Dong H. Lee

Bio: Dong H. Lee is an academic researcher. The author has contributed to research in topics: Survival analysis & Surgery. The author has an hindex of 1, co-authored 1 publications receiving 633 citations.

Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site.

Abstract: Although the significance of various prognostic factors, such as tumor size and mitotic index (MI), has been well established for smooth-muscle tumors of the stomach, the significance of these factors in other sites is less well defined. We studied 1004 patients with gastrointestinal smooth-muscle tumors for whom vital status could be determined. The average MI and tumor size varied significantly among the five major sites examined: esophagus (53 cases), stomach (524 cases), small bowel 252 cases), colon/rectum (108 cases), and omentum/mesentery/peritoneum (67 cases). There was a significant difference in site-specific survival (p = 0.001), with 10-year survival varying between 50% and 70%. Multivariate analysis demonstrated tumor location (p = 0.0320), size (p = 0.0003), MI (p < 0.0001), and patient age (p < 0.0001) to each carry independent prognostic value. The significance of MI was highly site dependent. Separation of survival curves for the stomach, using a threshold for analysis of either 5 or 10 mitotic figures/50 high-power fields, was very good. In contrast, small-bowel tumors showed little separation between survival curves, regardless of whether a threshold of 1, 5, or 10 mitotic figures MF/50 high-power fields was used to distinguish groups. In no site were tumor size and MI alone sufficient to provide an accurate long-term prediction of prognosis. Although tumor location, size, MI, and age have independent value in predicting the prognosis of patients with gastrointestinal smooth-muscle tumors, better methods are still required to accurately predict clinical course.

Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis.

Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastroin- testinal (GI) tract. They are defined here as KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cell or epithelioid neoplasms primary in the GI tract, omentum, and mesentery. GISTs typically present in old- er individuals and are most common in the stomach (60-70%), followed by small intestine (20-25%), colon and rectum (5%), and esophagus (<5%). Benign tumors outnumber the malignant ones by a wide margin. Ap- proximately 70% of GISTs are positive for CD34, 20-30% are positive for smooth muscle actin (SMA), 10% are positive for S100 protein and <5% are positive for desmin. The expression of CD34 and SMA is often reciprocal. GISTs commonly have activating mutations in exon 11 (or rarely exon 9 and exon 13) of the KIT gene that encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Ligand-independent activation of KIT appears to be a strong candidate for molecular pathogenesis of GISTs, and it may be a target for future treatment for such tumors. Other genetic changes in GISTs discovered using comparative genomic hybridization include losses in 14q and 22q in both benign and malignant GISTs and occurrence in various gains predominantly in malignant GISTs. GISTs have phenotypic similarities with the in- terstitial cells of Cajal and, therefore, a histogenetic ori- gin from these cells has been suggested. An alternative possibility, origin of pluripotential stem cells, is also possible; this is supported by the same origin of Cajal cells and smooth muscle and by the common SMA ex- pression in GISTs. GISTs differ clinically and pathoge- netically from true leiomyosarcomas (very rare in the GI tract) and leiomyomas. The latter occur in the GI tract, predominantly in the esophagus (intramural tumors) and the colon and rectum (muscularis mucosae tumors). They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. Other mesenchymal tumors that have to be separated from GISTs include inflamma- tory myofibroblastic tumors in children, desmoid, and dedifferentiated liposarcoma. Angiosarcomas and meta- static melanomas, both of which are often KIT-positive, should not be confused with GISTs.

Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up.

Abstract: Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. In this study, we analyzed 1869 cases originally classified as smooth muscle tumors of the stomach and found that 1765 (94%) of these were GISTs. The GISTs had a slight male predominance (55%) with a median age of 63 years. Only 2.7% of tumors occurred before the age of 21 years and 9.1% before the age of 40 years. The tumors varied from 0.5 to 44 cm (median, 6.0 cm) and most commonly presented with GI bleeding; 12% were incidentally detected. Several histologic variants were recognized among the spindle cell tumors (sclerosing, palisaded-vacuolated, hypercellular, and sarcomatous) and of epithelioid tumors (sclerosing, dyscohesive, hypercellular, and sarcomatous). Outcome was strongly dependent on tumor size and mitotic activity. Only 2% to 3% of tumors 10 cm and >5 mitoses/50 HPFs metastasized. However, tumors >10 cm with mitotic activity 5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were unfavorable factors (P <0.001), whereas tumor location in antrum was favorable (P <0.001). KIT expression was detected in 91% of the cases, CD34 in 82%, smooth muscle actin in 18%, and desmin in 5%; the latter two were favorable (P <0.001). KIT exon 11 mutations were detected in 119 cases; patients with point mutations fared better than those with deletions (P <0.01). PDGFRA exon 18 mutations (total 86 cases) were common in epithelioid GISTs and most commonly represented a D842V point mutation; none of these was prognostically significant. The above results may be helpful for setting the criteria for adjuvant treatment such as Gleevec.

Biology of gastrointestinal stromal tumors.

Abstract: Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.