Villitis of unknown etiology, chronic deciduitis, chronic chorioamnionitis and chronic histiocytic intervillositis in monozygotic and dizygotic twin pregnancies. A retrospective analysis of 16 cases.

INTRODUCTION: Villitis of unknown etiology (VUE), chronic chorioamnionitis (CC), chronic deciduitis (CD) and chronic histiocytic intervillositis (CHI) are most likely the result of a pathologic immune reaction caused by maternal anti-fetal rejection. We analyzed placentas of twin pregnancies with manifestation of these lesions in monozygotic and dizygotic instances. METHODS: Twin pregnancies from our archive with at least one chronic inflammatory lesion were selected for further analysis and assessed concerning zygosity (gender, chorionicity, short tandem repeat (STR)-analysis). RESULTS: The cohort comprised sixteen twin placentas, monozygotic in five cases and dizygotic in 11 cases, respectively. VUE (n = 4), CC (n = 1) and CHI (n = 3) manifested concordantly in both placentas of the monozygotic pregnancies and affected discordantly one of the twin placentas in the dizygotic instances. CD (n = 10) manifested concordantly in two and discordantly in one of the monozygotic placentas, and concordantly in three and discordantly in four of the dizygotic instances. Intrauterine fetal demise (n = 3), preterm birth (n = 9) and low birth weight (n = 2) were recognized. Discordant fetal growth in live born children was recognized in two dizygotic cases with discordant manifestation of VUE and CHI. DISCUSSION: The concordant manifestation of VUE, CC and CHI in monozygotic and the discordant pattern of inflammation in dizygotic pregnancies points to pathologic immune mechanisms against genetically determined fetal antigens being essential for the development of these entities. The heterogenous manifestation of CD could be a hint for diverse fetal or maternal etiologic factors that may contribute to this lesion.

Chronic Deciduitis With Plasma Cells: A Quantitative and Clinicopathological Analysis Concerning Different Trimesters.

Background: Chronic deciduitis is a chronic inflammatory placental disease. It is associated with severe perinatal complications, especially recurrent miscarriage, preterm birth, preterm labor, and preterm prelabor rupture of membranes.Methods: This study presents a detailed quantification of plasma cells and lymphocytes, and regards clinicopathological associations concerning different trimesters in 99 cases displaying chronic deciduitis with plasma cells (CD), 23 cases from the second trimester and 76 cases from the third trimester, respectively. The control group without CD consisted of matched placentas concerning the gestational weeks.Results: In every instance lymphocytes were more numerous than plasma cells. The mean value/highest score in ten high power fields were 50/321 for plasma cells, and 460/995 for lymphocytes, respectively. In the second trimester the scores for plasma cells were significantly higher than in the third trimester. In the third trimester preterm labor occurred significantly more often in cases with chronic deciduitis related to the control group (P < .05).Conclusion: In chronic deciduitis the plasma cell count is usually higher in the second compared to the third trimester. A brisk infiltration of the decidua with plasma cells could probably point to a more severe clinical manifestation and a higher risk for preterm labor and preterm birth.

Hypertensive disease, preterm birth, fetal growth restriction and chronic inflammatory disorders of the placenta: experiences in a single institution with a standardized protocol of investigation.

PURPOSE: Chronic inflammatory disorders of the placenta, in particular villitis of unknown etiology (VUE), chronic deciduitis (CD), chronic chorioamnionitis (CC), chronic histiocytic intervillositis (CHI), and eosinophilic/T-cell chorionic vasculitis (ETCV) can exclusively be diagnosed histologically. Using a standardized procedure for submission and pathological-anatomical examination of placentas in a single perinatal care center, we analyzed the association of chronic placental lesions to perinatal complications. METHODS: We reviewed all singleton placentas and miscarriages that were examined histologically over a period of ten years after having implemented a standardized protocol for placental submission in our hospital. Cases with chronic inflammatory lesions were identified, and clinical data were analyzed and compared with a focus on preterm birth, hypertensive disorders, and fetal growth restriction and/or fetal demise. RESULTS: In 174 placentas, at least one of the chronic inflammatory entities was diagnosed. CD was the most frequent disorder (n = 95), and had strong associations with preterm birth (47.3% of all cases with CD) and intrauterine fetal demise. VUE (n = 74) was exclusively diagnosed in the third trimester. This disorder was associated with a birth weight below the 10th percentile (45% of the cases) and hypertensive disease in pregnancy. Miscarriage and intrauterine fetal demise were associated with CHI (in 66.7% of cases, n = 18). CONCLUSIONS: Chronic inflammatory disorders are frequently observed and contribute to major obstetric and perinatal complications. Further studies are needed to get a better picture of the connection between adverse obstetric outcomes and chronic inflammation to aid in the better counseling of patients.

Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

Pulmonary echinococcosis: A rare pseudotumour of the lung.

Cystic echinococcosis is a widely endemic helminthic disease worldwide but occurs only rarely in Central Europe. Humans are infected as 'aberrant' hosts by Echinococcus granulosus and develop cysts in numerous different organs. 20%-30% of the affected individuals develop hydatid disease in the lungs with associated complications including pleuritis, lung abscess and pneumothorax. Radiologically, the pulmonary lesions of cystic echinococcosis occasionally pose difficulties in the differential diagnosis of primary lung carcinoma or metastatic disease and vice versa. Herein we report on a case of pulmonary hydatid disease in a 25-year-old Iraqi male presenting with a cystic lesion of the lung associated with thoracic pain and involuntary weight loss. Despite of its rare occurrence in Central Europe, clinicians, radiologists and pathologists should be aware of this entity and its pulmonary manifestations. During frozen section examination, imprint cytology specimens may facilitate the detection of the pathogens.

Villitis of unknown etiology and chronic deciduitis are not associated with human papilloma virus and enterovirus infection.

Villitis of unknown etiology (VUE) and chronic deciduitis with plasma cells (CD) are supposed to be non infectious placental lesions caused by a pathologic immune reaction similar to a host versus graft mechanism. In some investigations, infection of human trophoblastic cells with human papilloma virus (HPV) has been described, and a relationship with miscarriage, preeclampsia, and chronic inflammatory placental lesions has been suspected. Infection with enterovirus, especially Coxsackievirus, has been observed in cases with spontaneous abortion and adverse perinatal outcome, respectively. We investigated 20 cases with VUE and 30 cases with chronic deciduitis with plasma cells. The placenta specimens were analyzed for expression of HPV capsid protein by immunohistochemistry, for presence of HPV DNA via polymerase chain reaction (PCR), and for presence of enterovirus mRNA using RT-PCR, respectively. VUE was associated with maternal diseases: atopic lesions in 21%, other autoimmune diseases in 15.5%, and obesity in 31.5%, respectively. Birth weight below the 10th percentile was detected in 63% of the cases with VUE. Chronic deciduitis was associated with preterm labor and preterm premature rupture of membranes (26%). Intrauterine fetal demise occurred in 5 cases with CD (18.5%). HPV DNA, HPV capsid protein, and enterovirus mRNA were not detected in all investigated VUE or CD cases. Our investigations show that a causal role for enterovirus and human papilloma virus in the development of VUE and CD is unlikely. Therefore, HPV vaccination is unlikely to reduce the incidence of VUE and CD in the future.

Pathoanatomical Lesions in Placentas With Excessively Hypercoiled Umbilical Cords: Frequent Detection of Massive Perivillous Fibrin Deposition.

This study focused to investigate a possible association of extensive umbilical hypercoiling (displaying an umbilical coiling index [UCI] of at least 1.0 coils/cm), clinical outcome, and associated pathoanatomical placental lesions. Of the 771 singleton placentas from the second and third trimesters submitted for pathoanatomical evaluation, 15 cases (2%) displayed extensive hypercoiling. There was an association of excessive hypercoiling with hypotrophy of fetuses and children (11 cases) and fetal demise (12 cases). Thin cord syndrome and umbilical stricture were observed in 9 cases and 4 cases, respectively. Seven of the 15 cases with excessive umbilical hypercoiling showed increased placental fibrin deposition (47% of the cases with hypercoiling), in 4 cases sufficient for rendering the diagnosis of massive perivillous fibrin deposition. Signs of maternal vascular malperfusion (n = 6) and chorangiosis (n = 2) were also detected in cases with hypercoiling. Recurrence of excessive umbilical hypercoiling was observed in 2 families, suggesting a genetic predisposition for the development of this lesion. Extensive hypercoiling could be a hitherto underrecognized pathogenetic factor for the development of massive perivillous fibrin deposition. A high UCI measured in the second trimester by ultrasound may be predictive of fetal hypotrophy, and intensified fetal monitoring is warranted, particularly if there is a history of hypercoiling and adverse fetal outcome.

Complement receptor-associated CD163+/CD18+/CD11c+/CD206-/CD209- expression profile in chronic histiocytic intervillositis of the placenta.

INTRODUCTION: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a non-infectious, most probably immunologic placenta lesion. CIUE is associated with recurrent miscarriage, intrauterine growth restriction and stillbirth. Among the pathologic-anatomic defined placental lesions this entity displays the highest risk of recurrence in following pregnancies (about 67-100%). The histiocytic cells accumulate in the placental blood space but do not infiltrate into the villi or decidua. Sparsely known is the expression profile of these intervillous cells regarding histiocytic markers. METHODS: We analysed 5-22 markers by immunohistochemistry in a total of 41 placenta samples and evaluated decidual, villous and intervillous histiocytic cells. RESULTS: In CIUE, intervillous CD163+ histiocytes over-express CD11c/CD18 and down-regulate CD206/CD209, while CD163+ decidual and Hofbauer cells show low CD11c/CD18 and higher CD206/CD209 protein expressions. DISCUSSION: CD163 expression indicates a M2-like polarisation. CD11c and CD18 form the complement receptor 4 which could be related to a complement mediated trigger for aberrant cell accumulation in CIUE.

Discordancy for a Villous Maturation Defect in a Dizygotic Twin Placenta.

Background: Dizygotic twin pregnancies with discordant manifestation of abnormalities with unclear etiology are of interest because they arise in the same environment. Case report: We present a dizygotic third trimester twin placenta with discordant villous maturation, one placenta lacking developed syncytiocapillary membranes. The twins were eutrophic with no perinatal or postnatal complications. Conclusions: Discordant manifestation of villous maturation in dizygotic twin placentas could be a hint for a genetic rather than an environmental etiology. Villous maturation defect may be underrecognized and has been associated with perinatal morbidity and stillbirth in the late third trimester. Proper recognition is important because of the increased recurrence risk of villous dysmaturity.

Massive Perivillous Fibrin Deposition of an Enterovirus A-Infected Placenta Associated With Stillbirth: A Case Report.

Massive perivillous fibrin deposition (MFD) is a morphologically defined severe placental lesion associated with perinatal morbidity and mortality. The etiology is unknown, and recurrence risk in subsequent pregnancies is assumed to be high. In most cases, a pathologic immune reaction is supposed to be responsible for the lesion. We report a case of a pregnant woman's suffering from hand, foot, and mouth disease in the 20th gestational week. Subsequently, MFD developed in the placenta and was followed by intrauterine growth restriction and stillbirth in the 29th gestational week. Enterovirus A with high homology to Coxsackievirus A16 was detected in the placenta by means of immunohistochemisty and reverse transcription polymerase chain reaction. This infection could be a rare cause of MFD and should be taken into consideration in the differential diagnosis of the individual etiology. Recurrence risk of virus-related MFD is expected to be lower than in MFD without infectious association.

Papilloma of the Fallopian Tube: A Rare Gynecologic Neoplasm Harboring a BRAF (c.1799T>A) Mutation (V600E).

Papillomas of the fallopian tube are exceedingly rare benign tumors, and only very few cases have been reported in the literature. Clinically, they may present as a mass lesion or occur without symptoms. Histomorphologically, they are papillary tumors covered by nonatypical epithelium with occasional ciliated or goblet cells growing in the lumen, and they are most frequently located in the infundibular region of the fallopian tube. They require a number of differential diagnostic evaluations and can be mistaken for either other benign tumors or malignant neoplasms. Because of their rare occurrence, molecular data about this entity have been lacking so far. Herein, a case of a papilloma with a BRAF (c.1799T>A) mutation (V600E) in a 45-yr-old woman with tumor-like dilation of the fallopian tube is presented.

Expression of Toll-Like Receptors in Chronic Histiocytic Intervillositis of the Placenta.

Chronic histiocytic intervillositis of the placenta (CHI) shows monocytic/histiocytic infiltration of the intervillous space. Placental malaria has a CHI-like histopathology and induces an aberrant expression of Toll-like receptors (TLR) 3, 7-9. We hypothesized that, similar to placental malaria, CHI could be associated with increased TLR expression. TLR1-10 and other inflammation-associated factors were analyzed by real-time PCR and immunohistochemistry. A total of 31 formalin-fixed and paraffin-embedded placenta samples were evaluated: CHI (n = 9), and for control purposes, villitis of unknown etiology (VUE, n = 8) and placentas without inflammation (n = 14). CHI shows increased expression of monocytic TLR1, a receptor which is involved in bacterial lipopolysaccharide (LPS)-induced inflammation. This could indicate a TLR1-mediated immune mechanism in the placenta (e.g. triggered by transient, clinically inapparent maternal bacteraemia) which leads to massive monocytic/histiocytic accumulation in the intervillous space. The increased expression of TLR1 with no increased expression of TLR3 and TLR7-9 is different from that in malaria.

Discordancy for Placental Massive Perivillous Fibrin Deposition and Fetal Growth in Dichorionic Twins after In Vitro Fertilization.

Massive perivillous fibrin deposition (MFD) is a placental lesion of unknown etiology associated with perinatal morbidity and mortality and recurrence risk in subsequent pregnancies. We report a 34 weeks' gestation dizygotic twin pregnancy with discordancy for MFD and for intrauterine growth restriction after in vitro fertilization (IVF). Only the smaller twin corresponding to the placenta affected by MFD showed intrauterine growth restriction, with a weight below the 3rd percentile according to gestational age. The affected placenta showed a moderate increase in decidual lymphocytes. No difference in expression of complement factor C4d in umbilical veins could be observed. Development of MFD in one of the dizygotic placentas may be due to a pathologic immune response to one of the different fetal genotypes as semiallografts. The pathogenetic role of IVF as an environmental factor for development of MFD is unclear.

Partial hydatidiform mole with extensive angiomatoid vessel configuration in a first trimester miscarriage.

We report a first trimester miscarriage (9 wk gestation) with a macroscopic grape-like aspect due to extensive angiomatoid changes with widened communicating thin-walled villous vessels. Fluorescence in situ hybridization analysis and microsatellite analysis revealed a diandric triploidy of the trophoblastic tissue, so this miscarriage is indeed a genetic partial hydatidiform mole. This is remarkable since the typical morphologic hallmarks of partial hydatidiform mole, especially enhanced trophoblastic proliferation and marked villous cistern formation, were not prominent. The finding of extensive angiomatoid morphology is to our knowledge an undescribed morphology of an early partial hydatidiform mole. It serves as an example of the morphologic variability of this probably underestimated condition that has a slightly elevated risk for the development of gestational trophoblastic disease.

Array-CGH and quantitative PCR genetic analysis in a case with bilateral hypoplasia of pulmonary arteries and lungs and simultaneous unilateral renal agenesis.

We describe the clinical course and have characterised anatomically and genetically a unique case of a newborn with bilateral hypoplasia of pulmonary arteries, consecutive extremely hypoplastic lung tissue and associated unilateral renal agenesis. Intrauterine oxygenation by the placenta seemed to have allowed normotrophic body maturity but immediately after delivery, in the third trimester, progressive hypoxemia developed and the newborn succumbed to acute respiratory failure. Genetic analysis by array-based comparative genomic hybridisation and quantitative PCR revealed duplication of 1p21, which, however, might not be the disease causing aberration. This case might represent an extreme form of previously reported, rare cases with simultaneous dysorganogenesis of lungs and kidneys.

Conversion of a neonatal hepatic hemangioma to focal nodular hyperplasia.

Hepatic hemangioma and focal nodular hyperplasia are both frequently observed benign lesions of the liver. Whereas hepatic hemangioma is the most frequent benign liver tumor in children, focal nodular hyperplasia occurs predominantly in adult patients. Concomitance of both entities has been described in adults, suggesting a similar pathogenesis. We report on a 6-month-old child with a continuously shrinking hepatic hemangioma after interventional therapy and a growing hepatic mass 5 years later, which emerged as focal nodular hyperplasia at the site of the former hemangioma. Diagnostic and therapeutic strategies regarding this patient are discussed. The present case supports the theory that these two entities may share a similar pathomechanism.

[Necrotizing sialometaplasia: diagnosis of a rare entity]. / Die nekrotisierende Sialometaplasie: Diagnostik einer seltenen Entität.

A differential diagnosis of an ulcer on the hard palate must consider a wide variety of diseases and conditions, among them rare entities such as necrotizing sialometaplasia. We report the case of a patient who presented with a painful ulcer on the hard palate. A biopsy taken at the initial presentation of the patient revealed a diagnosis of necrotizing sialometaplasia. Histology showed foci of eosinophilic granulocytes with lobular infarction or necrosis, bland-appearing nuclear morphology of squamous cells, simultaneous metaplasia of ducts and mucous acini. The ulcer resolved spontaneously within seven weeks and required no specific treatment. The case presented here shows that early diagnosis of necrotizing sialometaplasia is important in order to prevent unnecessary treatment.

SELDI-MS-based expression profiling of ductal invasive and lobular invasive human breast carcinomas.

Expression profiling using proteomic techniques has a great potential to identify new biomarkers that might help to better diagnose and treat diseases such as breast cancer, which is one of the leading causes of cancer death in women. Surface-enhanced laser desorption ionization mass spectrometry (SELDI-MS) combines chromatographic separation of peptides and proteins with mass spectrometry and is a fast, user-friendly tool to analyze protein and peptide profiles. SELDI-MS was employed for a comparative analysis of lobular invasive versus ductal invasive breast tumors to find differentially expressed proteins and peptides, and to validate this technique for biomarker identification using complex samples such as tissue. After optimization of sample preparation using HMEC and MCF-7 cell lines, 20 breast tumors were analyzed, and about 550 mass signals corresponding to an estimated 140 native peptides and proteins were detected in each tumor. Only 14% of the mass signals were present in more than six tumors of one subgroup or in more than 12 tumors of both groups showing a great overall heterogeneity of the peptide and protein profiles obtained. Peptide mass signals specific for each of the analyzed groups were identified. In addition, we detected peptides from laser-microdissected ductal invasive and intraductal tumor parts corresponding to peptides present in whole tumors. The low amount of identified peptides and proteins and the observed heterogeneity suggest that SELDI-MS is not well suited for biomarker identification of and profiling experiments on complex samples such as tumor tissue.

Quantitative assessment of promoter hypermethylation during breast cancer development.

The aberrant methylation of cytosine residues in the promoter region of growth regulatory genes is now widely recognized as an additional mechanism for gene inactivation in cancer cells. In this study we analyzed the methylation status of four growth regulatory genes (p16, RASSF1A, cyclinD2, 14-3-3zeta) during breast cancer progression. For this purpose invasive and noninvasive tumor cell populations as well as hyperplastic cell proliferations were isolated from a series of archival breast tissue specimens (n = 57) using laser-assisted microdissection. A new real-time polymerase chain reaction-based assay was used for the sensitive and quantitative determination of the cell-specific methylation status. We found that aberrant promoter methylation was already prevalent in pure intraductal carcinoma with different frequencies and different methylation levels for the four genes analyzed. For RASSF1A and 14-3-3zeta promoter methylation was also demonstrated in epithelial hyperplasia and intraductal papillomas. By contrast, aberrant methylation of cyclinD2 and p16 was restricted to cancerous epithelium. Increased methylation of the cyclinD2 gene was significantly associated with a higher van Nuys grade. Furthermore, when intraductal and invasive tumor cells were compared, significant quantitative changes in the methylation level were detected primarily within the cyclinD2 gene. These results demonstrate that promoter methylation is an early and frequent event in breast cancer development, but displays great quantitative and gene-specific differences, and changes in a gene-specific manner during tumor progression.