenesis have redefined diagnostic criteria and have led to the development of molecularly targeted drug therapy. ...New treatment options mandate more accurate information regarding the incidence, prevalence, clinical behavior, and prognostic factors of GIST.
All patients (n=1460) who potentially had GIST diagnosed from 1983 to 2000 in western Sweden (population, 1.3-1.6 million) were reviewed, and 288 patients with primary GIST were identified. The incidence and prevalence of GIST were determined, and predictive prognostic factors, including current risk-group stratifications, were analyzed statistically.
Ninety percent of GISTs were detected clinically due to symptoms (69%) or were incidental findings at surgery (21%); the remaining 10% of GISTs were found at autopsy. Forty-four percent of symptomatic, clinically detected GISTs were categorized as high risk (29%) or overtly malignant (15%), with tumor-related deaths occurring in 63% of patients and 83% of patients, respectively (estimated median survival, of 40 months and 16 months, respectively). Tumor-related deaths occurred in only 2 of 170 of patients (1.2%) with very-low-risk, low-risk, or intermediate-risk tumors. The annual incidence of GIST was 14.5 per million. The prevalence of all GIST risk groups was 129 per million (31 per million for the high-risk group and the overtly malignant group).
GIST has been under recognized: Its incidence, prevalence, and clinical aggressiveness also have been underestimated. Currently existing risk-group stratification systems based on tumor size and mitotic rate delineate GIST patients who have a poor prognosis. Prognostication in patients with GIST can be refined using a proposed risk score based solely on tumor size and proliferative index.
Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic ...characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them. We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients. Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing. We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.
Background & Aims:
Gain-of-function mutations in the
KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor α (
PDGFRA) gene are important events in ...gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up.
Methods:
Genomic DNA from 177 GIST patients was analyzed for
KIT exons 9, 11, 13, and 17 and
PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing.
Results:KIT
exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT)
KIT and
PDGFRA were detected in 63;
KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and
PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST ≤1 cm had mutations in 73% and 33%, respectively.
KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST.
KIT exon 11 deletions adversely affected outcome.
KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively.
Conclusions: KIT
exon 11 deletion is an independent adverse prognostic factor in patients with GIST.
Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of ...SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.
BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like ...morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis.
Aims
Myoepithelial tumours of soft tissue are rare lesions with a broad morphological and clinical spectrum. Previous studies have found EWSR1 rearrangements in approximately half of all cases and ...PBX1, ZNF44 and POU5F1 have been identified as recurrent fusion partners. In bone, only a small number of myoepithelial tumours have been described. We investigated an intraosseous myoepithelioma of the sacrum in a 54‐year‐old man without EWSR1 rearrangement for the presence of other fusion genes.
Methods and results
G‐banding analysis, SNP‐array and fluorescence in situ hybridisation suggested rearrangement of the FUS and POU5F1 genes. RT‐PCR confirmed a chimeric in‐frame transcript fusing FUS exon 5 to POU5F1 exon 2. The clinical course after en bloc resection was without recurrence or metastasis over a period of 87 months.
Conclusion
We report a novel FUS‐POU5F1 fusion gene in an intraosseous myoepithelioma of the sacrum. This case highlights that FUS can replace EWSR1 as the N‐terminal transactivator in oncogenic fusion genes in myoepithelial tumours, similar to that which has previously been demonstrated in other tumour entities. Thus, in addition to EWSR1, also FUS needs to be considered as a potential fusion partner in the molecular work up of myoepithelial tumours.
