bluuebunny/crossref_metadata_2025 huggingface dataset:
Fascin Expression in Diffuse Large B-Cell Lymphoma, Anaplastic Large Cell Lymphoma, and Classical Hodgkin Lymphoma
Authors: Bakshi Nasir A. , Finn William G. , Schnitzer Bertram , Valdez Riccardo , Ross Charles W.
Published: February 2021

Context.—Fascin is an actin-bundling protein involved in the formation of dendritic processes. Fascin is a sensitive marker for classical Reed-Sternberg cells and has a high negative predictive value for diagnosis of classical Hodgkin lymphoma (CHL). Fascin has been used to distinguish CHL from non-Hodgkin lymphoma. Recently, it was shown that fascin might not help differentiate CHL from anaplastic large cell lymphoma (ALCL). Moreover, fascin has not been extensively studied in the context of other large cell lymphomas.

Objective.—To analyze fascin expression in diffuse large B-cell lymphoma (DLBCL) and also reexamine its usefulness in discriminating CHL from ALCL.

Design.—Formalin-fixed, paraffin-embedded tissue samples from 41 cases of DLBCL, 30 cases of CHL, and 30 cases of ALCL were analyzed. Fascin expression was compared across each type of lymphoma with additional correlation between fascin positivity and ALK-1 expression in ALCL performed.

Results.—Only 6 (14.6%) of 41 cases of DLBCL stained positively for fascin, with most neoplastic large cells exhibiting a weak staining pattern. Fifteen (50%) of 30 cases of ALCL showed positivity for fascin, with most large cells staining strongly. All 30 cases of CHL demonstrated intense positive staining. Sixty percent of fascin-positive ALCLs were positive for ALK-1, while 66.7% of fascin-negative ALCLs were positive for ALK-1.

Conclusions.—Fascin is highly sensitive for CHL and has a very high negative predictive value (100% in this series) for distinguishing CHL from DLBCL or ALCL. However, the specificity and positive predictive value for fascin are much higher in distinguishing CHL from DLBCL than in distinguishing CHL from ALCL. Expression of fascin appears more useful in the differential diagnosis of CHL versus DLBCL than in the differential diagnosis of CHL versus ALCL.
The Value of CD64 Expression in Distinguishing Acute Myeloid Leukemia With Monocytic Differentiation From Other Subtypes of Acute Myeloid Leukemia: A Flow Cytometric Analysis of 64 Cases
Authors: Dunphy Cherie H. , Tang Wohzan
Published: February 2021

Context.—Flow cytometric immunophenotyping is a useful ancillary tool in the diagnosis and subclassification of acute myeloid leukemias (AMLs). A recent study concluded that CD64 is sensitive and specific for distinguishing AMLs with a monocytic component (ie, AML M4 and AML M5) from other AML subtypes. However, in that study, the intensity of CD64 was not well defined and the number of non-M4/non-M5 AMLs was small.

Objective.—To evaluate the usefulness of CD64 by flow cytometric immunophenotyping in distinguishing AMLs with monocytic differentiation from other AML subtypes.

Design.—Sixty-four AMLs subclassified based on the French-American-British and World Health Organization classifications on pretreatment bone marrows were retrieved from our files (7 M0s, 11 M1s, 17 M2s, 7 M3s, 9 M4s, 7 M5s, 4 M6s, and 2 M7s). A standard panel of markers, including CD2, CD3, CD5, CD7, CD10, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD45, CD56, CD64, CD117, and HLA-DR, were analyzed by flow cytometric immunophenotyping in all AMLs (52 bone marrow samples; 12 peripheral blood samples).

Results.—CD64 was expressed in AML subtypes M0 to M5 in varying intensities: heterogeneously expressed in 1 of 7 M0s; dimly expressed in 3 of 11 M1s; dimly and moderately expressed in 6 and 2 of 17 M2s, respectively; dimly and moderately expressed in 5 and 1 of 7 M3s, respectively; dimly expressed in 4 of 9 M4s; and heterogeneously, moderately, and strongly expressed in 1, 3, and 3 of 7 M5s, respectively.

Conclusions.—Strong CD64 expression distinguishes AML M5; however, heterogeneous, dim, or moderate expression in itself does not distinguish M0 through M4 subtypes from M5 with dim to moderate CD64 expression. However, any CD64 expression associated with strong CD15 expression distinguishes AML M4 or M5, from other AML subtypes.
Comparison of Fungal Culture Versus Surgical Pathology Examination in the Detection of Histoplasma in Surgically Excised Pulmonary Granulomas
Authors: Weydert Jamie A. , Van Natta Timothy L. , DeYoung Barry R.
Published: February 2021

Context.—Granulomatous pulmonary nodules are common in areas endemic for Histoplasma infection, and may require surgical excision to exclude neoplasia. Surgeons may elect to routinely send material directly to the clinical microbiology laboratory for fungal and mycobacterial cultures.

Objective.—To determine if tissue from surgically excised pulmonary granulomatous nodules removed from patients in a geographic area endemic for Histoplasma infection should be routinely submitted for fungal culture.

Design.—Retrospective review and comparison of surgical pathology histochemical findings and clinical microbiology results of 30 surgical (wedge) lung excisions that demonstrated granulomatous nodule at the time of frozen section.

Results.—Twenty cases demonstrated fungal organisms consistent with Histoplasma species via histochemical fungal stains. Of these 20 cases, 17 were tested in the microbiology laboratory using direct smear examination and fungal culture; Histoplasma was detected in 1 case (1/17). Eight cases revealed no organisms by surgical pathology. Of these, 6 were tested in the microbiology laboratory, and all 6 were negative by culture and direct smear (0/6). The remaining 2 cases demonstrated organisms other than Histoplasma by surgical pathology examination.

Conclusions.—Surgical pathology examination of granulomatous pulmonary nodules detected Histoplasma organisms with greater sensitivity than culture and direct smear. There were no false-negative surgical pathology diagnoses when compared with microbiological results. These findings suggest that it is not necessary to routinely send material from solitary pulmonary granulomas for fungal culture when the material is removed from immunocompetent patients in a geographic area endemic for histoplasmosis.
Clinical Laboratory Reports in Molecular Pathology
Authors: Gulley Margaret L. , Braziel Rita M. , Halling Kevin C. , Hsi Eric D. , Kant Jeffrey A. , Nikiforova Marina N. , Nowak Jan A. , Ogino Shuji , Oliveira Andre , Polesky Herbert F. , Silverman Lawrence , Tubbs Raymond R. , Van Deerlin Vivianna M. , Vance Gail H. , Versalovic James
Published: February 2021

Context.—Molecular pathology is a rapidly growing area of laboratory medicine in which DNA and RNA are analyzed. The recent introduction of array technology has added another layer of complexity involving massive parallel analysis of multiple genes, transcripts, or proteins.

Objective.—As molecular technologies are increasingly implemented in clinical settings, it is important to bring uniformity to the way that test results are reported.

Data Sources.—The College of American Pathologists Molecular Pathology Resource Committee members summarize elements that are already common to virtually all molecular pathology reports, as set forth in the College of American Pathologists checklists used in the laboratory accreditation process. Consensus recommendations are proposed to improve report format and content, and areas of controversy are discussed. Resources are cited that promote use of proper gene nomenclature and that describe methods for reporting mutations, translocations, microsatellite instability, and other genetic alterations related to inherited disease, cancer, identity testing, microbiology, and pharmacogenetics.

Conclusions.—These resources and recommendations provide a framework for composing patient reports to convey molecular test results and their clinical significance to members of the health care team.
Hyperhomocysteinemia and Thrombosis: An Overview
Authors: Eldibany Mohamed M. , Caprini Joseph A.
Published: February 2021

Context.—Homocysteine, a sulfur-containing amino acid, absent in natural diets, is a metabolic intermediary in transmethylation and transsulfuration reactions. Such reactions are essential to normal cellular growth, differentiation, and function. Excess homocysteine is associated with vascular disease and related disorders.

Objective.—To review homocysteine metabolism, the pathogenesis and classification of hyperhomocysteinemia, and the published literature investigating the association of homocysteine and methylenetetrahydrofolate reductase defects with arterial and venous thromboembolism and related disorders. The role of vitamin supplementation in patients with hyperhomocysteinemia is addressed.

Data Sources.—Published medical and scientific literature. Articles addressing the objectives were selected and reviewed. Pertinent studies and conclusions were summarized, grouped, and contrasted.

Conclusions.—The association of hyperhomocysteinemia and arterial and venous thrombosis is controversial. Severe hyperhomocysteinemia is associated with atherosclerosis. The effect of mild hyperhomocysteinemia is less certain. Coinheritance of methylenetetrahydrofolate reductase defects and factor V Leiden is likely to increase the risk of venous thromboembolism. The association of methylenetetrahydrofolate reductase defects combined with no additional thrombophilic risk factors with venous thrombosis is less clear. High doses of folic acid to lower homocysteine levels might not be necessary.
Sclerosing Angiomatoid Nodular Transformation of the Spleen
Authors: Awamleh Ahlam A. , Perez-Ordoñez Bayardo
Published: February 2021

Sclerosing angiomatoid nodular transformation (SANT) is a recently recognized nonneoplastic vascular lesion of the spleen with fewer than 30 cases described. Microscopically, SANT consists of multiple well-circumscribed vascular/ angiomatoid nodules showing plump endothelial cell and extravasated erythrocytes. The nodules are surrounded by a variable lymphoplasmacytic infiltrate, spindle cells, and collagenous stroma. The vascular nodules display a complex mixture of endothelial phenotypes resembling splenic sinusoids (CD34−/CD31+/CD8+), capillaries (CD34+/ CD31+/CD8−), and small veins (CD34−/CD31+/CD8−). Focal expression of CD68 can also be seen. The differential diagnosis of SANT includes splenic hamartoma, inflammatory myofibroblastic tumor, littoral cell angioma, and hemangioendothelioma. It has been postulated that SANT represents a peculiar hamartomatous transformation of splenic red pulp in response to an exaggerated nonneoplastic stromal proliferation. SANT has a benign clinical course with splenectomy being curative.
Gastrointestinal Stromal Tumors: A Review of the Literature
Authors: Laurini Javier A. , Carter J. Elliot
Published: February 2021

Gastrointestinal stromal tumors are mesenchymal neoplasms with a spectrum of histologic appearances and biologic activity. The morphologic classification of these lesions has evolved over time, and molecular analysis has led to a better understanding of their nature. The histologic differential diagnosis for these lesions is broad and includes many spindle cell lesions of the gastrointestinal tract, including neoplasms of true smooth muscle and neural origin, proliferating fibrous lesions, metastatic neoplasms, and primary sarcomas of vascular and adipose origin. Immunohistochemical studies that include CD117 have become invaluable in the classification of mesenchymal lesions arising in the gastrointestinal tract. Treatment of gastrointestinal stromal tumors has historically been involved surgery, but the use of the chemotherapeutic agent imatinib mesylate for advanced disease has made accurate classification even more important. The molecular features have not only allowed us to understand the pathogenesis of these tumors but also have proven to be associated with response to kinase inhibitors.
Initial Margin Status for Invasive Ductal Carcinoma of the Breast and Subsequent Identification of Carcinoma in Reexcision Specimens
Authors: Skripenova Silvia , Layfield Lester J.
Published: February 2021

Context.

Margin status of lumpectomy specimens is related to frequency of local recurrence. Optimal surgical technique requires microscopic margins free of carcinoma by at least 2 mm. Recurrence following lumpectomy is associated with residual carcinoma secondary to inadequate resection.

Objective.

To review our series of breast excisions to determine the frequency of residual carcinoma for positive, close, and negative margins.

Design.

We reviewed lumpectomies and excisional biopsies for invasive ductal carcinoma that had subsequent reexcisions. Margin status of specimens was recorded as positive, less than 1 mm, 1 to 2 mm, or greater than 2 mm.

Results.

A total of 123 lumpectomies and excisional biopsies of invasive ductal carcinoma with reexcision were reviewed. Residual invasive carcinoma was found in 44% (17), 25% (6), 28% (8), and 16% (5) of cases with positive, less than 1 mm, 1 to 2 mm, and greater than 2 mm margins, respectively. Residual invasive carcinomas were found in 57% (8), 100% (5), 67% (2), and 100% (2) of mastectomies with positive, less than 1 mm, 1 to 2 mm, and greater than 2 mm margins, respectively, in the initial lumpectomy or excisional biopsy.

Conclusions.

Frequency of residual invasive carcinoma was related to margin status of the original lumpectomy/biopsy. Even when margins were positive, most reexcisions were free of carcinoma. Residual invasive carcinoma was found in greater than 25% of patients with margins less than 2 mm, supporting reexcision for patients with margins of less than 2 mm. Sixteen percent of cases with margins greater than 2 mm harbored residual invasive carcinoma. Evaluation of margin status was complicated by tissue distortion and fragmentation.
Tumor-to-Tumor Metastasis: Report of 2 Cases of Metastatic Carcinoma to Angiomyolipoma of the Kidney
Authors: Ricketts Reva , Tamboli Pheroze , Czerniak Bogdan , Guo Charles C.
Published: February 2021

Tumor-to-tumor metastasis is a rare phenomenon. Renal cell carcinoma is the most common recipient of tumor-to-tumor metastasis in malignant tumors. However, renal angiomyolipoma has not been reported to be a recipient. Here we report 2 cases of tumor-to-tumor metastasis to renal angiomyolipoma. In one case, the donor tumor originated from neuroendocrine carcinoma of the pancreas, and in the other case the donor tumor was from adenocarcinoma of the lung. The donor tumors showed morphologic features that did not easily fit into renal angiomyolipoma, and they also demonstrated patterns of immunoreactivity consistent with the primary tumors rather than with renal angiomyolipoma. To our knowledge, these are the first reported cases of tumor-to-tumor metastasis to renal angiomyolipoma. An awareness of this phenomenon is important to avoid an incorrect diagnosis when encountering unusual morphologic features in renal angiomyolipoma.
Concurrent Megakaryocytic and Erythroid Chronic Myelogenous Leukemia Blast Crisis
Authors: Westfall Danielle E. , Zhang Ling , Song Sophie , Lee Stephen
Published: February 2021

Chronic myelogenous leukemia with blast crisis is seen in 15% to 20% of patients with chronic myelogenous leukemia. Chronic myelogenous leukemia with either erythroid or megakaryocytic blast crisis is not uncommon in the clinical setting. The incidence ranges from 0% to 33% in accordance with literature reports. The diagnosis of erythroid or megakaryocytic blast phase is often challenging because the percentage of blasts in the blood or bone marrow required for diagnosis has not been firmly established. Also, some myeloblasts can have aberrant expression of either erythroid or megakaryocytic markers by flow cytometry during clonal evolution. Early recognition of this entity is crucial because either megakaryocytic or erythroid blast crisis predicts an aggressive clinical course. To our knowledge, the coexistence of megakaryocytic and erythroid blasts has not been reported. We report a unique case of chronic myelogenous leukemia with this rare bilineage blast crisis in the background of dysplasia and marked myelofibrosis. Related literature is also reviewed.
Benign Tumors and Tumorlike Conditions of the Lung
Authors: Borczuk Alain C.
Published: February 2021

Context.—Benign tumors and tumorlike conditions of the lung are encountered in the pathologic evaluation of asymptomatic and symptomatic lung nodules. Since many of these lesions are uncommon, they can be diagnostically challenging.

Objective.—To review the current classification of benign lung tumors, with emphasis on histopathology and useful ancillary studies.

Data Sources.—The current World Health Organization classification system for lung neoplasms and review of relevant publications.

Conclusions.—Despite improved imaging techniques, benign lung nodules are encountered in wedge biopsy and resection specimens. Histopathology, immunohistochemistry, and molecular techniques ensure accurate pathologic diagnosis and have shed light on the histogenesis of these unusual lesions.
Primary Pleural Neoplasia: Entities Other Than Diffuse Malignant Mesothelioma
Authors: Guinee Donald G. , Allen Timothy Craig
Published: February 2021

Context.—Overwhelmingly, the most common neoplasm involving the pleura is metastatic carcinoma. In contrast, diffuse malignant mesothelioma occurs relatively rarely; however, it is nonetheless the most common neoplasm primary to the pleura. Metastatic carcinoma and diffuse malignant mesothelioma each have their own prognostic and therapeutic characteristics. Other primary pleural neoplasms occur uncommonly or rarely, with their own prognostic and therapeutic characteristics.

Objective.—To review primary pleural neoplasms other than diffuse malignant mesothelioma, to better ensure correct diagnosis and optimal assessment of prognosis and treatment.

Data Sources.—Literature review and primary material from the authors' institutions.

Conclusions.—A nonexhaustive group of uncommon to rare benign and malignant primary pleural neoplasms— other than diffuse malignant mesothelioma—are presented, of which one must be aware in order to maintain an appropriate index of suspicion to include them in the differential diagnosis of a pleural tumor.
Lesions of the Adrenal Cortex
Authors: McNicol Anne Marie
Published: February 2021

Context.—In surgical pathology practice adrenal cortical tumors are rare. However, in autopsy series adrenal cortical nodules are found frequently. These are now being identified more commonly in life when the abdomen is scanned for other disease. It is important to differentiate between benign and malignant lesions as adrenal cortical carcinoma is an aggressive tumor. Molecular genetic investigations are providing new information on both pathogenesis of adrenal tumors and basic adrenal development and physiology.

Objective.—To provide an overview of current knowledge on adrenal cortical development and structure that informs our understanding of genetic diseases of the adrenal cortex and adrenal cortical tumors.

Data Sources.—Literature review using PubMed via the Endnote bibliography tool.

Conclusions.—The understanding of basic developmental and physiologic processes permits a better understanding of diseases of the adrenal cortex. The information coming from investigation of the molecular pathology of adrenal cortical tumors is beginning to provide additional tests for the assessment of malignant potential in diagnosis but the mainstay remains traditional histologic analysis.
Pheochromocytoma and Extra-adrenal Paraganglioma: Updates
Authors: Tischler Arthur S.
Published: February 2021

Context.—Advances in genetics and gene expression profiling have led to new ways of thinking about the pathobiology of pheochromocytoma and extra-adrenal paraganglioma. These developments are concurrent with the publication and dissemination of the 2004 World Health Organization bluebook on pathology and genetics of endocrine tumors.

Objective.—To summarize new information required by pathologists for effective participation in patient management and research.

Data Sources.—Literature review and primary material from Tufts Medical Center.

Conclusions.—The World Health Organization reserves the term pheochromocytoma for tumors arising from chromaffin cells in the adrenal medulla. Closely related tumors in extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. A pheochromocytoma is an intra-adrenal sympathetic paraganglioma. Although arbitrary, this nomenclature emphasizes important distinctive properties of intra-adrenal tumors, including an often adrenergic phenotype, relatively low rate of malignancy, and predilection to occur in particular hereditary syndromes. Malignancy is defined by presence of metastases not local invasion. Occult germline mutations characteristic of familial syndromes are now found in more than 20% of patients with apparently sporadic tumors, bringing the percentage of tumors with a known genetic basis close to 30%. In addition, tumor location and risk of malignancy vary with the underlying genetic defect. The “10 percent rule” for pheochromocytoma/paraganglioma—10% familial, 10% malignant, 10% extra-adrenal—is therefore no longer tenable. Current roles of pathology are limited to diagnosing primary or metastatic tumors and identifying features suggestive of malignant potential or hereditary disease. Future roles may involve more definitive assessment of malignancy, genotype-phenotype correlation, and identification of targets for therapy.
An Overview of Practical Issues in the Diagnosis of Gastroenteropancreatic Neuroendocrine Pathology
Authors: Chetty Runjan
Published: February 2021

Context.—Although somewhat uncommon, neuroendocrine tumors of the gastrointestinal tract and pancreas have come under scrutiny in recent times. With advances in imaging techniques, more of these tumors are being removed and sent for pathologic evaluation. It is important for the diagnostic pathologist to be aware of recent developments in this field.

Objective.—This overview focuses on nomenclature/terminology, classification, practical issues related to recent developments in immunohistochemical markers that aid diagnosis and may relate to prognosis, and molecular advances.

Data Sources.—Currently available literature and personal experience in the field of neuroendocrine pathology.

Conclusions.—The preferred terminology is neuroendocrine/tumor/carcinoma and it is recommended that the World Health Organization classification be used, taking note of the site variations that may occur. A large number of immunohistochemical markers are available but a core panel that is relevant to the site should be used. Cytokeratin 19 positivity is an independent marker of aggressive behavior in pancreatic neuroendocrine tumors. Gastrointestinal neuroendocrine tumors arise via the CpG island methylator phenotype pathway, whereas their pancreatic counterparts arise as a result of chromosomal instability. The MEN1 gene is implicated in both syndromic and sporadic forms of these tumors.
Call Subject Patterns Among On-Call Clinical Pathology Residents in an Academic Institution: How Can Tracking Changes in Patterns Over Time Benefit Resident Education?
Authors: Do Marie C. , Ben-Ezra Jonathan , McPherson Richard A.
Published: February 2021

Context.—On-call responsibility is an important part of residency training in clinical pathology. This task provides important consultative services for the hospital and serves as a valuable learning experience for the resident.

Objective.—To identify the types of calls received by residents at a large teaching hospital, to assess how and why these calls have changed over time, and to determine the educational value in tracking such changes.

Design.—A retrospective review of resident on-call records from 2 periods (2005–2006 and 1997–1998) was performed. Calls were classified based on the call subject and the caller.

Results.—Although some general patterns remained similar, several differences were identified between the time periods. Calls regarding mislabeled specimens fell, while calls concerning panic values and the blood bank (specifically therapeutic apheresis) increased.

Conclusions.—The different patterns identified in calls between the 2 periods reflect the ever-changing role of the clinical pathologist within the hospital system and provide evidence that monitoring these shifting patterns could be a valuable tool in the education of clinical pathology residents.
Hereditary Benign Intraepithelial Dyskeratosis: An Evaluation of Diagnostic Cytology
Authors: Cummings Thomas J. , Dodd Leslie G. , Eedes Christopher R. , Klintworth Gordon K.
Published: February 2021

Context.—Hereditary benign intraepithelial dyskeratosis (HBID) is a rare autosomal dominant disorder characterized by elevated epibulbar and oral plaques and hyperemic conjunctival blood vessels. The condition is predominantly seen in Native Americans belonging to the Haliwa-Saponi tribe located in northeastern North Carolina.

Objective.—To determine whether HBID can be diagnosed using cytologic preparations of the conjunctiva, and whether the cytologic findings correlated with the genetic linkage involving a duplication in chromosome 4 (4q35).

Design.—Cytologic preparations from conjunctival brushings in patients afflicted with HBID and from unaffected blood relatives with normal conjunctivas were compared in a masked fashion. Cytologic observations were correlated with molecular genetic analyses.

Results.—Papanicolaou-stained preparations from the conjunctiva showed the typical cytologic features of HBID, including rounded squamous epithelial cells with dense homogenous orange cytoplasm and hyperchromatic, pyknotic, or crenated nuclei. All cases with the diagnostic cytologic findings of HBID had a duplication in chromosome 4 (4q35).

Conclusion.—HBID is an entity with distinct clinical, histopathologic, and genetic features. The results of this study indicate the diagnosis can also be supported in an appropriate clinical setting when adequate epibulbar cytology preparations are obtained and the characteristic genetic attributes are present.
Best Practice in Diagnostic Immunohistochemistry: Prostate Carcinoma and Its Mimics in Needle Core Biopsies
Authors: Paner Gladell P. , Luthringer Daniel J. , Amin Mahul B.
Published: February 2021

Context.—The unrelenting challenge encountered when differentiating limited-volume prostate carcinoma and sometimes subtle variants from its many morphologic mimics has increased the use of ancillary immunohistochemistry in routine prostate needle biopsies. The availability of prostate cancer–associated and basal cell–associated markers has been an invaluable addition to diagnostic surgical pathology.

Objective.—To review commonly used immunohistochemical stains, including innovative combinations, for confirmation or differential diagnosis of prostate carcinoma, and to propose appropriately constructed panels using morphologic patterns in prostate needle biopsies.

Data Sources.—These best practices are based on our experience with routine and consultative case sign-outs and on a review of the published English-language literature from 1987 through 2008.

Conclusions.—Basal cell–associated markers p63, high-molecular-weight cytokeratin 34βE12, cytokeratin 5/6 or a cocktail containing p63 and high-molecular-weight cytokeratin 34βE12 or cytokeratin 5/6 and prostate carcinoma–specific marker α-methylacyl coenzyme A (coA) racemase alone or in combination are useful adjuncts in confirming prostatic carcinoma that either lacks diagnostic, qualitative or quantitative features or that has an unusual morphologic pattern (eg, atrophic, pseudohyperplastic) or is in the setting of prior treatment. The combination of α-methylacyl coA racemase positivity with negative staining for basal cell–associated markers supports a malignant diagnosis in the appropriate morphologic context. Dual chromogen basal cell– associated markers (p63 [nuclear] and high-molecular-weight cytokeratin 34βE12/cytokeratin 5/6 [cytoplasmic]) and α-methylacyl coA racemase in an antibody cocktail provide greater sensitivity for the basal cell layer, easing evaluation and minimizing loss of representation of the focal area interest because the staining is performed on one slide. In the posttreatment setting, pancytokeratin facilitates detection of subtle-treated cancer cells. Prostate-specific antigen and prostatic acid phosphatase markers are helpful in excluding secondary malignancies involving the prostate, such as urothelial carcinoma, and occasionally in excluding nonprostatic benign mimickers, such as nephrogenic adenoma, mesonephric gland hyperplasia, and Cowper glands. There is no role for ordering immunohistochemistry prospectively in all cases of prostatic needle biopsies.
Clear Cell Adenocarcinoma of Urinary Bladder and Urethra: Another Urinary Tract Lesion Immunoreactive for P504S
Authors: Sun Katherine , Huan Youming , Unger Pamela D.
Published: February 2021

Context.—Clear cell carcinoma of the urinary bladder/ urethra is a rare tumor histologically resembling the neoplasms in the female genital tract. Adequate characterization of this tumor has been hampered by its rarity. α-Methylacyl-CoA racemase (AMACR)/P504S has been reported to be positive in prostatic adenocarcinoma, papillary renal cell carcinoma, and gastrointestinal neoplasmas; however, it has never been studied in clear cell carcinoma of the lower urinary tract.

Objective.—To investigate the immunohistochemical staining profile in 4 primary clear cell carcinomas of the urinary tract, including P504S, which has not been previously evaluated in these tumors.

Design.—Four cases of clear cell adenocarcinoma were retrieved from our archives: 2 cases from the urinary bladder (one each from a man and a woman) and 2 cases from the urethra (both from women, 1 in a diverticulum). Immunohistochemistry performed on the cases were P504S, K903, cytokeratin (CK) 7, CK20, CA 125, and p63.

Results.—We found that clear cell carcinomas had a distinct immunoreactive profile: strongly positive for P504S, K903, and CK7, and negative for p63. Two cases were also positive for CA 125 and CK20.

Conclusion.—The immunohistochemical profile of clear cell carcinomas shares some similarity to conventional urothelial carcinoma; however, it deviates from those tumors in being positive for P504S and negative for p63. This staining profile may suggest a nonurothelial origin for these tumors, may serve as a useful tool in the differential diagnosis of this tumor, and may reflect its etiology. Because similar expression of P504S is also seen in nephrogenic adenomas, this marker should not be used to differentiate nephrogenic adenomas from clear cell adenocarcinomas.
Validation of the Circulating Monocyte Being Representative of the Cholesterol-Loaded Macrophage: Biomediator Activity
Authors: Devaraj Sridevi , Jialal Ishwarlal
Published: February 2021

Context.—Inflammation is pivotal to atherosclerosis. The monocyte-macrophage, a crucial cell in atherogenesis, is present during all stages of atherosclerosis. However, there is a paucity of data comparing circulating monocytes to cholesterol-laden macrophages (foam cells), with regard to their atherogenic properties, especially in subjects with established risk factors such as hyperlipidemia.

Objective.—To determine whether the circulating blood monocyte is representative of the cholesterol-loaded macrophage with regard to its proatherogenicity in healthy controls and hyperlipidemic patients.

Design.—Fasting blood was drawn from 32 subjects (n = 16 controls and n = 16 hyperlipidemic patients), and peripheral blood monocytes were obtained. Also, macrophages were cultured and loaded with acetyl low-density lipoprotein on day 10. Day 1 peripheral blood monocytes and day 11 cholesterol-loaded macrophages were assessed for release of superoxide anion and cytokines (interleukin 1, interleukin 6, tumor necrosis factor α); surface expression of CD11b, VLA-4, and CD40; and adhesion to human endothelium.

Results.—Monocyte and cholesterol-loaded macrophage superoxide anion release, cytokines, and adhesion of monocytes to human endothelium were significantly increased in hyperlipidemic patients compared with controls. Furthermore, following cholesterol loading, there were no significant differences in monocyte versus cholesterol-loaded macrophage activity (P = .71). Also, CD14 and CD11b surface expression on monocytes was significantly increased in hyperlipidemic patients as compared with controls. The magnitude of change in the monocytes versus cholesterol-loaded macrophages was similar.

Conclusions.—From these studies, we can conclude that the monocyte, which is readily accessible, is an appropriate cell to study for modulation of proatherogenic activity, especially with regard to genomic and proteomic analyses/ microarrays.
Sclerosing Adenosis in Sentinel Axillary Lymph Nodes From a Patient With Invasive Ductal Carcinoma: An Unusual Variant of Benign Glandular Inclusions
Authors: Chen Ying-bei , Magpayo John , Rosen Paul Peter
Published: February 2021

Benign glandular inclusions in axillary lymph nodes are very rare events that have to be distinguished from metastatic carcinoma. We report an exceptional instance in which a patient with invasive ductal carcinoma had benign glandular inclusions in the form of sclerosing adenosis in 2 sentinel lymph nodes. The lymph nodes did not contain metastatic carcinoma. Immunohistochemical studies facilitated the correct diagnosis.
The Effect of Continuous Monitoring of Cytologic-Histologic Correlation Data on Cervical Cancer Screening Performance
Authors: Raab Stephen S. , Jones Bruce A. , Souers Rhona , Tworek Joseph A.
Published: February 2021

Context.—The use of Papanicolaou (Pap) test cytologic-histologic correlation in quality improvement activities is not well studied.

Objective.—To determine if continuous monitoring of correlation data improves performance.

Design.—Participants in the College of American Pathologists Q-Tracks program (213 laboratories) self-reported the number of Pap test–histologic biopsy correlation discrepancies every quarter for up to 8 years. A mixed linear model determined if the length of participation in the Q-Tracks program was associated with improved performance. Main outcome measures were predictive value of a positive Pap test, Pap test sensitivity, sampling sensitivity, and proportion of positive histologic diagnoses following a Pap test diagnosis of atypical squamous cells or atypical glandular cells.

Results.—Institutions evaluated 287 570 paired Pap test– histologic correlation specimens and found 98 424 (34.2%) true-positive Pap test correlations, 19 006 (6.6%) false-positive Pap test correlations, and 6575 (2.3%) false-negative Pap test correlations. The mean predictive value of a positive Pap test, sensitivity, screening and interpretive sensitivity, sampling sensitivity, and proportion of positive histologic diagnoses following a Pap test diagnosis of atypical squamous or glandular cells were 83.6%, 93.7%, 99.2%, 94.2%, 60.3%, and 38.8%, respectively. Longer participation was significantly associated with a higher predictive value of a positive Pap test (P = .01), higher Pap test sensitivity (P = .002), higher Pap test sampling sensitivity (P = .03), and higher proportion of positive histologic diagnoses for a Pap test diagnosis of atypical squamous cells (P < .001).

Conclusions.—Long-term monitoring of cytologic-histologic correlation is associated with improvement in cytologic-histologic correlation performance.
Comparison of Primary and Metastatic Malignant Melanoma of the Esophagus: Clinicopathologic Review of 10 Cases
Authors: Sanchez Amy A. , Wu Tsung-Teh , Prieto Victor G. , Rashid Asif , Hamilton Stanley R. , Wang Huamin
Published: February 2021

Context.—Primary esophageal melanoma (PEM) is a rare disease and is difficult to distinguish from other esophageal malignancies and from metastatic melanoma.

Objective.—To develop diagnostic criteria for PEM, we compared the clinicopathologic features of 5 PEMs and 5 metastatic melanomas to esophagus.

Design.—Ten cases of esophageal melanoma, including 4 surgically resected specimens, 2 autopsy cases, and 4 cases reported on mucosal biopsies, were reviewed. The histologic parameters used in this study were well-characterized features for cutaneous melanoma, including junctional component (in situ melanoma), radial growth phase, modified Breslow thickness, depth of invasion, lymphovascular invasion, satellitosis, predominant type of cytology, and regional lymph node metastasis. Clinical and follow-up information was obtained by reviewing patients' medical records.

Results.—Previous history of cutaneous melanoma was present in all 5 cases of metastatic esophageal melanoma but was not present in the 5 patients with PEMs. In situ melanoma and/or radial growth phase were identified in all 5 PEMs but were not present in any of the metastatic cases. Among the 4 resected and 2 autopsy cases, melanocytosis and mixed epithelioid and spindle cell morphology was present in 2 (50%) of 4 PEMs but was not present in 2 (40%) of the metastatic melanomas. Melanin pigment was detectable in all cases. Patients with PEM had better survival than those who had metastatic melanoma to esophagus (P = .03).

Conclusions.—The presence of in situ melanoma, radial growth phase, melanocytosis, and mixed epithelioid and spindle cell morphology, in the context of no history of melanoma, distinguishes PEM from metastatic melanoma.
Molecular Testing in Solid Tumors: An Overview
Authors: Hunt Jennifer L.
Published: February 2021

Molecular testing in anatomic pathology is going to become more and more important during the next decade as we develop assays that can aid in diagnosis, prognosis, and predicting response to therapy. The anatomic pathologist needs to be familiar with the different assays available but also needs to be able to discern which are going to become standard of care and which will not. Three different types of tumors are reviewed: thyroid cancer, oligodendroglioma, and lung carcinoma. Molecular assays that are currently in use or on the near horizon, including translocation analyses for RET-PTC and PPARγ-PAX8, point mutation analysis for BRAF and epidermal growth factor receptor, and genetic loss for 1p and 19q, are discussed.
Medicolegal Issues in Pathology
Authors: Allen Timothy Craig
Published: February 2021

The various methods used by risk managers to assist clinicians in handling medicolegal risk, including improving communication with patients and better dealing with medical records issues, are not particularly of benefit to pathologists. An understanding of tort law, the theory of negligence, the principle of standard of care, and the role of the expert witness helps the pathologist generally assess and manage risk and put it into context with daily pathology practice. An understanding of the litigation process and techniques to better handle a deposition and high-risk specimens or diagnoses are of practical value in avoiding a lawsuit or increasing the likelihood for good outcome in medical malpractice litigation.
Survivin as a Useful Adjunct Marker for the Grading of Papillary Urothelial Carcinoma
Authors: Chen Ying-bei , Tu Jiangling J. , Kao Jean , Zhou Xi K. , Chen Yao-Tseng
Published: February 2021

Context.—Distinguishing low-grade and high-grade noninvasive papillary urothelial carcinoma based on morphologic criteria can be challenging and adjunct markers are highly desirable. Survivin, presumably an antiapoptotic protein, was previously proposed as a prognostic marker for urothelial carcinoma.

Objective.—To assess interobserver variability by 2004 World Health Organization classification and the value of survivin and Ki-67 as potential markers for grading noninvasive papillary urothelial carcinoma.

Design.—Fifty-one bladder biopsies were graded blindly by 5 experienced general surgical pathologists. The protein and messenger RNA expression of survivin and Ki-67 was evaluated by immunohistochemistry and quantitative reverse transcription–polymerase chain reaction using paraffin-embedded tissue. The immunohistochemistry result was quantitatively analyzed using a computer-based color deconvolution module.

Results.—The diagnostic agreement among 5 pathologists was fair to poor, with 32% of the cases graded differently by at least 2 raters. All cases were divided into 3 groups: consensus low-grade, consensus high-grade, and indeterminate. The percentage of urothelial cells with positive survivin nuclear staining (survivin score) was significantly higher in the high-grade than in the low-grade group (P < .001). Survivin score outperformed Ki-67 in separating the high-grade group from the low-grade group and showed a significantly higher predictive accuracy for high-grade recurrence than the histologic grade. The disagreement of grading for the indeterminate group could be resolved by their survivin scores in most cases. Survivin messenger RNA level correlated well with survivin score by immunohistochemistry but was not a more discriminating marker.

Conclusions—Significant interobserver variability exists in grading low-grade versus high-grade papillary urothelial carcinoma. Survivin immunohistochemical staining can be a useful adjunct tool for the grading of challenging cases.
Multiplex Immunoassay Analysis of Cytokines in Idiopathic Inflammatory Myopathy
Authors: Baird Geoffrey S. , Montine Thomas J.
Published: February 2021

Context.—Idiopathic inflammatory myopathies (IIMs), including dermatomyositis, polymyositis, and inclusion-body myositis, can be difficult to diagnose.

Objective.—To determine if a multiplex immunoassay for markers of inflammation in muscle homogenates correlates with a diagnosis of IIM.

Design.—Frozen archived muscle biopsy specimens from 30 patients with IIM and 34 patients without IIM were homogenized and analyzed for cytokine content with a multiplex microbead-based immunoassay system. Analyte concentrations were normalized to total lysate protein concentration prior to comparison.

Results.—Two cytokines, interleukin 1ra and monocyte chemoattractant protein 1, and 1 soluble adhesion molecule, intracellular adhesion molecule 1, were found at significantly greater concentrations in muscle samples from patients with IIM. Intracellular adhesion molecule 1 levels alone were 83% sensitive and 91% specific for IIM at a cutoff of 1240 pg/mg muscle protein.

Conclusions.—Immunoassays for selected inflammatory markers can serve in conjunction with histopathologic analysis as sensitive and specific tools for the diagnosis of IIM.
Arteriosclerosis in Kidneys From Healthy Live Donors: Comparison of Wedge and Needle Core Perioperative Biopsies
Authors: Haas Mark , Segev Dorry L. , Racusen Lorraine C. , Bagnasco Serena M. , Melancon J. Keith , Tan Miguel , Kraus Edward S. , Rabb Hamid , Ugarte Richard M. , Burdick James F. , Montgomery Robert A.
Published: February 2021

Context.—Although risks associated with live kidney donation are low, there are few pathologic studies of kidneys from live donors, and possible risk factors for development of hypertension or renal insufficiency remain unknown. There are many studies of histopathologic changes in deceased donor kidneys and how these changes affect subsequent graft function; most are based on wedge rather than needle core biopsies.

Objective.—To examine the frequency and severity of arterial fibrointimal thickening and other pathologic lesions in kidneys from healthy live donors and compare wedge and needle core biopsies as methods for evaluating these changes.

Design.—For 36 of 332 live donor renal transplantations performed from January 2004 through November 2006, a wedge biopsy of the transplanted kidney was done prior to and/or after implantation, and a needle core biopsy was done postimplantation or during the ensuing 7 days. For these 36 allografts, we compared pathologic features of the wedge and core perioperative biopsies.

Results.—Findings on core and wedge biopsies were similar, except for arterial fibrointimal thickening. Moderate thickening (Banff cv2) was present on 13 core biopsies, and mild thickening (cv1) was present on another 10; by contrast, no wedge biopsies showed cv2 lesions, and only 8 showed cv1. Arterial thickening on core but not wedge biopsies correlated significantly with increasing patient age.

Conclusions.—The findings indicate that needle core biopsies are superior to wedge biopsies for evaluating vascular changes in donor kidneys, and they suggest a need for studies correlating such changes with long-term outcomes of live donors, particularly older donors.
Application of Immunohistochemistry to Gynecologic Pathology
Authors: Mittal Khush , Soslow Robert , McCluggage W. G.
Published: February 2021

Context.—A large variety of tumors and lesions arise in the female genital tract. Although the majority of these can be correctly recognized on routine hematoxylin-eosin– stained slides, occasional cases present a diagnostic challenge. Immunohistochemical stains are extremely useful in resolving many of these problematic cases. As the knowledge in this area is constantly expanding, it is useful to have this updated information in a review form for easy access.

Objective.—To present our current knowledge of immunohistochemistry of the lesions of the female genital tract in a readily accessible form.

Data Sources.—The review is based on previously published articles on this topic.

Conclusions.—Immunohistochemical stains help in reaching a conclusive diagnosis in a variety of problematic lesions seen in gynecologic pathology. As in any other system, immunohistochemical findings need to be interpreted in light of the clinical history and morphologic findings.
Mönckeberg Sclerosis Revisited: A Clarification of the Histologic Definition of Mönckeberg Sclerosis
Authors: Micheletti Robert G. , Fishbein Gregory A. , Currier Judith S. , Fishbein Michael C.
Published: February 2021

Context.—Medial calcification of muscular arteries is known as Mönckeberg sclerosis (MS). Although this was first described in 1903, disagreement persists over its precise histologic appearance. Some, including Mönckeberg, have written that the media alone are calcified, whereas others maintain that both the media and internal elastic lamina (IEL) are involved. Since vascular calcification is of great interest to investigators and clinicians, defined criteria for classifying calcified arterial lesions are important.

Objective.—To clarify the histologic definition of MS with regard to calcification of the IEL.

Design.—We reviewed slides from 14 incisional and excisional surgical biopsies and autopsy specimens containing arteries with previously diagnosed MS. We looked specifically for medial and IEL calcification and used von Kossa, alizarin red, and trichrome/elastic stains to confirm our findings. We also performed a literature search on the histologic appearance of MS.

Results.—Both medial and IEL calcification were present in all specimens. Medial calcification extended alongside calcified IEL. In focal regions, calcification appeared limited to the IEL, with minimal medial calcification. Occasionally, calcified nodules in the media appeared separated from the IEL yet were connected to it in other planes of section. Despite these variations in appearance, IEL involvement was universal. Of 25 journal articles and texts, 10 state that MS involves the IEL with calcification, whereas 15 state or suggest that it does not.

Conclusions.—Our findings indicate MS involves both the IEL and media with calcification in spite of inconsistencies on this point in the medical literature.