Projects / Programmes
Characteristics of Malignant Neoplasms Important for Diagnosis, Prognosis and Treatment Outcome
July 1, 2004
- December 31, 2008
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| B520 |
Biomedical sciences |
General pathology, pathological anatomy |
| B490 |
Biomedical sciences |
Haematology, extracellular fluids |
cancer, prognostic factors, immunohistochemistry, tissue microarrays, cytometry, fine needle aspiration biopsy
Researchers (23)
Organisations (2)
Abstract
Microscopic examination of routinely stained slides with tumor tissue and the study of its morphology still plays the primary role in diagnosis of malignant and premalignant processes; however, their phenotypic and genetic characteristics can nowadays be better assessed by a number of modern techniques, such as immunocytochemistry, molecular biology and genetics, and flow and image cytometry. The aim of our study is to evaluate the value of these methods in diagnosis, prognostication and treatment planning in selected fields of oncology.
In the field of breast tumors, our research will be focused on early breast carcinoma. Prognostic value of various immunohistochemical markers will be assessed on a large number of tumors from patients with long follow-up using the tissue microarray (TMA) technology. Further studies will involve patients with axillary lymph node micrometastases. The incidence of these has been increasing due to extensive use of sentinel lymph node biopsy approach; however, their biologic significance is not clear.
The main area of research in the field of soft tissue tumors will be a retrospective study of tumors showing muscle differentiation, i.e. leiomyosarcoma and rhabdomyosarcoma, as well as tumors of the PNET/ES (primitive neuroectodermal tumor / Ewing sarcoma) group.
Another area of research will encompass malignant lymphomas and leukemias. Here, the focus will be on assessment of their phenotype and genotype and their changes during treatment, disease regression and progression. The feasibility of immunology, cytogenetics and molecular biology in the assessment of disease persistence or complete eradication will also be evaluated. Another area of concern will be immunophenotyping of fine needle aspiration biopsy (FNAB) samples obtained from lymph nodes and evaluation of its utility in diagnosis and follow up. FNAB material will also be used to prospectively study changes in thyroid carcinomas undergoing treatment with chemotherapy.
A part of the program will be devoted to studying preneoplastic changes, in particular those in the breast and uterine cervix; and to studying malignancy associated changes (MAC), i.e. changes that occur in non-neoplastic cells in the individuals with cancer. These changes can be detected by image cytometry and may have potential in early cancer detection.
Significance for science
The research in the field of breast carcinoma was mainly focused on DNA flow cytometry and evaluation of HER2 status. In the largest published series of patients in whom DNA flow cytometric analysis was performed on fine needle aspirates, we showed that S-phase fraction (SPF) was – in addition to lymph node status, histological grade and tumor size – an independendent prognostic factor for overall and desease-free survival. We showed that in routine practice HER2 status of breast carcinoma can be reliably determined on tissue microarrays (TMA) in 80% of cases, which reduces the cost of reagents by 75%. TMA approach makes parallel testing of each tumor by IHC and FISH affordable, thus allowing better characterization of HER2 status and, consequentially, more appropriate treatment of breast cancer patients. Our results indicate that the proportion of HER2-positive breast carcinomas (approx. 15%) is lower than previously thought and is strongly correlated to histologic grade, hormone receptor negativity and presence of lymphovascular invasion. In the group of grade 1 tumors this proportion is so low (1-2%) that in this subset HER2 testing should not be considered a standard of care for all patients. Our research on possible prognostic factors in follicular carcinoma of the thyroid indicates that, in addition to widely invasive pattern of growth, reduced expression of E-cadherin is an independent adverse factor for distant metastasis-free survival. DNA ploidy and SPF as determined by flow cytometry, as well as MIB1-labeling index as determined by immunohistochemistry, have no impact on survival. E-cadherin expression also retains its prognostic value in the subgroup of widely invasive follicular carcinomas. In the area of soft tissue tumors we showed that in synovial sarcoma, in contrast to some previous reports, there is no correlation between the type of chymeric transcript SYT-SSX and prognosis. It appears, however, that in Slovenian paatients the proportion of tumors with SYT-SSX2 transcript is significantly higher than in Western Europe or North America. We found that in follicular lymphoma, immunohistochemical markers of germinal center differentiation, in particular PU.1, add independent prognostic information to that provided by well established prognostic indices, such as IPI or FLIPI. We developed a new highly sensitive method for quantitative evaluation of platelet glicoprotein GPIIIa expresion and introduced modifications of the methods for flow cytometric immunophenotyping of fine needle aspiration biopsy (FNAB) samples, which significantly increased the proportion of routinely obtained samples on which this ancillary technique could be successfully applied. We evaluated the relative role of flow cytometric immunophenotyping and RT-PCR based detection of gene rearrangements in cytological diagnosis of B-cell and T-cell lymphomas. We also confirmed that various types of lymphomas show significantly different levels of expresion of CD52, the target for the new biological drug alemtuzumab. Malignancy associate changes (MAC) were studied by image analysis of buccal mucosa smears. We found that lung and breast cancer induce MACs in normal mucosal cells. Classifiers based on selected nuclear features correctly recognized more than 80% of cancer cases and MAC detection was not dependent on the tumor subtipe, size or stage. The presence of MAC in buccal mucosa cells offers the potential for developing a new noninvasive cancer screening test.
Significance for the country
The achievements of the programme group were published in distinguished international journals and presented at international scientific meetings, which should lead to better international recognition of Slovenia and further intesify the integration of Slovenian researchers in the international research community. At home, they lead to introduction of new methods and improvement of routine diagnostic work. As the mebers of the research group are affiliated to institutions that are involved with diagnosis, treatment and follow up cancer patients, many findings have already been incorporated into routine practice. Thus, the reliability and accuracy of diagnosing lymphomas from cytological samples and determining HER2 status in breast carcinoma have improved, which should lead to more appropriate and rational treatment of patients with this forms of cancer.
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