[The morphological and immunohistochemical characteristics of stratified mucin-producing intraepithelial lesion]. / Morfologicheskie i immunogistokhimicheskie osobennosti mnogosloinogo mutsinprodutsiruiushchego intraépitelial'nogo porazheniia.

Stratified mucin-producing intraepithelial lesion (SMILE) is a rare premalignant cervical lesion that combines the structural features of cervical intraepithelial neoplasia (CIN) and endocervical adenocarcinoma in situ (AIS). AIM: to analyze archival materials for the detection of SMILE and its subsequent morphological and immunohistochemical characterization. MATERIAL AND METHODS: Cervical cone specimens from 53 women with histologically verified CIN3 were examined. The diagnosis of SMILE was based on the positive mucicarmine staining and weak focal expression of p63. The samples containing SMILE were further immunohistochemically examined using the biomarkers P16, Ki-67, Oct4, CD117, CD34, p53, EMA, and CK15. SMILE was detected in 2 of the 53 patients and concurrent with CIN3 in both cases. SMILE was characterized by the stratified arrangement of atypical cells containing mucin, the positive mucicarmine staining of the entire layer of the atypical epithelium, weak focal p63 expression, high Ki-67 expression, and diffuse р16Іnk4а staining. Both SMILE samples showed weak diffuse p53 expression in the presence of single cells with the pronounced nuclear staining pattern for p53 in one female patient. Weak focal CK15 expression was visualized in SMILE. The expression of the stem cell markers Oct4 and CD117 and the angiogenic marker CD34 was absent in the examined cervical epithelial preparations. The diffuse and intense expression of the marker EMA, which was not different from that in the endocervical and stratified squamous epithelium, and CIN3 was established in SMILE. RESULTS: The findings suggest that SMILE is morphologically and immunohistochemically similar to CIN3. In this investigation, these abnormalities differed only in the mucicarmine staining and expression of p63. This may be indicative of the underdiagnosis of SMILE, attendant СIN3 in the routine practice of a clinical pathologist, as the diagnosis of CIN3 is primarily based on the results of assessment of only the preparations stained with hematoxylin and eosin; the expression of p16 and Ki-67 is evaluated in some cases, which fails to differentiate SMILE and CIN3 in a number of preparations. CONCLUSION: The diagnosis of SMILE can be made only by immunohistochemical examination.

[Expansion of secretory cells in the fallopian tubal epithelium in the early stages of the pathogenesis of ovarian serous carcinomas]. / Ékspansiia sekretornykh kletok épiteliia matochnoi truby na rannikh étapakh patogeneza seroznykh kartsinom iaichnika.

AIM: to investigate the frequency of the types of fallopian tubal secretory cell expansion (SCE) in diseases of the reproductive organs and to determine the immunophenotype and biological role of the cells in the early stages of the pathogenesis of high-grade ovarian serous carcinomas (HGOSC). SUBJECTS AND METHODS: The investigation enrolled 287 patients with extraovarian diseases and ovarian serous tumors varying in grade, whose fallopian tubes were morphologically and immunohistochemically examined using p53, Ki-67, PAX2, Bcl-2, beta-catenin, and ALDH1 markers. The material was statistically processed applying the Mann-Whitney test and χ2 test. RESULTS: The rate of secretory cell proliferation (SCP) (more than 10 consecutive secretory cells) and that of secretory cell overgrowth (SCO) (more than 30 consecutive secretory cells) increase with age in all investigated reproductive system diseases. The rate of SCP in the corpus fimbriatum of the patients with HGOSC was 5.9 times higher than that in those with extraovarian disease (p<0.01); when comparing the same patient groups, that of SCO was 3.4 times higher (p<0.05). The immunohistochemical characteristics of the investigated lesions (in scores) were as follows: PAX2 was expressed in the intact epithelium (2.8), in SCP (1.3), in SCO (1.2), in serous tubal intraepithelial carcinoma (STIC) (1.0), and in HGOSC (0.9); Bcl-2 was in the intact epithelium (2.2), in SCP (2.1), STIC (0.9), and in HGOSC (0.6), ß-catenin was in the intact epithelium (0.5), in SCP (2.85), in SCO (2.95), in STIC (0.6), and in HGOSC (0.5); ALDH1 was in the intact epithelium (0.5), in SCP (2.91), in SCO (2.92), in STIC (1.2), and in HGOSC (0.6). There were statistically significant differences with a 95% confidence interval (p<0.05) for: 1) PAX2 between the intact epithelium and pathology (fallopian tube lesions and HGOSC); 2) Bcl-2 between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 3) beta-catenin between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 4) ALDH1 between the intact epithelium and SCE, between and SCE and STIC, and between STIC and HGOSC. CONCLUSION: SCE was shown to be an independent intraepithelial lesion. The incidence of this abnormality increased with age and significantly differed in the patients with fallopian tubal lesions in extraovarian diseases from that in those with malignant ovarian serous tumors (by 5.3 times), while these groups showed a three-fold difference in SCO. Thus, SCP may serve as a more sensitive marker for the early stages of the pathogenesis of ovarian serous carcinoma. The studied types of SCE demonstrated multiple molecular events (loss of PAX2 expression and increased Bcl-2, beta-catenin, and ALDH1 expressions), some of which underwent considerable changes, by increasing the severity of a pathological process (loss of ALDH1, and beta-catenin, and bcl-2 expressions). Thus, therapeutic exposure in the early stages of pathogenesis may have a few points of application and just several molecules can serve as independent markers for early pathological changes in the fallopian tubal epithelium.

[The morphological and immunohistochemical characteristics of changes in the fallopian tube mucosa in ovarian epithelial tumors].

AIM: to study the incidence of fallopian tube lesions (secretory cell proliferations (SCP), p53 signature, serous tubal intraepithelial lesions (STIL), and serous tubal intraepithelial carcinomas (STIC) in ovarian epithelial tumors and to propose their pathogenetic association with a certain histotype of the ovarian tumor. MATERIAL AND METHODS: The investigation enrolled 136 patients with ovarian epithelial tumors, whose fallopian tubes were morphologically and immunohistochemically (IHC) examined using p53, Ki-67, and PAX2. Statistical analysis was carried out applying the Mann-Whitney test and χ(2) test. RESULTS: Lesions meeting the STIC criteria were found in 14.7% of cases (only in ovarian serous carcinoma (OSC)), those suspecting STICs were in 25.7%, and those without signs of STICs were in 59.6%. IFC examination diagnosed STIC in 10% of cases (only in OSC), STIL in 13.3%, p53 signature in 11.7% (only in serous tumors), and the normal/reactively changed tubal epithelium in 65%. The incidence of STILs correlated with the malignant potential of serous tumors significantly (p<0.05). There were significant differences in the incidence of STILs in patients with different histotypes of ovarian carcinomas (p<0.05). PAX2-negative SCP was detected in 75% of OSC, 60% of serous borderline tumors, and 40% of serous cystadenomas. The differences in the incidence of SCP between serous tumors of varying grade, between serous tumors and non-serous carcinomas, between OSC and non-serous carcinomas were significant (p<0.05). CONCLUSION: The investigation has shown that IHC examination should be used for the accurate diagnosis of STILs. It has also provided evidence for the pathogenetic association between STIC and high-grade OSC and revealed significant differences in the incidence of other fallopian tubal intraepithelial lesions in serous cystadenomas, borderline tumors, and OSC, in different ovarian carcinomas. The findings may suggest that the earliest stage in the pathogenesis of OSC is the development of SCP, followed by the formation of p53 signatures that may further give rise to STIL, and finally STC (due to the acquisition of additional mutations).

[The morphological and immunohiochemical features of foci of adenomyosis: in its concurrence with endometrial adenocarcinoma].

The purpose of the investigation was to study the morphological variants and molecular changes of the endothelial component of adenomyosis (AM) concurrent with endometrial adenocarcinoma (EAC). Monoclonal and polyclonal antibodies to ApoCas, Cl 2, 3, and 5, Ki-7, MMP-2, MMP-9, TIMP-1, E-cadherin, COX-2, EGFR, and VEGF were used as primary antibodies. The AM foci displayed the following types of epithelial changes: the epithelium corresponding to the proliferation stage; epithelial hyperplasia with and without atypia; atrophic epithelium. There was an increased expression of ApoCas, Ki-67, MMP-2, MMP-9, COX-2, VEGF, and EGFR, which increased from proliferation to hyperplasia with atypia. The maximum expression of the markers was seen in EAC. The foci of AM, which corresponded to epithelial hyperplasia with atypia, were characterized by the oncomarker changes supporting its malignant potential: elevated Ki-67 and EGRF, reduced E-cadherin, changes in MMP-2, MMP-9, TIMP-1, and claudins-2, -3, and -5.

Location and intensity of IL-8 and TGF-beta2 mRNA production in the fimbrial compartment of fallopian tubes and IL-10 in the endometrium in patients with pyoinflammatory adnexal diseases.

The location and level of IL-8 and TGF-beta2 expression in the fimbrial compartment of fallopian tubes and IL-10 expression in the endometrium of women with pyoinflammatory adnexal diseases were studied by in situ hybridization. These diseases are associated with considerable changes in the levels of local production of these cytokines. Inflammatory infiltration and epithelial cells were most active producers of IL-9 and TGF-beta2 in the fimbrial compartment of fallopian tubes, while in the endometrium IL-10 gene was expressed at a high level primarily in the glandular epithelial cells.

Apoptosis in fimbriae of fallopian tubes and endometrium in pyoinflammatory adnexal diseases.

In patients with pyoinflammatory adnexal diseases moderate or intense DNA degradation was observed in the majority of epithelial, stromal, and inflammatory infiltration cell in inflammatory foci in the fimbrial compartment of fallopian tubes without signs of tissue destruction. Expression of TNFR1 gene increased 2.7-fold and expression of Fas gene decreased 3.1-fold compared to intact endosalpinx, which indicates induction of apoptosis triggered by tumor necrosis factor-alpha and inhibition of the Fas-dependent pathway. No signs of apoptosis were detected in the endometrium. Generalized apoptosis in the fimbrial compartment of the tubes can be a mechanism limiting the inflammatory process.

Apoptosis in woman uterine cervix in pathologies associated with human papillomavirus.

The level of apoptosis in uterine cervical tissue was evaluated in healthy women and in patients with various pathologies. No signs of apoptosis were found in unchanged stratified epithelium, condyloma latum, and condyloma acuminatum. The level of apoptosis decreased with progression of neoplastic epithelial transformations, usually no apoptosis was observed in samples of stage III cervical intraepithelial neoplasms. The development of preinvasive carcinoma was accompanied by activation of apoptotic processes most pronounced in the upper third of the epithelium. In some stage I and stage I-II cervical intraepithelial neoplasms, apoptosis and elimination of the basal layer cells caused rejection of the epithelium which can explain regression of this pathology at the initial stages. The prevalence of human papillomavirus infection directly correlated with neoplastic changes in the cervical epithelium.

[Quantitative evaluation of the activity of nuclear Ca2+/Mg2+-dependent endonucleases in hyperplasia and cancer of the endometrium]. / Kolichestvennaia otsenka aktivnosti iadernykh Ca2+/Mg2+-zavisimykh éndonukleaz pri giperplazii i rake éndometriia.

Endometrial carcinoma is the most incident cancer of human reproductive system. There are unequivocal evidences of relationship between complex and atypical hyperplasia and development of cancer. Apoptosis plays a significant role in the maintenance of equilibrium between cell death and proliferation and contributes to prevention of tumorigenesis. Internucleosomal DNA fragmentation known as one of the most important criteria of apoptosis cannot be used for evaluating the risk of cancer development because it reflects the current level of apoptosis but is useless for evaluating the real limits of apoptosis intensity in certain types of tissue. For estimating the possibility of apoptosis development in endometrial tissues, a new method of quantitation of nuclear Ca(2+)/Mg(2+)-dependent endonuclease (NCME) activity has been developed. Fifteen samples of normal endometrial tissues at middle proliferative, secretory, premenstrual, and menstrual phases, 43 samples of hyperplastic endometrial tissues, 13 samples of endometrial polyps, and 17 samples of endometrial adenocarcinoma were collected by diagnostic curettage of the uterine cavity and by hysterectomy (carcinomas). The material was examined by 1) TUNEL method and 2) agarose gel electrophoresis of DNA cleaved by nuclear CME in isolated cell nuclei in the presence of Ca(2+) and Mg(2+) ions, followed by quantitation of CME activity. The activity of NCME was found to decrease from normal endometrium (1.1 +/- 0.12 U, without significant changes throughout the menstrual cycle) through polyps (0.9 +/- 0.15 U), cystic hyperplasia (0.45 +/- 0.06 U, p < 0.01), and adenomatous hyperplasia (0.32 +/- 0.08 U, p < 0.01) to adenocarcinoma (0.37 +/- 0.11 U, p < 0.01 for well differentiated, 0.16 +/- 0.08 U, p < 0.01 for moderately differentiated, and 0.03 +/- 0.02 U, p < 0.01 for poorly differentiated samples). The TUNEL-specific staining pattern in normal endometrium varied in a wide range during the menstrual cycle (from poorly stained individual cells in the proliferative phase to intensely stained cell clusters in the premenstrual phase). At the same time the difference between the normal endometrium in the proliferative phase and pathologically changed endometrium (hyperplasia or cancer) could not be detected by the TUNEL technique. Hence, TUNEL is useless for predicting cancer development in hyperplasia and precancer. By contrast, evaluation of NCME activity helps detect the early disorders in the proliferative processes coursing in endometrial tissues and thus prevent tumor development.

[Morphofunctional characteristics of the placenta of women living in extreme conditions of the Aral cost line]. / Morfofunktsional'naia kharakteristika platsenty zhenshchin, prozhivaiushchikh v ékstremal'nykh usloviiakh Priaral'ia.

Morphologic examination of the placenta from 41 puerperants living near the Aral sea revealed an increase of its mass and changes in other parameters. The detected pathologic processes: hemodynamic disorders and dystrophic changes--are not specific and contribute to the development of placental insufficiency. The majority (85.6%) of newborns were born in asphyxia. Morphofunctional features of the placentas of multiparous women and the status of their children permit regarding this population as the best adapted to pregnancy and delivery of viable children under the said extreme conditions.

[Changes in the hemostatic system in anomalous uterine hemorrhages and uterine myoma at perimenopause]. / Izmeneniia v sisteme gemostaza pri anomal'nykh matochnykh krovotecheniiakh i miome matki v perimenopauzal'nom periode.

Concentrations of some hemostasis system parameters in the total blood stream and in the menstrual fluid were measured in 58 patients of a perimenopausal age suffering from uterine bleedings and myomas. Plasminogen, fibrinogen, and fibrin/fibrinogen degradation product concentrations were increased in the menstrual fluid of patients with profuse uterine bleedings in comparison with patients with moderate menstrual discharge. These shifts were the most marked in the patients with submucous localization of uterine myoma. Gestrinon and danason exerted no pathologic effect on the studied hemostasis system parameters.

[Structural changes in the endometrium of puerperae with high risk of development of endometritis in the postpartum period]. / Strukturnye izmeneniia éndometriia u rodil'nits s vysokim riskom razvitiia éndometrita v poslerodovom periode.

The endometrium of 72 puerperae referred to a high-risk group in respect of developing infectious complications was examined on days 3-18 of the puerperium. The periods of epithelialization and regeneration onset in abnormal course of the puerperium were detected, and the morphologic criteria of these processes specified. In cases with cesarean sections these processes started 2-3 days later than after spontaneous delivery. Bacteriologic examination of the uterine cavity contents is an indirect test for the detection of an infection; the final diagnosis may be made only after a comprehensive assessment of the endometrial status.

[Clinical-morphological parallels in postpartum endometritis]. / Kliniko-morfologicheskie paralleli pri poslerodovom éndometrite.

Clinicomorphologic parallels were studied in 45 puerperants with postpartum endometritis. This condition was histologically confirmed in 42 of the 45 patients with its clinical symptoms (in 100% of patients with the grave, in 95% with the medium-severity, and in 83% of those with the benign form of the disease). The authors came to the conclusion that the severity of postpartum endometritis was directly dependent on the extent and depth of the uterine wall involvement in the inflammatory process. By the end of treatment the morphologic signs of inflammation persisted in 40% of patients even without clinical signs of endometritis. Such women should be referred to a group at high risk of developing chronic endometritis.

[Features of the endometrial steroid receptor system in habitual abortion with high risk of infectious complications]. / Osobennosti steroidretseptornogo apparata éndometriia pri privychnom nevynashivanii beremennosti s vysokim riskom infektsionnykh oslozhnenii.

Analysis of microbiologic and histologic findings and measurements of estrogen and gestagen receptors in the endometrium have shown manifest shifts in the endometrial steroid receptor system in women with asymptomatic chronic endometritis. The authors claim that disordered reception of steroid hormones may be regarded as one of the causes of spontaneous, abortions.

[Ultrastructure of the cervical epithelium in dysplasia]. / Ul'trastruktura épiteliia sheiki matki pri displazii.

A comparative and electron microscopic study was made of cervical tissue in 19 female patients with pseudoerosion, chronic endocervicitis and dysplasia with varying severity. The areas of dysplasia revealed cellular elements characteristic of squamous metaplasia, which suggested mild dysplasia arisen in mature and immature squamous metaplasia, severe dysplasia resulted in atypical immature metaplasia. The characteristics of a cellular population in dysplasia may be used to define the severity of the pathological process in question.

[Pathology of the cervix uteri as a consequence of hormonal therapy]. / Patologiia sheiki matki vsledstvie gormonal'noi terapii.

Morphological and functional characteristics are outlined for various types of endocervical hyperplasia attributed to prolonged administration of combined hormonotherapy with progestin-estrogenic and gestagen preparations for endometrial hyperplasia, external and internal endometriosis and myoma uteri. Endocervical hyperplasia belongs to iatrogenic pathology. Terminological issues of hyperplasia and differential diagnosis of atypical microglandular hyperplasia and adenocarcinoma are discussed.