Gestational diseases -- a workshop report.

Between 11% and 20% of all clinically recognised pregnancies are lost before the 20th week of gestation, with huge financial and personal implications. Immune mechanisms have been proposed to play a role in unexplained recurrent miscarriage. Considerable attention has focused on endometrial leucocyte populations in recurrent miscarriage, although the underlying pathogenesis remains largely unexplained. The mechanisms underlying sporadic miscarriage are even less well understood, although aneuploidy is the commonest attributable cause of early (

Metanephric adenoma-like tumors of the kidney: report of 3 malignancies with emphasis on discriminating features.

BACKGROUND: Metanephric adenoma is a very rare benign renal tumor; only 80 well-documented cases have been reported to date. We have seen several renal tumors that were originally incorrectly diagnosed as metanephric adenoma. DESIGN: We present 3 unusual renal tumors (2 primary and 1 metastatic), each of which illustrates important pathologic features useful in discriminating metanephric adenoma from malignant mimics. RESULTS: Case 1 involved a 46-year-old man with multiple small, cortical, solid, papillary (chromophil) renal cell carcinomas in his right kidney; the patient developed multiple, histologically identical, solid, papillary (chromophil) carcinomas in the opposite kidney 17 months later. Case 2 involved a 32-year-old woman with a 14-cm right renal tumor who developed soft tissue and bone metastases over a 17-year period. Case 3 involved a 52-year-old woman who presented with a 1.8-cm corticomedullary renal nodule, which eventually proved to represent a metastasis from a poorly differentiated (insular) carcinoma of the thyroid. All 3 tumors superficially resembled metanephric adenoma and consisted of primitive, dark-staining cells arranged in tubules or sheets. Each tumor, however, also had features inconsistent with the diagnosis of metanephric adenoma, including multifocal lesions with a variable nuclear-cytoplasmic ratio and diffuse cytokeratin 7 and epithelial membrane antigen immunopositivity in case 1, a 14-cm-diameter tumor with occasional mitoses in case 2, and a distinct fibrous capsule with capsular and vascular invasion in case 3. In addition, all 3 tumors lacked the cytologic features of bland overlapping nuclei with imperceptible cytoplasm consistently seen in metanephric adenoma. CONCLUSION: Adherence to strict histopathologic criteria will discourage misdiagnosis of a malignant or potentially malignant renal neoplasm as the rare and always benign metanephric adenoma.

Prevalence of hereditary hemochromatosis in a Massachusetts corporation: is Celtic origin a risk factor?

The prevalence of homozygous hereditary hemochromatosis (HHC) is estimated at 1:250 in Caucasian adults. Little is known about ethnic subpopulations that might be at increased risk for this disease. HLA data have suggested a Celtic origin for HHC. Screening for HHC was offered to all employees of the Massachusetts Polaroid Corporation. Participants with a transferrin saturation of >55% or >45% and an elevated serum ferritin concentration on two screenings were referred for liver biopsy. The diagnosis of HHC was based on histological criteria, quantitative hepatic iron determination, hepatic iron index, and the phlebotomy requirement for iron depletion. Participants completed a questionnaire regarding their ethnic background. Two thousand two hundred ninety-four employees were screened, and 5 cases of HHC were detected. All 5 cases involved Caucasian men, yielding a prevalence of 1:395 for the Caucasian population. Four of the 5 cases were of 100% British-Irish ancestry based on the country of origin of their grandparents. Additional analysis revealed that the majority of grandparents of all 4 individuals came from Ireland or Wales. The exact two-tailed trend test showed a significant association of HHC with Celtic background (P = .012). The estimated cost of screening per patient identified was $18,041. Polaroid Corporation has a high representation of employees of British-Irish ancestry. Our data suggest that they are at high risk for developing HHC. A significant association of HHC with Celtic ancestry was found in this subpopulation, supporting the concept of a Celtic origin for this disease.

Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development.

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a cytokine that is overexpressed in many tumors, in healing wounds, and in rheumatoid arthritis. VPF/VEGF is thought to induce angiogenesis and accompanying connective tissue stroma in two ways: 1), by increasing microvascular permeability, thereby modifying the extracellular matrix and 2), as an endothelial cell mitogen. VPF/VEGF has been reported in animal corpora lutea and we investigated the possibility that it might be present in human ovaries and have a role in corpus luteum formation. We here report that VPF/VEGF mRNA and protein are expressed by human ovarian granulosa and theca cells late in follicle development and, subsequent to ovulation, by granulosa and theca lutein cells. Therefore, VPF/VEGF is ideally positioned to provoke the increased permeability of thecal blood vessels that occurs shortly before ovulation. VPF/VEGF likely also contributes to the angiogenesis and connective tissue stroma generation that accompany corpus luteum/corpus albicans formation. Finally, VPF/VEGF was overexpressed in the hyperthecotic ovarian stroma of Stein-Leventhal syndrome in which it may also have a pathophysiological role.

Laser-assisted venous anastomosis: a comparison study.

A low-powered carbon dioxide laser was used to perform 25 vein grafts (50 anastomoses) on the femoral veins of Sprague-Dawley rats. The patency rate, clamp time, and bleeding time were compared with 50 conventional microvascular vein grafts (100 anastomoses). The patency of the laser-assisted anastomoses (LAVA) was 84 percent, while the conventional vein grafts yielded a 94 percent patency rate. The average clamp time and bleeding time for the LAVA were 47.2 min and 4.88 sec, respectively, while the conventional anastomoses required 57.6 min and had an average bleeding time of 9.44 sec. Histologically, both specimens healed at the same rate, but the laser-assisted anastomoses produced less inflammation and granulation tissue. These results suggest that the laser has potential as a tool for clinical application in microsurgery. In addition, the 94 percent patency rate achieved with the vein interposition graft would suggest that a decrease in the tension across the anastomosis can improve patency.

Placental protein distribution in maternal diabetes mellitus: an immunocytochemical study.

Placentas associated with maternal diabetes are generally characterized by features of villous immaturity. We correlated the villous histology with the immunocytochemical distribution of four trophoblastic proteins: beta human chorionic gonadotropin (beta HCG), placental alkaline phosphatase (PLAP), pregnancy specific beta-1-glycoprotein (SP1), and human placental lactogen (HPL) in 14 third-trimester placentas associated with diabetes mellitus. Staining was increased for beta HCG and decreased for PLAP, SP1, and HPL in the diabetic placentas compared to control placentas of similar gestational age. This pattern was most prominent in areas of marked architectural villous immaturity within individual placentas and suggests concomitant functional immaturity.

Immunocytochemical staining patterns of placentas associated with hydrops fetalis.

This study examined the morphology and immunocytochemical staining patterns of distribution of beta-human chorionic gonadotropin (beta-HCG), human placental lactogen (HPL), placental alkaline phosphatase (PLAP), and pregnancy-specific beta-1 glycoprotein (SP1) in 13 third-trimester placentas associated with hydrops fetalis and six normal control placentas matched for gestational age (+/- 2 weeks). Seven placentas were hydropic (540-1,080 g) and demonstrated histologic immaturity with large edematous chorionic villi showing few blood vessels, most of which contained immature hematopoietic elements. These placentas showed consistently increased staining for beta-HCG and decreased staining for PLAP when compared with control placentas, a pattern reminiscent of less mature placentas. HPL and SP1 staining were similar to those of controls. Six placentas were either sclerotic (four) or histologically unremarkable (two), and these did not differ in their immunocytochemical staining properties from control placentas. We conclude that third-trimester hydropic placentas, in addition to showing histologic immaturity, exhibit an immunocytochemical staining pattern associated with first-trimester placentas.

Neovascularization and coronary atherosclerotic plaque: cinematographic localization and quantitative histologic analysis.

A new technique was developed for analyzing the neovascularization associated with coronary artery atherosclerosis: cinematography during silicone polymer injection of the coronary arteries of fixed and cleared human hearts, followed by histologic analysis in routine and 1-micron-thick, Epon-embedded sections. Twenty-two hearts obtained at autopsy were studied. On the basis of cinematographic findings, individual regions of the coronary arteries were classified as negative, positive, or abundantly positive for neovascularization. Positive and abundantly positive areas, which invariably occurred in segments exhibiting changes of atherosclerosis, contained numerous small vessels in the adventitia and outer media (4.7 +/- 1.5 and 9.8 +/- 1.3 [SE] vessel profiles/artery cross-section in positive and abundantly positive areas, versus 1.0 +/- 0.6 in negative regions). Abundantly positive areas, which occurred in coronary artery segments demonstrating the most extensive atherosclerotic change, contained numerous small vessels in the inner media or in the plaque itself. Some of these microvessels were in close proximity to mast cells, which represent potentially rich sources of mediators affecting vascular tone and permeability. Vessels were not observed in the inner media or in atherosclerotic plaque in areas designated either positive or negative by cinematography. These findings show how our approach can be used both to define the three-dimensional, in situ configuration of coronary artery neovascularization and to characterize the histology of this process in detail. They also confirm previous work indicating that areas of coronary arteries involved by atherosclerosis frequently exhibit extensive neovascularization.

The immunocytochemical distribution of leukocytic subpopulations in human endometrium.

Thirty human endometria were selected from women aged 21-54 years who had undergone routine dilation and curettage procedures for tubal ligation, infertility dating, and irregular menstrual cycling. Histologic sections of the cases chosen were examined to exclude any major pathologic condition (including chronic endometritis). The specimens were stained with monoclonal antibodies to a common leukocytic antigen (H Leu-1 and PD7/26), pan-T-cell antigen (UCHT1), T helper/inducer and T suppressor/cytotoxic antigens (Leu-3a and UCHT4, respectively), pan-B cell antigen (To15 and Leu-12), and macrophage antigens (UCHM1 and Leu-M3). Other antibodies used included TAL-1B5 (anti-HLA-DR), Leu-7 (natural killer cell) and Na 1/34 (anti-T6/Langerhans/interdigitating reticulum cell). The endometria contained significant numbers of common leukocyte antigen-positive cells (occupying approximately 10-15% of the stroma), the numbers of which appeared to increase in the late secretory/pre-menstrual phase (20-25% of the stroma). The major leukocyte populations were T cells and macrophages; the latter, with neutrophils, appeared to account for the premenstrual increase in leukocytes. T cells were distributed both diffusely in the stroma and in periglandular stromal aggregates closely applied to the glands. The T8+ suppressor/cytotoxic population was predominant within the stromal nodules. In addition, scattered intraepithelial T suppressor/cytotoxic cells were present. Macrophages (UCHM1 and HLA-DR+) were also distributed diffusely in the stroma and as part of the periglandular stromal aggregates, in areas sending long cell processes into the epithelium. B cells appeared to be limited to scattered cells in the stroma, only increasing in number within lymphoid follicles. Natural killer cells, as defined by Leu-7+ cells, were also present, scattered singly in the stroma and within lymphoid follicles. The demonstration of large mononuclear dendritic-appearing Na 1/34+ cells within the glands of the endometrium in 5/30 cases suggests the presence of T6+ Langerhans/interdigitating reticulum cells in the endometrium. Thus, the normal endometrium has an important population of immunologically competent cells. Further study of these cell populations may elucidate their contribution, if any, to pathologic conditions in the endometrium.

Cutaneous tissue repair following CO2 laser irradiation.

We studied the mechanism of repair following exposure of normal skin to the CO2 laser in a focused mode. Exposed areas were biopsied at 0, 24, 48 h; 1, 2 weeks; 1, 2 1/2 months (pulse width varying from 0.1 to 1.0 s) after irradiation. The initial pattern was a V-shaped zone of cauterized collagen with a central crevice, the depth of which correlated with the total energy applied. The epidermal changes consisted of transepidermal cauterization and basal vacuolar changes lateral to the site of impact. Over a period of 1 week, the wound crevice decreased in depth and width and the central margins of the zone of cauterized collagen approximated. The cauterized collagen was extruded and was noted in the epidermal crust; minimal granulation tissue was present. Biopsies at later time periods showed formation of granulation tissue and retention of small amounts of necrotic collagen; the process of collagen extrusion was largely prevented by suturing. These observations show that dermal contraction and necrotic collagen extrusion are important components of initial tissue repair following limited dermal destruction produced by CO2 irradiation.

Low-fluence CO2 laser irradiation: selective epidermal damage to human skin.

The interaction of normal human skin with low-fluence CO2 laser irradiation was studied using a three-phase approach. In phase one, freshly excised skin was observed immediately after impact. In phase two, skin irradiated 2 h prior to excision was studied. In phase three, human volunteers were irradiated and biopsied at time zero, 24 h and 48 h. Seventy-five sites were exposed and 60 biopsies were performed. The earliest histologic changes were observed in the 6-10 J/cm2 fluence (radiant exposure) range and these changes included spindle and vacuolar changes in the basal layer of the epidermis. Papillary dermal coagulation was present to a maximum of 0.03 mm. At fluences of 10-25 J/cm2, superficial dermal necrosis (0.06-0.08 mm) was observed. At fluences above 25 J/cm2, transepidermal necrosis was present with increasing papillary dermal necrosis that was in proportion to the energy density delivered. At 2h, basal vacuolar changes were accompanied by diffuse keratinocytic cell death where contact was maintained between the epidermis and dermis, while where separation occurred limited keratinocytic death was observed. The earliest changes occurred at lower threshold fluences (4-6 J/cm2). After 24 h, these doses resulted in extensive epidermal necrosis with focal acute inflammatory infiltrates. At 48 h, the degree of epidermal "slough" was proportional to the energy density delivered and was maximal with a fluence of 5.7 J/cm2 delivered whereas with a fluence of 3.8 J/cm2 thin slough (0.02 mm) was observed. These findings suggest that low-dose CO2 laser irradiation may provide a new approach to selectively damage the epidermis with minimal dermal damage.

Healing of port-wine stains after argon laser therapy.

Studies have shown port-wine stains (PWSs) probably represent an aneurysmal dilation and ectasia of the cutaneous vascular plexus. The abnormal vessels are largely included within a 0.6-mm subepidermal zone, which is within the argon laser destruction range. Twenty-eight patients with PWSs underwent biopsies prior to argon laser treatment and repeated biopsies 4 1/2 months later. Those lesions (23) that contained large ectatic blood-filled vessels responded well to argon laser therapy in contrast to those (five) in which the vessels were relatively small and erythrocyte free. A similar histologic pattern was seen in the repeated biopsy specimens of both groups: the mean vessel area, the fraction of dermis occupied by vessels, vascular erythrocyte content, and vessel wall thickness sharply decreased, while the number of vessels tripled. Since lesion color strongly correlates with and probably is largely determined by erythrocyte content, the reason for the PWS lightening, despite increased vessel number, is the relative lack of erythrocytes in the newly formed vessels.

Interactions of normal, dysplastic, and malignant mammary epithelial cells with fibronectin in vivo and in vitro.

Previous studies have demonstrated that normal and malignant mouse mammary cells are indistinguishable in many surface-related properties that often denote transformation of other cell types such as fibroblasts. In the present investigation, the interactions of normal, dysplastic, and malignant mammary epithelial cells with fibronectin in tissues and cultures were examined by indirect immunofluorescence. Cells lining the lumina of ducts and alveoli in normal and dysplastic mouse and human mammary tissues abutted a layer of fibronectin along their basal surfaces that included the region of the basement membrane and the underlying stroma. Moreover, double staining for keratin and fibronectin revealed that myoepithelial cells were surrounded by the matrix protein. In contrast, tumor cells in adenocarcinomas and ductal carcinomas were not directly associated with fibronectin. The accumulation of fibronectin in primary cultures prepared from mouse mammary tissues paralleled the distribution seen in vivo. A matrix of fibronectin formed beneath normal and preneoplastic mammary cells within 4 to 6 days after plating, whereas tumor cells were negative, regardless of the age or density of the culture. This correlation with in vivo results did not extend to cells of established mammary tumor culture lines which readily accumulated pericellular networks of fibronectin. Addition of exogenous fibronectin to primary cultures enhanced formation of a basal matrix by normal cells but had no effect on the negative status of the tumor cells. The results indicate that mammary tumor cells in tissues and in primary cultures have an altered capacity to interact with fibronectin. However, this alteration is not necessarily expressed by established mammary tumor cell lines.