Search

Clots in the fetal circulation of the placenta may occlude or narrow the lumens of fetal vessels sufficiently to diminish the placental oxygen and nutritional exchange, causing significant reduction in placental function. When extensive, growth restriction, neonatal encephalopathy, and stillbirth may occur. Propagation of clots in other organs, such as brain, kidney, and liver, may affect the function of these organs, resulting in infarcts and neonatal stroke. This article presents an account of the placental pathology and clinical sequelae of this condition, called fetal thrombotic vasculopathy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to compare the screening efficiency of the umbilical artery systolic to diastolic ratio (S/D), pulsatility index (PI), and absent end-diastolic flow (AEDF) for adverse pregnancy outcomes and placental abnormalities in small for gestational age (SGA) fetuses., Methods: We conducted a retrospective cohort study of Doppler examinations of 161 nonanomalous SGA fetuses. The reliability of the S/D and PI were quantified by intraclass correlation coefficients. The association of the S/D, PI, and AEDF with adverse outcomes and placental abnormalities was compared by the chi(2) test., Results: There was a simple association of Doppler results with adverse outcomes, which was mitigated when controlled for gestational age. For all measures of adverse outcomes, the specificity of abnormal Doppler results exceeded the sensitivity, and the negative predictive value was greater than the positive predictive value. Comparing the S/D with the PI, there was no significant difference in the sensitivity; however, the specificity of the PI was at least 90% and exceeded that of the S/D for all outcomes. The intraclass correlation coefficients of the S/D and PI were similar, indicating no difference in reliability. Placental abnormalities were significantly more common in cases with abnormal Doppler values (positive predictive value, 94%) with no overlap in the types of placental lesions in most cases., Conclusions: As an initial screen for adverse outcomes in SGA fetuses, the umbilical artery Doppler S/D, PI, and AEDF were imprecise. However, these measures were all strongly and similarly predictive of placental abnormalities, especially lesions of maternal underperfusion and fetal vascular obstruction.

Poor communication, delayed communication, and failure to identify or evaluate significant placental lesions are major causes of failure to explain the cause of severe injuries in newborns. Families coping with stillbirth or a child with cerebral palsy need to have a sense that their bereavement deserves and is receiving major attention, and that a determined effort to explain the cause is being made and will be presented in a timely fashion. They are coping with long-lasting and devastating financial and emotional burdens. The obstetrician, neonatologist, and pathologist who have accepted the role of physician to these patients have a duty to cooperate as fully as they can to make those burdens as bearable as possible.

Frequently, placentas sent for pathologic examination include a clinical diagnosis that does not suggest a specific placental lesion. Pathologists who do not have great experience in this field may need some assistance with selecting the pertinent placental lesions to look for. This brief outline is included to define these conditions and present a list of the specific placental lesions that deserve consideration. The placental examination should be directed with the goal of identifying or noting and recording specifically the presence or absence of the relevant pathologic lesions. The syndromes or conditions considered in this context include neonatal encephalopathy, preterm birth, fetal growth restriction, maternal diabetes mellitus, thrombophilias, HELLP syndrome, and fetal hydrops.

Objective: The purpose of this study was to test the hypothesis that placental samples that are obtained by needle aspiration ex vivo are useful for the determination of villus gene expression., Study Design: Placental biopsy was performed with a spinal needle after uncomplicated deliveries. Villi were inspected microscopically, and RNA was extracted and analyzed with capillary electrophoresis. Gene expression was determined with quantitative polymerase chain reaction., Results: We obtained more placental villous fragments per aspiration using a 20-gauge needle (5.2 +/- 1.8 fragments) than with a 22-gauge needle (3.3 +/- 1.6 fragments; P < .01). RNA quality was adequate, based on the 28S and 18S recombinant RNA bands, with a mean 260/280 ratio of 1.88. The amount of extracted RNA correlated with the number of villous fragments per aspirate. Importantly, the expression of NDRG1 and hPL, both markedly altered in hypoxia, was consistent between villi that were obtained by either needle or standard biopsy., Conclusion: Placental samples that are obtained by ex vivo needle aspiration are useful for the extraction of RNA and for the determination of villous gene expression.

Using oligonucleotide microarrays we recently identified a set of transcripts that were up-regulated in hypoxic human trophoblasts. To test the hypothesis that expression of hypoxia-related placental transcripts depends on sampling site we analyzed nine different sites from term human placentas (n=6), obtained after uncomplicated pregnancies. These sites spanned the placental center to the lateral border and the basal to the chorionic plate. Relative gene expression at each site, determined using quantitative PCR, was correlated with villous histology. The expression of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF), the cytoskeleton proteins lamininA3 and alpha-tubulin, and the signal transduction protein Rad was enhanced in the subchorionic lateral border compared to medial basal site (1.6-2.9 fold, p<0.05). In contrast, the expression of NDRG1, adipophilin and human placental lactogen was unchanged. Enhanced villous maturation, syncytial knots and fibrin deposits were more frequent in the subchorionic placental lateral border, and correlated with up-regulation of hypoxia-related transcripts (p<0.05). The association between sample site and expression level was not observed in placentas with marginal cord insertion. The expression of hypoxia-related genes in the term human placenta is dependent on sampling site within the placental disk, likely reflecting local differences in villous perfusion.

The purpose of this study was to assemble and test the reliability of a complete set of the placental reaction patterns seen with chronic fetal vascular obstruction in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with fetal vascular obstructive lesions, 6 controls) were reviewed blindly by seven pathologists after agreement on a standard set of diagnostic criteria. Majority vote served as the gold standard and 80% of the 180 diagnoses rendered (9 diagnoses each for 20 cases) were agreed upon by at least six of the seven scores. The sensitivity of individual diagnosis relative to the group consensus averaged 83% (range, 69-100%) and specificity averaged 91% (range, 86-100%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2, poor; 0.2-0.6, fair/moderate; > 0.6, substantial. Kappa values for lesions of distal villi were generally superior to those for lesions involving large fetal vessels: avascular villi (0.49), villous stromal-vascular karyorrhexis (0.58), and villitis of unknown etiology (VUE) with stem villitis and avascular villi (0.65) versus large vessel thrombi (any vessel, 0.34; chorionic plate vessel, 0.40) and intimal fibrin cushions (recent, 0.47; remote, 0.78). Reproducibility for a global impression of any villous change consistent with chronic fetal vascular obstruction was substantial (0.63), while that for a more severe subgroup was moderate (0.44). Three points are worthy of emphasis. Our system separately recognizes, but later combines, uniformly avascular villi and villous stromal-vascular karyorrhexis as manifestations of the same underlying process. We propose that this combined group of villous lesions be dichotomized with the terms fetal thrombotic vasculopathy or extensive avascular villi (and/or villous stromal-vascular karyorrhexis) being reserved for the group with 15 or more affected terminal villi per section. Scattered foci of avascular villi (and/or villous stromal-vascular karyorrhexis) could be used to describe less severe cases. Finally, we distinguish VUE with stem villitis and avascular villi (obliterative fetal vasculopathy) as a distinct process with substantial perinatal morbidity.

Meconium-associated vascular necrosis (MAVN) is a histological abnormality of human placental chorionic vessels that is associated with poor neonatal outcome. We tested the hypothesis that MAVN shows apoptosis in the walls of chorionic vessels. Archival placental specimens with MAVN (n = 5) were compared with specimens from uncomplicated pregnancies at term (n = 5) and from placentas with intense chorionic vasculitis associated with acute chorioamnionitis with (n = 5) or without (n = 5) a clinical history of meconium in the amniotic fluid. Sections from all placentas were processed by the TUNEL method, and 2 observers who were blinded to specimen diagnosis quantified the immunofluorescent TUNEL staining in both the amnion-facing and villous-facing walls of the larger chorionic vessels in each specimen. Compared with the other 3 groups, only the amnion-facing wall of chorionic vessels in MAVN showed a significantly greater number of apoptotic cells. This was verified by morphological criteria and caspase 3 staining. There were limited or no detectable TUNEL-stained cells in either the villous-facing walls of vessels in the MAVN specimens or in any of the vessels of the placentas from uncomplicated pregnancies. There was a negligible level of apoptosis in chorionic vessels of placentas with intense chorionic vasculitis, with or without meconium, despite the inflammatory response or presence of meconium. We conclude that apoptosis contributes to the pathophysiology of MAVN.

Objective: We tested the hypothesis that apoptotic trophoblasts from pregnancies associated with fetal growth restriction caused by preeclampsia or cigarette use exhibit enhanced expression of the proapoptotic proteins p53 and Bax and diminished expression of the antiapoptotic protein Bcl-2., Study Design: Placentas were obtained from women with uncomplicated pregnancies (n = 4) or from women with pregnancies complicated by fetal growth restriction associated with preeclampsia, cigarette use, or both (n = 7). Placental sections were examined by means of hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, as well as by detection of cytokeratin 18 cleavage products indicative of apoptosis. The expression of p53 was examined by means of Western immunoblotting and immunohistochemistry. The expression of Bax, Bcl-2, Bak, and Bcl-X(L) was analyzed by immunoblotting., Results: More apoptosis was found in the trophoblast layer of villi from pregnancies complicated by fetal growth restriction than in the trophoblast layer of villi from control pregnancies. The enhanced apoptosis correlated with up-regulation of p53, primarily in cytotrophoblast nuclei. There was no difference between the two groups in expression of the proteins from the Bcl-2 family., Conclusions: The expression of p53, but not members of the Bcl-2 family of proteins is up-regulated in human placental villi from pregnancies complicated by fetal growth restriction. We speculate that conditions predisposing to placental hypoxia lead to p53-mediated apoptosis in trophoblasts and thereby contribute to placental dysfunction.

Thrombi in the fetal circulation of the placenta cause a pattern of clustered fibrotic villi called fetal thrombotic vasculopathy (FTV), which has been associated with serious injuries to neonates, especially brain injuries. Correlation of FTV with visceral thrombi in autopsy specimens might lead to a more accurate estimate of the prevalence of somatic thrombi as a significant and underrecognized cause of prenatal injury or perinatal death, and show the potential validity of placental FTV as an indicator of thrombotic lesions in the fetus and newborns who survive. Clinicopathologic correlation was used to perform a 3-year retrospective autopsy review. We identified 16 cases (19%) among 84 perinatal autopsy specimens in which placental FTV was associated with stillbirth, intrapartum, or neonatal death. Two liveborn neonates survived 2.5 hours, and one for 24 hours; there was one intrapartum death, and the rest were stillborn. Clinical evidence of severe central nervous system (CNS) injury to two of the liveborn infants was evident at birth. Twelve stillborns died from 12 to 48 hours before delivery. Placental FTV had features of organization that clearly antedated the fetal death. Autopsy findings confirmed somatic thrombi in six cases (37.5%) of the 16 with FTV, including cerebral thrombi or infarcts (three cases), renal thromboemboli (three cases), and pulmonary thromboemboli (two cases). One mother had history of deep vein thrombosis, and four of eight tested had abnormal coagulation test results. Placental FTV indicates a significant probability of thrombi in the fetus and represents an important, possibly underrecognized cause of perinatal mortality and neonatal injury. Parental coagulopathy as a significant factor in prenatal injury and death deserves more comprehensive study. The placenta remains an undervalued and underutilized surgical specimen in the evaluation of perinatal injury, especially cerebral palsy.

A 38-year-old woman with extensive hemorrhagic endometriosis causing back pain, pelvic masses, and hydronephrosis also had a palpable omental mass composed of abundant endometrial-type stroma in which the epithelial component was entirely tubal type glandular cells; the stroma in this area did not bleed. This difference in bleeding behavior supports the concept that patterns of differentiation of heterotopic müllerian tissues may depend in part on the influence of local factors and that endometrial epithelium may produce a local trophic or paracrine factor that is absent in tubal epithelium.

We compared the DNA content (DI) by cell image analysis with the karyotype and morphological phenotype of paraffin-embedded tissues from 51 spontaneous abortions. The study included 21 cases with triploid, 19 cases with diploid, and 11 cases with aneuploid (monosomic, trisomic, or mosaic) karyotype. Measurements were performed by image analysis on the trophoblastic and stromal cells of chorionic villi using 5-microm-thick, Feulgen-stained sections. At least 200 cells were analyzed. Results were interpreted using DI ranges of 1.3 to 1.7 for triploid and 0.9 to 1.1 for a diploid profile. All 21 cases with a cytogenetically confirmed triploid karyotype had DI values within the triploid range, and all 19 cases with a diploid karyotype had DI values within the diploid range. All of the trisomies and monosomies also had a DNA mass within the diploid range. However, eight cases with a triploid karyotype also had a peak in the diploid range: one case with a diploid karyotype and one case with a trisomic karyotype each had an additional peak in the triploid range. We did not find a morphological correlation either with image analysis or with karyotype. We conclude that cell image analysis is a reliable method for detection of triploidy in spontaneous abortions. This relatively rapid method allows visual discrimination of the areas to be analyzed, avoids the problem of maternal cell contamination, and may unmask mosaic karyotypes that would go unrecognized by cytogenetic studies alone.

A 46-year-old woman presented with a large abdominopelvic mass. Exploration revealed a large cystic mass that arose from the posterior leaf of the right broad ligament. The mass was lined by endometrial-like tissue and had an outer layer of smooth muscle that resembled myometrium. The inner wall was focally composed of a thick layer of intermixed smooth muscle and endometrial glands comparable to adenomyosis. This is the fourth reported case of "a uterus-like mass" and the first that is clearly extraneous to the ovary. We hypothesize that these masses may arise from subperitoneal mesenchymal cells that retain the ability to duplicate mullerian duct structures; other cases may represent mullerian duct fusion defects.

Fetal vessels in the placentas of 11 of 15 infants with cerebral palsy contained thrombi. An alternate basis for the injury was identified in the four placentas without thrombi. Autopsy findings in one infant who died at age 1 month confirmed the presence of cerebral thrombi and infarcts. It is concluded that thrombotic events in utero may explain the pathogenesis of many instances of cerebral palsy and that identification of a coagulopathy in parents could potentially identify those at risk and provide a basis for preventive treatment during pregnancy.

Objective: The purpose of cold knife conization is to ligate the descending cervical branch of the uterine artery and thus to decrease bleeding. The aim of this study was to investigate the actual frequency of ligation., Study Design: Two lateral sutures were placed in the cervix at the 3 and 9 o'clock positions in 97 patients (194 sutures) as part of vaginal hysterectomy. The position of each suture was determined during evaluation of the surgical specimen., Results: Because the specimens from 10 patients contained only single sutures, only 184 sutures were actually evaluated. Upon microscopic examination, 50 of the 184 (27%) appeared to contain no artery. Of the remaining 134 sutures, 95 (71%) enclosed an artery, and 9 (7%) lay within a 10 x field of a branch. Only 30 sutures (22%) missed the artery entirely. Thus, in the 73% of cases where an artery of significant size could be identified, the artery lay within a lateral stitch 71% of the time., Conclusion: If the descending cervical branch of the uterine artery supplies most of the blood to the cervix, advance placement of lateral sutures would be expected to reduce blood loss during conization.

The complex double circulation of the placenta adds diversity to the kinds of changes caused by thrombi and bleeding. Different lesions may have different clinical implications for the mother and fetus. The clinical history may be extremely important in directing the pathologic examination and in evaluating the significance of vascular lesions.

Objective: Our aim was to find out whether patients delivered preterm because of preterm labor or preterm premature rupture of membranes can be categorized according to clinical characteristics and placental pathologic findings., Study Design: We performed a case-control study of 105 patients who were delivered preterm, 42 because of preterm labor and 63 because of premature rupture of membranes, and 105 patients who were delivered at term after uncomplicated pregnancies., Results: Maternal placental vascular lesions were present in 14 (34.1%) patients with preterm labor, 19 (35.1%) patients with premature rupture of membranes, and 9 (11.8%) control patients (odds ratios 3.8 and 4.0, 95% confidence intervals 1.3 to 11.1 and 1.5 to 10.8, p = 0.0065 and 0.0022, respectively). Infection of the products of conception was found in 16 patients (38%) with preterm labor, 23 patients (36.5%) with premature rupture of membranes, and 19 control patients (18%) (odds ratios 2.7 and 2.6, 95% confidence intervals 1.1 to 6.6 and 1.2 to 5.6, p = 0.017 and 0.01, respectively). Patients with maternal placental vasculopathy had significantly different characteristics compared with those of infected patients., Conclusions: It is possible to identify two subgroups of patients among those who are delivered preterm because of preterm labor or premature rupture of membranes, one with infection of the products of conception and another with maternal placental vasculopathy.

Vascular lesions, most often mediated by thrombi, are second only to infections as a cause of fetal injury in the later weeks of pregnancy. In our experience many pathologists who examine placentas fail to conduct a proper search for vascular lesions and some even fail to recognize those exposed by their examination. This review is intended to define the typical clinical background or circumstances that suggest the presence of significant vascular problems, to define techniques calculated to display them well, and to identify criteria for diagnosis. Further research is needed to evaluate the prevalence of maternal and fetal hypercoagulable states and thrombi as a cause of fetal injury.

Variability in classification in anatomic pathology does not necessarily indicate that a mistake has been made. It is usually an artifact, created when pathologists choose a single category from among two or more justifiable alternatives. This is most common when standard classifications with uniform terminology are not used. It also can occur when classification systems are not constructed so as to insure mutual exclusivity of categories. It is proposed that a proficiency test in anatomic pathology should not be considered scientifically valid until a professional organization primarily concerned with anatomic pathology has endorsed its proposed classification system as having categories that are close to 100% mutually exclusive in the hands of expert pathologists not involved in developing the system. All possible precautions should be taken to insure that the "right answers" for any proficiency test are generated in a way that excludes the possibility of multiple justifiable alternatives.

Three postmenopausal patients with giant cell arteritis involving the female genital tract are presented. None of these patients had a prior history of vasculitis. The giant cell arteritis was confined to the myometrium in one patient, involved the cervix and myometrium in another, and involved all the internal genital organs in the third patient. Based on follow-up of our patients and analysis of similar cases in the literature, we conclude that asymptomatic patients may best be managed by close follow-up and monitoring of erythrocyte sedimentation rate levels, but that treatment may be unnecessary.

Very large chorioangiomas are a rare but well recognized cause of neonatal morbidity, while small ones are clinically insignificant. This study emphasizes that some chorioangiomas of intermediate size may be causally related to intrauterine growth retardation, and that they may be surprisingly difficult to detect in the unfixed placenta.

A clinicopathologic study of 18 vulvovaginal fibroepithelial polyps with a comparison to normal stroma is presented. Twelve cases were analyzed by immunohistochemical methods for the presence of vimentin, desmin, muscle-specific actin, myoglobin, S-100 protein, alpha 1-antitrypsin (AAT), alpha 1-antichymotrypsin (ACHT), cytokeratin (AE1/AE3), and epithelial membrane antigen. Stromal cells reacted with vimentin antiserum in eight cases. Desmin reactivity was detected in five of 12 cases, four of which coexpressed vimentin. Two cases exhibited muscle-specific actin reactivity, and a single case weak AAT reactivity. The stromal cells were unreactive with S-100 protein, epithelial membrane antigen, cytokeratin, ACHT, and myoglobin. Ultrastructurally, the stromal cells of four fibroepithelial polyps resembled fibroblasts and myofibroblasts. Our immunohistochemical and ultrastructural data suggest that the stromal cells of fibroepithelial polyps are a collection of functional fibroblasts that may be capable of differentiating along two or more cell lines. Dramatically elongated cytoplasmic processes extend from both normal vulvovaginal stromal cells and the cells of the polyps. The cell attachments to each other and to bundles of collagen suggest a potential for a physiologic role in tissue contractility, especially in the immediate postpartum state. The common association with pregnancy may represent a local exuberant response to some presently unidentified trophic or stimulating factor.

A case of polypoid sarcoma of the pulmonary trunk is described in an 80-year-old woman who had a 21-year history of episodic chest pain and hemoptysis. Ultrastructural examination revealed Z bands, characteristic of rhabdomyosarcoma, and leptomeric organelles. This is the 60th reported case of sarcoma of the pulmonary trunk. Symptoms in reported cases were variable, usually caused by tumor emboli to the lungs or by right ventricular outflow obstruction. Angiography was diagnostic. The tumor was characteristically polypoid, often multicentric, and by definition was fixed to the pulmonary trunk or valves. Non-differentiated sarcoma (often uniquely pleomorphic) was found in 37% of patients, leiomyosarcoma (once confirmed by electron microscopy) in 17%, myxosarcoma in 13%, elements of rhabdomyosarcoma in 8%, fibrosarcoma in 8%, elements of chondrosarcoma in 11%, and 5% were malignant mesenchymomas. The authors suggest that these tumors originate from the undifferentiated tissues of the bulbus cordis and propose the name myenchymoma for the tumor.

During the course of applying electron microscopy to diagnostic surgical pathological specimens, three malignant tumors (malignant melanoma, fibrous mesothelioma, lymphoblastic lymphoma) were found to contain annulate lamellae, distinctive intracytoplasmic organelles composed of membrane stacks interrupted by constrictions or pores. In one case both annuli and lamellae were present, a combination rarely described in human tissue and in animal models. In this material, the annuli of the annulate lamellae were structurally similar to nuclear pores. It is postulated that the abundant fibrils are probably related to the unusual configuration of the annulate lamellae. A morphologic relationship of the annulate lamellae to both the endoplasmic reticulum (cases 1 and 2) and the nuclear membrane (case 3) supports the theory that annulate lamellae may be related to both of these structures.

A papillary tumor occurred in the posterior-superior vaginal wall of a 5-year-old girl who was free of recurrence one year following surgical excision. The light microscopic features included papillae lined by eosinophilic cells with uniform, bland nuclei, solid areas of identical cells, and scattered glandular lumina which contained mucopolysaccharides. Foci of eosinophilic hyaline globules were another distinctive feature. Electron microscopy of the tumor demonstrated features associated with müllerian neoplasms including projecting microvilli, whorls of perinuclear cytoplasmic microfilaments, conspicuous lysosomes, squamous metaplasia, complex cytoplasmic interdigitations, and pseudoinclusions of "cytoplasmic" collagen. Previously described "mesonephric papillomas" of the vagina and cervix are compared with the tumor of the authors' patient. The previously described tumors share some histologic and clinical features, although they were superficial rather than intramural proliferations. The authors conclude that the ultrastructure, location, and documented presence of müllerian structures in the vagina favor a müllerian origin for this vaginal tumor. A number of other vaginal tumors that occur in children and young women show different light microscopic features.

Resected uteri from a series of 48 consecutive patients with atypical endometrial hyperplasia ("carcinoma in situ") identified in curettings were studied to determine the frequency of associated adenocarcinoma. Thirty-nine of the women had received estrogen or oral contraceptives. Twelve uteri (25%) contained small superficial foci interpreted as well differentiated adenocarcinoma. Consideration of this observation together with the absence of adenocarcinoma in the extensive experience reported in other studies of women with atypical hyperplasia treated with progestogens alone shows a deficit of patients with progression to invasive carcinoma. We reconcile this apparent conflict with the hypothesis that lesions classified as focal well-differentiated endometrial adenocarcinoma occurring with atypical hyperplasia in perimenopausal women exposed to estrogen are common and are consistently reversed by progestogen therapy.

This combined ultrastructural and immunohistochemical study of four alveolar soft-part sarcomas analyzes the characteristic granules in order to elucidate the histogenesis of this unusual neoplasm. The granules have the ultrastructural features and staining characteristics of renin, react with antiserum to renin, and like renin, incorporate zinc into the crystalline storage granules. The cell appears to be a modified smooth muscle cell analogous to renal juxtaglomerular cells and the cells of juxtaglomerular cell tumors. As there is no association with hypertension, it would appear that alveolar soft-part sarcomas either do not secrete or the product is a form of renin that does not act upon the angiotensin system.

Seventeen of 204 cases of gastroenteropancreatic tumors contained psammoma bodies (8%). Of these 17, ten were B cell tumors, representing 33% of the B cell tumors studied. Three tumors of the appendix and four tumors of the small bowel also had psammoma bodies. Electron microscopic studies revealed that the bodies appeared to have two possible sites of origin: intracellular (type I) and intraluminal from secretory products of the tumor cells (type II). Awareness by surgical pathologists of the fact that variable degrees of calcification in endocrine tumors of the gastroenteropancreatic system is a rather common occurrence may be important, especially in frozen section diagnosis.

We investigated seven uterine wall lesions, selected because of the presence of unexpected patterns or components, to determine their relationship to normal uterine constituents. These lesions included a bizarre leiomyoma, a palisading leiomyoma which resembled a schwannoma, two myxomas, irradiated myometrium, a plexiform tumor, and a leiomyoma with tubular structures. All of these lesions except for the epithelial component of the plexiform tumor showed ultrastructural characteristics of smooth muscle, demonstrating a common origin from the myometrium. Two tumors, the plexiform tumor and the leiomyoma with tubules, had the pattern of epithelial structures suggesting origin from müllerian mesencyme: the plexiform tumor resembled incompletely differentiated endometrium and the tubular structures in the leiomyoma had features of mesothelium. We conclude that these varied and often confusing morphologic patterns reflect the capacity of uterine smooth muscle and stroma to undergo a wide spectrum of alterations including differentiation toward epithelial structures. Changes of this type occur in benign and malignant uterine stromal neoplasms and do not in themselves have prognostic significance.

Four days following resection of a medullary carcinoma of the thyroid, a 49-year-old man experienced elevated serum calcitonin levels. There was no evidence of metastasis. A re-exploration of the patient's neck demonstrated a histologically normal thyroid remnant that demonstrated C-cell hyperplasia by immunoperoxidase staining. The lack of a familial history, a normal parathyroid, and the absence of C-cell hyperplasia in non-tumorous thyroid of the original resection support the concept that the patient had a sporadic tumor. Patients who had undergone incomplete thyroidectomies for non-familial disease are at risk for developing C-cell proliferation and possibly medullary carcinoma. We conclude that the C-cell hyperplasia in this thyroid remnant is the source of the elevated calcitonin level; this mechanism may also explain postoperatively elevated calcitonin levels in some patients with medullary carcinoma treated by partial thyroidectomy and high calcitonin levels for a variable period after complete thyroidectomy.

Seven pathologists independently classified 50 slides of ovarian tumors using category I of the World Health Organization classification (WHO I), each case being seen twice under different random code numbers. Intraobserver reproducibility and interobserver reproducibility, based on consistent interpretations, were both suboptimal. However, scrutiny suggested that no pathologist was a source of excessive variability, nor was suboptimal interobserver reproducibility simply due to intraobserver variability. Neither could excessive variability be attributed to skewing of results by a subgroup of unclassifiable cases. However, clearcut sources of variability were identified among the categories of WHO I, namely, mixed epithelial, unclassified epithelial, and undifferentiated carcinoma. There was also considerable variability in distinguishing serous and endometrioid neoplasms, and in identifying tumors of low malignant potential. These findings should not be misconstrued as implying that pathologists in routine practice cannot diagnose common ovarian cancers reproducibly for patient care purposes. Availability of clinical and macroscopic data, extensive sampling, histochemistry, and consultation combine, in an uncontrolled and highly individualistic fashion, to render routine service work very different from this highly controlled formal exercise. Furthermore, at the current state of the therapeutic art, many of the taxonomic problems identified in this study may have little clinical significance. Nonetheless, this study has strengthened the evidence that there may be important problems in classifying common ovarian cancers reproducibly using WHO I, and that WHO I may require greater clarity to enhance reproducibility. Current emphasis on quality assurance dictates reconsideration of the literature on reproducibility of histopathologic taxonomy, which has tended to inculpate pathologists as sources of variability. Virtually all of this literature is subject to some degree of skepticism due to deficiencies in methodology. Consideration of the question of how to measure reproducibility in anatomic pathology leads us to suggest that the community of pathologists should address the need to decrease ambiguity in classification systems as an important step toward optimizing reproducibility.

A retrospective study of 54 patients with histologically proven malignant mixed müllerian tumors of the uterus was undertaken with main emphasis on the evaluation of the effects of irradiation on pelvic tumor control. The tumors were staged according to the FIGO classification for endometrial carcinoma and 24 were classified as Stage I, 10 as Stage II, 13 as Stage III and seven as Stage IV. Patients with Stage I and II were treated with surgery alone (9 patients, three surviving) or preoperative intracavitary irradiation (13 patients, eight surviving) or preoperative combination of intracavitary and external irradiation (12 patients, six surviving). Five patients with Stage III and IV were treated with surgery alone, two were treated with a combination of irradiation and surgery and 11 with radiation alone. None of these patients survived. In seven patients showing no residual tumor in the uterine specimen after irradiation, no pelvic failures were noted, whereas seven of 17 (41.2%) with residual tumor developed pelvic recurrences. In patients with Stage I treated with surgery alone, three out of six recurred in the pelvis whereas only three of 17 (17%) receiving preoperative irradiation developed pelvic recurrences. However, in Stage II six of eight patients treated with preoperative irradiation failed in the pelvis. Correlation with the doses of irradiation given to the uterus or the pelvic lymph nodes indicate that with doses below 5000 rads a significantly higher number of pelvic recurrences take place, whereas these are uncommon with doses over 6000 rads. The difference in pelvic recurrences between dosage levels is not, however, statistically significant. It is suggested that patients with Stage I and II malignant mixed müllerian tumors of the uterus should be treated with preoperative radiation and total hysterectomy with bilateral salpingo-oophorectomy. Patients with more advanced disease have extremely poor prognosis and should be treated with radiation therapy alone. This tumor has a high propensity to spread through lymphatics and hematogenous metastases are seen in approximately 75% of the patients. Because of this dissemination, significant improvements in survival rate will not be seen until effective cytotoxic agents are available.

Four examples of noninfectious granulomas of the ovary were studied. All four occurred in premenopausal women. One patient had a salpingo-oophorectomy for a symptomatic ovarian mass; the other three examples were incidental findings in hysterectomy and salpingo-oophorectomy specimens. None of the patients had a history of systemic granulomatous disease, nor have any of the patients developed any symptoms on follow-up, which varies from 2 to 7 years.

Previous bacteriologic studies of the placenta have been hampered by a high rate of contamination of vaginal flora. In the present study, cultures of the subchorionic fibrin layer of the placenta were compared to conventional swab-cultures of the surface of the fetal membranes for recovery of aerobic and anaerobic bacteria. Parallel cultures of membrane surface and subchorionic fibrin (SCF) were done in the placentas of 33 deliveries suspected clinically of being complicated by infection (CD). Placentas from 46 uncomplicated deliveries were similarly cultured to serve as controls. SCF cultures were positive in 11 of 33 CD placentas and in only 1 of 46 controls (P less than 0.001). SCF cultures showed contaminating vaginal flora in 2 of 79 while surface cultures showed vaginal contamination in 16 of 79 (P less than 0.01). Recovery of pathogens was similar by the two methods: 10 of 33 and 14 of 33 respectively. One hundred ninety-one additional CD placentas were cultured by the SCF technique. Forty-nine of the 224 SCF cultures yielded pathogens with a predominance of group B hemolytic streptococci, anaerobic gram positive cocci and anaerobic gram negative rods (81 total isolates). Escherichia coli was isolated in 5 cases. Cultures showing exclusively contaminating vaginal flora were obtained from only 3 of the 224 placentas. Subchorionic fibrin cultures combine technical simplicity, low rate of contamination and excellent recovery of pathogens. The bacterial types found by this method are the predominant species that cause endometritis, pelvic infections, and neonatal septicemia. Subchorionic fibrin culture is a useful technique for the bacteriologic diagnosis of infection in the placenta.

Using morphologic and bacteriologic techniques, we examined placentas from 224 deliveries considered potentially complicated by infection. The severity of the chorioamnionitis was graded histologically according to the intensity of the inflammatory infiltrate. Chorioamnionitis or funisitis occurred in 111 placentas. Neonatal morbidity in this group was 48 (43%) as compared with 14 (12%) in those without chorioamnionitis. Pathogens were cultured from 49 of the 111 placentas with chorioamnionitis. Neonatal morbidity or mortality occurred in 28 (58%) of the group with positive cultures but occurred also in 20 (32%) of the 63 with chorioamnionitis from which no pathogens were cultured. Perinatal mortality was especially high (64%) among premature infants (less than 30 weeks) with infection. A comparison of culture techniques (surface swab versus swab of subchorionic fibrin after searing amnionic surface) showed similar rates of recovery but less contamination using the deep culture technique. Neonatal morbidity and mortality with severe chorioamnionitis (grades II and III; 62% and 82%) were significantly greater than with little or no chorioamnionitis (grades I and 0; 43% and 36%). Higher grades of histologically demonstrable chorioamnionitis are associated significantly with the highest rates of neonatal morbidity or mortality. In many instances, pathogens are not recovered by conventional aerobic and anaerobic bacteriologic study. A search for other infectious agents (viruses, mycoplasmas, chlamydiae) deserves attention.

Thirteen patients with a diagnosis of very well-differentiated endocervical adenocarcinoma were studied in order to characterize the histological and immunohistochemical features of minimal deviation adenocarcinoma (MDA). Five of these patients had neoplasms composed of structures almost identical to normal endocervical glandular patterns. These five neoplasms, representing MDA, were characterized by a haphazard proliferation of both large, claw-shaped glands, and smaller, slit-shaped, pointed glands. Focal mild cytologic atypia was identified in each case. Immunohistochemical stains displayed focal cytoplasmic carcinoembryonic antigen (CEA) in each neoplasm. Two of the five patients with MDA died of their neoplasms; both presented with advanced disease. Three well-differentiated adenocarcinomas lacked the deceptively bland appearance of MDA. Two of these three well-differentiated endocervical adenocarcinomas also contained CEA. Atypical endocervical gland proliferations originally diagnosed as MDA in five patients were reclassified as benign lesions on the basis of histologic pattern, findings after subsequent surgical procedures, and benign subsequent clinical courses. Of these five benign lesions, only reserve cell hyperplasia was found to contain CEA. Minimal deviation adenocarcinoma should be distinguished from the more common well-differentiated endocervical adenocarcinoma and from atypical benign lesions. Criteria for these distinctions are presented. While the histological appearance of an endocervical gland proliferation is the paramount basis for identifying an MDA, immunohistochemical staining represents a useful diagnostic aid.

We report 12 cases of silent neuroendocrine neoplasms of the stomach and proximal duodenum masquerading clinically as common polyps. Five lesions were in the stomach, while seven were in the duodenum. Excision by endoscopic polypectomy usually did not remove all neoplastic tissue. The prognosis of these lesions is good even when the tumors are incompletely resected, although bleeding and secretory-product-related morbidity may precipitate surgery. Morphologic features by light or electron microscopy were not predictive of any given secretory product(s).