Suzanne M. Jacques

Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome

Objective: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). Methods: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. Results: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm labor and intact membranes and 55.6% (15/27) in patients with preterm PROM. The median values of fetal plasma IL-6 in patients with funisitis, chorioamnionitis without funisitis, and non-inflamed membranes were 51.4, 18.4 and 5.2 pg/ml, respectively. After log transformation of the fetal plasma IL-6 concentration, the means differed significantly from each other (ANOVA, p < 0.02). There was no difference in log fetal plasma IL-6 concentration between patients with funisitis and those with chorioamnionitis without funisitis. The difference in mean concentration of log fetal plasma IL-6 between patients with funisitis or chorionic vasculitis and those without inflammation was highly significant (post-hoc test, p = 0.01 and p < 0.01, respectively). Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of histological signs of inflammation in the extraplacental membranes and umbilical cord than those with fetal plasma IL-6 < 11 pg/ml (funisitis: 55.6% (15/27) vs. 27.8% (5/18), p < 0.05; chorionic vasculitis: 55.6% (15/27) vs. 12.5% (2/16), p < 0.01; chorioamnionitis only: 25.9% (7/27) vs. 16.7% (3/18), p < 0.05; no inflammation: 18.5% (5/27) vs. 55.6% (10/18), p < 0.05, respectively). Fetuses with funisitis had significantly higher rates of clinical and histological chorioamnionitis, and neonatal infectious morbidity (proven + suspected sepsis) than fetuses without funisitis (40% (8/20) vs. 8% (2/25), 90% (18/20) vs. 36% (9/25), and 40% (8/20) vs. 4% (1/25), respectively; p < 0.01 for each). Fetuses with chorionic vasculitis had significantly higher rates of clinical and histological chorioamnionitis as well as neonatal infectious morbidity (proven + suspected sepsis) than fetuses without chorionic vasculitis (100% (17/17) vs. 42.3% (11/26), p < 0.01; 82.4% (14/17) vs. 50.0% (13/26), p = 0.05; and 41.2% (7/17) vs. 7.7% (2/26), p = 0.01). Conclusion: Fetal plasma IL-6 concentration is significantly associated with the presence of inflammatory lesions in the extraplacental membranes and umbilical cord. Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of funisitis and/or chorionic vasculitis than fetuses with fetal plasma IL-6 < 11 pg/ml. These findings suggest that funisitis/chorionic vasculitis is the histological manifestation of the fetal inflammatory response syndrome.

Ovarian cancer: changes in patterns at diagnosis and relative survival over the last three decades

OBJECTIVE The purpose of this study was to examine patterns of diagnosis and relative survival in women who had a diagnosis of primary invasive epithelial ovarian cancer (EOC) from 1973 to 1997, with follow-up through the end of 1999. STUDY DESIGN From the population-based Surveillance, Epidemiology and End Results (SEER) Program, 32,845 women diagnosed between 1973 and 1997 were used for analysis. The study population was divided in three cohorts based on year of diagnosis and the cohorts were compared with respect to variables of interest by using chi(2) tests and relative survival analysis by the life table method. RESULTS There was an increase in the proportions of minorities diagnosed with EOC, of women 60 years or older at diagnosis, and of women undergoing surgery over time. Survival continuously improved over time, although older patients (60 years or older) and African Americans continued to have the poorest survival. CONCLUSION Over time, relative survival of women who had primary invasive EOC diagnosed improved.

Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement

CONTEXT -The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. OBJECTIVE -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. DATA SOURCES -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. CONCLUSIONS -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Pre-eclampsia and expression of heparin-binding EGF-like growth factor

BACKGROUND Pre-eclampsia is a disorder of pregnancy associated with poor extravillous cytotrophoblast invasion and above-normal rates of apoptosis in the trophoblast. Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) has strong cytoprotective activity and is an important signalling protein that regulates trophoblast invasion during early placentation. We aimed to establish whether HB-EGF expression is altered in placentae of pre-eclamptic women. METHODS We assessed the expression of HB-EGF mRNA and protein by in-situ hybridisation and immunohistochemical techniques, respectively, in archived placental tissues from pregnancies terminated at around 20 weeks of gestation, and from women delivering between weeks 19 and 35 of gestation with preterm labour, small for gestational age infants, or pre-eclampsia. FINDINGS HB-EGF mRNA and protein were expressed in villous and extravillous cytotrophoblast cells up to week 35 of gestation in placentae from women who delivered preterm. Similar levels of HB-EGF protein were found in the placentae of women who were not in labour. HB-EGF expression was reduced about five-fold (p=0.0001) in pre-eclamptic pregnancies. Fetal growth retardation, which has been linked with shallow trophoblast invasion and moderate apoptosis, was associated with placentae expressing intermediate levels of HB-EGF. INTERPRETATION In pre-eclampsia, deficient HB-EGF signalling during placental development could impair trophoblast survival, differentiation, and invasion, leading to poor placental perfusion and hypertension.

Chronic chorioamnionitis: A clinicopathologic and immunohistochemical study

Lymphocytic inflammation of the fetal membranes is unusual and has been termed chronic chorioamnionitis. We report the clinicopathologic and immunohistochemical findings in 31 placentas with chronic chorioamnionitis. The most common histopathologic association was chronic villitis of unknown etiology, which was identified in 22 (71%) of the 31 placentas. The severity of the chronic villitis did not correlate with the severity of chronic chorioamnionitis. Additional placental findings included chronic intervillositis in two, fetal vessel thrombosis in five, hemorrhagic endovasculitis in four, decidual chronic vasculitis in three, and atherosis in one. Maternal history included pregnancy-induced hypertension in six and diabetes in one. Twelve infants were preterm, and five had intrauterine growth retardation. There was no neonatal sepsis or death. Immunohistochemical staining in areas of chronic chorioamnionitis showed CD3+ and CD8+ cells present in moderate numbers, and CD4+ cells in smaller numbers. CD20+ and CD56+ cells were rare or absent. Chronic chorioamnionitis is commonly associated with chronic villitis of unknown etiology, shares similar clinical associations, and may have a related cause, possibly immunologic.

Interinstitutional surgical pathology review in gynecologic oncology: II. Endometrial cancer in hysterectomy specimens

SummaryDuring an 8-year period, 76 post-hysterectomy women with endometrial cancer were referred to our institution for evaluation or treatment, and had slides from the hysterectomy specimen sent for review at the request of the gynecologic oncologist (interinstitutional consultation). The original diagnosis was retrospectively compared to the review diagnosis and discrepancies were recorded. The most frequent discrepancy, identified in 24 (31.6%) of the 76 cases, involved assessment of myometrial invasion; 19 of these 24 had an original diagnosis of inner or middle third myometrial invasion and a review diagnosis of no myometrial invasion. The main reason for this discrepancy was irregularity of the endomyometrial junction, or, less commonly, extension of tumor into superficial adenomyosis. Additional discrepancies noted in 11 (14.4%) of the 76 cases included: 1) histologie tumor classification in 6 (7.9%); 2) assessment of angiolymphatic space invasion in 2 (2.6%); 3) identification of meta-static carcinoma in 1 (1.3%); and 4) change in diagnosis from adenocarcinoma to complex atypical hyperplasia and atypical polypoid adenomyoma in 1 each (2.6%). A significant subgroup of patients in this series had modifications in diagnosis; the most frequent discrepancy involved overdiagnosis of myometrial invasion, underscoring the difficulty sometimes encountered in this determination.

Diagnosis of congenital syphilis from placental examination: Comparison of histopathology, steiner stain, and polymerase chain reaction for Treponema pallidum DNA

Congenital syphilis is often a presumptive diagnosis (based on serologies), because confirmation requires identification of Treponema pallidum in fetal/neonatal tissues or in the placenta. Placental histological features associated with congenital syphilis include the triad of enlarged hypercellular villi, proliferative fetal vascular changes, and acute or chronic villitis. The authors blindly evaluated 49 formalin-fixed, paraffin-embedded placentas (38 with positive maternal syphilis serologies; 11 with negative serologies) and compared results of histology, Steiner stain, and polymerase chain reaction (PCR) for T pallidum DNA. Histology was categorized as positive (triad present), suspicious (two thirds of triad present), or negative. Treponemal DNA was detected by amplifying a 189 base pair region of the 47 kd treponemal membrane antigen with 44 cycles of PCR; products were detected by Southern blot. Placentas from the 11 seronegative mothers were all negative by histology, Steiner stain, and PCR. Among the 38 placentas from serologically positive mothers, 4 had positive histology (2 of 4 positive Steiner, 4 of 4 positive PCR); 6 had suggestive histology (0 of 6 positive Steiner; 1 of 6 positive PCR); and, 28 had negative histology (0 of 28 positive Steiner; 1 of 28 positive PCR). PCR identification of treponemal DNA was significantly associated with the triad (P = .0003), proliferative fetal vascular changes (P = .0003), acute villitis (P = .003), chronic villitis (P = .004), and spirochetes on Steiner stain (P = .01). These results (1) confirm a strong association between placental histopathologic features and congenital syphilis; (2) indicate that when such features are present, PCR of placental tissue may confirm the diagnosis of congenital syphilis; and (3) suggest that even when such features are absent, PCR of placental tissue may identify additional cases of histologically unsuspected congenital syphilis.

Placenta accreta : mild cases diagnosed by placental examination

We describe 36 placentas in which microscopic foci of myometrial tissue were adherent to the basal plate with deficient intervening decidua, consistent with a mild or focal form of placenta accreta. In only four cases was a diagnosis of placenta accreta considered clinically, and none of the cases resulted in hysterectomy. Twenty-one of the mothers underwent cesarean section for the current pregnancy, with 10 of the mothers having a history of previous cesarean section. The placenta failed to separate spontaneously in eight of the 15 vaginal deliveries necessitating manual removal of the placenta. Additional maternal factors included multiparity in 33, placenta previa in two, leiomyomas in two, and previous spontaneous abortion or voluntary interruption of pregnancy in 23. Four cases were complicated by retained placental fragments and three by postpartum hemorrhage. We conclude that these milder cases of placenta accreta are frequently associated with previous uterine operations and multiparity, and although not uncommon, are frequently not clinically suspected. Placental examination is useful in making the diagnosis of placenta accreta in cases not requiring hysterectomy, particularly if the basal plate is well sampled.

Anti-DNA antibodies cross-reacting with laminin inhibit trophoblast attachment and migration: implications for recurrent pregnancy loss in SLE patients.

PROBLEM: Systemic lupus erythematosus (SLE), an autoimmune disease, is associated with reduced fetal survival, recurrent abortions, and other pregnancy complications. Some of the autoantibodies found in SLE bind to laminins (LNs), which play an important role in the implantation of the fertilized ovum in humans.
 METHOD OF STUDY: To elucidate the role of these specific autoantibodies, chorionic villous explants from 6–7‐week‐old human placentas were established as organ cultures on laminin‐1 (LN‐1), collagen IV (CN‐IV) or uncoated culture dishes. The cultures were then exposed to a mouse monoclonal anti‐DNA/anti‐LN‐1 antibody, to human polyclonal lupus antibodies cross‐reacting with LN‐1, a function‐blocking polyclonal antibody to LN‐1, polyclonal antibodies to CN‐IV, or IgG control.
 RESULTS: The explants attached to LN‐1 and CN‐IV, but not to uncoated culture dishes. LN‐1 promoted migration of trophoblast, whereas CN‐IV promoted migration of fibroblast‐like cells. Trophoblast attachment and migration were abolished in a dose‐dependent manner by all three antibodies to LN‐1, but not by antibodies to CN‐IV or IgG control. Furthermore, the effect of anti‐LN antibodies was abolished by preincubating them with LN‐1.
 CONCLUSIONS: These studies suggest that anti‐DNA antibodies cross‐reacting with LNs may play a role in early pregnancy failure in SLE patients by interfering with placental implantation.

Candida funisitis: A clinicopathologic study of 32 cases.

ABSTRACT We report on 32 cases of Candida funisitis and describe the associated clinicopathologic features. The Candida funisitis was characterized grossly by small, circumscribed, yellow-white nodules on the umbilical cord surface and, microscopically, by subamnionic microabscesses in which fungal organisms were demonstrable. Chorioamnionitis was present in all cases. Twenty-four (75%) of the 32 infants were premature. There were 7 perinatal deaths, all in immature fetuses. Five (16%) of the 32 fetuses had congenital candidiasis. Five (16%) of the mothers had a history of intrauterine foreign body, including intrauterine contraceptive device in three and cervical cerclage in two. The diagnosis of Candida funisitis should prompt a careful examination for fetal infection, even though it is associated with congenital candidiasis in only a minority of the cases.