Jeffrey W. Prichard

Plasmablastic Lymphoma of the Cervical Lymph Nodes in a Human Immunodeficiency Virus–Negative Patient: A Case Report and Review of the Literature

We report a case of plasmablastic lymphoma presenting in cervical lymph nodes in an 82-year-old, human immunodeficiency virus-negative man. Cytologic and histologic examinations demonstrated a large cell lymphoma with plasmacytic differentiation. The tumor cells were positive for CD138, CD38, epithelial membrane antigen, CD30, and lysozyme, but lacked expression of leukocyte common antigen, T-cell, and B-cell markers. Abundant Epstein-Barr virus-encoded RNA transcripts were identified by in situ hybridization. A monoclonal rearrangement of kappa-light- chain gene was demonstrated. The cytologic, histologic, immunohistochemical, and molecular features of plasmablastic lymphoma are reviewed. The potential diagnostic pitfalls and differential diagnoses, especially in a fine-needle aspiration specimen, are addressed.

Immunohistochemical Evaluation of GATA-3 Expression in ER-Negative Breast Carcinomas

OBJECTIVES Estrogen receptor (ER), gross cystic disease fluid protein 15 (GCDFP-15), and mammaglobin (MGB) are commonly used breast-specific immunomarkers; however, about half of metastatic breast carcinomas are negative for all three. GATA-binding protein 3 (GATA-3) has emerged recently as a sensitive and relatively specific immunomarker for breast and urothelial carcinomas, but the data documenting its expression in ER-negative breast carcinomas are limited; this often poses a dilemma in the setting of metastases. The purpose of this study is to investigate expression of GATA-3 in ER-negative breast carcinomas. METHODS Immunohistochemical evaluation of GATA-3, GCDFP-15, and MGB on 96 ER-negative breast carcinomas was performed. RESULTS Overall, 69% (66/96), 15% (14/96), and 35% (34/96) of ER-negative breast carcinomas expressed GATA-3, GCDFP-15, and MGB, respectively. CONCLUSIONS Our data suggest that GATA-3 is, so far, the best breast-specific immunomarker, especially when encountering ER-negative metastatic breast carcinomas. GATA-3 should be included in the panel of immunomarkers in the workup of tumors of unknown primary.

Rectal Pulse Granuloma

Pulse granuloma is a rare benign entity, most likely representing a foreign body reaction to vegetable particles. We report a case of a pulse granuloma involving the rectum. The patient presented with a submucosal and intramuscular mass lesion found at routine rectal examination and subsequent colonoscopy. The mass was excised and the microscopic examination revealed acute and chronic inflammatory cells, foreign-body giant cells, vegetable matter, and convoluted hyaline rings and scattered circular structures containing basophilic granules, consistent with pulse granuloma. There are a few reports in the literature of pulse granulomas, with most occurring in the oral cavity or lungs. To the best of our knowledge, this is the first reported example of pulse granuloma in the rectum. Although rare, familiarity with this entitys distinctive histopathologic features may avoid a delay in diagnosis and prevent the expense of distinguishing it from its histologic lookalikes.

Overview of automated immunohistochemistry.

CONTEXT The increasing demand for immunohistochemistry for clinical diagnostics, in combination with an ongoing shortage of staff in the histology laboratory, has brought about a need for automation in immunohistochemistry. The current automated staining platforms vary significantly in their design and capabilities. OBJECTIVE To review how technology has been applied to automating the process of immunohistochemical staining. DATA SOURCES Literature review, vendor interviews, and personal practice experience. CONCLUSIONS Each of the commercially available, automated immunohistochemistry platforms has strategic design differences that produce advantages and disadvantages. Understanding those differences can help match the demands of testing volumes, turnaround time, standardization, and labor savings to the appropriate automated instrumentation.

Diagnostic utility of von Hippel-Lindau gene product, maspin, IMP3, and S100P in adenocarcinoma of the gallbladder

Our recent study demonstrated the up-regulation of maspin, IMP3, and S100P and down-regulation of von Hippel-Lindau gene product (pVHL) in ductal adenocarcinoma of the pancreas. Distinction of adenocarcinoma of the gallbladder from benign/reactive glandular epithelium can be challenging if based on hematoxylin and eosin-stained sections alone. Immunohistochemical stains for pVHL, maspin, IMP3, and S100P were performed on 82 gallbladder specimens, including adenocarcinoma (n = 33) and normal/reactive gallbladder (n = 49). The results demonstrated (1) only 6.0% of adenocarcinoma cases were focally positive for pVHL, and all normal and most reactive cases (85%) were diffusely positive for pVHL; (2) maspin, IMP3, and S100P were positive in 100%, 81.8%, and 75.8% of adenocarcinoma cases, respectively; in contrast, 53.1%, 12.2%, and 30.6% of normal/reactive cases were only focally and weakly positive for maspin, IMP3, and S100P, respectively; and (3) 90.3% of adenocarcinoma cases were pVHL-negative and positive for 2 or more positive markers, whereas none of the benign/reactive cases showed this staining profile. This study demonstrates that the immunostaining profile of pVHL-/IMP3+/maspin+/S100P+ is useful in the distinction of adenocarcinoma of the gallbladder from normal/reactive conditions.

A Tissue Systems Pathology Assay for High-Risk Barrett's Esophagus

Background: Better methods are needed to predict risk of progression for Barretts esophagus. We aimed to determine whether a tissue systems pathology approach could predict progression in patients with nondysplastic Barretts esophagus, indefinite for dysplasia, or low-grade dysplasia. Methods: We performed a nested case–control study to develop and validate a test that predicts progression of Barretts esophagus to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), based upon quantification of epithelial and stromal variables in baseline biopsies. Data were collected from Barretts esophagus patients at four institutions. Patients who progressed to HGD or EAC in ≥1 year (n = 79) were matched with patients who did not progress (n = 287). Biopsies were assigned randomly to training or validation sets. Immunofluorescence analyses were performed for 14 biomarkers and quantitative biomarker and morphometric features were analyzed. Prognostic features were selected in the training set and combined into classifiers. The top-performing classifier was assessed in the validation set. Results: A 3-tier, 15-feature classifier was selected in the training set and tested in the validation set. The classifier stratified patients into low-, intermediate-, and high-risk classes [HR, 9.42; 95% confidence interval, 4.6–19.24 (high-risk vs. low-risk); P < 0.0001]. It also provided independent prognostic information that outperformed predictions based on pathology analysis, segment length, age, sex, or p53 overexpression. Conclusion: We developed a tissue systems pathology test that better predicts risk of progression in Barretts esophagus than clinicopathologic variables. Impact: The test has the potential to improve upon histologic analysis as an objective method to risk stratify Barretts esophagus patients. Cancer Epidemiol Biomarkers Prev; 25(6); 958–68. ©2016 AACR.

TissueCypher™: A systems biology approach to anatomic pathology

Background: Current histologic methods for diagnosis are limited by intra- and inter-observer variability. Immunohistochemistry (IHC) methods are frequently used to assess biomarkers to aid diagnoses, however, IHC staining is variable and nonlinear and the manual interpretation is subjective. Furthermore, the biomarkers assessed clinically are typically biomarkers of epithelial cell processes. Tumors and premalignant tissues are not composed only of epithelial cells but are interacting systems of multiple cell types, including various stromal cell types that are involved in cancer development. The complex network of the tissue system highlights the need for a systems biology approach to anatomic pathology, in which quantification of system processes is combined with informatics tools to produce actionable scores to aid clinical decision-making. Aims: Here, we describe a quantitative, multiplexed biomarker imaging approach termed TissueCypher™ that applies systems biology to anatomic pathology. Applications of TissueCypher™ in understanding the tissue system of Barretts esophagus (BE) and the potential use as an adjunctive tool in the diagnosis of BE are described. Patients and Methods: The TissueCypher™ Image Analysis Platform was used to assess 14 epithelial and stromal biomarkers with known diagnostic significance in BE in a set of BE biopsies with nondysplastic BE with reactive atypia (RA, n = 22) and Barretts with high-grade dysplasia (HGD, n = 17). Biomarker and morphology features were extracted and evaluated in the confirmed BE HGD cases versus the nondysplastic BE cases with RA. Results: Multiple image analysis features derived from epithelial and stromal biomarkers, including immune biomarkers and morphology, showed significant differences between HGD and RA. Conclusions: The assessment of epithelial cell abnormalities combined with an assessment of cellular changes in the lamina propria may serve as an adjunct to conventional pathology in the assessment of BE.

Pathologic quiz case : Elderly man with bright red blood per rectum

71-year-old white man with no prior history of malignancy and a 2-week history of obstipation, increasing abdominal girth, and abdominal cramping sought medical attention after he began passing bright red blood per rectum. He underwent colonoscopy, which revealed a fungating and hemorrhagic rectosigmoid mass lesion. Shortly after colonoscopy, the patient experienced a rapid decrease in oxygen saturation and required intubation with mechanical respiration. During the next several days, he developed acute renal failure leading to multiple organ system failure and eventually death. Before he died, the patient was sent for computed tomographic scans of the chest, abdomen, and pelvis, which revealed extensive ‘‘metastatic disease’’ involving the lungs, liver, and multiple bony sites. While in radiology, a computed tomographic scan‐guided needle biopsy of a tumor nodule in the bony pelvis was conducted. The needle aspiration slides were relatively hypocellular and contained a mixture of discohesive cells. Some of these cells displayed overt cytologic features of malignancy, including large irregular nuclei and prominent eosinophilic nucleoli (Figure 1). Osteoclast-type giant cells were admixed with the malignant cells. The core biopsy demonstrated a sheetlike expanse of the same malignant cells, some of which possessed long, tapering cytoplasm. A smattering

A Tissue Systems Pathology Test Detects Abnormalities Associated with Prevalent High-Grade Dysplasia and Esophageal Cancer in Barrett's Esophagus

Background: There is a need for improved tools to detect high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barretts esophagus. In previous work, we demonstrated that a 3-tier classifier predicted risk of incident progression in Barretts esophagus. Our aim was to determine whether this risk classifier could detect a field effect in nondysplastic (ND), indefinite for dysplasia (IND), or low-grade dysplasia (LGD) biopsies from Barretts esophagus patients with prevalent HGD/EAC. Methods: We performed a multi-institutional case–control study to evaluate a previously developed risk classifier that is based upon quantitative image features derived from 9 biomarkers and morphology, and predicts risk for HGD/EAC in Barretts esophagus patients. The risk classifier was evaluated in ND, IND, and LGD biopsies from Barretts esophagus patients diagnosed with HGD/EAC on repeat endoscopy (prevalent cases, n = 30, median time to HGD/EAC diagnosis 140.5 days) and nonprogressors (controls, n = 145, median HGD/EAC-free surveillance time 2,015 days). Results: The risk classifier stratified prevalent cases and non-progressor patients into low-, intermediate-, and high-risk classes [OR, 46.0; 95% confidence interval, 14.86-169 (high-risk vs. low-risk); P < 0.0001]. The classifier also provided independent prognostic information that outperformed the subspecialist and generalist diagnosis. Conclusions: A tissue systems pathology test better predicts prevalent HGD/EAC in Barretts esophagus patients than pathologic variables. The results indicate that molecular and cellular changes associated with malignant transformation in Barretts esophagus may be detectable as a field effect using the test. Impact: A tissue systems pathology test may provide an objective method to facilitate earlier identification of Barretts esophagus patients requiring therapeutic intervention. Cancer Epidemiol Biomarkers Prev; 26(2); 240–8. ©2016 AACR.

Improving American Healthcare Through “Clinical Lab 2.0”: A Project Santa Fe Report

Project Santa Fe was established both to provide thought leadership and to help develop the evidence base for the valuation of clinical laboratory services in the next era of American healthcare. The participants in Project Santa Fe represent major regional health systems that can operationalize laboratory-driven innovations and test their valuation in diverse regional marketplaces in the United States. We provide recommendations from the inaugural March 2016 meeting of Project Santa Fe. Specifically, in the transition from volume-based to value-based health care, clinical laboratories are called upon to provide programmatic leadership in reducing total cost of care through optimization of time-to-diagnosis and time-to-effective therapeutics, optimization of care coordination, and programmatic support of wellness care, screening, and monitoring. This call to action is more than working with industry stakeholders on the basis of our expertise; it is providing leadership in creating the programs that accomplish these objectives. In so doing, clinical laboratories can be effectors in identifying patients at risk for escalation in care, closing gaps in care, and optimizing outcomes of health care innovation. We also hope that, through such activities, the evidence base will be created for the new value propositions of integrated laboratory networks. In the very simplest sense, this effort to create “Clinical Lab 2.0” will establish the impact of laboratory diagnostics on the full 100% spend in American healthcare, not just the 2.5% spend attributed to in vitro diagnostics. In so doing, our aim is to empower regional and local laboratories to thrive under new models of payment in the next era of American health care delivery.