Auer rod-like inclusions in circulating lymphoma cells.

Circulating malignant lymphocytes from a 55-year-old woman with small cleaved follicular center cell lymphoma contained azurophilic splinter-shaped cytoplasmic inclusions. By light microscopic and ultrastructural criteria, these structures closely resembled Auer rods found in acute myeloid leukemia; however, the authors could not find cytochemical evidence of lysosomal origin (results were negative for myeloperoxidase, Sudan black B, acid phosphatase, and periodic acid-Schiff). Immunostaining and flow cytometric analysis confirmed a monoclonal IgM-kappa immunophenotype of the circulating malignant lymphoid cells. The inclusions did not show specific immunoglobulin staining by light microscopic or electron microscopic immunostaining techniques. The authors conclude that these membrane-bound inclusions probably represent aberrant lysosomes in the malignant cells.

Changes of plasminogen activator in human uterine tissue induced by intrauterine contraceptive devices.

Potassium thiocyanate-extractable uterine plasminogen activator activity was determined to be highest in the endometrium surrounding intrauterine devices (IUDs). Such activity was significantly higher than that encountered in control endometrium or in the endometrium remote to IUDs. As in control cases, extracted endometrial activity fluctuated during the intermenstrual ovarian cycle. It was highest in the pre- or periovulation part of the cycle, and it rose again prior to menstruation. These peaks of activity seem to correspond to times in the cycle when metrorrhagia and abnormal menstruation are usually encountered. Possible implications of the myometrial and endometrial patterns of plasminogen activator in control and IUD-exposed uterine tissue are discussed.

PIP: This research study was designed to determine the relative activator concentration in uterine tissue depressed by, adjacent to, and remote from the IUD and to compare these concentrations to control uterine tissues. Uterine tissue used in the study was obtained following hysterectomy in 22 women wearing IUDs. All analyzed tissues were acquired from uteri containing either Lippes loop D or large Saf-T-Coils. These IUDs had been in place for a minimum of 1 year and a maximum of 8 years. Hysterectomies were performed primarily for indications related to symptomatic pelvic relaxation secondary to multiparity. No patient was taking hormonal medication or contraceptives for 12 months prior to hysterectomy. No cases included specimens with significant uterine pathology other than that related to the IUD. Ovarian cycle phase was determined for all specimens analyzed by histologic criteria on adjacent slices of the excised samples. Cases included the following phases: menstrual; early proliferative; mid to late proliferative; early to mid secretory; and late secretory. The myometrium contained considerably more extractable activator than the endometrium in terms of activity per milligram of tissue protein. Variation of endometrial plasminogen activator (PA) showed the same pattern as did previously analyzed control specimens at different stages of the intermenstrual ovarian cycle. Values reached the highest levels in mid to late proliferative endometrium with a fall during the early to mid secretroy phase to the lowest levels, followed by a rise in late secretory endometrium. Myometrium did not parallel endometrium as closely as reported for control cases. In IUD cases, the highest myometrial levels were encountered in the late follicular phase and a fall occurred in the secretory phase, as was the case with endometrium, but no myometrial rise occurred prior to menses. Comparison of mean activator results of depressed, adjacent, and remote endometrial sites from IUD cases and mean endometrial activator levels from control cases revealed the highest values in IUD depressed endometrial tissues. The next highest were in IUD adjacent endometrium. Significantly lower results occurred in IUD remote endometrial samples. These comparisons were not considered to be biased by interphase differences in activator since equal proportions of all 4 menstrual phases existed among the 3 IUD sampling sites and the total control material studied. In sum, uterine PA activity plays an important role in IUD associated menorrhagia, and the results indicate that it is also important in IUD associated metrorrhagia. The causes of cyclic physiologic fluctuation and of IUD stimulated increases in uterine PA activity are poorly understood at this time.

Immunohistochemical identification of mast cells in paraffin- and epon-embedded tissues using platelet factor 41.

An immunoperoxidase method has been developed for staining heparin in the granules of mast cells. The method employs human platelet factor 4 (or anti-heparin) and a rabbit antiserum to this polypeptide. Platelet factor 4 binds to mast cell heparin and provides the basis for immunoperoxidase staining using the rabbit antiserum. Preliminary studies of mast cells in various tissues indicate that the stain is quite specific for the content of mast cell granules, presumably heparin and possibly other glycosaminoglycans.

Effects of a progesterone-releasing intrauterine contraceptive device on endometrial blood vessels: a morphometric study.

The concentration of microscopically detectable blood vessels was significantly lower in endometrium exposed to progesterone-releasing intrauterine contraceptive devices (IUDs) than in control endometrium (mean vessel density 2.39 and 3.92, respectively). The percentage of vessels with defects was significantly higher in IUD samples (35.0%) than in control samples (13.4%). There was no significant difference in hemostatic response to vessel injury between the IUD and control samples. Although they were more defective than in controls, the blood vessels of progesterone IUD-exposed endometrium were far fewer in number, which may account for significantly less uterine blood loss in the users of these devices. In addition, the progesterone IUDs do not appear to inhibit hemostasis in the endometrium so that blood loss from injured vessels may be minimized.

PIP: It has been previously demonstrated that increased vascularity, vessel defect formation, and poor hemostasis are prime factors in the increased endometrial bleeding associated with plastic IUDs. This paper presents the results of a morphologic sutdy on progestogen IUD-exposed endometrium to determine the reasons for long-term decreased menstrual blood loss and short-term increased intermenstrual blood loss following insertion of such an IUD. Endometrial biopsies were collected from 8 women wearing a Progestasert at various times in the cycle, and from 9 control women during the middle to late luteal phase of the menstrual cycle. All morphometric and electron microscopic studies were done at the Women's Hospital, Los Angeles County/USC Medical Center. Biopsies from the Progestasert users were taken 54 months after initial insertion. Each progesterone-IUD was replaced approximately every 24 months. Electron microscopy was used to examine the tissue samples. Chi-square test and the Mann-Whitney U Test according to Siegel were used in statistical analysis. Average blood vessel density for the 8 progesterone users was 2.39 (range, 13.0 to 3.71) compared to 3.92 for the controls (range, 3.33 to 4.68); the difference was significant at p0.01, Mann-Whitney test. Vessel concentration ratio of experimental to control endometrium was 3.5. Defective vessels for control cases expressed as a percentage of total vessels ranged from 0% to 24%. For progesterone IUD-endometrium, values per case varied from 7.1% to 64%. Average percentage of defective vessels for controls was 13.4 and for Progestasert users, 35.0%; the difference was significant at p0.001, Chi-square test. Majority of defects in the Progestasert users were associated with degenerative changes in endothelium. The increased concentration of vascular defects in the progesterone IUD-exposed endometria compared to control tissue in this series confirm earlier studies with plastic IUDs and defective vessels. Several factors contribute to decreased endometrial bleeding in women who have worn a progestrone-releasing IUD for at least 6 months. 2 critical factors include: 1) decreasing concentration of blood vessels in the endometrial functionalis (possibly the cause for progressive endometrial atrophy); and 2) no apparent inhibition of platelet hemostasis.

Quantitative menstrual and intermenstrual blood loss in women using Lippes Loop and Copper T intrauterine devices.

PIP: 127 women were studied during 3 consecutive menstrual cycles preceding, and 6 non-consecutive menstrual cycles during the 1st year following insertion of either Lippes Loop C or Copper T. Both (MBL) menstrual blood loss and (IMBL) intermenstrual blood loss were quantified during these cycles. When postinsertion MBL was averaged and compared to mean preinsertion MBL, the Lippes Loop and Copper T devices increased the volume of menstrual bleeding by 99 and 42% respectively. In spite of this, mean hemoglobin levels did not change significantly during the period of study. Quantifiable MBL was experienced primarily during the 1st cycle postinsertion. The incidence was 90% in women inserted with the Lippes Loop C and 48% in those women inserted with the Copper T during this cycle. The volume of IMBL was extremely variable among the women studied (0.7 - 398 ml). In several cases the volume nearly equalled or even exceeded the MBL of the 1st cycle. Incidence of IMBL fell to 6.5% and 5.0% in the 2nd postinsertion cycle for women with loops and copper devices, respectively. Thereafter the incidence was neglibible. This marked decrease in incidence was not due to closures for bleeding. Less than 10% of the total blood loss experienced during the 1st year postinsertion was the result of IMBL and following the 1st postinsertion cycle, it contributed less than 2% of the total blood loss. The conclusion is that IMBL, while contributory to IUD discontinuation rates, does not contribute significantly to total blood loss and thus to iron loss following IUD insertion.^ieng

Vessel density in endometrium of women with and without intrauterine contraceptive devices: a morphometric evaluation.

Increased vascularity was found in the endometrial functionalis in uteri of women wearing intrauterine contraceptive devices (IUDs) as compared to uteri of women without IUDs (control subjects). Vessel concentration was highest in endometrial tissue adjacent to that tissue which was depressed by the IUD. In control tissues there was a significant variation in vascularity according to geographic location in the following order of magnitude: fundus greater than corpus greater than cornua greater than isthmus. No significant variation was found, however, among different phases of the ovarian cycle in either control or IUD cases. Increased endometrial vascularity could be a reaction to vessel damage caused by the IUD and for several reasons may contribute to IUD-induced endometrial bleeding.

Morphologic studies on IUD-induced metrorrhagia. I. Endometrial changes and clinical correlations.

Morphologic studies on human hysterectomy specimens indicate the IUD elicits a vascular reaction which is most pronounced in the endometrium adjacent to the device. This reaction includes increased vascularity, congestion and increased permeability, and degeneration with defect formation. In addition, there is poor hemostatic responsiveness to vascular permeability and damage. The reaction leads to interstitial hemorrhage which undoubtedly causes metrorrhagia. A likely cause for initial vascular damage is mechanical stress transmitted by the IUD through the endometrium to its vascular network. Vascular reaction and poor hemostatic responsiveness may be perpetuated during each cycle by the products released from endothelial cell degeneration and necrosis. Bleeding is one of the most frequent complications leading to discontinuation of an otherwise effective form of long-term contraception and family spacing. Therefore, its solution could be of crucial importance to world-wide population control. Our findings suggest that better understanding of the mechanism of IUD-induced metrorrhagia should result from closer study of the endometrium adjacent to that which is compressed by the IUD.

Morphologic studies on IUD-induced metrorrhagia. II. Surface changes of the endometrium and microscopic localization of bleeding sites.

Surface changes were extensively studied by light and electron microscopy in human endometrium exposed to IUD's. A wide variety of alterations in the covering epithelium and its basal lamina (basement membrane) was observed. These ranged from essentially no alteration to a covering basement membrane completely denuded of its epithelium. Erosions or discontinuities of the surface basement membrane were uncommon, and when they occurred were most often associated with extrusion of fluid and cellular elements from the stroma into the uterine lumen. Metrorrhagia associated with IUDs probably results from two basic types of hemorrhage through the endometrial surface. Tissue adjacent to the IUD with interstitial hemorrhage bleed into the uterine cavity by (1) red cell transmigration through surface membranes (surface epithelium and its basal lamina), and (2) high interstitial pressure breaks in these same membranes.