False-negative Papanicolaou tests in women with biopsy-proven invasive endocervical adenocarcinoma/adenocarcinoma in situ: a retrospective analysis with assessment of interobserver agreement.

INTRODUCTION: The objectives of our study were to identify factors contributing to false-negative Papanicolaou (Pap) tests in patients with endocervical adenocarcinoma (EA) or adenocarcinoma in situ (AIS), and to analyze the impact of educational instruction on interobserver agreement in these cases. MATERIALS AND METHODS: False-negative Pap tests from patients with EA/AIS were reviewed by a consensus group and by 12 individual reviewers in 2 rounds, with an educational session on glandular neoplasia in Pap tests conducted between the 2 rounds. RESULTS: Of 79 Pap tests from patients with EA/AIS, 57 (72.2%) were diagnosed as abnormal and 22 (27.8%) as negative. Of the 22 false-negative cases, 10 remained negative on consensus review, with false-negative diagnoses attributed to sampling variance. The other 12 cases were upgraded to epithelial abnormalities (including 8 to glandular lesions). The false-negative diagnoses were attributed to screening variance in 2 cases and interpretive variance in 10 cases. On individual review, abnormal cells were misinterpreted as reactive glandular cells or endometrial cells in 7 of 8 and 5 of 8 cases upgraded to glandular abnormalities, respectively. With education, the proportion of individual reviewers demonstrating at least moderate agreement with the consensus diagnosis (Cohen's kappa >0.4) increased from 33% (4 of 12) to 75% (9 of 12). CONCLUSIONS: Sampling and interpretive variance each accounted for nearly one-half of the false-negative Pap tests, with underclassification as reactive glandular or endometrial cells the main source of the interpretive variances. Educational instruction significantly decreased the interpretive variance and interobserver variability in the diagnosis of glandular abnormalities.

Negative Pap tests in women with high-grade cervical lesions on follow-up biopsies: Contributing factors and role of human papillomavirus genotyping.

BACKGROUND: Previous studies have indicated that negative Papanicolaou (Pap) tests can precede high-grade cervical lesions (HGCL) on biopsy. This study aims to determine the contributing factors for cytologic discrepancy and the potential role of human papilloma virus (HPV) testing in risk evaluation of women with negative Pap tests. METHODS: Of 42,797 Pap tests interpreted as negative for intraepithelial lesion or malignancy (NILM) from March 1, 2013 to December 30, 2014, 426 had available HPV testing and follow-up biopsy. The NILM Pap tests with biopsy-confirmed HGCL were reviewed. RESULTS: Among 426 cytology-negative cases, the biopsies showed benign histology in 243 (57%), low-grade squamous intraepithelial lesion in 157 (37%), HGCL in 22 (5%), and endometrial adenocarcinoma in 4 (1%) cases. The sensitivity/specificity/positive predictive values (PPV) of high-risk HPV (hrHPV) and HPV16/18 tests in predicting HGCL was 91%/45%/8% and 55%/76%/11%, respectively. Upon review of NILM Pap tests with biopsy-confirmed HGCL, the contributing factors to negative cytology included absence of abnormal cells (12/21, 57%) or diagnostic high-grade cells (6/21, 29%), unsatisfactory samples (2/21, 10%), and interpretation variances (1/21, 5%). Interpretation variances in three high-risk lesions (1 HSIL, 2 ASC-H) were influenced by marked obscuring inflammation. CONCLUSIONS: Our study demonstrated that 5% of women underwent co-testing with negative Pap tests had HGCL on follow-up biopsy. Absence of diagnostic cells was the leading cause for cytology discrepancy and interpretation variances were influenced by marked obscuring inflammation. HPV testing and genotyping had limited value in risk stratification due to extremely low PPV. Focused rescreening of hrHPV-positive NILM with obscuring factors may help reduce interpretation variances.

Programmed Death Ligand-1 (PD-L1) Expression in Either Tumor Cells or Tumor-Infiltrating Immune Cells Correlates With Solid and High-Grade Lung Adenocarcinomas.

CONTEXT: - Programmed death ligand-1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC) is heterogeneous and known to be underestimated on small biopsies. Correlation of PD-L1 expression with clinicopathologic features may provide additional useful information. To our knowledge, the clinicopathologic features of NSCLC have not been reported for subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. OBJECTIVE: - To investigate the clinicopathologic characteristics of NSCLC subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. DESIGN: - PD-L1 immunohistochemistry with the SP142 clone was performed on whole-tissue sections and given semiquantitative scores (0/1/2/3) according to percent of PD-L1+ tumor cells (TCs) and percent tumor area with PD-L1+ tumor-infiltrating immune cells (ICs). RESULTS: - Adenocarcinoma cases that were scored either TC 1/2/3 or IC 1/2/3 included most (22 of 34; 65%) high-histologic grade cases and most (25 of 36; 69%) solid subtype cases. Compared with the adenocarcinoma TC 0 and IC 0 subset, the TC 1/2/3 or IC 1/2/3 subset correlated with higher histologic grade (P = .005, χ2 test for trend) and solid subtype (P < .001, Fisher exact test). Compared with the adenocarcinoma TC 0/1 or IC 0/1 subset, the TC 2/3 or IC 2/3 subset correlated with higher histologic grade (P = .002, χ2 test for trend), solid subtype (P < .001, Fisher exact test), and higher smoking pack-years (P = .01, Mann-Whitney test). CONCLUSIONS: - Lung adenocarcinoma subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells correlated with high histologic grade, solid subtype, and high smoking pack-years.

Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology.

Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver.

Determination of HER2/neu status: a pilot study comparing HER2/neu dual in situ hybridization DNA probe cocktail assay performed on cell blocks to immunohistochemisty and fluorescence in situ hybridization performed on histologic specimens.

CONTEXT: Validation of new methodologies for determining human epidermal growth factor receptor 2 gene (HER2/neu) amplification status is crucial for advancing the standard of care and determining treatment for patients with primary and/or metastatic breast carcinoma. OBJECTIVE: To compare results of HER2/neu gene amplification status by 2-color chromogenic in situ hybridization (ISH) on cell block material to HER2/neu status by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) in the corresponding resection specimen or previous biopsy specimen. DESIGN: Formalin, thrombin, and Cellient cell blocks were prepared from cytologic samples obtained from resection specimens from 27 patients with invasive breast carcinoma. In situ hybridization was performed on cell block sections from 18 of the collected cases, on both the Ventana BenchMark ULTRA and the Ventana BenchMark XT, and the HER2/neu gene amplification status was determined. This was then compared to the HER2/neu status by IHC and/or FISH in the resection specimen or previous biopsy specimen. RESULTS: Comparison of HER2/neu status by ISH on the quantifiable cell block sections showed 100% correlation with the HER2/neu status determined by IHC or FISH in the corresponding histologic specimens. The results from thrombin and formalin cell blocks were statistically superior to the results from Cellient cell blocks on both Ventana instruments. CONCLUSIONS: While further validation and study are needed, preliminary results show that the HER2/neu gene amplification status of breast carcinomas can reliably be determined on thrombin and formalin cell block material by using ISH. More consistent staining and better signal integrity was obtained with the Ventana BenchMark ULTRA than the BenchMark XT.

Nasal gout presenting as nasal obstruction.

IMPORTANCE: We describe a case of nasal gout presenting as nasal obstruction, a rare etiology for a common presentation. OBSERVATIONS: We report a single case of a 56-year-old man with history of multiple nasal traumas, obstructive sleep apnea, referred for nasal obstruction and congestion, having failed attempts at medical management. He had severe septal deviation, elements of external and internal nasal valve collapse, and a nasal dorsal mass suspicious for gouty tophus. He was brought to the operating room for septorhinoplasty through an open incision with nasal tip reconstruction, which exposed a 4 × 3-cm mass on the nasal dorsum, extending to the tip, supertip, and into the septal plane at the level of the upper lateral cartilages. Final pathologic findings revealed gouty tophus. He has done well since, and breathing and sleep are significantly improved. CONCLUSIONS AND RELEVANCE: This case demonstrates a rare etiology for nasal obstruction that may complicate the workup, evaluation, and management of such a patient. It highlights the ways in which a rare diagnosis adds complexity to the workup and management of a patient with nasal obstruction, and serves as an important reminder about rarer pathologies that can present in an everyday clinic.

Digital slide imaging in cervicovaginal cytology: a pilot study.

CONTEXT: Digital whole slide imaging is the anticipated future of anatomic pathology, where sign-out of glass slides will be replaced by scanned images. Whole slide imaging has been successfully used in surgical pathology, but its usefulness and clinical application have been limited in cytology for several reasons, including lack of availability of z-axis depth focusing and large file size. Recently, several systems have become available in the United States for whole slide imaging with z-axis technology. OBJECTIVE: To determine the accuracy and efficiency of whole slide imaging, as compared with traditional glass slides, for use in cervicovaginal diagnostic cytology. DESIGN: Eleven cervicovaginal cytology cases (ThinPrep and SurePath) scanned at ×20, ×40, and ×40 z-stack magnifications using the BioImagene iScan Coreo Au 3.0 scanner were evaluated by 4 cytotechnologists and 3 pathologists in a blinded study. Different magnification scans were recorded as separate cases and presented in a randomized sequence. Corresponding glass slides were also reviewed. For each case, the diagnoses and total time to reach each diagnosis were recorded. RESULTS: Diagnostic accuracy was higher and average time per case was lower with glass slides as compared with all digital images. Among the digital images, the ×40 or ×40 z-stack had the highest diagnostic accuracy and lowest interpretation time. CONCLUSIONS: Whole slide imaging is a viable option for the purposes of teaching and consultations, and as a means of archiving cases. However, considering the large file size and total time to reach diagnosis on digital images, whole slide imaging is not yet ready for daily cervicovaginal diagnostic cytology screening use.

Comparison of breast carcinoma prognostic/predictive biomarkers on cell blocks obtained by various methods: Cellient, formalin and thrombin.

OBJECTIVE: To compare results of immunohistochemical (IHC) assays for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) performed on thrombin, formalin and Cellient cell blocks to those performed on tissue. STUDY DESIGN: Formalin, thrombin and Cellient cell blocks were prepared from cytologic samples obtained from resection specimens of 31 patients with invasive breast carcinoma. ER, PR, HER2 and MIB-1 (Ki-67) IHC stains were performed on all three types of cell blocks and compared to the same stains performed on the patient's paraffin-embedded biopsy or resection. Cell and tissue blocks with equivocal staining for HER2 were submitted for fluorescence in situ hybridization (FISH). RESULTS: Adequate Cellient blocks were obtained for all 31 cases. Comparison of results of ER IHC assays on all three types of cell blocks showed 100% correlation with tissue. Both Cellient and thrombin blocks showed 100% correlation with tissue for HER2 IHC and FISH results. The only statistically significant difference between cell block methods was found in PR staining, where false-negative results occurred with Cellient and thrombin blocks. CONCLUSION: Breast biomarker IHC assays performed on Cellient blocks are reliable and correlate with tissue block results, particularly for ER and HER2, the most clinically important markers.

Malignant hepatic angiomyolipoma: report of a case and review of literature.

Hepatic angiomyolipoma, a constituent of the group of tumors showing differentiation resembling perivascular epithelioid cells, is primarily appreciated in its benign form. Regardless of their location, this family of tumors is characterized by the presence of mature adipocytes, blood vessels, and spindle-epithelioid cells. These tumors also possess similar immunohistochemical profiles, including positivity for melanocytic (HMB-45) and smooth muscle (smooth muscle actin) markers. Here, we present a case of malignant hepatic perivascular epithelioid cells that was initially confined to the liver, treated by resection, and subsequently recurred within and metastasized beyond the liver. We take this opportunity to report the fourth case of malignant hepatic angiomyolipoma (HAML) and review the literature. We will discuss the features that aid in distinguishing between benign and malignant HAML, and their similarities. In summary, the common features of both benign and malignant HAML include the following: the 3 basic histologic components of AML, expression of melanocytic and smooth muscle markers, invasion into adjacent normal parenchyma, and cytologic atypia. The unique features of malignant HAML are as follows: clinical evidence of aggressive behavior such as metastasis or death owing to disease, coagulative necrosis, and loss of CD 117 expression.