Statistical analysis of pathologic risk factors for intramyometrial lymphvascular space involvement in myoinvasive endometrial carcinoma.

In a retrospective study using univariate analysis, we identified tumor type (nonendometrioid vs endometrioid), depth of myoinvasion (MI), mode of MI (infiltrative vs cohesive), and direct anatomic invasion of the cervical wall from the isthmus as significant positive risk factors for intramyometrial lymphvascular space involvement (LVSI). On multivariate analysis, tumor grade, depth of MI, and mode of MI retained their significance. We created a grid for the relative risks of LVSI with respect to these variables individually or in combination. We suggest that our indirect estimate of the risk of LVSI can help in assessing prognosis and determining the need for adjuvant therapy whenever LVSI is important in clinical decision making, but its pathologic diagnosis is uncertain.

Microsatellite instability in endometrioid endometrial carcinoma: correlation with clinically relevant pathologic variables.

This study of 218 patients with endometrioid endometrial carcinoma explores the relationship between microsatellite instability (MSI) as established by the BAT26 method and the common pathologic variables of prognostic and therapeutic significance. MSI was positively correlated with grade, associated endometrial atrophy, squamous metaplasia, isthmic involvement, depth of myoinvasion, vascular invasion-associated changes, extrauterine tumor spread, and extramyometrial angiolymphatic spread. There was no significant correlation with carcinoma developing in adenomyosis, mucinous metaplasia, tumor size, cornual involvement, cervical extension, uterine serosal involvement, and targeted lymphoid response. The positive correlations are discussed in terms of molecular genetics.

Variable MLH1 promoter methylation patterns in endometrial carcinomas of endometrioid subtype lacking DNA mismatch repair.

A lack of DNA mismatch repair (MMR) is observed in approximately 20% of sporadic endometrial tumors, but few of these tumors have mutations in MSH2 or MLH1, the two major MMR genes. Promoter methylation is an important means of silencing transcription, and methylation of the MLH1 promoter has been reported as an important cause of MLH1 inactivation in endometrial cancers. Studies have shown that specific CpG sites within the MLH1 gene promoter are critical for gene expression, but other studies have shown that methylation of both more proximal and more distal sequences are important for MLH1 gene regulation. Here, we used a microsatellite instability assay and MLH1 immunohistochemistry to identify a subset of endometrial carcinomas of the endometrioid subtype lacking MMR. Sequencing of bisulphite-treated DNA from these tumors determined the methylation status of 42 CpG sites across the MLH1 promoter (spanning -204 to -702 bp upstream of the transcriptional start). Unlike the 4 normal endometrial samples that were unmethylated, 17 of 21 MMR-deficient samples showed complete or near-complete methylation and the remaining 4 MMR-deficient samples had a considerable degree of methylation (approximately 50% or greater). Five tumors demonstrated isolated unmethylated CpG sites, despite methylation throughout the rest of the promoter. This underscores the importance of examining the methylation status of at least several CpG sites within the promoter as methylation is not always consistent across DNA. Overall, our findings support the model that density of methylation of CpG sites across the MLH1 promoter is important in determining gene expression.

Invasive squamous cell carcinoma of the vagina during pregnancy.

BACKGROUND: Squamous cell carcinoma of the vagina in pregnancy is rare. CASE: A 28-year-old primigravida with antepartum bleeding at 20 weeks' gestation was diagnosed with squamous cell carcinoma after biopsy of a vaginal mass. The histology revealed an invasive grade 3 squamous cell carcinoma of large-cell, nonkeratinizing type. The patient declined pregnancy termination and immediate radiation treatment. She continued to have episodes of vaginal bleeding and was admitted at 30 weeks' gestation. A decision was made in consultation with the neonatal unit to deliver her at 32 weeks' gestation. After corticosteroid treatment, she was delivered by cesarean delivery. Positive pelvic lymph nodes were noted at surgery. Postoperatively, she received external beam radiation and brachytherapy and concurrent cisplatin chemotherapy. She is disease free 3 years from her original diagnosis. CONCLUSION: This case emphasizes the importance of a thorough pelvic examination to assess the vaginal walls and cervix at the first prenatal visit and with any antepartum bleeding episode.

Hyperplacentosis: a novel cause of hyperthyroidism.

Human chorionic gonadotropin (hCG), which is capable of thyrotropic activity, is believed responsible for the hyperthyroidism of gestational trophoblastic disease and hyperemesis gravidarum. Hyperplacentosis is a condition of heightened trophoblastic activity characterized by increased placental weight and circulating hCG levels higher than those associated with normal pregnancy. We report the first case of hyperthyroidism associated with hyperplacentosis. Correction of the hyperthyroidism occurred after hysterotomy and correlated with declining hCG levels. Hyperplacentosis should be included among the causes of hCG-mediated hyperthyroidism.

Fetus-in-fetu presenting as cystic meconium peritonitis: diagnosis, pathology, and surgical management.

Fetus-in-fetu (FIF), a rare congenital anomaly, is a fetus incorporating the well-differentiated tissue of its twin. The authors describe a newborn who presented with massive abdominal distension and severe respiratory distress. Abdominal x-rays showed multiple calcifications. The diagnosis of meconium pseudocyst was made. At emergency laparotomy an irregular fetiform mass was found in the retroperitoneum lying within a fluid-filled amniotic sac. It contained a vertebral column, 10 limblike structures, and cranial and caudal ends, supporting the diagnosis of fetus-in-fetu. This case highlights several important points. FIF often is overlooked in the differential diagnosis of a newborn abdominal mass and, as in this case, may be confused with meconuim pseudocyst. FIF should be differentiated from a teratoma because of the latter's malignant potential. Because this diagnosis is not made until pathological analysis, all parts of the mass should be removed to prevent malignant recurrence.

Pathology of female infertility.

This review concentrates on the structural and functional aspects of lesions of the female genital tract that cause infertility, including cervical changes after treatment for neoplasia, uterine malformations, leiomyoma, endometrial aberrations, infection-related tubal lesions, ovarian disorders (oocyte defects, premature ovarian failure, corpus luteum dysfunction, and polycystic ovary-related abnormalities), and endometriosis.

Is there an association of Down syndrome and omphalocele?

The possible association of Down syndrome (DS) with omphalocele is controversial. We reviewed the 2,979 live births and stillbirths with DS born from 1983 to 1993 in the catchment area of the California Birth Defects Monitoring Program (CBDMP). We observed one infant with both defects, a number that did not differ significantly from what was expected (P < 0.40). We also reviewed the pathological reports of one of us (L.H.H.) from a series of 36 DS fetuses and neonatal deaths; none had an omphalocele. We then reviewed the literature for epidemiological studies of DS and for epidemiological, surgical, prenatal, and familial studies of omphalocele. Possible biases inherent in each type of study were evaluated. The majority of epidemiological studies showed no association of DS with omphalocele. In surgical series, the occasional infant with both defects was more likely to undergo surgery than infants with omphalocele and trisomies 13 and 18 or other severe birth defects. Inclusion of both omphalocele and umbilical hernia in the same ICD-9 code may explain some of the correlations with DS noticed in a few epidemiological studies. In conclusion, our data suggest that trisomy 21 does not predispose the fetus to an increased risk for an omphalocele.

Exfoliative cytology of adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix.

Cervical scraping smears from two cases of histologically confirmed adenoma malignum of the uterine cervix were reviewed. In one case, several irregular sheets of benign-appearing glandular cells with slightly enlarged nuclei, conspicuous nucleoli, and clear cytoplasm were found. In the other case, in addition to sheets of benign-appearing glandular cells, there were clustered malignant glandular cells with prominent nucleoli. The sheets of benign-appearing glandular cells in both cases displayed wispy cytoplasmic extensions or "tails." Cytologic differential diagnosis with other glandular lesions of the cervix such as clear cell carcinoma, microglandular hyperplasia, diffuse laminar glandular hyperplasia, tubal metaplasia, and well-differentiated invasive or in situ adenocarcinoma is briefly discussed.

Pathology of female infertility.

This review focuses on infertility-related anatomical (ligneous cervicitis and postsurgical stenosis) and functional (abnormal mucus production, local cervical isoimmunity, and incompetence) disorders of the cervix, congenital anomalies, and underperfusion of the uterine corpus, myometrial lesions, endometrial failure, tubal obstruction, polycystic ovary syndrome, and endometriosis.

Possible association between the hernia of Morgagni and trisomy 21.

Of the 5 liveborn infants with the hernia of Morgagni recorded in the California Birth Defects Monitoring Program, 3 had trisomy 21. This significant association (P < 10(-6)) between the hernia of Morgagni and trisomy 21 may reflect defective dorsoventral migration of rhabdomyoblasts from the paraxial myotomes, caused by increased cellular adhesiveness in trisomy 21.

Amplification of the gene encoding the alpha-subunit of the mitochondrial ATP synthase complex in a human retinoblastoma cell line.

A cDNA clone encoding the precursor of the alpha-subunit of the human mitochondrial ATP synthase (F1-ATPS) complex was isolated from a library prepared from the poly(A)+ RNA present in a retinoblastoma (RB) cell line. Northern blot analysis of RNAs derived from a variety of transformed cell lines as well as from normal human fetal tissues indicated that RNA expression was significantly higher in two of the four RB cell lines analysed, Y79 (10- to 30-fold) and RB522A (3- to 8-fold), than in other cell lines or tissues. The increased mRNA level was apparently the result of gene amplification in Y79, but not in RB522A.

A population-based study of congenital diaphragmatic hernia.

From 1983 through 1987, in a California population of 718,208 births, 237 infants were born with a congenital diaphragmatic hernia (CDH), a birth prevalence of 3.30 per 10,000 total births (live births and stillbirths). We proposed that the various types of this defect, characterized by their different pathogeneses, would be reflected in differences in their descriptive epidemiologies. We evaluated various demographic, maternal, and infant characteristics for three major types of defects, the Morgagni hernia, the pars sternalis hernia, and the posterolateral hernia, categorizing the latter type into isolated defect (N = 129), multiple congenital anomalies including nonchromosomal syndromes (N = 86), trisomies (N = 10), and chromosomal anomalies other than trisomies (N = 2). For the posterolateral hernia, we present the distribution of associated anomalies (43%) and specifically of midline defects (19%). Although the number of cases for the Morgagni hernia (N = 5) and the pars sternalis hernia (N = 5) were small, comparisons with the posterolateral hernia suggested lower sex ratios, of borderline significance for the pars sternalis hernia (P < 0.09), and higher mean maternal ages for both groups. Within the posterolateral type, we found a significantly higher male to female ratio (M/F = 1.58) only for the isolated subgroup compared to the population (P < 0.03), and a borderline significant rural/urban difference in prevalences (2.12 vs. 1.45 per 10,000) (P < 0.06). Additionally, the distribution of monthly prevalence rates adjusted for gestational age suggested opposite seasonal trends between the isolated and the other posterolateral hernias; within this latter subgroup the difference between the highest monthly rate (1.68) and the lowest (0.96) was of borderline significance (P < 0.09). Our results suggest the need to consider the respective types and subgroups of CDH separately in epidemiologic studies.

Perinatally acquired neonatal tuberculosis: report of two cases.

Perinatally acquired neonatal tuberculosis occurs rarely, is difficult to diagnose, may be the indicator of untreated tuberculosis in the mother, and could result in nosocomial transmission to neonatal patients, visitors to neonatal intensive care units, and health care workers. The disease may be more common in certain ethnic and social groups. Neonatal mortality approaches 30%. We report two cases with different outcomes. A neonate was treated for clinical miliary tuberculosis and survived; Mycobacterium tuberculosis was cultured from bronchoscopic washings, maternal genital fluids, and tissues. A second infant died at age 46 days, and autopsy disclosed miliary tuberculosis of lungs, mediastinal and mesenteric nodes, liver, spleen, and bone marrow. The lungs were most severely affected, but the placenta and central nervous system were not involved. The histopathology was not granulomatous. After the diagnosis in the infant, the mother was ascertained to have pulmonary and genital tuberculosis. Fetal and neonatal tuberculosis could be acquired transplacentally as prenatal tuberculous chorioamnionitis, perinatally through aspiration and ingestion of infected maternal genital tissues and fluid, or postnatally through droplet spread from cases of active tuberculosis. These two neonates probably acquired the disease perinatally from maternal genital tuberculosis.

Postsalpingostomy intercornual bridging with hematosalpinx, chronic salpingitis and perisalpingeal endometriosis. A case report.

Two years after a left salpingo-oophorectomy for a tuboovarian mass from endometriosis and a right salpingostomy for hydrosalpinx, a 28-year-old, infertile woman underwent pelvic surgery for severe pain and progressive endometriosis. The closed, swollen tube arched over the posterior aspect of the uterus, bridging the two cornua; it was filled with blood and showed severe chronic salpingitis and widespread perisalpingeal endometriosis.

Partial hydatidiform moles have impaired differentiated function (human chorionic gonadotropin and human placental lactogen secretion) in response to epidermal growth factor and 8-bromo-cyclic adenosine monophosphate.

OBJECTIVE: The null hypothesis is that partial hydatidiform moles have normal differentiated function (human chorionic gonadotropin and human placental lactogen secretion) in response to epidermal growth factor and 8-bromo-cyclic adenosine monophosphate. STUDY DESIGN: Two complete moles, 10 partial hydatidiform moles, and 19 normal first-trimester placentas in monolayer culture were exposed to 10 ng/ml epidermal growth factor, 1 mmol/L 8-bromo-cyclic adenosine monophosphate plus 1 mmol/L theophylline, or control. Human chorionic gonadotropin and human placental lactogen secretion was measured. Frequency of response to stimuli was compared by chi 2 analysis, and hormone secretion was compared by analysis of variance. RESULTS: Partial moles demonstrated reduced frequencies of response of human chorionic gonadotropin and human placental lactogen to epidermal growth factor (partial moles 2/8 and 2/8, respectively; normal placentas 16/19 and 7/18, respectively; p less than 0.025) and of human chorionic gonadotropin to 8-bromo-cyclic adenosine monophosphate (partial moles 3/5, normal placentas 13/16; p less than 0.005). CONCLUSION: Partial hydatidiform moles demonstrate impaired human chorionic gonadotropin and human placental lactogen secretory responsiveness to epidermal growth factor and cyclic nucleotides in comparison with normal first-trimester trophoblast.

Postmenopausal hyperandrogenism of ovarian origin. A clinicopathologic study of four cases.

Postmenopausal hyperandrogenism with overt clinical effects is rare and often related to ovarian stromal disorders. We present a clinicopathologic study of 4 cases. The patients (age range 41-75 years; mean 62 years) had evidence of hirsutism or frank virilization. Their serum testosterone was elevated with or without increases in their serum androstenedione and DHEA levels. There were two right-ovarian hilus cell tumors, one associated with left-ovarian stromal hyperplasia and the other with bilateral hyperthecosis and nodular hilus cell hyperplasia. The other tumor was a small corticomedullary stromal luteoma with bilateral hyperthecosis and nodular hilus cell hyperplasia. The fourth patient had bilateral hilus cell hyperplasia with mild cortical-stromal hyperplasia. All these patients had rapid normalization of androgen levels after surgery without recurrence after a 2- to 10-year follow-up.

Inherent radiosensitivity testing of tumor biopsies obtained from patients with carcinoma of the cervix or endometrium.

The inherent radiosensitivity of tumor biopsies obtained from a series of patients with carcinoma of the uterine cervix or endometrium has been characterized. Early passage cell lines were irradiated and assayed for cell survival using a clonogenic assay system. Survival curves were generated using the alpha/beta model and the surviving fraction at 2 Gy (SF2) was estimated. A wide range of SF2 values was observed among histologically similar tumors. The mean (+/- SD) SF2 value was 0.29 +/- 0.12 (range = 0.11-0.59) for the cervical biopsies and 0.30 +/- 0.13 (range = 0.11-0.67) for the endometrial biopsies. No correlation between inherent radiosensitivity and tumor DNA index or histopathology was observed. Patient accrual continues with the expectation that these results may help to determine whether SF2 values are of clinical value in predicting the response of individual patients to treatment with radiotherapy.