Endometrial cancer constitutes a heterogeneous group of diseases, in terms of clinical course, underlying molecular disorders, morphology and therapeutic strategy. The most frequent variety is type I or endometrioid cancer. As compared with type II, or non-endometrioid cancer, it usually develops in younger women as a result of prolonged estrogen stimulation within endometrium with features of atypical hyperplasia or a condition defined as endometrial intraepithelial neoplasia (EIN). In terms of morphology, it usually forms an exophytic (rarely endophytic) tumor and presents a high or moderate grade of differentiation. Patients usually present at an initial stage of the disease, with tumor infiltrate rarely exceeding half of uterine wall thickness; lymph node metastases are rare too. Non-endometrioid cancer usually affects older women, where it develops within a flat, atrophic endometrium with no signs of hyperplasia. It is always qualified as poorly differentiated and according to WHO classification its degree of differentiation is not graded. It usually presents an aggressive clinical course, infiltrating over one half of uterine wall thickness, invades the serous membrane and regional lymph nodes. Types I and II of endometrial cancer differ also in terms of underlying molecular disorders. Type I is associated with mutations of genes K-ras, PTEN and MLH1 (DNA repair). Type II is associated with mutation of TP53. The key issue in developing therapeutic strategy is microscopic assessment of type and grade of histological maturity, as well as clinical-pathological stage of cancer. An important issue is to apply currently valid WHO, TNM and FIGO classifications. Objective difficulties in interpretation of microscopic features in some cases result in increasingly frequent use of molecular and immunohistochemical studies in routine pathological diagnostic work-up.
Background: Angiogenesis is a key process in the development of a malignant tumor, enabling both growth of primary lesion and spread of metastases. Most potent stimulators of normal and pathological angiogenesis are proteins of the vascular endothelial growth factor (VEGF) family. Regulation of angiogenesis process is also mediated by neuropilin-1 (NP-1), as coreceptor VEGFR-2. NP-1 plays a crucial role controlling both normal angiogenesis during embryonal development and pathological angiogenesis in malignant tumors. The aim of this paper was to assess NP-1 expression in ovarian cancer and to analyze correlations between NP-1 expression and selected clinical-pathological factors in a group of ovarian cancer patients. Material and method: Analyzed was the relative level of NP-1 in 168 surgical specimens collected during surgical procedures performed at the Department of Oncologic Gynecology of Medical University in Gdańsk. Tissue samples included: 32 healthy tissues, 42 benign tumors, 10 borderline tumors, 76 ovarian cancers, 8 metastatic tumors. Relative NP-1 level was assessed using Western blotting technology. Results: Overexpression of NP-1 was seen significantly more often in early clinical stages of ovarian cancer (p=0.01), in cancers other than serous (p=0.04) and in patients with peritoneal exudate (p=0.03). Log-rank test did not reveal any significant correlation between NP-1 expression and favorable response to chemotherapy, disease-free survival or total survival time. Conclusions: Elevated NP-1 level seen in initial clinical stages of ovarian cancer may indicate crucial role of neoangiogenesis in the early phase of tumor development.
Introduction: Treatment outcome in patients with ovarian cancer are still unsatisfactory, mainly due to considerably advanced stage of disease at diagnosis. Patients not eligible for primary cytoreductive surgery increasingly frequently undergo neoadjuvant chemotherapy. Aim of paper: The aim of this paper was to assess treatment outcome in patients with FIGO stage III ovarian cancer undergoing standard treatment (primary cytoreductive surgery with subsequent paclitaxel- and platinum analog-based chemotherapy) compared with neoadjuvant chemotherapy with delayed cytoreductive surgery. Analysis encompassed early and late treatment outcomes and complications in both groups. Material and method: Analysis included patients with FIGO stage III ovarian cancer, treated at the Department of Female Genital Tumors at the Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, since 2003 thru 2005. Original group of 86 patients meeting inclusion criteria was subdivided into subgroups, depending on treatment protocol implemented. Control group included 45 patients after primary optimal cytoreduction and complementary chemotherapy. Study group included 26 patients receiving neoadjuvant chemotherapy with delayed surgery. Results: Mean follow-up was 38.5 months. A noticeable initial intergroup difference consisted in higher incidence of ascites and higher baseline titer of CA-125 in the neoadjuvant chemotherapy group. Surgery was considered radical in 63.4% of patients undergoing primary surgery and in 80.8% of those operated on after 3 cycles of chemotherapy. Delayed surgery was associated with a significantly lower blood loss. Therapeutic response and progression-free or recurrence-free survival did not differ in both groups. Conclusions: Neoadjuvant chemotherapy with delayed cytoreductive surgery in many cases improves the outlook of initially inoperable patients.
Radiotherapy implemented in the treatment of patients with female genital malignancies consists in fractionated irradiation of the patients in the same therapeutic position, lasting for 4 to 6 weeks. Currently used conformal techniques with intense dose modulation (intensity modulated radiation therapy, IMRT) precisely define treated area and critical organs located within. This paper explores the difference in volume of treated and protected areas in patients with cervical cancer and endometrial cancer placed prone for radiotherapy in a belly board BBD support, as compared with traditional positions used to date, i.e. supine or prone position BBD support. Treatment plans were elaborated for 20 patients for these three therapeutic positions and treated and protected areas were compared. Analysis revealed that only obese patients (BMI>27) in prone position with BBD support had smaller volume of irradiated bowel as compared with prone position without support (p=0.049), and particularly with supine position (p=0.008). Other patients with normal BMI value or slim persons did not benefit from the use of BBD support. After an at least 24 months’ long follow-up we monitored the incidence of radiation-induced reactions among patients using the BBD support and persons irradiated according to the same conformal technique but placed prone without BBD support. The study revealed that the incidence and severity of radiation-induced reaction in both groups of patients were similar.
Hyperthermia may be defined as a way of controlled elevation of temperature, targeted on neoplasm or adjacent tissues, organs, body part(s) or entire body. The first medical application of hyperthermia in modern medicine was described by Westermark in 1898: he used containers with continuous flow of water at temperature of 42-44°C to treat inoperable cervical cancer. In studies performed to date, hyperthermia was combined with standard therapeutic modalities – radiotherapy and chemotherapy, both intravenous and intraperitoneal. Studies revealed that effects of hyperthermia include induction of apoptosis, both mediated by suppressor protein p53 and by an independent mechanism. Depending on the range of temperatures used, hyperthermia may be classified as mild (about 39°C), moderate (40-41°C) and intense (over 42°C). Chemotherapeutic agents whose effect is enhanced by concomitant hyperthermia include alkylating drugs (ifosfamide, cyclophosphamide), antineoplastic antibiotics (bleomycin, adriamycin, mitomycin C and actinomycin), platinum derivatives, antimetabolites (5-fluorouracil) and gemcitabine (administered a day before or a day after heating). Hyperthermia combined with radiotherapy has a synergistic effect. This effect depends on degree of temperature elevation in target tissue (the higher the temperature, the greater the effect), duration of heating and chronologic order of implementation of both modalities. It appears that hyperthermia may contribute to improvement of still unsatisfactory treatment outcomes in gynecologic oncology, particularly in patients with ovarian cancer, cervical cancer and endometrial cancer.
The paper is a detailed review of recent advances in the treatment of ovarian cancer patients using intraperitoneal chemotherapy. Theoretical basis of intraperitoneal treatment is discussed, this being understood as passage of substances through semipermeable membrane, where rate of passage depends on peritoneal clearance, size and electric charge of particles and concentration gradient. History of intraperitoneal treatment is reviewed, starting with early works by Green and Kottmeier dating back to the ‘50s, and ending with recent studies, including a meta-analysis of 8 randomized trials of first-line treatment published within the past 12 years, which included a total of 1819 patients. The authors discuss reasons for issuing pertinent recommendations by the US National Cancer Institute, emphasizing the leading role of intraperitoneal chemotherapy in the treatment of ovarian cancer patients. Effectiveness of platinum derivates-based chemotherapy in consolidation treatment is discussed, supported by a review of pivotal papers concerning this subject. The paper presents and discusses key reports on implementation of intraperitoneal chemotherapy in consecutive lines of treatment of ovarian cancer, as well as the role of cisplatin and carboplatin in intraperitoneal therapy, highlighting differences in outcome after application of both agents. Emphasized are also limitations of the method. Next, the authors review surgical complications arising during procedures associated with implementation of intraperitoneal chemotherapy, as well as several aspects of complications resulting in premature interruption of intraperitoneal chemotherapy (on the average: 50% of cases; up to 60% in the GOG 172 trial). Critique of the method, mainly on the part of European centers, is referred to.
Immunotherapy nowadays becomes an increasingly important topic in oncology. Immunotherapeutic strategies implemented to date focused mainly on stimulation or supplementation of function of effector cells. Past decade witnessed a tremendous progress in our understanding of mechanisms whereby tumors acquire an ability to escape host’s immune surveillance. There appeared the notion of cancer-dependent “immunosuppressive network”. An indicator of immunosuppression in tumor microenvironment is the presence of regulator T lymphocytes (Tregs) of the CD4+T subgroup. Expression of FOXP3 is directly associated with suppressive function of these cells. Other studies revealed that indoleamine 2.3-dioxygenase (IDO) induces peripheral immune tolerance to tumor antigens. In physiological conditions, IDO is indispensable in creation of a microenvironment preventing destruction of selected tissues by “hyperactive” immune system. It is currently believed that IDO-dependent increase of immune suppression enables survival and proliferation of cancer cells. Analysis of expression of FOXP3 antigens and IDO will provide an insight to the extent of “immunosuppressive network” in direct neighborhood of vulvar cancer cells and in adjacent lymphatic system. Further research focused on tumor-dependent “immunosuppressive network” is of paramount importance, as it may provide entirely new targets for therapeutic intervention, this time using low-molecular-weight compounds instead of biological factors used hitherto in immune therapies. This paper explains basic concepts of immunoedition theory and describes the role of IDO and regulatory T lymphocytes (Tregs) in the escape of cancer cells from immune surveillance.
Cervical cancer is, after breast cancer, the second most common malignant tumor in females. As in a significant proportion of cases it is detected only at a late clinical stage, early diagnosis thereof, at best at the stage of dysplastic conditions, is a vital issue in oncologic gynecology. Diagnostic work-up is based on cytological studies, colposcopy, virusological tests and histological examination of tissue samples. Results of microscopic studies are crucial in this setting. Precise and reliable diagnosis requires representative tissue samples. This is particularly important in the case of low-grade or multifocal lesions. Such requirements are met by photodynamic method. The essence of photodynamic diagnosis (PDD) is comparison of fluorescence of normal and pathological tissue. This method makes use of endogenous fluorochromes (autofluorescence) or exogenous photosensitizing substances. Intensity of fluorescence in tumor tissue differs from that seen in healthy tissue. Application of a photosensitizer significantly enhances quality of images obtained, as it increases detection of light emitted by photosensitizer accumulated in pathological tissue. In order to excite fluorescence, energy must be applied to the tissue, of wavelength corresponding to wavelength absorbed by the photosensitizer. Photodynamic method precisely localizes pathological tissue, thus enabling a more reliable diagnosis of neoplastic conditions of the cervix. This enables selection of an optimal location for sampling tissue, providing information on extent and topography of lesions, which is crucial for adequate planning of therapy.