A Description of the Imaging Innovations for Placental Assessment in Response to Environmental Pollution Study.

OBJECTIVE: The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. STUDY DESIGN: Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. RESULTS: In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. CONCLUSION: Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. KEY POINTS: · MRI was acceptable and feasible for the study of the human placenta in vivo.. · Functional imaging of the placenta by MRI showed a significant decrease in high placental blood flow.. · Measures of environmental exposures are further being analyzed to predict IPD..

Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency.

Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2-/- ) were generated. Emp2-/- females are fertile but have reduced litter sizes when carrying Emp2-/- but not Emp2+/- fetuses. Placentas of Emp2-/- fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen-poor environment, the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was examined. Placentas from Emp2-/- fetuses had increased total HIF-1α expression in large part through an increase in uterine NK (uNK) cells, demonstrating a unique interplay between uNK cells and trophoblasts modulated through EMP2. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2. EMP2 was significantly reduced in both villous and extravillous trophoblast populations in IUGR placentas. Experiments in vitro using human trophoblast cells lines indicate that EMP2 modulates angiogenesis by altering HIF-1α expression. Our results reveal a novel role for EMP2 in regulating trophoblast function and vascular development in mice and humans, and suggest that it may be a new biomarker for placental insufficiency. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors.

A diagnosis of neuroendocrine carcinoma is often morphologically straight-forward; however, the tumor site of origin may remain elusive in a metastatic presentation. Neuroendocrine tumor subtyping has important implications for staging and patient management. In this study, the novel use and performance of a 92-gene molecular cancer classifier for determination of the site of tumor origin are described in a series of 75 neuroendocrine tumors (44 metastatic, 31 primary; gastrointestinal (n=12), pulmonary (n=22), Merkel cell (n=10), pancreatic (n=10), pheochromocytoma (n=10), and medullary thyroid carcinoma (n=11)). Formalin-fixed, paraffin-embedded samples passing multicenter pathologist adjudication were blinded and tested by a 92-gene molecular assay that predicts tumor type/subtype based upon relative quantitative PCR expression measurements for 87 tumor-related and 5 reference genes. The 92-gene assay demonstrated 99% (74/75; 95% confidence interval (CI) 0.93-0.99) accuracy for classification of neuroendocrine carcinomas and correctly subtyped the tumor site of origin in 95% (71/75; 95% CI 0.87-0.98) of cases. Analysis of gene expression subsignatures within the 92-gene assay panel showed 4 genes with promising discriminatory value for tumor typing and 15 genes for tumor subtyping. The 92-gene classifier demonstrated excellent accuracy for classifying and determining the site of origin in tumors with neuroendocrine differentiation. These results show promise for use of this test to aid in classifying neuroendocrine tumors of indeterminate primary site, particularly in the metastatic setting.

Abdominal imaging can misdiagnose submassive hepatic necrosis as cirrhosis in acute liver failure.

Patients with acute liver failure (ALF) can be listed status I for liver transplantation (LT) whereas patients with cirrhosis must follow the MELD scoring system. Liver imaging can mistakenly diagnose submassive hepatic necrosis in ALF as cirrhosis. The purpose of our study was to assess the accuracy of ultrasound (US) and computed tomography (CT) in distinguishing cirrhosis from ALF. All patients listed for ALF and transplanted during the study period were included. Controls were age- and gender-matched cirrhotic patients who underwent LT during the same period. Abdominal US or CT scans obtained on all patients were independently reviewed by three blinded abdominal radiologists. Explants from all patients were reviewed by two blinded pathologists, and histological diagnosis was correlated with radiological diagnosis. Forty-one patients with ALF and 42 patients with cirrhosis were analyzed. Univariate and multivariate analyses both revealed overall accuracy of 85% for ultrasound and 93% for CT. US and CT scans both provide high levels of accuracy in terms of discriminating ALF from cirrhosis but measures taken to determine whether a patient has ALF vs. cirrhosis needs to approach 100% accuracy. Thus, imaging studies alone should not definitively diagnosis one etiology of liver failure over the other.

Hints to the diagnosis of mixed acinar-endocrine carcinoma on pancreatic fine-needle aspiration: avoiding a potential diagnostic pitfall.

BACKGROUND: Mixed acinar-endocrine carcinoma (MAEC) is a rare mixed tumor of the pancreas defined by both acinar and endocrine cell differentiation. CASE: We present 2 cases of MAEC initially diagnosed as pancreatic endocrine neoplasm on fine-needle aspiration. Both patients were male, aged 51 and 75 years, and presented with 16-mm and 6-mm pancreatic masses, respectively. Aspirates showed loose aggregates and dispersed single plasmacytoid cells with moderate nuclear size variation, slightly irregular nuclear contours, fine to coarsely granular chromatin, occasional prominent nucleoli, and scant to moderate finely granular cytoplasm. Rare mitotic figures and pyknotic forms were noted in one of the cases. Endocrine differentiation was confirmed by immunocytochemistry which led to an initial diagnosis of pancreatic endocrine neoplasm. Trypsin and lipase immunocytochemistry were later obtained, confirming a component of acinar cell differentiation. Findings were confirmed on surgical excision. CONCLUSION: Because of their potentially more aggressive clinical course and different therapeutic implications, MAECs are an important consideration in the differential diagnosis of pancreatic neoplasms. Certain cytomorphologic features and immunocytochemical markers of acinar cell differentiation may be helpful in raising the possibility of MAEC on cytology.

This is Jeopardy! A flexible coverage-based schedule model to address wellness for pathology training programs.

Scheduling rotations for a pathology training program involves balancing educational requirements, service coverage, and paid time off (PTO). Absences can affect training as residents cross-cover, managing multiple services at once. Other specialties utilize a "Jeopardy" based system for covering absences. In this system, residents on outpatient services are "jeopardized" to cover inpatient services for trainee absences. Borrowing this concept, we created a schedule model with a "Jeopardy-Elective" (JE) rotation to support resident absences. Prior to 2018-19, our residency program consisted of a 12 month-long rotation schedule. We adopted a 13 four-week block rotation model system, adding four JE rotations per resident over the course of training. The JE resident covered services during trainee absences and spent the remaining rotation on elective. We then conducted a pre- and post-intervention survey of all residents who trained in both systems. Following the change in schedule model, our results showed a statistically significant increase in resident satisfaction with taking PTO (p = 0.0014), finding coverage (p = 0.0006), and taking a sick day (p = 0.03). The mean number of days covered by the JE resident was 8.5 ± 2.7 workdays (out of 20). PTO usage increased from 16 to 20 days/resident while mean number of sick days decreased from 1.7 to 1.3 days per resident. There was overwhelming support with 82% of residents wanting to retain the new system going forward. Through use of the JE rotation, our program improved service coverage issues and resident satisfaction, with the long-term goal of enhanced resident well-being and enriched resident learning experiences.

Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development.

Thyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024-0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.

Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas.

B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.

Should histologic type be taken into account when considering neoadjuvant chemotherapy in breast carcinoma?

Neoadjuvant chemotherapy is becoming the standard of care in locally advanced breast cancers. With complete pathologic response, patients may have a better overall survival. However, most patients do not have a complete pathologic response, and it is unclear how this impacts survival and whether histologic subtype or chemotherapeutic histologic changes play a role. We retrospectively identified 49 cases of invasive breast carcinoma treated with neoadjuvant chemotherapy (40 ductal, nine lobular) and examined histologic and biologic features of ductal and lobular carcinoma before and after chemotherapy. Patients with lobular carcinomas presented at a later age and had lower grade tumors that were more likely estrogen and progesterone receptor positive. Ductal carcinomas had a greater frequency of HER-2/neu amplification and increased Ki-67 rate. After chemotherapy, none of the lobular carcinomas had complete pathologic response compared with 28% of the ductal carcinomas (p = 0.01). Lobular carcinomas had more lymph node metastases. At the time of clinical follow-up, no lobular carcinomas had evidence of disease. Only one lobular carcinoma case had any histologic changes after chemotherapy compared with 37-68% of ductal carcinomas (p < 0.05). In ductal carcinomas, higher grade and negative estrogen receptor expression before chemotherapy and presence of foam cell clusters, HER-2/neu expression, and absence of lymphatic or vascular space invasion after chemotherapy correlated with pathologic response (p < 0.05). Decreased Ki-67 rate after chemotherapy correlated with survival (p = 0.024). Breast biomarker status changed in 9% of all lobular carcinomas and 19% of all ductal carcinomas. Lobular carcinomas respond poorly to neoadjuvant chemotherapy as evidence by lack of complete pathologic response and rare histologic tissue response.

Aldehyde dehydrogenase isoforms and inflammatory cell populations are differentially expressed in term human placentas affected by intrauterine growth restriction.

OBJECTIVE: Intrauterine growth restriction (IUGR) is a complication of pregnancy that has both short- and long-term sequelae for affected mothers and offspring. The pathophysiology of disease stems from poor nutrient and oxygen provision to the fetus, resulting in increased oxidative stress within the placenta. As the milieu within the local microenvironment alters macrophage differentiation, we hypothesized that macrophage plasticity may be altered in placentas associated with IUGR, and that macrophages would show hallmarks of lipid peroxidation including altered aldehyde metabolism. METHODS: In human placentas taken from normal pregnancies resulting in appropriate-for-gestational-age (AGA) newborns and placentas associated with IUGR, placental macrophages were evaluated by immunohistochemistry and shown in IUGR to resemble pro-inflammatory activated M1-type macrophages. To link oxidative stress to macrophages, the expression of aldehyde dehydrogenase (ALDHs) isozymes ALDH1, ALDH2, and ALDH3 was assessed. RESULTS: All three isozymes displayed preferential staining for distinct cellular populations within the term human placenta. ALDH1 and ALDH2 were strongly expressed in placental Hofbauer and decidual stromal cells. ALDH3, in contrast, was present in extravillous trophoblasts. Comparing AGA and IUGR-associated placentas, ALDH1 and ALDH2 trended to have greater expression in macrophage populations but lower expression in decidual cell populations in IUGR-associated placentas. ALDH3 had higher expression in IUGR-associated placentas but localized specifically to extravillous trophoblast populations. CONCLUSION: Therefore, we speculate that specific ALDH isozymes have cell-specific functions related to differentiation, inflammation, or oxidative stress responses that are altered in IUGR-associated term human placentas. This family of isozymes may be a novel method to identify human placentas affected by placental insufficiency/IUGR.

Breast Hyperplasias, Risk Signature, and Breast Cancer.

We address the dilemma faced by oncologists in administering preventative measures to "at risk" patients diagnosed with atypical and nonatypical hyperplasias due to lack of any molecular means of risk stratification and identifying high-risk subjects. Our study purpose is to investigate a four marker risk signature, MMP-1, CEACAM6, HYAL1, and HEC1, using 440 hyperplastic tissues for identifying high-risk subjects who will benefit from preventative therapies. We assayed the markers by IHC and combined their expression levels to obtain a composite value from 0-10, which we called a "Cancer Risk Score." We demonstrate that the four marker-based risk scores predict subsequent cancer development with an accuracy of 91% and 86% for atypical and nonatypical subjects, respectively. We have established a correlation between risk scores and cancer rates by stratifying the samples into low risk (score ≤ 0.5); intermediate risk (score ≤ 5.4), and high risk (score >5.4) groups using Kaplan-Meier survival analysis. We have evaluated cancer rates at 5, 10, and 15 years. Our results show that the average cancer rates in the first 5 years among low- and intermediate-risk groups were 2% and 15%, respectively. Among high-risk group, the average cancer rates at 5 years were 73% and 34% for atypical and nonatypical subjects, respectively. The molecular risk stratification described here assesses a patient's tumor biology-based risk level as low, intermediate, or high and for making informed treatment decisions. The outcomes of our study in conjunction with the available prophylactic measures could prevent approximately 20%-25% of sporadic breast cancers.

An Unusual Adenomatoid Tumor of Fimbria with Pronounced Psammoma Bodies in a BRCA Positive Patient as a Pitfall for Carcinoma on Frozen Section.

BACKGROUND: BRCA gene mutations significantly increase the risk of breast and ovarian cancers where the lifetime risk of the ovarian cancer is about 40%. Therefore, many women with such mutations undergo prophylactic bilateral mastectomy and salpingo-oophorectomy. About 5-6% of these individuals display occult carcinomas in tubo-ovarian locations of which over 85% are tubal in origin. The objective of this case study was to emphasize emergence of benign lesions mimicking cancer under these circumstances. CASE REPORT: We present a case with positive BRCA1 mutation who underwent the prophylactic procedure where a small mass was identified in her fallopian tube. Our initial encounter with this tumor was during intraoperative consultation. The tumor was associated with extensive psammoma bodies arranged in closely packed small tubules, mimicking serous carcinoma. Frozen section limitations including artifact, time constraint, and lack of ancillary studies as well as the clinical history further complicated our diagnostic assessment, which was deferred. A diagnosis of adenomatoid tumor was rendered on permanent sections. CONCLUSION: It is important to be familiar with this morphologic presentation of adenomatoid tumor as it is a pitfall for carcinoma, particularly on frozen section, and inaccurate diagnosis could lead to further unnecessary extensive procedures.

Comparison of Cytopathologist-Performed Ultrasound-Guided Fine-Needle Aspiration With Cytopathologist-Performed Palpation-Guided Fine-Needle Aspiration: A Single Institutional Experience.

CONTEXT.­: Although fine-needle aspiration (FNA) practice by pathologists is now well established, it has been primarily performed by manual palpation. In recent years, pathologists have begun to venture into ultrasound-guided FNAs (UGFNAs). Reports on experiences with this relatively new technique for pathologists have shown promising results. However to date, there have been few studies in the literature comparing pathologist-performed UGFNA with the more traditional pathologist-performed palpation-guided FNA (PGFNA). OBJECTIVE.­: To compare UGFNA to PGFNA by cytopathologists at an academic medical center. DESIGN.­: A retrospective study of FNAs performed by cytopathologists within the University of California, Los Angeles (UCLA) pathology departmental FNA clinic was performed. Data collected included performance technique (UGFNA versus PGFNA), lesion site and size, adequacy status (nondiagnostic rate), and number of passes per procedure. Corresponding surgical pathology/flow cytometric/cytogenetic result follow-up was compared to FNA results. Findings between UGFNA and PGFNA cases were compared. RESULTS.­: Of 1029 FNA cases during the study period, there were 449 UGFNA cases (43.6%) and 580 PGFNA cases (56.4%). Nondiagnostic rates with UGFNA and PGFNA were 6.7% (30 of 449 cases) and 20.7% (120 of 580 cases), respectively. Nondiagnostic rate was also significantly lower with UGFNA than with PGFNA for lesions within the thyroid (6.0% versus 33.3%), head and neck (6.6% versus 21.2%), and salivary gland (6.2% versus 17.1%), and across all nodule sizes. A total of 495 of 1029 FNA cases (48.1%) had follow-up. Discordance rate was significantly lower with UGFNA than with PGFNA (5.4% versus 12.8%). CONCLUSIONS.­: This study shows improved performance characteristics of cytopathologist-performed UGFNA versus PGFNA.

Prometastatic Molecular Profiles in Breast Tumors From Socially Isolated Women.

BACKGROUND: Social isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial-mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients. METHODS: EMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion. RESULTS: Tumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (ß= -.29) but no difference in blood vessel density. TELiS promoter-based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of ß-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19). CONCLUSIONS: Primary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.

Humanin (HN) and glucose transporter 8 (GLUT8) in pregnancies complicated by intrauterine growth restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) results from a lack of nutrients transferred to the developing fetus, particularly oxygen and glucose. Increased expression of the cytoprotective mitochondrial peptide, humanin (HN), and the glucose transporter 8, GLUT8, has been reported under conditions of hypoxic stress. However, the presence and cellular localization of HN and GLUT8 in IUGR-related placental pathology remain unexplored. Thus, we undertook this study to investigate placental expression of HN and GLUT8 in IUGR-affected versus normal pregnancies. RESULTS: We found 1) increased HN expression in human IUGR-affected pregnancies on the maternal aspect of the placenta (extravillous trophoblastic (EVT) cytoplasm) compared to control (i.e. appropriate for gestational age) pregnancies, and a concomitant increase in GLUT8 expression in the same compartment, 2) HN and GLUT8 showed a protein-protein interaction by co-immunoprecipitation, 3) elevated HN and GLUT8 levels in vitro under simulated hypoxia in human EVT cells, HTR8/SVneo, and 4) increased HN expression but attenuated GLUT8 expression in vitro under serum deprivation in HTR8/SVneo cells. CONCLUSIONS: There was elevated HN expression with cytoplasmic localization to EVTs on the maternal aspect of the human placenta affected by IUGR, also associated with increased GLUT8 expression. We found that while hypoxia increased both HN and GLUT8, serum deprivation increased HN expression alone. Also, a protein-protein interaction between HN and GLUT8 suggests that their interaction may fulfill a biologic role that requires interdependency. Future investigations delineating molecular interactions between these proteins are required to fully uncover their role in IUGR-affected pregnancies.

Classical pathology versus molecular pathology in renal cell carcinoma.

Renal cell carcinoma (RCC) has been characterized based on histology, stage, and grading to predict behavior and guide therapy; however, RCC is still unpredictable, with poor prognosis in metastatic disease. The classification of RCC has been revised to account for molecular characteristics, and there has been an increasing understanding of the hereditary forms of RCC. This has led to further elucidation of pathways in the development of RCC including the hypoxia-inducible pathway and angiogenesis. Many other promising molecular modalities are in development, including gene expression profiling, nuclear parameters, and proliferation/apoptotic markers. This article discusses the current understanding of the classical pathologic features of RCC and highlights recent developments in the cellular and molecular characterization of RCC, which aim to improve the classification, prognostication, and treatment of RCC.

Metastatic Pituitary Carcinoma to Cervical Lymph Node: Diagnosis by Fine Needle Aspiration and Review of the Literature.

BACKGROUND: Pituitary carcinomas are rare neoplasms whose designation requires demonstration of metastatic disease. No specific morphologic features can reliably distinguish pituitary carcinomas from pituitary adenomas, rendering the diagnosis particularly challenging. Furthermore, as reports of pituitary carcinoma on fine needle aspiration (FNA) biopsy are exceedingly rare in the literature, the cytological features of pituitary carcinoma are poorly characterized. CASE REPORT: Here we describe a case of pituitary carcinoma in a 67-year-old woman with history of recurrent adrenocorticotropic hormone (ACTH)-producing pituitary adenoma who presented with a persistent left cervical nodule for 2 years. Ultrasound-guided FNA of the nodule consisted of loosely cohesive clusters of epithelioid cells with marked cytologic atypia, intermediate to large nuclei, relatively irregular nuclear contour, coarse granular chromatin, prominent nucleoli, and delicate finely granular cytoplasm. Immunohistochemical stains performed on the cell block revealed positivity for synaptophysin, chromogranin and ACTH with an increased Ki-67 proliferation index (approximately 25%). Review of the patient's previously resected pituitary tumor showed similar cytomorphologic features. CONCLUSION: Given the similar cytologic features of pituitary carcinomas compared to other neuroendocrine tumors, it is important to obtain a complete clinical history and maintain a high index of suspicion in order to make a correct diagnosis of pituitary carcinoma on FNA.

Immunologic evaluation of the endometrium with a levonorgestrel intrauterine device in solid organ transplant women and healthy controls.

OBJECTIVE: The objective was to describe the endometrial milieu of stable transplant patients and healthy women before and after levonorgestrel intrauterine system (LNG-IUS) insertion. STUDY DESIGN: Women between 18 and 45 years of age desiring LNG-IUS insertion were enrolled with a 2:1 ratio of healthy to stable solid organ transplant patients. The first visit entailed a blood draw, uterine lavage and endometrial biopsy followed by LNG-IUS insertion. Follow-up visit involved a repeat serum draw, uterine lavage and endometrial biopsy. Cytokine levels were measured in the uterine lavage and serum by quantifying inflammatory biomarkers. Immunohistochemistry staining was performed on the endometrial tissue to measure macrophage levels. Statistical analysis included a nonparametric analysis that compared medians of the marker levels before and after intrauterine device (IUD) insertion within the group and between the two groups. RESULTS: Sixteen participants completed the study: 5 solid organ transplant patients and 11 healthy patients. For the serum, there were no marked changes in the cytokines or soluble receptor levels in either group after IUD insertion. However, in the uterine lavage, there was an increase in cytokine levels post-IUD insertion for both healthy and transplant women. For the endometrial tissue, there was evidence of macrophage activity in both groups after device insertion. CONCLUSIONS: This pilot study investigated the uterine environment of the transplant patient population. Findings have pointed to the strong local inflammatory response following LNG-IUS insertion for the transplant recipients. In addition, these preliminary findings will help power a larger study that can investigate the safety and effectiveness of the IUD in this patient population. IMPLICATIONS: Findings from this pilot study suggest that the IUD is inducing a local inflammatory reaction in the uterus of the transplant patient as in the healthy control. A larger study can build on these preliminary results to pursue the efficacy and safety of IUD use among solid organ transplant patients.

Effect of malignancy rates on cost-effectiveness of routine gene expression classifier testing for indeterminate thyroid nodules.

BACKGROUND: The value of gene expression classifier (GEC) testing for cytologically indeterminate thyroid nodules lies in its negative predictive value, which is influenced by the prevalence of malignancy. We incorporated actual GEC test performance data from a tertiary referral center into a cost-effectiveness analysis of GEC testing. METHODS: We evaluated consecutive patients who underwent GEC testing for Bethesda category III and IV nodules from 2012 to 2014. Routine GEC testing was compared with conventional management by the use of a decision tree model. Additional model variables were determined via literature review. A cost-effectiveness threshold of $100,000 per quality-adjusted life-year (QALY) was used. RESULTS: The prevalence of malignancy was 24.3% (52/214). Sensitivity and specificity of GEC testing were 96% and 60%. Conventional management cost $11,119 and yielded 22.15 QALYs. Routine GEC testing was more effective and more costly, with an incremental cost-effectiveness ratio of $119,700/QALY, making it not cost-effective. At malignancy rates of 15, 25, or 35%, routine GEC testing became cost-effective when the cost of GEC testing fell below $3,167, $2,595, or $2,023. CONCLUSION: The cost-effectiveness of routine GEC testing varies inversely with the underlying prevalence of malignancy in the tested population. The value of routine GEC testing should be assessed within the context of institution-specific malignancy rates.

Systematic assessment of HER2/neu in gynecologic neoplasms, an institutional experience.

BACKGROUND: HER2/neu overexpression and/or amplification has been widely studied in a number of solid tumors, primarily in the breast. In gynecologic neoplasms, determination of HER2/neu status has not been well studied as a predictive biomarker in anti-HER2/neu treatment. METHODS: We systematically evaluated the HER2/neu reactions by immunohistochemistry and fluorescent in situ hybridization in malignant gynecologic neoplasms as experienced in our institution. RESULTS: The HER2/neu overexpression or amplification occurred in 8 % of the cancers of the gynecological organs in our series. Majority of the HER2/neu overexpression and/or amplification occurred in clear cell (27 %) and serous (11 %) carcinomas. HER2/neu positivity was also seen in undifferentiated as well as in mixed clear cell and serous carcinomas. Discordant IHC and FISH results (positive by FISH but not IHC) was seen in 2 cases. Majority of the HER2/neu overexpression and/or amplification occurs in the endometrium rather than the ovary. Heterogeneity of the HER2/neu by IHC staining was in < 2 % of the tumors in our series. CONCLUSIONS: We recommend the HER2/neu studies on Müllerian carcinomas of clear cell, serous, and undifferentiated types, particularly when they arise in the endometrium. Since there are some discordant IHC/FISH results, we also propose performing the HER2/neu testing by FISH when the IHC score is less than 3 + .