Spindle cell tumor of urinary bladder serosa with phenotypic and genotypic features of gastrointestinal stromal tumor

Most mesenchymal tumors of the gastrointestinal tract are now referred to as gastrointestinal stromal tumors (GISTs). The tumors differ from ordinary leiomyomas and schwannomas in several respects: the GISTs typically express c-kit protein (CD117) and CD34, 30% to 50% of them are (often focally) positive for alpha-smooth muscle actin, and all are negative for desmin and S100 protein. Recently, mutations in the exon 11 of the c-kit gene have been identified and confirmed as a molecular genetic marker for the subset of GISTs. In this report, we describe a mesenchymal tumor removed from the pelvic cavity of a 52-year-old woman, who is alive without disease 36 months after the surgery. The 5-cm tumor was densely attached to the external aspect of the urinary bladder but was attached to small intestine by only filmy adhesions. The tumor grossly resembled a leiomyoma and was histologically composed of sheets of spindle cells with a dense collagenous background. The mitotic activity was low, less then 1 per 50 high-power fields. Immunohistochemically, the tumor cells were negative for alpha-smooth muscle actin and desmin and positive for CD117 and CD34. Molecular genetic analysis of the exon 11 of the c-kit gene revealed a point mutation in the region commonly mutated in GISTs. This mutation substituted T for A in the codon 557, leading to the change of amino acid sequence (tryptophan for arginine) of the KIT protein. This case illustrates that tumors phenotypically and genotypically similar to GISTs may present in sites other than the tubular gastrointestinal tract.     

Patterns of nestin and other intermediate filament expression distinguish between gastrointestinal stromal tumors,leiomyomas and schwannomas

The KIT-positive specific gastrointestinal stromal tumors (GISTs), leiomyomas, and schwannomas are the three most common types of primary mesenchymal tumors of the gastrointestinal (GI) tract. The intermediate filaments are abundant cytoskeletal proteins commonly used as cell differentiation markers in diagnostic immunohistochemistry. Their patterns have not been fully characterized in GI mesenchymal tumors, and could offer differential diagnostically useful parameters. Very recently, nestin, a class VI intermediate filament expressed in neuroectodermal stem cells and skeletal muscle progenitor cells, has been shown in GISTs and suggested as a marker for these tumors. In this study we immunohistochemically examined the expression of nestin and other intermediate filament proteins, including desmin, keratins (Ks), glial fibrillary acidic protein (GFAP), neurofilament, and vimentin in GISTs of different sites, esophageal leiomyomas and GI schwannomas. Nestin was nearly consistently present in GISTs of different locations whether spindle cell or epithelioid, and benign or malignant. It was also detected in 23 of 24 (96%) GI schwannomas, whereas leiomyomas were uniformly negative. Vimentin was present in both GISTs and schwannomas, whereas it was typically absent in leiomyomas (25% positive, usually focally). Desmin was present in all leiomyomas, whereas only 3% of GISTs (4 of 140) were positive, and all schwannomas were negative. K18 was detected in a minority of GISTs, leiomyomas, and schwannomas. Malignant GISTs were more commonly keratin positive than the benign ones; there was 18% K18 positivity in malignant gastric and small intestinal GISTs, but 9% K18 positivity in benign gastric and small intestinal GISTs. Moreover, K8, albeit to a lesser degree, was detected in a minority of GISTs, but K7, K14, K19 and K20 were not detected. GFAP was present in the majority of schwannomas, whereas all GISTs were negative; some leiomyomas had weak cytoplasmic positivity. These results document distinctive patterns of intermediate filament proteins in GI mesenchymal tumors. Nestin is confirmed to be consistently expressed in GISTs but it is also present in most GI schwannomas; GFAP is helpful when separating GISTs and schwannomas, since only the latter are positive. The potential presence of K8 and K18 in GISTs should not lead to the misdiagnosis of carcinoma on biopsy.     

Diagnosis of gastrointestinal stromal tumors: A consensus approach

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.     

Peripheral blood CD4+CD8+ lymphocytes in cynomolgus monkeys are of resting memory T lineage

In this study, we analyzed peripheral blood CD4+CD8+ double-positive (DP) lymphocytes in adult cynomolgus monkeys (Macaca fascicularis). Forty of 55 monkeys had > 5% of the peripheral blood DP subpopulation (9.3 +/- 5.9%; mean +/- SD) in peripheral blood lymphocytes (PBL) in contrast to a low percentage of peripheral blood DP cells in humans and mice. In a cross-sectional study, the peripheral blood DP cells were found to increase in proportion with age. To clarify whether peripheral blood DP lymphocytes were immature precursors released from thymus without prior differentiation, the expressions of CD8 chains and CD1b on peripheral blood DP lymphocytes were compared with those on thymocytes. The peripheral blood DP lymphocytes were CD8 alpha + beta- and CD1b-, while thymic DP lymphocytes were CD8 alpha + beta + and CD1b +, suggesting that the peripheral blood DP cells are extrathymic T lymphocytes. Furthermore, the peripheral blood DP lymphocytes exhibited a resting memory T cell phenotype with CD2hiCD3+CD28-CD29hiCD49dhiCD69- CD80lo. Taken together, adult cynomolgus monkeys possess a unique peripheral blood DP T cell subpopulation which expresses a resting memory T cell phenotype. In addition, similar phenotypic properties of DP lymphocytes were distributed in the spleen and lymph nodes, although the proportion was less in the spleen and much less in lymph nodes than in PBL.      

Mutations in gastrointestinal stromal tumors--a population-based study from Northern Norway

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30-year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild-type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST.     

Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells

Macrophages and dendritic cells (DC) are APC, which regulate innate and adaptive immune responses. Macrophages function locally mainly, maintaining inflammatory responses in tissues, whereas DC take up microbes, mature, and migrate to local lymph nodes to present microbial antigens to na?ve T cells to elicit microbe-specific immune responses. Blood monocytes can be differentiated in vitro to macrophages or DC by GM-CSF or GM-CSF + IL-4, respectively. In the present study, we performed global gene expression analyses using Affymetrix HG-U133A Gene Chip oligonucleotide arrays during macrophage and DC differentiation. During the differentiation process, 340 and 350 genes were up-regulated, and 190 and 240 genes were down-regulated in macrophages and DC, respectively. There were also more that 200 genes, which were expressed differentially in fully differentiated macrophages and DC. Macrophage-specific genes include, e.g., CD14, CD163, C5R1, and FcgammaR1A, and several cell surface adhesion molecules, cytokine receptors, WNT5A and its receptor of the Frizzled family FZD2, fibronectin, and FcepsilonR1A were identified as DC-specific. Our results reveal significant differences in gene expression profiles between macrophages and DC, and these differences can partially explain the functional differences between these two important cell types.     

A (9;11)(q34;q13) translocation in a hibernoma

The diagnosis of hibernoma has historically been made by histopathologic examination and finding of characteristic brown fat cells with granular multivacuolated cytoplasm. The diagnosis of hibernoma may be complicated, however, because seemingly diagnostic cells could be mistakenly identified as lipoblasts, leading to the erroneous diagnosis of well-differentiated liposarcoma. Cytogenetic alterations in lipomatous tumors are well established and could be used for diagnostic purposes. Previous cytogenetic abnormalities reported in hibernomas have included alteration of 11q13 region. Here, we present a case of a hibernoma with a novel cytogenetic alteration involving a reciprocal translocation between 9q and 11q that was useful in establishing the final diagnosis.