The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology.

CONTEXT.­: The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limited. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical markers for newly classified genitourinary neoplasms and their differential diagnosis is needed. OBJECTIVE.­: To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohistochemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnoses and potential pitfalls are discussed. DATA SOURCES.­: Review of current literature and our own experience. CONCLUSIONS.­: Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of the genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.

The Role of the Pathologist in Population Health.

CONTEXT.­: As part of its value-based care initiative, the College of American Pathologists has pursued research to better understand the role pathologists can have in population health. OBJECTIVES.­: To answer the following questions: (1) what is the impact of population health and population health management on pathologists; (2) what roles are pathologists playing in population health management; (3) is population health something that pathologists in both larger and smaller settings can engage in; (4) are pathologists in a position to analyze laboratory data for population health, and, if so, what are the key information sources those pathologists must access; and (5) what steps can a pathologist take to become involved in population health? DESIGN.­: We conducted 10 semistructured interviews with pathologists and other medical laboratory leaders who have been active in population health. These interviews were supplemented with a review of the medical literature. RESULTS.­: Pathologists have demonstrated that laboratory data can provide unique value-added contributions to improving the health of populations. These contributions are not limited to pathologists in large, integrated settings. However, pathologists need to be proactive to contribute to health systems' population health efforts and may need to both enhance their own skills and the quality of their data to maximize the value of their contributions. CONCLUSIONS.­: Although not necessarily a definitive summary of the roles that pathologists are playing in population health, this article identifies some of the promising and innovative activities occurring among pathologists and laboratorians.

Employee Engagement Is Vital for the Successful Selection of a Total Laboratory Automation System.

OBJECTIVE: To concretely outline a process for selecting a total laboratory automation system that connects clinical chemistry, hematology, and coagulation analyzers and to serve as a reference for other laboratories. METHODS: In Phase I, a committee including the laboratory's directors and technologists conducted a review of 5 systems based on formal request for information process, site visits, and vendor presentations. We developed evaluation criteria and selected the 2 highest performing systems. In Phase II, we executed a detailed comparison of the 2 vendors based on cost, instrument layout, workflow design, and future potential. RESULTS: In addition to selecting a laboratory automation system, we used the process to ensure employee engagement in preparation for implementation. CONCLUSION: Selecting a total laboratory automation system is a complicated process. This paper provides practical guide in how a thorough selection process can be done with participation of key stakeholders.

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.

Pathologists' place in the electronic health record landscape.

With growth spurred by recent federal efforts, electronic health records (EHRs) are transforming the practice of medicine and have important implications for pathologists, their laboratories, and the patients they serve. Beyond new EHR-related regulatory requirements, EHRs fundamentally alter the way clinicians interact with laboratory information, including test order entry and result reviewing. This article is the first in a series of 5 related articles whose goal is to provide a "framework" for empowering pathologists to adapt to, and to succeed in, the era of expanding EHR use. This series aims to describe the environment for EHR uptake, to raise awareness of EHR-related issues that pathologists and laboratories face, and to explore new professional roles for pathologists as stewards of patients' laboratory information in EHRs.

Stand-alone laboratory information systems versus laboratory modules incorporated in the electronic health record.

The increasing availability of laboratory information management modules within enterprise electronic health record solutions has resulted in some institutional administrators deciding which laboratory information system will be used to manage workflow within the laboratory, often with minimal input from the pathologists. This article aims to educate pathologists on many of the issues and implications this change may have on laboratory operations, positioning them to better evaluate and represent the needs of the laboratory during this decision-making process. The experiences of the authors, many of their colleagues, and published observations relevant to this debate are summarized. There are multiple dimensions of the interdependency between the pathology laboratory and its information system that must be factored into the decision. Functionality is important, but management authority and gap-ownership are also significant elements to consider. Thus, the pathologist must maintain an active role in the decision-making process to ensure the success of the laboratory.

Management of laboratory data and information exchange in the electronic health record.

In the era of the electronic health record, the success of laboratories and pathologists will depend on effective presentation and management of laboratory information, including test orders and results, and effective exchange of data between the laboratory information system and the electronic health record. In this third paper of a series that explores empowerment of pathology in the era of the electronic health record, we review key elements of managing laboratory information within the electronic health record and examine functional issues pertinent to pathologists and laboratories in the exchange of laboratory information between electronic health records and both anatomic and clinical pathology laboratory information systems. Issues with electronic order-entry and results-reporting interfaces are described, and considerations for setting up these interfaces are detailed in tables. The role of the laboratory medical director as mandated by the Clinical Laboratory Improvement Amendments of 1988 and the impacts of discordance between laboratory results and their display in the electronic health record are also discussed.

Accreditation and regulatory implications of electronic health records for laboratory reporting.

The Clinical Laboratory Improvement Amendments of 1988 include strict regulations for reporting content, and it falls on the named director to ensure that this content is available to the caregiver. With the electronic health record serving as the conduit to the end user of the laboratory data, the laboratory generally, and the director specifically, must verify accurate transmission of these content components. An understanding of regulatory and accreditation requirements is essential both to allow the proper discharge of these mandated responsibilities and to enforce the role and authority that the pathologist must have to ensure that these requirements are satisfied by the reporting system. The regulatory requirements will be discussed in the context of the Clinical Laboratory Improvement Amendments of 1988 standards; however, interpretation and expansion on these regulations exist both in Clinical Laboratory Improvement Amendments of 1988 inspection guidelines from the Centers for Medicare and Medicaid Services and in accreditation program requirements. This regulatory expectation both places the laboratory director in a position of risk and provides leverage to ensure meaningful and accurate communication of laboratory information.

Pathologists as stewards of laboratory information.

Just as electronic health records are transforming the practice of medicine and health care information management, practicing in the era of the electronic health record offers opportunities, if not imperatives, for pathologists to take on new and "transformative" professional and leadership roles for the organizations they serve. Experience indicates that clinicians will perceive pathologists and laboratories as responsible for all aspects of laboratory testing and information management, including order entry and results reporting, even though such functions may fall beyond the control of the laboratory. As described and expanded upon in the previous 4 articles of this series, the use of electronic health records dictates changes in how clinicians interact with laboratory information. In this environment, pathologists are uniquely positioned to act as the stewards for laboratory information in electronic health records and throughout health care organizations.

The application of immunohistochemical biomarkers in urologic surgical pathology.

CONTEXT: Tumors of the genitourinary tract can be diagnostically challenging, particularly in core biopsies and cystoscopic biopsies with limited material. Immunohistochemistry is a valuable tool to use when morphology alone is insufficient for diagnosis. OBJECTIVES: To review tumors and benign lesions of the kidney, urinary bladder, prostate gland, testis, and paratesticular structures with an emphasis on difficult differential diagnoses, as well as staining patterns in normal tissue. Recommended immunohistochemical stain panels are discussed that can assist in the diagnostic workup. DATA SOURCES: Review of current literature. CONCLUSIONS: Immunohistochemistry is a valuable tool, assisting in the diagnosis of problematic tumors and benign lesions of the genitourinary tract.

Fresh frozen plasma as a source of cholesterol for newborn with Smith-Lemli-Opitz syndrome associated with defective cholesterol synthesis.

The Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive condition that is characterized by a mutation in the DHCR7 encoding the 7-dehydrocholesterol-Δ7 reductase, the enzyme that catalyzes the last step in cholesterol biosynthesis. The syndrome occurs in 1:20,000 newborns with an estimated gene carrier frequency in US Caucasian population of 1 to 2%. The severe form of SLOS in newborns leads to multiple malformations and mental retardation. The malformations present were facial dysmorphisms, cleft palate, congenital heart disease, genitourinary abnormalities, and syndactyly of the toes. The identification of the biochemical basis of SLOS has led to the development of therapeutic regimes based on dietary cholesterol supplementation. In this case report, we present a case of SLOS that was treated by fresh frozen plasma to increase the level of serum Cholesterol since oral and rectal cholesterol replacement was not possible in this instance.

Immunohistochemical evaluation of ERG expression in various benign and malignant tissues.

The transmembrane protease, serine 2-E twenty-six related gene (TMPRSS2-ERG) fusion leading to ERG overexpression, was detected in approximately 50% of prostate cancers (ranging from 35-70%). However, the published data on ERG expression in tumors from other organs and normal tissues were limited. In this study, we investigated the expression of ERG in TMA sections of various normal tissues (N=452) and carcinomas (N=1,129) from various organs, including 90 cases of low to intermediate-grade (L-MG) prostatic adenocarcinomas and 36 cases of high-grade (HG) prostatic adenocarcinomas, using a single immunostaining system (Dako). Also included were prostatic biopsies of radiation atypia (N=20), atrophy (N=20), and high-grade prostatic intraepithelial lesion (HGPIN) (N=18). ERG expression was detected in 44% (40/90) of L-MG prostatic adenocarcinomas; in 22% (8/36) of HG prostatic adenocarcinomas; and in 22% (4/18) of HGPIN. No ERG expression was detected in non-prostate carcinomas, normal tissues including prostate and seminal vesicles, benign prostatic tissue with radiation atypia, and atrophy. Our data demonstrate that ERG is a highly specific marker, which may have important implications in the interpretation of prostate biopsies with limited cancers. In addition, its high diagnostic specificity may be useful in identifying a prostatic primary when working on a tumor of uncertain origin. Partly presented at the United States and Canadian Academy of Pathology Annual Meeting in March 2011.

Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas.

GATA3 expression has been reported in urothelial and breast carcinomas; however, the published data on GATA3 expression in tumors from other organs are limited. Immunohistochemical evaluation of GATA3 expression in 1,110 carcinomas and 310 cases of normal tissue using tissue microarray sections, 48 breast and bladder biopsy specimens, and 53 breast fine-needle aspiration biopsy specimens was performed. Sixty-two of 72 urothelial carcinomas (86%) and 138 of 147 breast carcinomas (94%) tested positive for GATA3. All other cases, except for 2 of 96 endometrial carcinomas, tested negative for GATA3. On fine-needle aspiration biopsy samples, 88% of primary breast carcinomas and 82% of metastatic breast carcinomas tested positive for GATA3. Our study revealed that GATA3 is a sensitive and specific marker for the diagnosis of breast and urothelial carcinomas. When working on a tumor of unknown origin, GATA3 should be routinely included in the initial screening panel if either a breast or urothelial primary tumor is suspected.

Expression of von Hippel-Lindau gene product (pVHL) and S100P in cystic neoplasms of the pancreas--with an implication for their roles in tumorigenesis.

Our recent study demonstrated the inverse correlation of expression of S100P and von Hippel-Lindau gene product (pVHL) in pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA). This study investigates whether there is a correlation of expression of these two markers in common cystic neoplasms of the pancreas. Immunohistochemical stains for S100P and pVHL were performed on 97 cystic neoplasms of the pancreas, including 23 mucinous cystic neoplasms (MCNs), 39 intraductal papillary mucinous neoplasms (IPMNs), 12 solid pseudopapillary tumors (SPTs), and 23 serous microcystic adenomas (SMAs). The results demonstrated a nuclear and cytoplasmic staining pattern of S100P in 91.3% of MCNs and 100% of IPMNs. In contrast, none of the SPTs or SMAs was positive for S100P. All IPMNs and SPTs, and all S100P-expressing MCNs were negative for pVHL, including 20 MCNs and 20 IPMNs with low-grade dysplasia. All cases of SMA were positive for pVHL. Our data suggest 1) the inverse correlation of expression of S100P and pVHL in MCN and IPMN is similar to that in PanIN and PDA, suggesting a role of these two proteins in early tumorigenesis; 2) the loss of pVHL expression in MCN and IPMN supports the recent recategorization of these neoplasms without any cytological atypia as low-grade dysplasia instead of adenoma; 3) the loss of expression of pVHL in SPT supports the concept of an uncertain malignant potential of this entity; and 4) the lack of expression of S100P and expression of pVHL in SMA supports the benign nature of this entity.

Informatics tools for quality in anatomic pathology.

This article reviews three informatics tools developed as part of an overall quality program in an anatomic pathology laboratory. These tools include a tracking monitor for analyzing the entire testing process through pre-analytic, analytic, and postanalytic phases; the use of digital imaging in quality control of immunohistochemistry in the analytic phase; and a results-reporting monitor for flow of postanalytic data to patient data repositories.

Usefulness of S100P in diagnosis of adenocarcinoma of pancreas on fine-needle aspiration biopsy specimens.

Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.

Histologic evaluation of the testicular remnant associated with the vanishing testes syndrome: is surgical management necessary?

OBJECTIVES: There is controversy surrounding the optimal management of the testicular remnant associated with the vanishing testes syndrome. Some urologists advocate the need for surgical exploration, whereas others believe this is unnecessary. These differing opinions are based on the variable reports of viable germ cell elements found within the testicular remnants. To better understand the pathology associated with this syndrome and the need for surgical management, we reviewed our experience regarding the incidence of viable germ cell elements within the testicular remnant. METHODS: An institutional review board-approved, retrospective review was performed of all consecutive patients undergoing exploration for a nonpalpable testis at Eastern Virginia Medical School and Geisinger Medical Center between 1994 and 2006. Patients who were found to have spermatic vessels and a vas deferens exiting a closed internal inguinal ring were included in this analysis. RESULTS: Fifty-six patients underwent removal of the testicular remnant. Patient age ranged from 11 to 216 months. In 8 of the specimens (14%), we identified viable germ cell elements. In an additional 4 patients (7%), we identified seminiferous tubules without germ cell elements. CONCLUSIONS: In our review, we identified that a significant number of testicular remnants associated with the vanishing testes syndrome can harbor viable germ cell elements or seminiferous tubules. The exact fate of these residual elements remains unknown; however, there may exist the potential for malignant transformation. Given the potential for malignant degeneration, we believe that these remnants should be removed.