It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype.
Gastrointestinal stromal tumor (GIST) is now defined as a specific, KIT-expressing and KIT-signaling driven mesenchymal tumor of the gastrointestinal (GI) tract. The specific identification of GIST has become more important after the availability of KIT-selective tyrosine kinase inhibitor Imatinib mesylate, STI571, commercially known as Gleevec/Glivec (Novartis Pharma, Basel, Switzerland) in the treatment of unresectable and metastatic tumors. GISTs are the most common mesenchymal neoplasms of the GI tract, and encompass most tumors previously classified as gastric and intestinal smooth muscle tumors. GISTs typically present in adults over 40 years (median age 55-60 years) and only exceptionally in children. They can present anywhere in the GI-tract from the lower esophagus to the anus. A great majority of GISTs occur in the stomach (60-70%) or small intestine (25-35%). Colon, rectum, appendix (together 5%) and esophagus (2-3%) are rare sites. Some GISTs are primary in the omentum, mesentery or retroperitoneum, unrelated to the tubular GI-tract, but most GISTs in these sites are metastases from gastric or intestinal primary. Histologically GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones, and morphology differs somewhat by site. By definition, GISTs are KIT(CD117)-positive. Positivity for nestin (90-100%) and CD34 (70%) are also characteristic but less specific features. Smooth muscle actins (20-30%) and heavy caldesmon (80%) are often expressed, whereas desmin is usually absent. Predictive of malignancy are mitotic rate over 5 per 50 HPF or size over 5 cm. However, mitotically inactive intestinal tumors can metastasize, and gastric tumors are in average less often malignant than the intestinal ones. True smooth muscle tumors, GI-schwannoma and undifferentiated sarcomas are the most important differential diagnoses. KIT activating mutations occur in 70-80% of cases. Their signaling consequences, clinical correlation and response to tyrosine kinase inhibitors, and specific genetic alterations are under intense investigation. Majority of these mutations are in-frame-deletions and missense mutations clustering in the 5'-end of juxtamembrane domain (exon 11). A rare mutation, an Ala502-Tyr503 duplication in exon 9, is specific for intestinal GISTs.
Adult T-cell leukemia (ATL) was first reported as a distinct clinical entity in 1977 in Japan. The predominant physical findings are skin lesions, lymphadenopathy and hepatosplenomegaly. The ATL cells are of mature T-helper phenotype and have a characteristic appearance with indented nuclei. There is striking frequent hypercalcemia with increased numbers of osteoclasts. Central to the identification of the disease is a striking geographic clustering in southwestern Japan and the isolation of human T-cell lymphotropic virus type-1 (HTLV-1) from the cell lines of patients. Worldwide epidemiological studies have been made through international collaborations. Several diseases were found to be related to HTLV-1 infection. Moreover, it was noted that an immunodeficiency state may be induced by HTLV-1 infection. In Japan, HTLV-1 carriers have been estimated to be 1.2 million, and more than 700 cases of ATL have been diagnosed each year.
Since 1978 the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG) has conducted six consecutive clinical trials against aggressive adult T-cell leukemia-lymphoma (ATL). ATL patients were included in the three earlier trials for advanced non-Hodgkin's lymphoma (NHL) [JCOG7801 (1978-80), JCOG8101 (1981-83) and JCOG 8701 (1987-96)]. The 4-year survival rate of ATL patients in the JCOG8101 and JCOG8701 was only 8% and 12%, respectively, and prognostic factor analyses of both studies revealed that a diagnosis of ATL was significantly associated with shortened survival. Thus, the following three trials have been conducted exclusively for ATL: JCOG9109 (1991-93), JCOG9303 (1994-96) and JCOG9801 (1998-). Based on the promising results of deoxycoformycin (DCF) in ATL patients, a phase IT study of DCF-containing combination chemotherapy was conducted (JCOG9109). However, the clinical outcome of ATL patients was not improved: complete response (CR) rate, 28% (17/60); median survival time (MST), 7 months;, 2-year survival rate, 17%. In 1994, a phase 11 study of a granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy (JCOG9303) was initiated. In this protocol, LSG15, ranimustine and carboplatin were included to overcome the multidrug resistance of ATL cells. The overall response rate was 81% (75/93), and the CR rate was 36%. The MST was 13 months and 2-ycar survival rate was 31%. The therapeutic results of JCOG9303 were superior to those obtained by the previous JCOG-LSG trials. To confirm whether the LSG15, a G-CSF-supported multi-agent treatment strategy, is a new standard in ATL chemotherapy, a randomized phase III study (JCOG9801) comparing it with biweekly CHOP is going on.Despite the consecutive clinical trials by the JCOG-LSG to develop more effective chemotherapy regimens, most ATL patients are still incurable with current chemotherapies. Further efforts to incorporate new innovative treatment modalities are needed such as new anticancer agents, monoclonal antibody therapies and allogeneic hematopoietic stem cell transplantation (HSCT) including non-myeloablative HSCT.
