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* Context.--Digital pathology using whole slide images has been recently approved to support primary diagnosis in clinical surgical pathology practices. Here we describe a novel imaging method, fluorescence-imitating brightfield imaging, that can capture the surface of fresh tissue without requiring prior fixation, paraffin embedding, tissue sectioning, or staining. Objective.--To compare the ability of pathologists to evaluate direct-to-digital images with standard pathology preparations. Design.--One hundred surgical pathology samples were obtained. Samples were first digitally imaged, then processed for standard histologic examination on 4-im hematoxylin-eosin-stained sections and digitally scanned. The resulting digital images from both digital and standard scan sets were viewed by each of 4 reading pathologists. The data set consisted of 100 reference diagnoses and 800 study pathologist reads. Each study read was compared to the reference diagnosis, and also compared to that reader's diagnosis across both modalities. Results.--The overall agreement rate, across 800 reads, was 97.9%. This consisted of 400 digital reads at 97.0% versus reference and 400 standard reads versus reference at 98.8%. Minor discordances (defined as alternative diagnoses without clinical treatment or outcome implications) were 6.1% overall, 7.2% for digital, and 5.0% for standard. Conclusions.--Pathologists can provide accurate diagnoses from fluorescence-imitating brightfield imaging slide-free images. Concordance and discordance rates are similar to published rates for comparisons of whole slide imaging to standard light microscopy of glass slides for primary diagnosis. It may be possible, therefore, to develop a slide-free, nondestructive approach for primary pathology diagnosis., While in vivo methods for disease detection and classification, including radiology and liquid biopsy, continue to improve with respect to spatial resolution (radiology) and molecular information, they have not, to [...]

Context.--Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.Objective.--To provide updated, practical guidelines for the pathologic diagnosis of MM.Data Sources.--Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks.Conclusions.--There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of mM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.(Arch Pathol Lab Med. 2018;142:89-108; doi: 10.5858/arpa.2017-0124-RA), The pathologic diagnosis of malignant mesothelioma (MM) continues to evolve and be refined as more antibodies and molecular tests become available for general use. This is especially applicable to distinguishing [...]

Context.--There are a number of critical factors that can lead to incorrect results if the diagnostic pathologist performing immunohistochemistry is unaware of, or not vigilant about, their influence. Objective.--To highlight 3 arenas in which errors may be introduced. Data Sources.--For choosing the correct primary antibody, selection of the most appropriate antibodies for a given clinical application can be aided by obtaining information from the vendor; however, this can yield incomplete information. There are a number of online databases that have comparisons of antibodies from different vendors, particularly with respect to their use and properties. Reading the published literature can assist in this process, particularly with respect to determining antibody sensitivity and specificity, but it is a daunting task to keep up with all of the immunohistochemistry-related papers published. Finally, Web sites of a number of quality assurance organizations are accessible and can provide a wealth of information comparing the 'real world' performance characteristics of different antibodies to the same target protein. False-positive signals can result from a number of factors, including the use of inappropriately high antibody concentration, and 'pseudospecific' signal that is in the wrong compartment of the cell. False-negative signal can result from factors such as use of a nonoptimized epitope retrieval method. It is critical that epitope retrieval methods be optimized for each antibody employed in the laboratory. Conclusions.--By paying attention to these potential problems, the 'black box' of diagnostic immunohistochemistry can be made more transparent. (Arch Pathol Lab Med. 2016; 140:893-898; doi: 10.5858/arpa.2016-0119-RA), The great British science fiction writer, inventor, and futurist Arthur C. Clarke noted that 'any sufficiently advanced technology is indistinguishable from magic.' (1) Immunohistochemistry (IHC), a technique invented in the [...]

Context.--Identification of the site of origin of carcinoma of unknown primary using immunohistochemistry is a frequent requirement of anatomic pathologists. Diagnostic accuracy is crucial, particularly in the current era of targeted therapies and smaller sample sizes. Objectives.--To provide practical guidance and suggestions for classifying carcinoma of unknown primary using both proven and new antibodies, as well as targeting panels based on integration of morphologic and clinical features. Data Sources.--Literature review, the authors' practice experience, and authors' research. Conclusions.--With well-performed and interpreted immunohistochemistry panels, anatomic pathologists can successfully identify the site of origin of carcinoma of unknown primary. It is crucial to understand not only the diagnostic uses of the many available antibodies but also the potential limits and pitfalls. (Arch Pathol Lab Med. 2016; 140:508-523; doi: 10.5858/arpa.2015-0173-CP), It is estimated that approximately 4% of all patients with cancer present with carcinomas of unknown primary (CUPs), representing a higher incidence than known malignancies such as non-Hodgkin lymphoma or [...]

Context.--Numerous immunohistochemical stains have been shown to exhibit exclusive or preferential positivity in breast myoepithelial cells relative to their luminal/epithelial counterparts. These myoepithelial markers provide invaluable assistance in accurately classifying breast proliferations, especially in core biopsies. Although numerous myoepithelial markers are available, they differ in their sensitivity, specificity, and ease of interpretation, which may be attributed, to a large extent, to the variable immunoreactivity of these markers in stromal cells including myofibroblasts, vessels, luminal/epithelial cells, and tumor cells. Objective.--To review commonly used myoepithelial markers in breast pathology and a selection of diagnostic scenarios where they may be useful. Data Sources.--The information outlined in this review article is based on our experiences with routine cases and a review of English-language articles published between 1987 and 2008. Conclusions.--To demonstrate the presence or absence of myoepithelial cells, a panel-based approach of 2 or more markers is recommended. Markers that most effectively combine sensitivity, specificity, and ease of interpretation include smooth muscle myosin heavy chains, calponin, p75, p63, P-cadherin, basal cytokeratins, maspin, and CD10. These markers, however, display varying cross-reactivity patterns and variably reduced expression in the myoepithelial cells bordering in situ carcinomas. The choice of a myoepithelial marker should be dependent on a combination of factors, including published evidence on its diagnostic utility, its availability, performance characteristics that have been achieved in a given laboratory, and the specific diagnostic scenario. When its use is deemed necessary, immunohistochemistry for myoepithelial cells in breast pathology is most effective when conceptualized as supplemental, rather than central to routine morphologic interpretation., At the light microscopic level, 2 distinct cell populations can be recognized lining the human mammary ductal and terminal ductolobular units: a luminally located layer of polarized epithelial cells and [...]

* Context.--Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. Objective.--To develop practical guidelines for the pathologic diagnosis of MM. Data Sources.--A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting. Conclusions.--There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the differential diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist. (Arch Pathol Lab Med. 2009;133:1317-1331), As part of the International Mesothelioma Interest Group biennial meeting held in Chicago (October 2006), there was a pathology half-day workshop that included invited lecturers and an open forum on [...]

* Context.--Immunohistochemistry plays a crucial role in the diagnosis of hepatocellular carcinoma and in its distinction from other primary and metastatic neoplasms. Because limited tissue is available with fine-needle and core biopsies, appropriate selection of antibodies is imperative. Objective.--To review the antibodies used for the diagnosis of hepatocellular carcinoma and to outline an immunohistochemical approach in commonly encountered clinical situations. Data Sources.--Our experience and review of research articles published in the English literature between 1987 and 2006. Conclusions.--Hep Par 1 and polyclonal carcinoembryonic antigen are the most reliable markers for hepatocellular differentiation, but they have low sensitivity for poorly differentiated cases. Immunohistochemistry for glypican-3 shows promise for the diagnosis of poorly differentiated hepatocellular carcinoma and for its distinction from benign processes such as hepatic adenoma. Further studies with a large number of cases are required before it can be widely used. The combination of Hep Par 1 and MOC-31 will allow for the diagnosis of hepatocellular carcinoma in most cases and will guide the selection of immunohistochemical markers for further workup. (Arch Pathol Lab Med. 2007;131:1648-1654), The distinction of hepatocellular carcinoma (HCC) and other neoplasms involving the liver can be difficult and is especially challenging in core and fine-needle aspiration biopsies. Several immunohistochemical markers are available [...]

* Background.--Renal angiomyolipoma is a benign tumor histologically characterized by proliferation of spindle cells, epithelioid cells, and adipocytic cells in concert with many thick-walled blood vessels. To add further diagnostic confusion, an epithelioid cell-predominant variant of renal angiomyolipoma has recently been described. HMB-45 immunoreactivity correlates with ultrastructural striated organelles that closely resemble premelanosomes, although no evidence of melanogenesis has been documented in this tumor. Objective.--To further characterize the immunopheno. typic and ultrastructural profile of renal angiomyolipoma based on phenotypic cell type (epithelioid, spindle, and adipocytic cell). Design.--Formalin.fixed, paraffin-embedded tissues from 27 renal angiomyolipomas and 8 renal cell carcinomas were immunostained with monoclonal antibodies to the melanoma-associated antigens HMB-45, HMB-50, NKI/C3 (CD63), and tyrosinase; the smooth muscle-related antigens calponin and muscle-specific actin (HHF-35); S100; and cytokeratin (CK). All renal angiomyolipomas were also immunostained with a polyclonal antibody to renin. Ultrastructural examination was performed on 9 selected cases. Results.--All renal angiomyolipomas stained positive for HMB-45, HMB-50, NKI/C3, muscle-specific actin (HHF35), and calponin. Overall, HMB-45, HMB-50, and NKI/ C3 preferentially stained the epithelioid cells. Tyrosinase staining was present in 50% of the renal angiomyolipomas with adequate tissue for staining (12 of 24 cases); positive staining and intensity paralleled HMB.45, HMB-50, and NKI/C3. Muscle-specific actin (HHF.35) and calponin preferentially stained the spindle cells. The adipocytic cells stained positive for both melanoma-associated antigens and smooth muscle antigens. Epithelioid cells, spindle cells, and adipocytic cells were CK, S100, and renin negative. Ultrastructural findings paralleled immunohistochemical staining patterns. Premelanosome-like organelles and electron dense granules were more readily detected in the epithelioid cells within the tumor, whereas ultrastructural characteristics of smooth muscle cells were more easily found in the spindle cells. All renal cell carcinomas stained positive for CK, NKI/C3 staining was variable, and all were negative for HMB-45, HMB-50, smooth muscle actin (HHF-35), and calponin. Conclusion.--In renal angiomyolipoma, the epithelioid and spindle cells have preferential staining patterns for melanoma-associated antigens versus smooth muscle antigens, respectively. Positivity in renal angiomyolipoma for HMB-50, NKI/C3, and tyrosinase, in addition to HMB-45, provides evidence for the presence of different melanoma-associated gene products. Immunophenotypic overlap of the 3 histologically distinct renal angiomyolipoma cell populations suggests a common cell line, supporting a unitarian concept for renal angiomyolipoma. Ultrastructural characteristics of the 3 renal angiomyolipoma cell phenotypes parallel the immunophenotype, giving further support to a common cell line. Our study lends further credence to the perivascular epithelioid cell concept as proposed by Bonetti and colleagues. (Arch Pathol Lab Med. 2001 ;125:751-758), Renal angiomyolipoma is an unusual, generally benign tumor that has been associated with tuberous sclerosis and is characterized by a histologic triad of tortuous, thick-walled blood vessels, phenotypic smooth muscle [...]