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Presents case report on limb necrosis associated with twin-twin transfusion syndrome treated with YAG-laser coagulation. Characteristics of twin-twin transfusion syndrome; Case history of a 21-year old woman with polyhydramnios; Failure of preventing peripheral necrosis through aggressive therapy of both YAG-laser coagulation.

OBJECTIVE: The objective of the study was to test the hypothesis that the total number of cells in the cortical part of the cerebral wall is the same in intrauterine growth-restricted (IUGR) fetuses, compared with normally grown fetuses. STUDY DESIGN: The total cell number in the cerebral wall was estimated in 9 severely affected IUGR fetuses and 15 controls using the optical fractionator. Cell numbers were estimated within 4 developmental zones. The gestational ages were 19-41 weeks. RESULTS: The total cell number in the future cortex was significantly reduced in the IUGR fetuses, compared with controls. The daily increase in brain cells in the future cortex was only half of that of the controls. In the 3 other developmental zones, no significant differences in cell numbers could be demonstrated. CONCLUSIONS: IUGR in humans is associated with a severe reduction in cortical growth and a significant decrease in cell number in the future cortex. [ABSTRACT FROM AUTHOR]

Study Question: How are germ cell numbers and initiation of folliculogenesis affected in fetal Turner syndrome (TS) ovaries?, Summary Answer: Germ cell development was severely affected already in early second trimester pregnancies, including accelerated oogonia loss and impaired initiation of primordial follicle formation in TS ovaries, while the phenotype in TS mosaic ovaries was less severe., What Is Known Already: Females with TS are characterized by premature ovarian insufficiency (POI). This phenotype is proposed to be a consequence of germ cell loss during development, but the timing and mechanisms behind this are not characterized in detail. Only few studies have evaluated germ cell development in fetal TS and TS mosaic ovaries, and with a sparse number of specimens included per study., Study Design, Size, Duration: This study included a total of 102 formalin-fixed and paraffin-embedded fetal ovarian tissue specimens. Specimens included were from fetuses with 45,X (N = 42 aged gestational week (GW) 12-20, except one GW 40 sample), 45,X/46,XX (N = 7, aged GW 12-20), and from controls (N = 53, aged GW 12-42) from a biobank (ethics approval # H-2-2014-103)., Participants/materials, Setting, Methods: The number of OCT4 positive germ cells/mm2, follicles (primordial and primary)/mm2 and cPARP positive cells/mm2 were quantified in fetal ovarian tissue from TS, TS mosaic and controls following morphological and immunohistochemical analysis., Main Results and the Role of Chance: After adjusting for gestational age, the number of OCT4+ oogonia was significantly higher in control ovaries (N = 53) versus 45,X ovaries (N = 40, P < 0.001), as well as in control ovaries versus 45,X/46,XX mosaic ovaries (N = 7, P < 0.043). Accordingly, the numbers of follicles were significantly higher in control ovaries versus 45,X and 45,X/46,XX ovaries from GW 16-20 with a median range of 154 (N = 11) versus 0 (N = 24) versus 3 (N = 5) (P < 0.001 and P < 0.015, respectively). The number of follicles was also significantly higher in 45,X/46,XX mosaic ovaries from GW 16-20 compared with 45,X ovaries (P < 0.005). Additionally, the numbers of apoptotic cells determined as cPARP+ cells/mm2 were significantly higher in ovaries 45,X (n = 39) versus controls (n = 15, P = 0.001) from GW 12-20 after adjusting for GW., Limitations, Reasons for Caution: The analysis of OCT4+ cells/mm2, cPARP+ cells/mm2 and follicles (primordial and primary)/mm2 should be considered semi-quantitative as it was not possible to use quantification by stereology. The heterogeneous distribution of follicles in the ovarian cortex warrants a cautious interpretation of the exact quantitative numbers reported. Moreover, only one 45,X specimen and no 45,X/46,XX specimens aged above GW 20 were available for this study, which unfortunately made it impossible to assess whether the ovarian folliculogenesis was delayed or absent in the TS and TS mosaic specimens., Wider Implications of the Findings: This human study provides insights about the timing of accelerated fetal germ cell loss in TS. Knowledge about the biological mechanism of POI in girls with TS is clinically useful when counseling patients about expected ovarian function and fertility preservation strategies., Study Funding/competing Interest(s): This work was supported by the International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC)., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. KS patients display a varying adult phenotype but usually present with azoospermia due to testicular degeneration, which accelerates at puberty. The timing of the germ cell loss and whether it is caused by dysgenetic fetal development of the testes is not known. We investigated eight fetal KS testes and found a marked reduction in MAGE-A4-positive pre-spermatogonia compared with testes from 15 age-matched controls, indicating a failure of the gonocytes to differentiate into pre-spermatogonia. Transcriptome analysis by RNA-sequencing of formalin-fixed, paraffin-embedded testes originating from four fetal KS and five age-matched controls revealed 211 differentially expressed transcripts in the fetal KS testis. We found a significant enrichment of upregulated X-chromosomal transcripts and validated the expression of the pseudoautosomal region 1 (PAR1) gene, AKAP17A. Moreover, we found enrichment of long non-coding RNAs in the KS testes (e.g. LINC01569 and RP11-485F13.1). In conclusion, our data indicate that the testicular phenotype observed among adult men with KS is initiated already in fetal life by failure of the gonocyte differentiation into pre-spermatogonia, which could be due to aberrant expression of long non-coding RNAs., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: Germ cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome., Methods: We identified paediatric GCTs from the Danish Childhood Cancer and National Pathology Registries and reviewed the case records for patient characteristics, tumour characteristics and clinical outcome., Results: We identified 403 (71% female) paediatric GCTs and the crude incidence was 1.43 per 100 000. Of these, 79 (20%) were malignant, 39 (10%) were potentially malignant and 285 (70%) were benign. Extragonadal GCTs (39%) were mainly observed in early childhood and were predominately sacrococcygeal teratomas. Gonadal GCTs (61%) in late childhood were most frequently mature teratomas in the ovaries. Nearly all patients underwent surgery. Of the malignant tumours, 62% were treated with chemotherapy. Radiotherapy was only administered to intracranial GCTs. In the cohort, 12 patients died (3%)., Conclusion: Paediatric GCTs in Denmark were mainly benign and mortality was low, even for malignant tumours. We identified a peak of extragonadal GCTs in early childhood and a peak of gonadal GCTs in late childhood, which was comparable to previous reports., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Observations in patients with an activating mutation of fibroblast growth factor receptor 3 (FGFR3) suggest a role for FGFR3 signalling in promoting proliferation or survival of germ cells. In this study, we aimed to identify the FGFR3 subtype and the ontogeny of expression during human testis development and to ascertain whether FGFR3 signalling is linked to germ cell proliferation and the pathogenesis of testicular germ cell tumours (TGCTs) of young adult men. Using RT-PCR, immunohistochemistry and Western blotting, we examined 58 specimens of human testes throughout development for FGFR3 expression, and then compared expression of FGFR3 with proliferation markers (PCNA or Ki67). We also analysed for FGFR3 expression 30 TGCTs and 28 testes containing the tumour precursor cell, carcinoma in situ (CIS). Fetal and adult testes expressed exclusively the FGFR3IIIc isoform. FGFR3 protein expression was restricted to the cytoplasm/plasma membrane of spermatogonia and was most prevalent at mid-gestation, infancy and from puberty onwards. Phosphorylated (p)FGFR was detected in pre-spermatogonia at mid-gestation and in spermatogonia during puberty and in the adult testis. Throughout normal human testis development, expression of FGFR3 did not directly correlate with proliferation markers. In preinvasive CIS cells and in TGCTs, including classical seminoma and embryonal carcinoma, FGFR3IIIc was detected only in a small number of cells, with a heterogeneous expression pattern. FGFR3 is an excellent marker for human pre-/spermatogonia throughout development. Signalling through this receptor is likely associated with spermatogonial survival rather than proliferation. FGFR3 is not expressed in gonocytes and may not be essential to the aetiology of TGCTs stemming from CIS.

We evaluated the correlation between prenatal diagnosis by ultrasound and autopsy findings, based on 52 second-trimester pregnancies terminated due to fetal malformations or chromosome aberrations diagnosed at a gestational age of 12-25 weeks. In 24 pregnancies, there was full agreement between ultrasound and autopsy. In 23 fetuses, the main diagnosis was confirmed and additional or more specific findings were observed on autopsy. In five fetuses, there were considerable differences. Discrepancies between ultrasound and autopsy findings were mainly anomalies undetectable by ultrasound and thus expected; however, about one-third of the discrepancies were not expected, representing findings that were 'missed' at ultrasound. The main ultrasound diagnoses were confirmed in the majority of the pregnancies, but the additional information obtained at autopsy in more than half of the fetuses clearly shows the value and benefit of postmortem fetal examination following termination of a pregnancy., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from A(dark) spermatogonia., (Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

During a 1-year period 4785 intraoperative consultations were performed. The pathology reports were retrospectively reviewed to determine the accuracy of frozen section diagnosis in various tissue types. Skin for evaluation of section margins and axillary sentinel lymph nodes for evaluation of metastatic disease were most frequently sent for frozen section diagnosis. The number of discordant cases were 182, 178 were false negative and four were false positive. When frozen section diagnoses were compared with permanent section diagnoses, the overall diagnostic concordance was 95.1%. The number of deferred specimens was 57. The accuracy of frozen section diagnosis varied between tissue types, and axillary sentinel lymph nodes accounted for the greatest number of discordances. In conclusion, the frozen section diagnosis is a reliable method with varying concordance and deferral rates between tissue types. We suggest regular monitoring of the performance in frozen section diagnosis., (© 2011 The Authors. APMIS © 2011 APMIS.)

The development of the human neocortex is a complex and highly regulated process involving a time-related expression of many transcription factors including the homeobox genes Pax6 and Meis2. During early development, Pax6 is expressed in nuclei of radial glia cells in the neocortical proliferative zones and controls the differentiation and neurogenetic fate of these cells in the dorsal telencephalon in rodents. Animal studies on the Meis2 gene have revealed expression in the developing telencephalon and Meis2 is known to regulate the expression of Pax6 in the eye and pancreas. Because of this functional relation between Pax6 and Meis2, we studied the spatial and temporal expression of PAX6, and MEIS2 using a developmental series of human fetal brains at 7-19 postconceptional weeks with emphasis on the forebrain to investigate whether the two genes are expressed in the same regions and zones in the same time window. We demonstrate by in situ hybridization and immunohistochemistry that the two homeobox genes are expressed during early fetal brain development in humans. PAX6 mRNA and protein were located in the proliferative zones of the neocortex and in single cells in the cortical preplate at 7 fetal weeks and in the developing cortical plate from 8 or 9 to 19 fetal weeks. The expression of PAX6 expanded into the ganglionic eminence just prior to the stage at which a stereological estimation showed an exponential rise in total cell number in this area. The MEIS2 gene was also present in the proliferative zones of the human fetal neocortex and a higher expression of MEIS2 than PAX6 was observed in these areas at 9 fetal weeks. Further, MEIS2 was expressed at a very high level in the developing ganglionic eminence and at a more moderate level in the cortical plate., (Copyright 2010 S. Karger AG, Basel.)

Objective: Testicular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms., Methods: Fetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-alpha (INHalpha)., Results: GATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHalpha and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative., Conclusions: Differential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.

Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore compared brains of DS fetuses aged 19 weeks of gestation with normal control brains. The cell numbers were estimated using the optical fractionator method. The total cell number in the neocortical part of four DS human fetal forebrain was found to be substantially smaller in DS compared to the normal fetus. The average total cell number of 6.85 billion was equal to a reduction by 34% compared to the 10.4 billion cells in a normal fetal brain of that age. This study indicates that the mental retardation found in DS is based on a structural deficit in the human fetal brain already present in the second trimester.

Two early-2nd-trimester fetuses were aborted as a result of nuchal edema and suspected severe heart malformation. At autopsy one fetus demonstrated nuchal edema, mild hydronephrosis, and cor triatriatum dexter associated with ventricular septal defect and tubular hypoplasia of the aortic arch. The other fetus demonstrated severe nuchal edema, and cor triatriatum dexter was the only malformation. Cor triatriatum dexter is a rare cardiac malformation characterized by division of the right atrium into 2 compartments by a usually fenestrated membrane representing remnants of the right valve of the embryonic sinus venosus. This malformation has been diagnosed in adults and children by echocardiography, surgery, or autopsy but has not previously been published in fetuses.

Neural tube defects (NTDs) are congenital malformations of the central nervous system (CNS) secondary to abnormal closure of the neural tube during embryonic development. This study provides information on NTD rate, distribution, associated morphologic anomalies and organ weights in a Danish fetal and perinatal autopsy series during a 16 year period. The data were extracted from the autopsy reports of a consecutive series of 1984 fetal and perinatal autopsies from the Copenhagen area performed in the period 1989-2004. Registered parameters included: The location and morphology of the NTD, associated morphological anomalies, and organ weights. Organ weights were evaluated according to new fetal autopsy standards and grouped as low, normal or high. Ninety-seven NTD cases were found (4.9%): Spina bifida (38 cases), cephalocele (17 cases) and anencephaly (42 cases). 63% of NTD cases had associated morphologic anomalies. Among the most common were hydrocephalus, NTD in another region, and anomalies in the urogenital system. 58% of the NTD cases had abnormal weight of one or more organs. Most notable was low adrenal weight not only in anencephalic fetuses but also in cases with cephalocele, suggesting a possible association.

We present a case of a previously healthy 14-month-old girl with malignant ventricular tachycardia, which developed in relation to acute gastroenteritis. Autopsy revealed histiocytoid cardiomyopathy.

Standards for body parameters and organ weights are important tools in fetal and perinatal pathology. Previously there has been only a weak emphasis on the effect of maceration on dimensions and weights. This study provides autopsy standards for body weight, body dimensions, and fresh organ weights for nonmacerated fetuses and for mildly, moderately, and markedly macerated fetuses at 12 to 43 weeks of gestation. Cases were selected from a consecutive series of 1800 fetal and perinatal autopsies. Cases with malformations, hydrops, infection, or chromosomal abnormality, fetuses from multiple births, and infants who lived longer than 24 h were excluded. In each case the maceration was graded and body weight and 4 body dimensions were recorded before organ examination. Organs were weighed immediately and before fixation. Growth curves were fitted according to appropriate mathematical methods and the effects of maceration on each value were tested statistically. We found that weights of the liver, thymus, and spleen markedly decrease with increasing maceration. The weights of the lungs, kidneys, and adrenals decreased modestly, whereas weights of the heart and brain changed only slightly. Body length increased slightly with maceration, whereas body weight and head circumference were unaffected. User-friendly charts and tables of mean values and standard deviations for nonmacerated and macerated fetuses are provided.

Purpose: Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2gamma and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia., Experimental Design: We analyzed expression pattern of AP-2gamma at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid., Results: We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells., Conclusions: AP-2gamma is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2gamma is a novel marker of testicular CIS and CIS-derived tumors.

Background: To investigate how long fetal germ cells retain pluripotency, which may be linked to their ability to transform into histologically variable tumours, we examined the expression of OCT-3/4 (POU5F1), a transcription factor essential for the maintenance of totipotency in embryonic stem cells., Methods: The ontogeny of expression of OCT-3/4 was studied in 74 specimens of normal human gonads during development and in 58 samples of gonads from cases with testicular dysgenesis syndrome (TDS), including disorders of sex differentiation and malignant changes., Results: OCT-3/4 expression was found in primordial germ cells during migration to the gonadal ridges and in the indifferent gonad. The expression in testes gradually decreased until approximately 20 weeks of gestation, and thereafter it was more rapidly down-regulated, but persisted in a few cells until 3-4 months of postnatal age, which coincides with the final differentiation of gonocytes into infantile spermatogonia. Subsequently, OCT-3/4 was not detected in normal testes. In the ovaries, OCT-3/4 was expressed in primordial oogonia, but was down-regulated in oocytes that formed primary follicles. The pattern of expression was heterogeneous in dysgenetic and intersex cases, with OCT-3/4-positive gonocytes detected in this series until 14 months of age. Visibly neoplastic gonadoblastoma and carcinoma in situ (CIS) expressed abundant OCT-3/4 regardless of the age., Conclusions: In the human ovary, OCT-3/4 is silenced at the onset of the first meiotic prophase, whereas in the testis, down-regulation of OCT-3/4 is a gradual process associated with differentiation of gonocytes. This normal pattern of expression is disturbed in dysgenetic gonads, especially in rare intersex cases, thus increasing the risk of malignant transformation. The high abundance of OCT-3/4 in CIS cells is consistent with their early fetal origin and pluripotency.

The total number of cells--including both neurons and glial cells - was estimated in the neocortical part of the human fetal telencephalon in 22 normal brains within four major developmental zones: the cortical plate/marginal zone, the subplate, the intermediate zone and the ventricular/subventricular zone. The fetal ages ranged from 13 to 41 weeks of gestation. The cellular growth in the human fetal forebrain appears to be two-phased: one rapid, exponential phase from 13 to 20 weeks of gestation and a second and slower phase, which increases linearly, from approximately 22 weeks of gestation to term. From 13 to 20 weeks of gestation the total number of cells increases by a factor of 4.3 from 3 x 10(9) cells to 13 x 10(9) cells at 20 weeks of gestation. From mid-gestation to term, the total cell number increases by a factor of 2.9 to 38 x 10(9) cells in the newborn infant. Studying cellular growth in the normal human fetal brain is important since it may serve as a useful parameter for the assessment of cortical growth in non-invasive and histological studies, and thus improve the analysis of fetal brain disturbances.

The ontogeny of expression of anti-Müllerian hormone (AMH) was examined by immunohistochemistry in 135 human gonadal tissue specimens of various developmental age, ranging from 6 weeks of fetal development to 38 yr of postnatal age. The series included specimens from normal testes and ovaries and from individuals either with pathological conditions affecting gonadal development or with idiopathic infertility manifested as azoospermia or severe oligozoospermia. AMH expression was found only in Sertoli and granulosa cells. A 6-week-old fetal testis at the indifferent gonad stage did not yet express AMH. The protein was first visible at 8.5 weeks of development, when sex cords have not yet been formed. Afterward, a majority of testicular specimens, including those from pathological conditions, strongly expressed AMH through fetal development and childhood until puberty. Markedly prolonged expression of AMH was observed in a 20-yr-old 46,XY female with androgen insensitivity syndrome, who retained prepubertal testicular morphology. In normal testes, the switch-off of AMH expression was usually associated with the appearance of primary spermatocytes, suggesting that their presence had an inhibitory effect on AMH. However, in adolescent boys lacking germ cells because of cancer treatment and in a majority of infertile adult men with idiopathic germ cell aplasia, AMH expression was also down-regulated despite the complete lack of spermatogenesis. The decrease in AMH expression thus reflects the terminal differentiation of Sertoli cells and is probably only partially dependent upon a regulatory factor associated with the onset of meiosis. In fetal ovaries, AMH was first detected at 36 weeks gestation in granulosa cells of preantral follicles. Thus, the onset of ovarian expression is at the end of fetal life and not in infancy as previously reported.

The purpose of this study was to report on the morphological findings in placentae from abortions, stillbirths and perinatal deaths, and to assess the value of the results of the placental examinations. The material included 341 placentae and their matched autopsies. Fifty placentae came from abortions induced for medical reasons, 194 from spontaneous abortions, 84 from stillbirths, and 13 from livebirths. Histological slides from all placentae were reviewed and the placental diagnoses were related to the autopsy diagnoses. Frequently observed placental lesions were inflammation of the membranes and/or umbilical cord, placental edema, vascular lesions, single umbilical artery, and degenerative lesions. The placental examination in pregnancies terminating with fetal or perinatal death was of value in half the cases. Some placental lesions provide us with clues when assessing the cause of fetal death, but such lesions are rare. Two important groups of lesions, acute inflammation of the membranes and/or umbilical cord and lesions consistent with uteroplacental vascular insufficiency, seen mainly as infarction and decidual arteriopathy, were observed. Gross examination is informative, though microscopic examination is often necessary.

A woman had two pregnancies terminated in the 20th and 21st weeks of gestation after ultrasonographic detection of enlarged hyperechoic kidneys in both fetuses. The combination of polycystic kidneys and steatotic liver found at autopsy suggested glutaric aciduria type II (GA II), which was confirmed by biochemical investigation. GA II or multiple acyl-CoA dehydrogenase deficiency is an autosomal recessively inherited defect of mitochondrial energy metabolism, which usually results in neonatal death. When pregnancy is terminated because of enlarged hyperechoic kidneys in the fetus, autopsy is crucial for establishing the correct diagnosis. The combination of polycystic kidneys and steatotic liver should bring GA II to mind, and prompt appropriate biochemical investigations so that genetic counselling and first trimester diagnosis can be offered in future pregnancies.

Bcl-2 is a proto-oncogene inhibiting apoptosis, and p53 is a tumor supressor gene which induces apoptosis. Both seem to take part in tumorigenesis. An inverse relationship between the two genes has been reported in some neoplasms, although the exact mechanism is not fully understood. We have analyzed the expression of bcl-2 and p53 in 18 fetal thymuses and 18 clinically benign and malignant thymomas: bcl-2 was expressed by most medullary lymphocytes and epithelial cells of the normal thymus; p53 was not expressed at all. Bcl-2 and p53 were co-expressed in the majority of the thymomas and the staining reaction was stronger in the clinically malignant ones. It is concluded that although co-expression of bcl-2 and p53 is of doubtful prognostic relevance, the staining pattern of bcl-2 supports the histogenetic classification system of Müller-Hermelink.

Three cases of lung hypoplasia occurring in two siblings and in an unrelated child are reported. All three cases had been exposed to valproate in utero. The two female siblings had no other malformations, whereas the third female had a number of defects consistent with the fetal valproate syndrome. Thus, none of the known major causes of lung hypoplasia was present in any of the three cases. It is discussed whether pulmonary hypoplasia may be a separate disease entity, or caused by prenatal exposure to valproate.

The glycosylation of epithelial cell surface antigens follows cellular differentiation, and changes in the pattern of expression are seen in various premalignant and malignant epithelial lesions. The distribution of type-2 chain ABH-carbohydrate structures (N-acetyl-lactosamine, H-type 2 chain, Le-y, Le-x and sialyl-Le-x) of the ABO-histo-blood group system was investigated in 19 normal fetal thymuses (gestational age 16 to 39 weeks) and in 19 thymomas in order to study possible tumor-associated changes in the glycosylation pattern. The material was investigated by immunochemical stainings of formalin-fixed paraffin-imbedded tissue using monoclonal antibodies with defined specificity. In fetal thymus the epithelial cells of the medulla and the Hassal's bodies strongly expressed elongated carbohydrate structures (Le-y, Le-x and sialyl-Le-x). In a few cases the cortical epithelial cells weakly expressed Le-x and sialyl-Le-x. Compared with fetal thymus 16 of the thymomas showed a total loss, or a very much reduced expression of elongated carbohydrate structures. Three thymomas, which histologically had been reclassified according to Kirchner & Müller-Hermelink (14) as high grade thymic carcinomas, revealed strong expression of Le-y, moderate expression of Le-x and weak expression of sialyl-Le-x. This is of interest as in other tumors Le-y is correlated with increased cell motility and with poor prognosis.

Objective: Placental insufficiency has been considered the cause of increased morbidity in infants delivered postmaturely. Former quantitative studies have indicated a decrease in some placental structures just before term. In this study we describe a method of dual perfusion fixation to provide tissue for stereologic examination. Postmature placentas were examined with this method., Study Design: Eleven postmature placentas and 14 placentas delivered at term were fixed by dual perfusion. The volume and the surface area of villi, the trophoblast volume, and the volume, surface area, and length of villous capillaries were estimated by stereologic examination. The Mann-Whitney test (p < or = 0.05) was used for statistical analysis., Results: Morphologic features were normal in all placentas. No significant differences were disclosed in the stereologic estimates of placentas delivered at term and postmature placentas., Conclusion: No morphologic or significant quantitative changes were found in postmature placentas.

Background: It has been hypothesized that carcinoma in situ of the testis (CIS), which is the precursor of invasive testicular germ cell tumours, may arise from fetal germ cells during fetal development rather than later in life. In order to corroborate this hypothesis, we undertook the present study., Experimental Design: Normal human germ cells from 10 first-trimester fetuses and 76 second- and third-trimester testes were investigated for the immunohistochemical expression of the markers of testicular carcinoma in situ. The panel of markers included in the study consisted of placental-like alkaline phosphatase, the protooncogene c-kit protein product, and the antigens for the monoclonal antibodies TRA-1-60 and M2A. The relative numbers of fetal germ cells that demonstrated positive reaction with the markers were calculated., Results: The vast majority of the germ cells (75-100%) in the first-trimester gonads were positive for placental-like alkaline phosphatase, TRA-1-60, and M2A. The c-kit protein was detected in three out of the ten first-trimester gonads. The relative number of germ cells positive for all the markers studied declined rapidly during the first part of the second trimester, and the decrease continued with the fetal age., Conclusions: The expression of adult carcinoma in situ markers in normal fetal germ cells is consistent with the hypothesis that CIS cells may arise from fetal germ cells, although re-expression of the antigens in postnatally arising CIS cells could provide an alternative explanation. However, we speculate that a transformation of normal fetal germ cells into CIS cells may take place before the end of the 9th week of fetal development. Furthermore, the expression of c-kit in early human fetal germ cells indicates that the c-kit and its ligand play a role in the early human testicular development.

The purpose of the present study was to investigate the axial skeleton related to the notochord in human anencephalic fetuses in order to elucidate the pathogenesis. Fifteen second trimester fetuses were examined. The spine and the cranial base were dissected and radiographed. Comparison with normal fetuses was performed. Two patterns of abnormal ossification were seen. Anencephalic cases without cervical rachischisis (Groups I and II) differed markedly from cases with cervical rachischisis (Group III). Morphological characteristics, such as bilateral narrowing of the basilar part of the occipital bone combined with normal cranio-caudal dimension, were found in cases without cervical rachischisis. In these cases frontal clefting of vertebral corpora occurred. Caudocranial shortening of the basilar part of the occipital bone was found in cases with cervical rachischisis, where complete median clefting of vertebral corpora also occurred. Because the vertebral corpora and the basilar part of the occipital bone develop around the notochord, which interacts also in the process of neurulation, the defects might indicate a notochordal insufficiency. The study showed that when the initial closure of the neural groove failed, the skeletal deviations were more extensive. The study supports the hypothesis that the notochord is an important clue to an understanding of the pathogenesis in anencephaly.

The purpose of this study was to describe the midline maxillofacial skeleton (the axial skeleton anterior to the sella turcica) in 15 human anencephalic fetuses (14-19 weeks of gestation) by radiography and histology, and to relate the findings to skeletal patterns in the remaining part of the axial skeleton. Four patterns in the maxillofacial skeleton were recognized: normal structures, slightly deformed (6 cases); cleft palate (3 cases); incomplete nasal septum (3 cases); multilocular ethmoid cartilage (3 cases). No association was found between skeletal patterns in the different parts of the axial skeleton. The study demonstrates the existence of a developmental borderline in the anencephalic axial skeleton in the region of the sella turcica. It is presumed that this borderline indicates the boundary between skeletal tissue developed around the notochord (posterior axial skeleton) and the anterior skeletal components derived from neural crest cells.

Histological samples from 60 invasive ductal breast carcinomas were investigated for immunoreactivity for the receptor for urokinase-type plasminogen activator (uPAR) with the use of two monoclonal antibodies recognizing different epitopes. In 51 cases, uPAR immunoreactivity was observed, and in 49 of these specimens, a population of periductal tissue macrophages showed pronounced uPAR immunoreactivity in areas with infiltrating and intraductal carcinoma. In the 2 remaining positive specimens no stromal immunoreactivity was seen. The carcinoma cells were found to contain uPAR immunoreactivity in 8 of the 51 positive cases, including the two specimens that did not show stromal immunostaining. Immunoactivity was not found in the epithelial cells of carcinoma in situ components occasionally seen in the specimens, but stromal macrophage-like cells which had invaded such lesions were positive. In most specimens a subpopulation of tissue neutrophils was also positive. Normally appearing epithelium in all specimens investigated was negative, and no other tissue elements were stained in any of the samples. Ten samples of normal female breast tissue were negative. This is the first report on the immunohistochemical distribution of uPAR in human cancer tissue, and the results provide evidence for a role of the urokinase receptor in providing tissue macrophages a means of directing proteolysis at sites of breast cancer invasion. This macrophage-mediated proteolytic activity is suggested to be involved in the invasion and subsequent distant spreading of this malignancy.

The aim of this radiographic study of human fetuses was to examine the pattern and sequence of ossification in the occipital bone and the spinal vertebrae. Together with previous studies of ossification of the human fetal basal cranium, this study can serve as a reference for normalcy in future studies of fetuses with neural tube defects and associated pathological development of the axial skeleton. Thirty-nine normal fetuses aborted between 9 and 14 weeks of gestation were examined. Based on the appearance of ossification centers in the bones under study, the fetuses could be grouped in four well-defined developmental stages, which were named occipito-spinal stages I-IV (OS I-IV). The OS stage was closely related to gestational age, crown-rump length, foot length, and degree of ossification in the hands and feet.

Closure of the palatal shelves during normal prenatal palate formation is commonly supposed to be the result of a complex interaction between tissue growth processes and functional factors such as mandibular and tongue movements. The purpose of the present study was to analyze tongue and palatine bone positions during palatal shelf closure. The material consisted of 40 normal human fetuses (CRL 26-57 mm). The series covers the developmental stages in which palatal shelf closure takes place. The spatial relation between the tip of the tongue and the lips was examined by visual inspection, and radiographic/cephalometric methods were used for analyzing palatine bone positions. On axial radiographs of the upper jaws, the angle in the horizontal plane between the vertical plates of the palatine bones was measured. The study revealed that the vertical plates of the palatine bones rotate on their vertical axes during palatal closure, the mean interpalatine angle changing from 23.7 degrees (SD 2.0 degrees) to 13.3 degrees (SD 3.2 degrees), P < 0.001. The rotation of the palatine bones occurred while the cranial base was still unossified. Moreover, the tip of the tongue became visible between the lips immediately after palate closure. In the present study the rotational changes observed in skeletal tissue provided information about soft tissue changes during palatal closure. These normal developmental aspects are discussed in relation to skeletal deviations in congenital cleft palate malformations.

The purpose of the present study was to describe normal midsagittal craniofacial morphology in second trimester human fetuses. Measurements of the cranial base angle and the prognathism of the maxilla and the mandible were performed on radiographs of cranial midsagittal tissue blocks of 52 fetuses with a gestational age from 13 to 27 weeks. Special procedures were developed for the definitions of the nasion and sella reference points on the radiographs in the early stages of fetal development. Mean data were reported for stages of crown rump length (CRL) and maturation of the fetal cranial base (MSS), usable as reference in assessment of pathological fetal crania in reports and autopsy procedures. Regression equations were determined for the regression of the angular values on CRL, MSS, and general skeletal maturation (TNO). The cranial base angle was found to decrease significantly, and the angles of prognathism to increase significantly with increasing CRL, TNO, and MSS values. It was suggested that these simultaneous and similar changes in the three angles could be accounted for by the upwards movement of the sella point produced by a cranial displacement of the pituitary fossa caused by local cartilagenous growth and bony remodelling during the period of study. The study thus reflects the influence of cranial skeletal maturation on the early development in shape of the craniofacial complex.

A new radiography technique for examining second trimester abortions permits an accurate analysis of growth and maturation of the fetal skull. Reference material for normal development has been previously published. The potential of the method is demonstrated with three examples: thanatophoric dysplasia, Arnold-Chiari malformation, and anencephaly.

Tissue from 13 human pleomorphic adenomas was transplanted to a total of 64 nude mice. Eight of the tumors were transplanted into a second passage of mice, 17 in all. In 39 mice of first passage, there was a definite increase in graft size. Microscopic examination showed no change in the histologic pattern from the donor tumor to the transplanted tissue. The heterochromatin pattern after staining with the DNA-specific fluorochrome D287/170 allowed distinction between human and murine cells and showed that both epithelial and mesenchymal cells were of human derivation. Autoradiographic studies with tritiated thymidine showed that both epithelial and mesenchymal tumor cells were labeled. Our results thus show that cell proliferation in the human pleomorphic adenoma takes place in epithelial areas as well as in mesenchymal areas.

In a follow-up study of 1 000 patients subjected to Billroth II resection for duodenal ulcer in the period 1948-1956, the late mortality up to the end of 1977 (522 patients) was analyzed. The observed mortality was compared with the expected mortality calculated by the life-table method and indirectly standardized for age, sex, domicile and time and cause of death. The overall mortality rate was significantly increased, mainly due to suicide, which occurred at five times the expected rate and could be related to excessive alcohol consumption and psychiatric disturbances. Malignant neoplasms, including gastric carcinoma, were not more common than expected as causes of death. The same applied to pulmonary tuberculosis, other respiratory disorders, cardiovascular, gastro-intestinal and urogenital disease and to accidents. It is concluded that the main mortality risk factors were psychiatric disease and alcohol consumption.

Grafts of human skin on nude mice were subjected to a single dose of either 2 1/2 min or 4 min of radiation from two different commercial dental light curing units with emission mainly in the visible light spectrum but also with a small fraction of UV-A light. Seventy-two hours after exposure the tissue was examined for presence of Langerhans cells using monoclonal antibody OKT6 double layer immunofluorescence staining. Epithelial hyperplasia and reduced reactivities for OKT6 were seen after 2 1/2 min exposure. After 4 min of exposure OKT6 positive cells were completely absent from the epithelium. The results indicate that emission from dental light curing units can affect Langerhans cells in human epithelium and could thus modify the local immunologic response.

Primary biopsies from 52 patients with cancer of the larynx were examined by two pathologists working independently. The malignancy of each case was graded twice with an interval of 1--1 1/2 month according to a histological scoring system elaborated by Jacobsson. The reproducibility of the system was found poor for individual prognostic purposes and no connection between histological grade and clinical course was demonstrated.

Effects of the tumor initiator 7,12-dimethylbenz(a)anthracene (DMBA) and of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) on epidermis of human fetal and adult skin were studied in the nude mouse/human skin model. Human skin grafts on NC nude mice were exposed to two topical applications of 1 mg of DMBA in 50 microliter of acetone with an interval of 3 days and/or to applications of 10 micrograms of TPA in 50 microliter of acetone twice weekly. In some animals, it was attempted to augment the susceptibility of the grafts to the tumor-initiating effect of DMBA by pretreatment with TPA or ultraviolet light. The mice were sacrificed 8-32 wk after the initial treatment. Tumors did not appear in the central portions of any of the grafts, but epidermal tumors were seen at the graft border in 34.9% of the DMBA-treated animals. To identify human epidermis on the grafts and to determine the species origin of the induced tumors, two independently working histological marker methods were applied. (a) The first is detection of a human Blood Group B-like antigen present in mouse epidermis and in chemically induced murine epidermal tumors. This antigen cannot be demonstrated in human epidermis and in epidermal tumors of human patients. (b) The second is histological staining with the DNA-specific fluorochrome, bisbenzimide, displaying a characteristic pattern of 5-10 intranuclear fluorescent bodies in murine nonneoplastic epidermal cells and in murine epidermal tumor cells. Such a pattern is not seen in human epidermis and in epidermal tumors of human patients. The studies showed that TPA treatment resulted in epidermal hyperplasia in both the human epidermis and the adjacent mouse epidermis and that the induced tumors were derived from murine tissue. The mechanisms behind the DMBA action in the nude mouse/human skin model are discussed, and suggestions for future carcinogenesis studies on the model are given.

A case is presented in which a cystic process occupying the body and tail of the pancreas peroperatively was regarded as a pancreatic pseudocyst but post-operatively showed a microscopic picture of cystic malignant schwannoma. It is concluded that in case of a presumed pancreatic pseudocyst, peroperative microscopy--when possible--of frozen sections of the cyst wall before performing a drainage operation is indicated.

The purpose of the present study was to establish a model for in vivo studies of human pleomorphic adenomas by heterotransplantation of tumour tissue to nude mice. Tissue from 7 tumours was transplanted to a total of 34 mice. Take with obvious growth occurred in 12 mice, and survival of the tissue was seen in an additional 8 mice. The overall histological picture was unchanged from the donor tumours to the transplanted tissue. The possibilities of the model are discussed.

Sera from 7 patients with primary Sjögren's syndrome and from two control persons were administered intraperitoneally to athymic nude mice transplanted with normal human skin. Seven days after transfer of serum from 5 of the patients, intra-epidermal IgG1 and IgG3 deposits were demonstrated in the skin grafts by immunofluorescence. The deposits closely resembled in vivo deposits found in the skin of these patients. No correlation was found between the presence of epidermal deposits and levels of IgG1 and IgG3 in serum. No IgG deposits were found in skin grafts on animals given control serum, and neither could human IgG be detected in mouse skin adjacent to the grafts. Epidermal deposits of human-IgM, -IgA, -fibrinogen, -C3c and mouse-Ig were not demonstrated in biopsies from grafts or mouse skin. The results support the hypothesis that epidermal in vivo deposits of IgG in patients with primary Sjögren's syndrome are the result of Fc-receptor-mediated binding to epidermal cells.

We investigated 14 oral lesions and 10 skin lesions with epithelial dysplasia and 10 oral squamous cell carcinomas by immunofluorescence staining using monoclonal antibodies to two blood group antigen A and B precursor structures: Type 2 chain H-antigen (Fuc alpha 1 leads to 2 Gal beta 1 leads to 4 GlNAc leads to R; A and B precursor) and N-acetyllactosamine (Gal beta 1 leads to 4 GlNAc leads to R; H precursor). Both precursors were in oral epithelium found on the cell membrane of basal cells; in skin they were present on spinous and granular cells. In 12 of the 14 oral lesions the H-antigen was found on all cells throughout the epithelium in higher titers than in normal adjacent epithelium. All 10 carcinomas showed an irregular distribution of H. Some tumor cells did not express H whereas others did. In all 10 skin lesions on the contrary the H-antigen was lost in the dysplastic epithelium. N-acetyllactosamine was found neither in premalignant or malignant oral nor in premalignant skin lesions. The accumulation of Type 2 chain H-antigen in oral premalignant lesions and the loss of the same antigen in skin premalignant lesions may prove helpful in early diagnosis of epithelial malignancy.

A series of lectins were examined in order to find suitable epidermal species markers for the human skin/nude mouse model. In histological sections of formalin-fixed and paraffin-embedded material it was found that the lectins GSA I and PNA could serve as suitable markers for murine and human epidermis, respectively.