Debra S. Heller

Amniotic Infection Syndrome: Nosology and Reproducibility of Placental Reaction Patterns

Clinically responsive placental examination seeks to provide useful information regarding the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to assemble and validate a complete set of the placental reaction patterns seen with amniotic fluid infection in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with amniotic fluid infection, 6 controls) were reviewed blindly by six pathologists after agreement on a standard set of diagnostic criteria. After analysis of initial results, criteria were refined and a second, overlapping set of cases were reviewed. Majority vote served as the gold standard. Grading and staging of maternal and fetal inflammatory responses was found to be more reproducible using a two- versus three-tiered grading system than a three- versus five-tiered staging system (overall agreement 81% vs. 71%). Sensitivity, specificity, and efficiency for individual observations ranged from 67–100% (24/30 > 90%). 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 the 12 lesions evaluated in 20 cases by the six pathologists were: acute chorioamnionitis/maternal inflammatory response (any, 0.93; severe 0.76; advanced stage, 0.49); chronic (subacute) chorioamnionitis (0.25); acute chorioamnionitis/fetal inflammatory response (any, 0.90; severe, 0.55; advanced stage, 0.52); chorionic vessel thrombi (0.37); peripheral funisitis (0.84); acute villitis (0.90); acute intervillositis/intervillous abscesses (0.65), and decidual plasma cells (0.30). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a framework for future clinical research.

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

Abstract The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) project was co-sponsored by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) and included 5 working groups; three work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted upon at the consensus meeting. The final approved recommendations standardize biologically-relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

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

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

Handbook of placental pathology

Introduction Development of the Placenta Structure of the Placenta Examination of the Placenta in the Clinical Setting Clinical Data to be Sent to the Pathologist Indications for Pathological Examination Pathologic Examination of the Placenta Gross Abnormalities of the Placenta Histologic Lesions of the Placenta Lesions of the Placenta as a Whole of of the Placental Disk Lesions of the Umbilical Cord Lesions of the Membranes Abnormalities of the Decidua Lesions of the Placenta in Maternal Disorders Lesions of the Placenta in Fetal Disorders Iatrogenic Lesions of the Placenta Traumatic Lesions of the Placenta Placenta in Pregnancies After In Vitro Fertilization (IVF) and Embryo Transfer (ET) Specimens Related to Placental Laser Surgery Comment Index

Malignant Adenomyoepithelioma of the Breast With Malignant Proliferation of Epithelial and Myoepithelial Elements A Case Report and Review of the Literature

Malignant adenomyoepithelioma of the breast is a rare lesion characterized by malignant proliferation of epithelial and myoepithelial cells that show characteristic histologic and immunohistochemical features. Eleven cases have been reported, 4 of which showed evidence of distant metastasis. The authors report a case of malignant adenomyoepithelioma in the axillary tail of a 71-year-old woman, one of the oldest patients described so far, and review the literature. Malignancy in the current case was evidenced by the presence of local invasion, high mitotic rate, and severe cytologic atypia. The tumor was associated with adenosis and lobular adenomyoepithelial hyperplasia. Malignant adenomyoepithelioma is a rare neoplasm, diagnosable by light microscopy and immunohistochemistry. To date, it has only been reported in women, who ranged in age from 26 to 76 years. Metastases have only been documented in tumors 2.0 cm in diameter or larger.

Predictors of ovarian follicle number

OBJECTIVE To identify factors associated with ovarian follicle density in women of reproductive age. DESIGN Women undergoing incidental oophorectomy responded to structured interviews. Grossly normal ovaries were sectioned and assessed for follicle density. SETTING University hospital. PATIENT(S) 102 women undergoing hysterectomy with incidental oophorectomy who had morphologically normal ovaries. MAIN OUTCOME MEASURE(S) Follicle density, age, parity, oral contraceptive use, body size, smoking, and alcohol consumption. RESULT(S) Follicle density decreased with age and with current or past cigarette smoking. Other factors were not associated with follicle density, although the study had adequate power to detect only strong associations. CONCLUSION(S) Some of the adverse effects of smoking on reproductive health may be due to irreversible follicular depletion.

The relationship between perineal cosmetic talc usage and ovarian talc particle burden.

OBJECTIVE Epidemiologic studies support the hypothesis of a dose-related risk of epithelial ovarian cancer with perineal talc usage exposure. Frequency and duration of talc has not been previously correlated with ovarian talc content. STUDY DESIGN Ovaries were studied from 24 women undergoing incidental oophorectomy who were interviewed regarding talc usage. Twelve subjects reported frequent perineal talc applications; the twelve controls reported no use. Ovarian tissue blocks were digested and analyzed by polarized light microscopy and analytic electron microscopy to identify and quantify talc. RESULTS Talc was identified in all 24 cases by either light or electron microscopy. Talc particle counts were completely unrelated to reported levels of perineal talc exposure. CONCLUSIONS The detection of talc in all ovaries demonstrates that it can reach the upper genital tract. Widespread exposure to talc during diapering may contribute to the ubiquitous presence of talc in ovarian tissue.

Blocking eIF5A Modification in Cervical Cancer Cells Alters the Expression of Cancer-Related Genes and Suppresses Cell Proliferation

Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.