Birth anthropometry predicts neonatal and infant mortality in rural Bangladesh: a focus on circumferential measurements.

BACKGROUND: Low birth weight predicts risk of infant death. However, several birth measurements may be equally predictive, for which cutoffs and associated risks are less explored. OBJECTIVES: We assessed and optimized population cutoffs of birth length, weight, and midupper arm circumference (MUAC), head circumference (HC), and chest circumference (CC) for predicting neonatal (≤28 d) and infant (≤365 d) mortality in northwest Bangladesh. METHODS: Among 28,026 singletons born in an antenatal micronutrient supplement trial, 21,174 received anthropometry ≤72 h after birth, among whom 583 died in infancy. Optimization for predicting mortality for each measurement was guided by the Youden Index (sensitivity + specificity - 1). Relative risk ratios (RRRs) and positive predictive values (PPVs) were calculated across cutoff ranges for individual and any pair of measurements. RESULTS: Optimal cutoffs, harmonized to 100-g or 0.5-cm readings, for neonatal and infant mortality were 44.5 cm for length, 2200 g for weight, 9.0 cm for MUAC, 31.0 cm for HC, and 28.5 cm for CC, below which all predicted mortality. However, a CC <28.5 cm, alone and combined with HC <31.0 cm, yielded the highest RRR [9.68 (95% CI: 7.84, 11.94) and 15.74 (95% CI: 12.54, 19.75), respectively] and PPV (11.3% and 10.7%) for neonatal mortality and highest RRR [6.02 (95% CI: 5.15, 7.02) and 9.19 (95% CI: 7.72, 10.95)] and PPV (16.3% and 14.5%) for infant mortality. Pairs of measurements revealed a higher RRR for neonatal and infant mortality than individual measurements of any one pair, although the ranges of PPV remained comparable. CONCLUSIONS: In Bangladesh, multiple birth measurements alone or in combination, particularly chest circumference, predict neonatal and infant mortality.

Autism spectrum disorder in a rural community in Bangladesh: A mid-childhood assessment.

Population-based studies employing standardized diagnostics are needed to determine the burden of autism spectrum disorder (ASD) in low-resource settings. A community-based study was conducted among 8-11 year old children in rural, northwestern Bangladesh to establish the prevalence of ASD. A standardized screening and diagnosis protocol was adapted and deployed comprising the social communication questionnaire (SCQ), and the autism diagnostic observation schedule 2, (ADOS-2), and the autism diagnostic interview, revised (ADI-R), respectively. A year-long research training was conducted for a clinical psychologist to be certified to administer ADOS-2 and ADI-R. Over 8000 children were visited at home and administered the SCQ leading to some, based on their score, being further evaluated using the ADOS-2 and ADI-R by the clinical psychologist. Based on ADOS-2 applying the diagnoses of autism or autism spectrum, the prevalence was 40 (95% CI: 27, 54) per 10,000. Autistic disorder using ADI-R was found at 12 (95% CI: 5, 20) per 10,000. Boys were at a higher risk than girls with the rates among boys being 46 (95% CI: 25, 67) using ADOS-2 and 19 (95% CI:6, 33) using ADI-R. Among girls the rates were 34 (95% CI:16, 52) and 5 (95% CI:0, 12) per 10,000, respectively. Challenges to undertaking ASD research in a rural South Asian context are discussed. There was a low-to-moderate prevalence of ASD in a rural, child population in Bangladesh. Future research is needed to estimate rates of ASD and its causes and socioeconomic consequences in rural and urban settings of South Asia. LAY SUMMARY: In a study of over 8000, 8-11 year old children in a rural area of Bangladesh, two to four out of 1000 had ASD. Boys more than girls had ASD. Conducting ASD assessment in this setting was difficult, but more such research is needed to understand what causes ASD and its consequences for the individual, families and the society in rural and urban areas of low-income countries.

Household food insecurity is associated with low dietary diversity among pregnant and lactating women in rural Malawi.

OBJECTIVE: To examine the association between household food insecurity and dietary diversity in the past 24h (dietary diversity score (DDS, range: 0-9); minimum dietary diversity (MDD, consumption of three or more food groups); consumption of nine separate food groups) among pregnant and lactating women in rural Malawi. DESIGN: Cross-sectional study. SETTING: Two rural districts in Central Malawi. SUBJECTS: Pregnant (n 589) and lactating (n 641) women. RESULTS: Of surveyed pregnant and lactating women, 66·7 and 68·6 %, respectively, experienced moderate or severe food insecurity and only 32·4 and 28·1 %, respectively, met MDD. Compared with food-secure pregnant women, those who reported severe food insecurity had a 0·36 lower DDS (P<0·05) and more than threefold higher risk (OR; 95 % CI) of not consuming meat/fish (3·19; CI 1·68, 6·03). The risk of not consuming eggs (3·77; 1·04, 13·7) was higher among moderately food-insecure pregnant women. Compared with food-secure lactating women, those who reported mild, moderate and severe food insecurity showed a 0·36, 0·44 and 0·62 lower DDS, respectively (all P<0·05). The risk of not achieving MDD was higher among moderately (1·95; 1·06, 3·59) and severely (2·82; 1·53, 5·22) food-insecure lactating women. The risk of not consuming meat/fish and eggs increased in a dose-response manner among lactating women experiencing mild (1·75; 1·01, 3·03 and 2·81; 1·09, 7·25), moderate (2·66; 1·47, 4·82 and 3·75; 1·40, 10·0) and severe (5·33; 2·63, 10·8 and 3·47; 1·19, 10·1) food insecurity. CONCLUSIONS: Addressing food insecurity during and after pregnancy needs to be considered when designing nutrition programmes aiming to increase dietary diversity in rural Malawi.

Unintended pregnancy is a risk factor for depressive symptoms among socio-economically disadvantaged women in rural Bangladesh.

BACKGROUND: Little is known about the relation between unwanted pregnancy and intention discordance and maternal mental health in low-income countries. The study aim was to evaluate maternal and paternal pregnancy intentions (and intention discordance) in relation to perinatal depressive symptoms among rural Bangladeshi women. METHODS: Data come from a population-based, community trial of married rural Bangladeshi women aged 13-44. We examined pregnancy intentions among couples and pregnancy-intention discordance, as reported by women at enrollment soon after pregnancy ascertainment, in relation to depressive symptoms in the third trimester of pregnancy (N = 14,629) and six months postpartum (N = 31,422). We calculated crude and adjusted risk ratios for prenatal and postnatal depressive symptoms by pregnancy intentions. RESULTS: In multivariable analyses, women with unwanted pregnancies were at higher risk of prenatal (Adj. RR = 1.60, 95% CI: 1.37-1.87) and postnatal depressive symptoms (Adj. RR = 1.32, 95% CI: 1.21-1.44) than women with wanted pregnancies. Women who perceived their husbands did not want the pregnancy also were at higher risk for prenatal (Adj. RR = 1.42, 95% CI: 1.22-1.65) and postnatal depressive symptoms (Adj. RR = 1.30, 95% CI: 1.19-1.41). Both parents not wanting the pregnancy was associated with prenatal and postnatal depressive symptoms (Adj. RR = 1.34, 95% CI: 1.19-1.52; Adj. RR = 1.13, 95% CI: 1.06-1.21, respectively), compared to when both parents wanted it. Adjusting for socio-demographic and pregnancy intention variables simultaneously, maternal intentions and pregnancy discordance were significantly related to prenatal depressive symptoms, and perception of paternal pregnancy unwantedness and couple pregnancy discordance, with postnatal depressive symptoms. CONCLUSIONS: Maternal, paternal and discordant couple pregnancy intentions, as perceived by rural Bangladeshi women, are important risk factors for perinatal maternal depressive symptoms.

Modelling stunting in LiST: the effect of applying smoothing to linear growth data.

BACKGROUND: The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older. METHODS: We identified datasets with serial measurements of children's lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children's stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next ("stunting-to-stunting ORs") using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs. RESULTS: A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights. CONCLUSIONS: Smoothing of children's measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions.

General intelligence is associated with subclinical inflammation in Nepalese children: A population-based plasma proteomics study.

Improving child cognition in impoverished countries is a public health priority. Yet, biological pathways and associated biomarkers of impaired cognition remain poorly understood and largely unknown, respectively. This study aimed to explore and quantify associations between functional plasma protein biomarkers and childhood intellectual test performance. We applied proteomics to quantify proteins in plasma samples of 249 rural Nepalese children, 6-8years of age who, 1year later at 7-9years of age, were administered the Universal Nonverbal Intelligence Test (UNIT). Among 751 plasma proteins quantified, 22 were associated with UNIT scores, passing a false discovery rate threshold of 5.0% (q<0.05). UNIT scores were higher by 2.3-9.2 points for every 50% increase in relative abundance of two insulin-like growth factor binding proteins (IGFBPs), six subclasses of apolipoprotein (Apo) and transthyretin, and lower by 4.0-15.3 points for each 50% increase in relative abundance of 13 proteins predominantly involved in inflammation. Among them, IGFBP-acid labile subunit, orosomucoid 1 (ORM1), Apo C-I, and pyruvate kinase isoenzymes M1/M2 jointly explained 37% of the variance in UNIT scores. After additional adjustment for height-for-age Z-score and household socio-economic status as indicators of long-term nutritional and social stress, associations with 6 proteins involved in inflammation, including ORM1, α-1-antichymotrypsin, reticulocalbin 1, and 3 components of the complement cascade, remained significant (q<0.05). Using untargeted proteomics, stable, constitutive facets of subclinical inflammation were associated with lower developmental test performance in this rural South Asian child population. Plasma proteomics may offer opportunities to identify functional, antecedent biomarkers of child cognitive development.

Plasma Proteome Biomarkers of Inflammation in School Aged Children in Nepal.

Inflammation is a condition stemming from complex host defense and tissue repair mechanisms, often simply characterized by plasma levels of a single acute reactant. We attempted to identify candidate biomarkers of systemic inflammation within the plasma proteome. We applied quantitative proteomics using isobaric mass tags (iTRAQ) tandem mass spectrometry to quantify proteins in plasma of 500 Nepalese children 6-8 years of age. We evaluated those that co-vary with inflammation, indexed by α-1-acid glycoprotein (AGP), a conventional biomarker of inflammation in population studies. Among 982 proteins quantified in >10% of samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Magnitude and significance of association varied more among proteins positively (n = 41) than negatively associated (n = 58) with AGP. The former included known positive acute phase proteins including C-reactive protein, serum amyloid A, complement components, protease inhibitors, transport proteins with anti-oxidative activity, and numerous unexpected intracellular signaling molecules. Negatively associated proteins exhibited distinct differences in abundance between secretory hepatic proteins involved in transporting or binding lipids, micronutrients (vitamin A and calcium), growth factors and sex hormones, and proteins of largely extra-hepatic origin involved in the formation and metabolic regulation of extracellular matrix. With the same analytical approach and the significance threshold, seventy-two out of the 99 proteins were commonly associated with CRP, an established biomarker of inflammation, suggesting the validity of the identified proteins. Our findings have revealed a vast plasma proteome within a free-living population of children that comprise functional biomarkers of homeostatic and induced host defense, nutrient metabolism and tissue repair, representing a set of plasma proteins that may be used to assess dynamics and extent of inflammation for future clinical and public health application.

GATA-3 expression in trophoblastic tissues: an immunohistochemical study of 445 cases, including diagnostic utility.

Immunohistochemical expression of GATA-3 is seen predominantly in non-neoplastic bladder and breast epithelium and their respective carcinomas; however, data on expression in normal and lesional trophoblastic tissues are limited. Immunohistochemical staining for GATA-3 was assessed in a range of normal/lesional trophoblastic tissues and tumors in the differential diagnosis (n=445), including nonmolar products of conceptions/second and third trimester placentas/ectopic pregnancies, hydatidiform moles, placental site nodules, normal/exaggerated implantation sites, choriocarcinomas, epithelioid trophoblastic tumors, placental site trophoblastic tumors, atypical smooth muscle tumors (including leiomyosarcoma), and cervical and pulmonary squamous cell carcinomas. The extent of expression (0 to 4+) and intensity (weak to strong) were recorded. All cases with developing trophoblast/non-neoplastic trophoblastic proliferation and 81% of trophoblastic neoplasms were positive. Of all non-neoplastic trophoblast cell types, expression was observed in cytotrophoblast in 89% of cases, syncytiotrophoblast in 50%, intermediate trophoblast in 100%, and villous trophoblastic columns in 100%. Increasing gestational age was associated with a decrease in extent/intensity of expression in non-neoplastic cytotrophoblast and syncytiotrophoblast, whereas intermediate trophoblast maintained diffuse and strong expression from early to late gestation (P<0.0001). Eighty-nine percent of normal/exaggerated implantation sites showed 3+ or 4+ expression, whereas staining in 55% of placental site nodules was 1+ or 2+. Staining for GATA-3 was present in 78% of choriocarcinomas, 95% of epithelioid trophoblastic tumors, and 71% of placental site trophoblastic tumors. Although the number of choriocarcinomas and placental site trophoblastic tumors that showed a spectrum of expression ranging from negative to diffuse was relatively evenly distributed, 81% of epithelioid trophoblastic tumors had 3+ or 4+ staining. None of the atypical smooth muscle tumors and 3% of squamous cell carcinomas were positive, all of which exhibited weak staining. We conclude that GATA-3 is frequently expressed in normal and lesional trophoblastic tissues. It is also differentially expressed in intermediate trophoblast and cytotrophoblast/syncytiotrophoblast, which varies according to time during pregnancy. This study expands the spectrum of neoplasms known to express GATA-3. Thus, recognition of expression in trophoblastic tumors is important, because it can present a diagnostic pitfall in the assessment of suspected metastatic bladder or breast carcinomas involving the gynecologic tract. In the evaluation of diagnostically problematic tumors for which trophoblastic neoplasms are in the differential diagnosis, such as leiomyosarcoma and squamous cell carcinoma, GATA-3 can be included as part of an immunohistochemical panel particularly when other trophoblastic markers are either not available or yield ambiguous results.

PAX8 expression in uterine adenocarcinomas and mesonephric proliferations.

PAX8 is a useful immunohistochemical marker for the diagnosis of gynecologic tract malignancies. Several studies have described PAX8 expression in a wide variety of epithelial neoplasms, including ovarian and endometrial carcinomas. The goal of this study was to evaluate PAX8 expression in various types of uterine adenocarcinomas and mesonephric proliferations. Ninety-four cases of uterine adenocarcinomas (52 endometrial endometrioid carcinomas, 21 endometrial serous carcinomas, and 21 human papillomavirus-related endocervical carcinomas), 11 cases of benign mesonephric proliferations (remnants/hyperplasia), and normal endometrial and endocervical glandular epithelium in 58 cases were studied. Immunohistochemical staining was performed with the rabbit polyclonal anti-PAX8 antibody. All adenocarcinoma groups demonstrated a high frequency of PAX8 expression but with relatively high variability in the extent of staining among different subtypes. Both serous carcinomas and endometrioid carcinomas were positive in most cases (95% and 96%, respectively), but serous carcinomas displayed a significantly higher level of expression (immunohistochemical composite scores based on combined extent and intensity of expression) compared with endometrioid carcinomas (mean immunohistochemical composite scores: 8.3 vs. 5.3, respectively; P<0.006). Endocervical adenocarcinomas also had a high frequency of PAX8 expression (86% of cases), but the level of expression was significantly less than that of endometrial adenocarcinomas (mean immunohistochemical composite scores: 2.9 vs. 5.3-8.3, respectively; P<0.004). Among benign glandular epithelia, normal endocervical glands exhibited a significantly lower level of expression compared with either normal endometrial glands or benign mesonephric proliferations (mean immunohistochemical composite scores: 2.6 vs. 6.6-11.2, respectively; P<0.0006). We conclude that PAX8 is expressed in the vast majority of uterine adenocarcinomas, including those of both endometrial and endocervical origin, and that the level of expression based on combined extent and intensity is highest in endometrial serous carcinoma and lowest in endocervical adenocarcinoma. However, the high prevalence of PAX8 expression in the various types of uterine adenocarcinomas precludes use of this marker for distinguishing these tumors. In extrauterine sites, PAX8 can serve as a useful marker for adenocarcinomas of uterine origin (also positive in the majority of ovarian carcinomas), being most sensitive for identification of endometrial adenocarcinomas (both serous and endometrioid). The sensitivity for identifying metastatic endocervical adenocarcinomas is likely less and dependent on the degree to which the significantly lower extent of expression in these tumors is maintained in metastatic sites.

Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis.

Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies; yet, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, and 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunostaining and genotyping. Cases were classified by 3 gynecologic pathologists on the basis of H&E slides (masked to p57 immunostaining and genotyping results) into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists) were determined. Genotyping results were used as the gold standard for assessing diagnostic performance. Sensitivity of a diagnosis of CHM ranged from 59% to 100% for individual pathologists and from 70% to 81% by consensus; specificity ranged from 91% to 96% for individuals and from 94% to 98% by consensus. Sensitivity of a diagnosis of PHM ranged from 56% to 93% for individual pathologists and from 70% to 78% by consensus; specificity ranged from 58% to 92% for individuals and from 74% to 85% by consensus. The percentage of correct classification of all cases by morphology ranged from 55% to 75% for individual pathologists and from 70% to 75% by consensus. The κ values for interobserver agreement ranged from 0.59 to 0.73 (moderate to good) for a diagnosis of CHM, from 0.15 to 0.43 (poor to moderate) for PHM, and from 0.13 to 0.42 (poor to moderate) for NM. The κ values for intraobserver agreement ranged from 0.44 to 0.67 (moderate to good). Addition of the p57 immunostain improved sensitivity of a diagnosis of CHM to a range of 93% to 96% for individual pathologists and 96% by consensus; specificity was improved from a range of 96% to 98% for individual pathologists and 96% by consensus; there was no substantial impact on diagnosis of PHMs and NMs. Interobserver agreement for interpretation of the p57 immunostain was 0.96 (almost perfect). Even with morphologic assessment by gynecologic pathologists and p57 immunohistochemistry, 20% to 30% of cases will be misclassified, and, in particular, distinction of PHMs and NMs will remain problematic.

Pathogenesis of ovarian clear cell adenofibroma, atypical proliferative (borderline) tumor, and carcinoma: clinicopathologic features of tumors with endometriosis or adenofibromatous components support two related pathways of tumor development.

The clinicopathologic features of 472 ovarian epithelial clear cell neoplasms (4 adenofibromas [AFs], 41 atypical proliferative [borderline] tumors [APTs], and 427 carcinomas [CAs]) were studied in order to elucidate the morphologic steps involved in the pathogenesis of these tumors and determine whether clear cell CA is a type I or type II tumor in the dualistic model of ovarian carcinogenesis. Thirty-three percent of the CAs had an adenofibromatous background [CA(AF+)], and 67% did not [CA(AF-)]. Endometriosis was found in all types of tumors, but tumors arising in endometriotic cysts were more frequent with CA(AF-)s (p<0.0001). The subset of women with CA(AF-)s with endometriosis were younger (p<0.0001), their tumors were more frequently cystic (p<0.0001), they more commonly had a mixed carcinoma component of non-clear cell type (p=0.006), and they were more frequently oxyphilic (p=0.015) compared with CA(AF+)s. The architecture of the former tumors was more commonly papillary compared to tubulocystic in the latter (p=0.0006). Atypical endometriosis was more common in CA(AF-)s than in AFs, APTs, and CC(AF+)s [p=0.004]. The subset of CA(AF-)s without endometriosis presented more frequently in advanced stage (>I) and were higher grade compared to CA(AF+)s or CA(AF-) with endometriosis (p-values, <0.0001 to 0.0071). All AFs and APTs were stage I compared to 79% of CA(AF+)s. An increase in mean tumor size correlated with each respective tumor category from AF (6.8 cm) to CA(AF+) [12.9 cm]. Notable nuclear atypia was absent in all AFs but was focally present in 27% of APTs and in the adenofibromatous background of 24% of the CA(AF+)s. An increase in the proportion of carcinoma in the CA(AF+)s correlated with an increase in grade and advanced stage. In summary, ovarian clear cell CA appears to develop along two pathways, both of which are related to endometriosis. We speculate that, in one, epithelial atypia arises in an endometriotic cyst and then evolves into clear cell CA, and, in the other, non-cystic endometriosis induces a fibromatous reaction resulting in the formation of AF, which then develops into APT and subsequently a clear cell CA. The absence of endometriosis or adenofibromatous components in CC(AF-)s may be due to overgrowth and obliteration by the invasive carcinoma. Finally, the findings in this study support the view that both types of clear cell CA [CC(AF+) and CC(AF-)] are more closely related to type I tumors.

Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases.

Uterine serous carcinomas typically have a characteristic morphology (papillary architecture, high-grade nuclei) and immunoprofile (diffuse/strong p53 expression, loss of hormone receptor expression) that distinguish them from most endometrial endometrioid carcinomas. However, glandular variants of serous carcinoma can simulate Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade 2 endometrioid carcinomas, and some serous carcinomas lack p53 expression and retain hormone receptor expression, making classification difficult. P16 expression patterns distinguish endometrioid carcinomas (patchy) from human papillomavirus (HPV)-related endocervical adenocarcinomas (diffuse/strong) but utility for distinction of serous carcinomas from endometrioid carcinomas and endocervical adenocarcinomas has not been evaluated in a large series. Immunohistochemical analysis of p16 expression was performed on 201 uterine and endocervical adenocarcinomas in hysterectomy specimens, including 49 serous carcinomas, 101 endometrial endometrioid carcinomas (44 FIGO grade 1, 40 FIGO grade 2, and 17 FIGO grade 3), and 51 HPV-related endocervical adenocarcinomas. All serous carcinomas demonstrated diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 95%/100%). In contrast, endometrial endometrioid carcinomas exhibited less diffuse and less intense expression, with percent of positive tumor cells ranging from 10% to 90% (mean/median: 38%/30%; staining intensity: variable). Similar to serous carcinomas, all endocervical adenocarcinomas exhibited diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 94%/90%). P16 can serve as an additional diagnostic marker, used as part of an immunohistochemical panel, including p53 and hormone receptors, for distinction of uterine serous carcinomas from endometrioid carcinomas. Distinction of serous carcinomas from endocervical adenocarcinomas (HPV-related type), both of which share diffuse p16 expression and frequently lack hormone receptor expression, relies on morphology and diffuse/strong p53 expression in the former and detection of HPV in the latter.

Women with undiagnosed colorectal adenocarcinomas presenting with ovarian metastases: clinicopathologic features and comparison with women having known colorectal adenocarcinomas and ovarian involvement.

Recognition of an ovarian tumor as a metastasis from an undiagnosed primary gastrointestinal tract carcinoma can be difficult when specific symptoms referable to the primary tumor are lacking and the tumor simulates a primary ovarian neoplasm grossly and microscopically. Ovarian metastases of colorectal adenocarcinomas, in particular, continue to pose diagnostic challenges both clinically and pathologically. Clinicopathologic features of 20 cases of ovarian metastases from undiagnosed colorectal adenocarcinomas (U-CRAs) were compared with those of 22 cases having metastases from known colorectal adenocarcinomas (K-CRAs). Women with ovarian metastases from U-CRAs were significantly younger (mean age, 48 years; median, 47 years) than those with ovarian metastases from K-CRAs (mean, 61 years; median, 63 years) (P = 0.002), presented with clinical findings related to the ovarian metastases, often had elevated CA-125 levels, and lacked specific symptoms due to the colorectal carcinomas, which were diagnosed only at the time of intraoperative evaluation of the ovarian tumors. Mean/median ovarian tumor sizes (12.8/13.0 cm for U-CRAs; 14.1/15.8 cm for K-CRAs) and frequencies of bilaterality (45% for U-CRAs and 36% for K-CRAs) were not significantly different for the 2 groups; frequencies of clinically unilateral tumors of more than 10 cm were similar in both groups (30% for U-CRAs and 45% for KCRAs). Other features more commonly observed in ovarian metastases from U-CRAs included mucinous differentiation, extracellular mucin production, and some degree of cytokeratin 7 expression; endometrioid-like differentiation was more common in metastases from K-CRA, but a garland pattern of necrosis and the presence of a confluent glandular, rather than infiltrative, pattern of invasion were similarly common in both groups. In cases having ovarian metastases from U-CRA, the younger age of the women, uniform presentation as pelvic masses without symptoms referable to the bowel, elevated CA-125 levels, occasional presentation as a large clinically unilateral tumor, frequent mucinous differentiation, and frequent coexpression of cytokeratin 7 are features that can contribute to misclassification of these metastases as primary ovarian neoplasms.

Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification.

Distinction of primary ovarian mucinous tumors from metastatic/secondary mucinous tumors involving the ovaries is often challenging, not only at the time of intraoperative assessment when requested for surgical management (staging decisions) but also for final pathologic diagnosis. Previous studies have shown that a simple algorithm using tumor size and laterality (bilateral tumors of any size, or unilateral tumor <10 cm=metastatic; unilateral tumor > or =10 cm=primary) can accurately classify a substantial majority of tumors. To assess the general utility of this algorithm for distinction of primary and secondary mucinous tumors in the ovary and address the occurrence of exceptions (large unilateral metastases), analysis of tumor size and laterality data was performed using 194 tumors (52 primary tumors and 142 metastases), with metastases subclassified by primary site [colorectum (46), appendix (28 low-grade tumors, 20 carcinomas), pancreaticobiliary tract (20), small intestine (3), stomach (5), and endocervix (20)]. Performance of the algorithm was evaluated using the originally proposed method and modified size criteria were analyzed to optimize tumor classification. The original algorithm correctly classified 84% of tumors overall, including 100% of primary ovarian tumors and 77% of all metastases (colorectal: 74%; appendiceal: 79% of low-grade tumors, 100% of carcinomas; pancreaticobiliary: 95%; small intestinal: 33%; gastric: 80%; endocervical: 55%). By adjusting the size criterion to 12 cm, performance of the algorithm was both maintained for primary ovarian tumors and improved for metastases, with correct classification of 86% of tumors overall, including 100% of primary tumors and 80% of metastases. Performance was optimized at 13 cm, with correct classification of 87% of tumors overall, including 98% of primary tumors and 82% of metastases (colorectal: 80%; appendiceal: 79% of low-grade tumors, 100% of carcinomas; pancreaticobiliary: 100%; small intestinal: 33%; gastric: 100%; endocervical: 70%). Of the more common metastases, metastatic colorectal and endocervical carcinomas provided the greatest number of exceptions, even when analyzed with the optimized size criterion. Recognition that metastatic colorectal carcinomas represent the most common metastases and have a greater tendency to violate the algorithm should prompt lowering of the threshold for suggesting the possibility of metastatic colorectal carcinoma for tumors displaying any microscopic features suggestive of that diagnosis, even when a history of primary colorectal carcinoma is lacking. Use of the algorithm is intended as an adjunct to the complete clinicopathologic evaluation that ideally should occur when problematic mucinous tumors in the ovary are encountered.

Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7.

Recent studies have demonstrated conflicting results regarding the value of CDX2 for distinguishing primary ovarian mucinous tumors from metastatic mucinous carcinomas in the ovary. Utility of coordinate expression of cytokeratins 7 and 20 is restricted to distinction of ovarian mucinous tumors from lower gastrointestinal tract metastases and data comparing coordinate expression of all three markers is limited. Immunohistochemical studies were performed to compare expression of CDX2 and cytokeratin 20, both markers of intestinal differentiation, in conjunction with coordinate expression of cytokeratin 7, in 90 mucinous tumors involving the ovary: 42 primary ovarian mucinous tumors (31 atypical proliferative (borderline) mucinous tumors (gastrointestinal type), 11 mucinous carcinomas) and 48 metastatic mucinous carcinomas of upper (pancreaticobiliary tract: 14; stomach: five) and lower (colon and rectum: 25; appendix: four) gastrointestinal tract origin. Primary ovarian tumors expressed CDX2 (40%) less frequently than cytokeratin 20 (83%) (P<0.0001). CDX2 expression in primary ovarian tumors (40%) was lower than CDX2 expression in metastatic carcinomas of both upper (74%; P=0.016) and lower gastrointestinal tract origin (90%; P<0.0001). Cytokeratin 20 expression was similar in primary ovarian tumors (83%) and metastases of upper (89%; P=0.071) and lower gastrointestinal tract origin (93%; P=0.29). Thus, as a single marker CDX2 offers some advantage over cytokeratin 20 because it is less frequently positive in primary ovarian tumors. In the almost universally cytokeratin 7-positive primary ovarian tumors and metastases of upper gastrointestinal tract origin, CDX2 coordinate expression was less common in primary ovarian tumors (36%) than in metastases of upper gastrointestinal tract origin (63%) (P=0.022) whereas cytokeratin 20 coordinate expression was identical in both tumor types (79%). In the almost universally cytokeratin 7-negative metastases of lower gastrointestinal tract origin, coordinate expression of CDX2 (83%) and cytokeratin 20 (86%) were equivalent (P=1.00). CDX2 was comparable to cytokeratin 20 in distinguishing metastases of lower gastrointestinal tract origin (usually cytokeratin 7-negative and CDX2/cytokeratin 20 positive) from primary ovarian tumors and metastases of upper gastrointestinal tract origin (usually cytokeratin 7-positive and CDX2/cytokeratin 20 variable). CDX2 provided some advantage over cytokeratin 20 for distinguishing primary ovarian mucinous tumors from metastases of upper but not lower gastrointestinal tract origin; however, the advantage in the former was limited due to the occurrence of shared coordinate expression profiles in both tumor types. Cytokeratin 7 provides the predominant discriminatory value among these markers yet is limited to distinction of primary ovarian tumors from metastases of lower gastrointestinal tract origin.