bluuebunny/crossref_metadata_2025 huggingface dataset:
A Proposed Histopathologic Classification, Scoring, and Grading System for Renal Amyloidosis: Standardization of Renal Amyloid Biopsy Report
Authors: Şen Sait , Sarsık Banu
Published: February 2021

Context.—A disease associated with amyloid deposits, called amyloidosis, is associated with characteristic electron microscopic appearance, typical x-ray pattern, and specific staining. Renal involvement mainly occurs in AA amyloidosis and AL amyloidosis and usually progresses to renal failure.

Objective.—The renal histopathologic changes with amyloidosis comprise a spectrum. Clear relationships between the extent of amyloid deposition and the severity of clinical manifestations have not been demonstrated. Whether there is a lack of clinicopathologic correlation is not clear, but studies have revealed the need for standardization of the renal amyloid biopsy report. With these objectives in mind, we proposed a histopathologic classification, scoring, and grading system. Renal amyloidosis was divided into 6 classes, similar to the classification of systemic lupus erythematosus. Amyloid depositions and other histopathologic lesions were scored. The sum of these scores was termed the renal amyloid prognostic score and was divided into 3 grades.

Data Sources.—AA amyloidosis was detected in 90% of cases, mostly related to familial Mediterranean fever. Positive correlations between class I and grade I, class VI and grade III, and class III and grade II were observed. Also, a positive correlation was identified between severity of glomerular amyloid depositions, interstitial fibrosis, and inflammation. Because of the inadequacy of the patients' records and outcomes, different therapy regimes, and etiologies, clinical validation of this study has not been completed.

Conclusions.—Standardization of the renal amyloid pathology report might be critical for patients' medication and comparison of outcome and therapeutic trials between different clinics. Because of our AA to AL amyloidosis ratio and the predisposition of familial Mediterranean fever–related AA amyloidosis, there is a need for further international collaborative studies.
Cystic Diseases of the Kidney: Molecular Biology and Genetics
Authors: Deltas Constantinos , Papagregoriou Gregory
Published: February 2021

Context.—Cystic diseases of the kidney are a very heterogeneous group of renal inherited conditions, with more than 33 genes involved and encompassing X-linked, autosomal dominant, and autosomal recessive inheritance. Although mostly monogenic with mendelian inheritance, there are clearly examples of oligogenic inheritance, such as 3 mutations in 2 genes, while the existence of genetic modifiers is perhaps the norm, based on the extent of variable expressivity and the broad spectrum of symptoms.

Objectives.—To present in the form of a mini review the major known cystic diseases of the kidney for which genes have been mapped or cloned and characterized, with some information on their cellular and molecular biology and genetics, and to pay special attention to commenting on the issues of molecular diagnostics, in view of the genetic and allelic heterogeneity.

Data Sources.—We used major reviews that make excellent detailed presentation of the various diseases, as well as original publications.

Conclusions.—There is already extensive genetic heterogeneity in the group of cystic diseases of the kidney; however, there are still many more genes awaiting to be discovered that are implicated or mutated in these diseases. In addition, the synergism and interaction among this repertoire of gene products is largely unknown, while a common unifying aspect is the expression of nearly all of them at the primary cilium or the basal body. A major interplay of functions is anticipated, while mutations in all converge in the unifying phenotype of cyst formation.
Glomerulocystic Kidney: One Hundred–Year Perspective
Authors: Lennerz Jochen K. , Spence David C. , Iskandar Samy S. , Dehner Louis P. , Liapis Helen
Published: February 2021

Context.—Glomerular cysts, defined as Bowman space dilatation greater than 2 to 3 times normal size, are found in disorders of diverse etiology and with a spectrum of clinical manifestations. The term glomerulocystic kidney (GCK) refers to a kidney with greater than 5% cystic glomeruli. Although usually a disease of the young, GCK also occurs in adults.

Objective.—To assess the recent molecular genetics of GCK, review our files, revisit the literature, and perform in silico experiments.

Data Sources.—We retrieved 20 cases from our files and identified more than 230 cases published in the literature under several designations.

Conclusions.—Although GCK is at least in part a variant of autosomal dominant or recessive polycystic kidney disease (PKD), linkage analysis has excluded PKD-associated gene mutations in many cases of GCK. A subtype of familial GCK, presenting with cystic kidneys, hyperuricemia, and isosthenuria is due to uromodullin mutations. In addition, the familial hypoplastic variant of GCK that is associated with diabetes is caused by mutations in TCF2, the gene encoding hepatocyte nuclear factor–1β. The term GCK disease (GCKD) should be reserved for the latter molecularly recognized/inherited subtypes of GCK (not to include PKD). Review of our cases, the literature, and our in silico analysis of the overlapping genetic entities integrates established molecular-genetic functions into a proposed model of glomerulocystogenesis; a classification scheme emerged that (1) emphasizes the clinical significance of glomerular cysts, (2) provides a pertinent differential diagnosis, and (3) suggests screening for probable mutations.
Quantitative Evaluation of Protein Expression as a Function of Tissue Microarray Core Diameter: Is a Large (1.5 mm) Core Better Than a Small (0.6 mm) Core?
Authors: Anagnostou Valsamo K. , Lowery Frank J. , Syrigos Konstantinos N. , Cagle Philip T. , Rimm David L.
Published: February 2021

Context.—Tissue microarrays (TMAs) have emerged as a high-throughput technology for protein evaluation in large cohorts. This technique allows maximization of tissue resources by analysis of sections from 0.6-mm to 1.5-mm core “biopsies” of standard formalin-fixed, paraffin-embedded tissue blocks and by the processing of hundreds of cases arrayed on a single recipient block in an identical manner.

Objective.—To assess the expression of a series of biomarkers as a function of core size. Although pathologists frequently feel better if larger core sizes are used, there is no evidence in the literature showing that large cores are better (or worse) than small cores for assessment of TMAs.

Design.—Estrogen receptor, HER2/neu, epidermal growth factor receptor, STAT3, mTOR, and phospho-p70 S6 kinase were measured by immunofluorescence with automated quantitative analysis. One random 0.6-mm field (one 0.6-mm spot) was compared to 6 to 12 fields per spot, representing 1-mm and 1.5-mm cores, for 3 different tumor types.

Results.—We show that measurement of a single random 0.6-mm spot was comparable to analysis of the whole 1-mm or 1.5-mm spot (Pearson R coefficient varying from 0.87–0.98) for all markers tested.

Conclusions.—Since TMA technology is now being used in all phases of biomarker development, this work shows that TMAs with 0.6-mm cores are as representative as those with any common larger core size for optimization of standardized experimental conditions. Given that a greater number of 0.6-cores can be arrayed in a single master block, use of this core size allows increased throughput and decreased cost.
Surgical Pathology Case Reviews Before Sign-Out: A College of American Pathologists Q-Probes Study of 45 Laboratories
Authors: Nakhleh Raouf E. , Bekeris Leonas G. , Souers Rhona J. , Meier Frederick A. , Tworek Joseph A.
Published: February 2021

Context.—To avoid errors many surgical pathology services mandate review of a case by a second pathologist before reports are released (signed out).

Objective.—To study the extent and characteristics of such review.

Design.—Participants retrospectively examined up to 400 cases to identify a maximum of 30 cases reviewed by at least one additional pathologist before sign-out. For each case, participants documented the organ system, primary disease type, number of additional pathologists consulted, and the reason for case review. The main outcome measure was the fraction of surgical pathology cases that underwent second pathologist review before sign-out.

Results.—From 45 laboratories, examination of 18 032 surgical pathology cases yielded 1183 (6.6%) cases that had been reviewed before sign-out. The median laboratory reviewed 8.2% of cases. Three-fifths of reviews focused on 4 organ systems: gastrointestinal (20.5%), breast (16.0%), skin (12.7%), and female genital tract (10.0%). Malignant neoplasm far exceeded all other categories of disease in reviewed cases (45.3%). Cases were reviewed by one additional pathologist 78% of the time. Two dominant reasons for case review emerged: difficult diagnosis (46.2%) and audit required by departmental policy (43.0%). Most laboratories (71%) had departmental policies regarding review of cases. These laboratories reviewed cases about 33% more often than laboratories without policies (9.6% versus 6.5%).

Conclusions.—Review of selected surgical pathology cases before sign-out is widely accepted with 71% of participant laboratories following policies to this effect. About 1 case in 15 (6.6%) were reviewed with the median laboratory of participants reviewing about 1 in 12 (8.2%).
Proficiency Testing Performance in US Laboratories: Results Reported to the Centers for Medicare & Medicaid Services, 1994 Through 2006
Authors: Howerton Devery , Krolak John M. , Manasterski Adam , Handsfield James H.
Published: February 2021

Context.—Beginning in 1994, clinical laboratories performing nonwaived testing were required, under the regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA), to enroll and participate in a proficiency testing (PT) program approved by the Centers for Medicare & Medicaid Services. Successful PT performance is a requirement for maintaining CLIA certification to perform testing in certain specialties and subspecialties and for specific analytes.

Objective.—To evaluate the PT performance from 1994 through 2006 of hospital and independent laboratories (HI) compared with all other testing sites (AOT) for selected commonly performed tests and analytes.

Design.—Proficiency testing data, from 1994 through 2006, were electronically reported to the Centers for Medicare & Medicaid Services by approved PT programs as required by CLIA regulations. Approximately 16 million PT event scores from 36 000 unique testing sites were sorted into 2 groups based on the type of testing facility: HI or AOT.

Results.—The PT performance scores for 15 of the most commonly performed tests demonstrated a decline in failure rates for both HI and AOT laboratory groups during 1994 through 2006 (analyte/test values reported in this article include alanine aminotransferase, amylase, bilirubin, cholesterol, digoxin, glucose, hemoglobin, leukocyte count, potassium, prothrombin time, theophylline, thyroxine, triglycerides, white blood cell differential, and uric acid). For most analytes, the difference in failure rates between HI and AOT was statistically significant. The AOT group started with higher failure rates, and remained higher for all analytes, during most years when compared with the HI group; although, over time, that difference diminished. The AOT group showed a greater decline in PT failure than the HI group. For all analytes, the AOT group performance improved during this period.

Conclusions.—The PT performance improved dramatically for the AOT group from 1994 through 2006 as measured by a decrease in the percentage of laboratories with unsatisfactory performance for 15 selected analytes. The PT performance in the HI group improved modestly for some analytes during this same period, whereas, for other analytes, the group showed no apparent improvement.
Cervical and Endometrial Metastases of Appendiceal Goblet Cell Carcinoid
Authors: Pan Zenggang , Repertinger Susan , Leonard Ronald , Bewtra Chhanda , Gatalica Zoran , Sharma Poonam
Published: February 2021

Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patient's invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.
Thyroid-Type Carcinoma of Struma Ovarii
Authors: Zhang Xuchen , Axiotis Constantine
Published: February 2021

Struma ovarii is a monodermal variant of ovarian teratoma. Thyroid-type carcinoma arising in struma ovarii is rare. The most common type is papillary carcinoma, followed by typical follicular carcinoma, and the new entity of follicular carcinoma—highly differentiated follicular carcinoma of ovarian origin; other forms occur rarely. Consensus on the surgical and postoperative treatment of patients with thyroid-type carcinoma arising in struma ovarii has not been reached. Surgical treatment ranges from total abdominal hysterectomy, plus bilateral salpingo-oophorectomy with omentectomy, to conservative surgery, involving unilateral oophorectomy or strumectomy (cystectomy) for fertility preservation. Adjuvant therapy includes external radiotherapy, chemotherapy, thyroidectomy, and radioactive iodine ablation. Thyroid-type carcinomas arising in struma ovarii, especially the newly recognized entity—highly differentiated follicular carcinoma of ovarian origin—have a favorable prognosis.
Gluten-Sensitive Enteropathy (Celiac Disease): Controversies in Diagnosis and Classification
Authors: Ensari Arzu
Published: February 2021

Context.—Celiac disease, or gluten-sensitive enteropathy, is a chronic inflammatory disorder of the small intestine characterized by malabsorption after ingestion of gluten in individuals with a certain genetic background. Clinical presentation can vary from full-blown malabsorption to subtle and atypical symptoms. Diagnosis currently relies on clinicopathologic studies including mucosal biopsy, serologic tests, and the effects of a diet free of gluten on the symptoms. Mucosal pathologic features are also variable, ranging from mild abnormalities, including intraepithelial lymphocytosis, to completely flat mucosa. Since patients with minimal histologic lesion of intraepithelial lymphocytosis often present with normal serologic findings, biopsy diagnosis becomes more important for identifying such individuals. Classification of mucosal pathology in gluten-sensitive enteropathy has been a subject of controversy among pathologists and needs to be revised according to the current understanding of the disease.

Objectives.—To highlight the variations in clinical and pathologic presentation of gluten-sensitive enteropathy, to emphasize the importance of small-intestinal biopsy evaluation in the diagnosis, and to propose a new classification of mucosal pathology in gluten-sensitive enteropathy, in an effort to overcome the problems related to the classification systems currently available.

Data Sources.—A review of the literature on clinicopathologic features and the morphologic spectrum of gluten-sensitive enteropathy is presented.

Conclusions.—Considering that there are many entities in the differential diagnosis of gluten-sensitive enteropathy, because of the varied clinicopathologic spectrum of the disease, diagnosis depends on good clinicopathologic communication. The classification that is presented in this review is a simple and practical approach to improve clinicopathologic correlation in gluten-sensitive enteropathy.
Epithelioid Angiosarcoma: A Brief Diagnostic Review and Differential Diagnosis
Authors: Hart Jesse , Mandavilli Srinivas
Published: February 2021

Epithelioid angiosarcoma is a highly aggressive endothelial cell malignancy, most commonly arising in the deep soft tissues, but a variety of primary sites, including the adrenals, thyroid, skin, and bone, are encountered. On hematoxylin-eosin–stained sections, the pathologist encounters sheets of large, mildly to moderately pleomorphic epithelioid cells, with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Obvious vasoformative foci may not be present, creating confusion with metastatic carcinomas, malignant mesothelioma, melanoma, anaplastic lymphoma, epithelioid peripheral nerve sheath malignancies, and epithelioid sarcoma. Moreover, malignancies with apparent vascular differentiation must be distinguished from less aggressive vascular neoplasms, including epithelioid hemangioendothelioma. Given the range of clinical presentation, the diversity of primary sites, and the nonspecific initial histopathologic appearance, here we review the histologic findings and immunohistochemical profiles of epithelioid angiosarcoma and neoplasms in its differential diagnosis.
Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa: An Increasing Diagnostic Problem With a Wide Differential Diagnosis
Authors: Brown Ian , Mino-Kenudson Mari , Deshpande Vikram , Lauwers Gregory Y.
Published: February 2021

Context.—An increased intraepithelial lymphocyte density in an architecturally normal proximal small intestinal mucosal biopsy is a common finding facing surgical pathologists dealing with gastrointestinal biopsy specimens. Approximately 1% to 2% of all proximal small intestinal biopsies will show this change. It is increasingly recognized by surgical pathologists that gluten-sensitive enteropathy is an important cause of this pattern; however, gluten-sensitive enteropathy accounts for the minority of all cases. A wide variety of immunologic stimuli can raise intraepithelial lymphocyte numbers. Among the other common associations are enteric infection, autoimmune disease, drugs, and gastric Helicobacter infection.

Objective.—To outline the causes of intraepithelial lymphocytosis, to highlight the importance and the difficulties faced in establishing gluten-sensitive enteropathy as the cause, and to aid the surgical pathologist in the routine sign out of these cases.

Data Sources.—A review of the literature detailing the causes or associations of proximal small intestinal intraepithelial lymphocytosis is presented.

Conclusions.—Increased lymphocyte numbers in the epithelium of architecturally preserved proximal small intestinal biopsies is a morphologic feature associated with a broad differential diagnosis.
Extra-adrenal Myelolipoma in the Renal Hilum: A Case Report and Review of the Literature
Authors: Talwalkar Sameer S. , Shaheen Saad Paul
Published: February 2021

Myelolipoma most commonly arises in the adrenal gland. Extra-adrenal myelolipomas are rare; to our knowledge, approximately 37 previous cases have been reported. We report a myelolipoma presenting as a localized mass in perirenal adipose tissue juxtaposed to the renal hilum in a 65-year-old Caucasian man who presented with back pain, weight loss, hematuria, and flank pain. The most likely diagnostic considerations were pyelonephritis or primary renal malignancy. However, histology revealed mainly mature adipose tissue along with multiple scattered islands of hematopoietic precursor cells. Representation of all the three hematopoietic cell lineages (granulocytic, erythroid, and megakaryocytic) was present. Perirenal masses such as morphologically identified myelolipomas are rarely, if ever, considered in differential diagnosis. The purpose of this report is to elicit consideration of extra-adrenal myelolipoma when formulating a differential diagnosis for perirenal and retroperitoneal tumors. Although primary and secondary malignant retroperitoneal tumors are much more common and aggressive neoplasms, establishing the correct diagnosis has important therapeutic and prognostic implications.
Fluorescent In Situ Hybridization and Array Comparative Genomic Hybridization: Complementary Techniques for Genomic Evaluation
Authors: Morrison Carl
Published: February 2021

During the past few years a new high-throughput molecular technology, array comparative genomic hybridization, has received a great deal of attention. As a DNA-based tool, this technique is presumably more reproducible than expression arrays. In this review, I discuss how array comparative genomic hybridization is remarkably similar with regard to genome analysis to fluorescent in situ hybridization, a technique that is generally regarded as one of the more accurate and reproducible molecular techniques in diagnostic surgical pathology. A thorough understanding of this technology will be useful for all surgical pathologists in the near future, as this technology will no doubt have some influence on our daily practice.
Bronchioloalveolar Carcinoma: A Review of Current Concepts and Evolving Issues
Authors: Yousem Samuel A. , Beasley Mary Beth
Published: February 2021

Context.—The concept of bronchioloalveolar carcinoma underwent considerable refinement between the publications of the 1981 and 1999 World Health Organization classifications of lung tumors. Both pathologic and clinical aspects of this carcinoma are the subject of considerable interest.

Objective.—To review and summarize the evolution of the current concept of bronchioloalveolar carcinoma and evolving issues that are under further investigation.

Data Sources.—Pertinent peer-reviewed literature emphasizing historical classification and evolution as well as current and evolving concepts.

Conclusions.—Small, solitary, nonmucinous bronchioloalveolar carcinomas are associated with a markedly better prognosis compared with conventional invasive adenocarcinomas. Such tumors may be cured by surgical resection and may be more responsive to epidermal growth factor receptor–targeted therapy. The prognosis and staging of multifocal disease remain unresolved, as does the question of whether a small amount of invasion adversely affects prognosis. Mucinous bronchioloalveolar carcinoma appears to be a markedly different entity than the nonmucinous subtype.
Myelodysplastic Syndromes in Children: A Critical Review of Issues in the Diagnosis and Classification of 887 Cases From 13 Published Series
Authors: Elghetany M. Tarek
Published: February 2021

Context.—Pediatric myelodysplastic syndromes (MDSs) are uncommon disorders, which may be difficult to diagnose, particularly in the absence of increased blasts. Pediatric MDSs have several unique features including their association with inherited/constitutional disorders in approximately one third of patients. The classification of pediatric MDSs has undergone significant evolution in the past 20 years.

Objective.—To critically review existing classifications of pediatric MDSs and to evaluate their applicability on previously published large series.

Data Sources.—Previously published pediatric MDS series containing more than 10 patients from the English literature between 1982 and 2005.

Conclusions.—Data were available on 887 patients from 13 published series. Most cases (68.7%) were idiopathic/ de novo, 23.9% were associated with constitutional/inherited disorder, and 7.4% were therapy related. Approximately 10% of cases could not be classified by the French-American-British classification. Eighty-seven percent of unclassified cases were appropriately classified using the World Health Organization classification (2001), whereas 96% of them were classified with the modified World Health Organization classification for pediatric MDSs (2003). The impact of cytogenetics and constitutional/inherited disorders on the biology and outcome of the disease needs to be studied further.
Intraductal Carcinoma of the Prostate Gland With Transmucosal Spread to the Seminal Vesicle: A Lesion Distinct From High-Grade Prostatic Intraepithelial Neoplasia
Authors: Cohen Ronald J. , Shannon Beverly A. , Weinstein Sydney L.
Published: February 2021

Intraductal carcinoma of the prostate (IDC-P) gland represents an intraluminal neoplastic proliferation that is distinct from high-grade prostatic intraepithelial neoplasia (HG-PIN) and almost always coexists with large-volume, high-stage, and high-grade invasive carcinoma. We document an unusual presentation of apparently “early” IDC-P without an aggressive invasive element that, despite being confined to the acinar-ductal system, has gained access to the ejaculatory duct and seminal vesicle by transmucosal spread. This finding confirms that IDC-P, in contrast to HG-PIN, is inherently aggressive and has the ability to spread beyond the prostate gland. In this case, the absence of an aggressive invasive element suggests that IDC-P has most likely evolved within the lumens directly from HG-PIN.
Update on Cardiac Transplantation Pathology
Authors: Tan Carmela D. , Baldwin William M. , Rodriguez E. Rene
Published: February 2021

Context.—The endomyocardial biopsy is the mainstay for monitoring acute allograft rejection in heart transplantation. Objective and accurate assessment of cellular and humoral types of rejection is important to optimize immunosuppressive therapy, avoid therapeutic complications, and improve patient outcome. The grading system for evaluation of heart transplant biopsies published in 1990 was revised in 2004 after more than a decade of implementation.

Objective.—In this review, we focus on a practical approach to the evaluation of human heart transplant biopsies as diagnostic surgical pathologic specimens. We discuss the revised International Society of Heart and Lung Transplantation working formulation.

Data Sources.—We reviewed pertinent literature, incorporating ideas and vast experience of participants in various work groups that led to the revision of the 1990 grading system.

Conclusions.—The grading system for cellular rejection is presented with detailed light microscopic morphology and comparison of the 1990 and 2004 International Society of Heart and Lung Transplantation working formulations. We show how the pathologic recognition of cellular rejection and antibody-mediated rejection has evolved. We emphasize the interpretation of immunostains for complement components C4d and C3d in the diagnosis of antibody-mediated rejection. Evidence of regulation of complement activation in human heart transplant biopsies is presented in this context. We also discuss the pitfalls, caveats, and artifacts in the interpretation of allograft endomyocardial biopsies. Lastly, we discuss the pathology of human cardiac allograft vasculopathy in practical detail.
Pancreas Allograft Biopsies in the Management of Pancreas Transplant Recipients: Histopathologic Review and Clinical Correlations
Authors: Gaber Lillian W.
Published: February 2021

Context.—Pancreas transplantation has become a therapeutic option for patients with type 1 diabetes mellitus who are in end-stage renal failure. It also is indicated for a subset of nonuremic, insulin-dependent diabetics who experience extreme difficulties in maintaining proper glucose homeostasis by insulin therapy that compromises their productivity and safety.

Objective.—To provide a review of the literature and expert experiences for understanding the histologic findings in pancreas transplantation.

Data Sources.—The published literature between 1990 and 2005 was reviewed for this report. Additionally, personal files of the author were used, along with biopsy slides that were used for figures.

Conclusions.—Pancreas transplantation reestablishes the physiologic state of insulin secretion, and pancreas transplant recipients are able to maintain a state of long-term euglycemia and are less likely to be exposed to hyperglycemia and its systemic complications. Key to the success of transplantation is the scrupulous management and close monitoring of the pancreas transplant recipients. To that end, histologic evaluation of pancreas allografts assumed a pivotal role in management of pancreas allograft dysfunction episodes, and in some centers surveillance biopsies are used to monitor immunologically high-risk situations.
The Clinicopathologic Spectrum of Posttransplantation Lymphoproliferative Disorders
Authors: Tsao Lawrence , Hsi Eric D.
Published: February 2021

Context.—Posttransplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring in the setting of solid organ or bone marrow transplantation. They show a clinical, morphologic, and molecular genetic spectrum ranging from reactive polyclonal lesions to frank lymphomas. The close association with Epstein-Barr virus has been established and the pathogenetic role of this virus is becoming better understood. Although they are relatively uncommon, PTLDs are a significant cause of morbidity and mortality in transplant patients.

Objective.—To review the incidence, risk factors, clinical features, pathogenesis, and classification of PTLDs.

Data Sources.—We reviewed relevant articles indexed in PubMed (National Library of Medicine), with emphasis on more recent studies. The classification of PTLDs is based on the most current World Health Organization classification text.

Conclusions.—Posttransplantation lymphoproliferative disorders are a heterogeneous group of disorders showing a wide clinical and morphologic spectrum. Although relatively uncommon, PTLDs represent a serious complication after transplantation. Many risk factors for PTLD are well established, including transplanted organ, age at transplant, and Epstein-Barr virus seronegativity at transplant. However, other factors have been implicated and still require additional examination. Recent studies are shedding some light on the pathogenesis of PTLDs and defining relevant pathways related to Epstein-Barr virus. As the pathogenesis of PTLDs is further elucidated, the classification of PTLDs will most likely evolve.
Immunohistochemical Analysis of Chromophobe Renal Cell Carcinoma, Renal Oncocytoma, and Clear Cell Carcinoma: An Optimal and Practical Panel for Differential Diagnosis
Authors: Liu Lina , Qian Junqi , Singh Harpreet , Meiers Isabelle , Zhou Xiaoge , Bostwick David G.
Published: February 2021

Context.—The separation of chromophobe renal cell carcinoma, oncocytoma, and clear cell renal cell carcinoma using light microscopy remains problematic in some cases.

Objective.—To determine a practical immunohistochemical panel for the differential diagnosis of chromophobe carcinoma.

Design.—Vimentin, glutathione S-transferase α (GST-α), CD10, CD117, cytokeratin (CK) 7, and epithelial cell adhesion molecule (EpCAM) were investigated in 22 cases of chromophobe carcinoma, 17 cases of oncocytoma, and 45 cases of clear cell carcinoma.

Results.—Vimentin and GST-α expression were exclusively observed in clear cell carcinoma. CD10 staining was more frequently detected in clear cell carcinoma (91%) than in chromophobe carcinoma (45%) and oncocytoma (29%). CD117 was strongly expressed in chromophobe carcinoma (82%) and oncocytoma (100%), whereas none of the cases of clear cell carcinomas were immunoreactive. Cytokeratin 7 was positive in 18 (86%) of 22 cases of chromophobe carcinoma, whereas all oncocytomas were negative for CK7. EpCAM protein was expressed in all 22 cases of chromophobe carcinoma in more than 90% of cells, whereas all EpCAM-positive oncocytomas (5/17; 29%) displayed positivity in single cells or small cell clusters.

Conclusions.—Using the combination of 3 markers (vimentin, GST-α, and EpCAM), we achieved 100% sensitivity and 100% specificity for the differential diagnosis of chromophobe carcinoma, oncocytoma, and clear cell carcinoma. The pattern of “vimentin−/GST-α−” effectively excluded clear cell carcinoma, and homogeneous EpCAM expression confirmed the diagnosis of chromophobe carcinoma rather than oncocytoma. CD117 and CK7 were also useful markers and could be used as second-line markers for the differential diagnosis, with high specificity (100%) and high sensitivity (90% and 86%, respectively).
Population-Based Analysis of Pathologic Data: A New Approach to the Investigation of Uterine Endometrial and Ovarian Endometrioid Carcinomas
Authors: Henson Donald Earl , Schwartz Arnold M. , Tilara Amy , Grimley Philip M. , Anderson William F.
Published: February 2021

Context.—Population-based analysis of the histopathology of endometrioid adenocarcinoma of the endometrium and ovary combined with epidemiologic techniques offer a new approach to exploring the relationship of tumors that share a similar range of morphologic phenotypes.

Objective.—To evaluate the contribution of the Surveillance, Epidemiology, and End Results database to our understanding of gynecologic pathology. Specifically, to test and compare whether the etiology/pathogenesis of ovarian endometrioid cancer is as dependent upon the reproductive environment as uterine endometrial carcinoma.

Design.—Graphic plots of the epidemiologic patterns were analyzed relating to incidence and age-specific rates of ovarian and uterine endometrioid carcinomas. The graphic analysis included evaluation of age frequency density plots and logarithmic plots (log-log) of age-specific incidence rates.

Results.—At all ages, uterine endometrioid carcinomas have higher incidence rates than their ovarian homologues. Up to the age of 50 years, the log-log plots of age-specific incidence rates for each of these tumors remain essentially parallel. In contrast, after age 50 (menopause), the incidence rates begin to diverge: the rates for uterine endometrial carcinomas continue to rise, whereas the rates for ovarian endometrioid carcinomas plateau. This divergence persists even when the age-specific incidence is stratified according to histologic grade. Interestingly, endometrial stromal sarcomas follow an incidence rate pattern nearly identical to that of ovarian endometrioid carcinomas.

Conclusions.—The continuum of cellular and molecular events predisposing to gynecologic cancers of endometrioid phenotype apparently cease to operate in the ovary after menopause, but additional cellular and molecular events appear to occur in the ageing uterine endometrium.
Mucoepidermoid Carcinoma of the Bronchus: A Review
Authors: Liu Xiuli , Adams Amy L.
Published: February 2021

Although mucoepidermoid carcinoma of the salivary gland is relatively common, mucoepidermoid carcinoma arising from the mucous glands of the bronchus is rare. Bronchial mucoepidermoid carcinoma usually presents as an intraluminal mass producing luminal occlusion. Symptoms are airway obstruction and recurrent pneumonia. Macroscopically, mucoepidermoid carcinoma appears as an exophytic intrabronchial mass with intact or ulcerated bronchial mucosa. Microscopically, the tumors are located in the submucosa of the large bronchi. The tumors are usually well differentiated and contain a combination of mucus-secreting, squamous, and intermediate cells. The increased frequency of this tumor in the pediatric population suggests a genetic abnormality. Recent genetic studies have demonstrated reciprocal chromosomal translocations including t(1;11)(p22;q13), t(11;19)(q14-21;p12), and t(11; 19)(q21;p13). Chromosome 11 in the first translocation appears to have been altered resulting in up-regulation of the cyclin D1 gene and overexpression of cyclin D1. The t(11;19)(q21;p13) encodes a novel fusion product capable of disrupting the Notch signaling pathway.
New Immunohistochemical Markers in the Evaluation of Central Nervous System Tumors: A Review of 7 Selected Adult and Pediatric Brain Tumors
Authors: Takei Hidehiro , Bhattacharjee Meenakshi B. , Rivera Andreana , Dancer Yeongju , Powell Suzanne Z.
Published: February 2021

Context.—Immunohistochemistry (IHC) has become an important tool in the diagnosis of brain tumors.

Objective.—To review the latest advances in IHC in the diagnostic neuro-oncologic pathology.

Data Sources.—Original research and review articles and the authors' personal experiences.

Data Synthesis.—We review the features of new, useful or potentially applicable marker antibodies as well as the new uses of already established antibodies in the area of diagnostic neuro-oncologic pathology, focusing on the use of IHC for differential diagnosis and prognosis. We discuss (1) placental alkaline phosphatase, c-Kit, and OCT4 for germinoma, (2) α-inhibin and D2-40 for capillary hemangioblastoma, (3) phosphohistone-H3 (PHH3), MIB-1/Ki-67, and claudin-1 for meningioma, (4) PHH3, MIB-1/Ki-67, and p53 for astrocytoma, (5) synaptophysin, microtubule-associated protein 2, neurofilament protein, and neuronal nuclei for medulloblastoma, (6) INI1 for atypical teratoid/ rhabdoid tumor, and (7) epithelial membrane antigen for ependymoma. All the markers presented here are used mainly for supporting or confirming the diagnosis, with the exception of the proliferation markers (MIB-1/Ki-67 and PHH3), which are primarily used to support grading and are reportedly associated with prognosis in certain categories of brain tumors.

Conclusions.—Although conventional hematoxylin-eosin staining is the mainstay for pathologic diagnosis, IHC has played a major role in differential diagnosis and in improving diagnostic accuracy not only in general surgical pathology but also in neuro-oncologic pathology. The judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. In addition, IHC is also of great help in predicting the prognosis for certain brain tumors.
Cytokeratin and Epithelial Membrane Antigen Expression in Angiosarcomas: An Immunohistochemical Study of 33 Cases
Authors: Al-Abbadi Mousa A. , Almasri Nidal M. , Al-Quran Samer , Wilkinson Edward J.
Published: February 2021

Context.—Expression of epithelial cell markers can occur in mesenchymal tumors and has been reported in angiosarcomas with variable frequency. In these situations, establishing the diagnosis becomes problematic.

Objective.—To determine the expression of cytokeratin and epithelial membrane antigen in angiosarcoma.

Design.—To address this issue, 33 well-documented cases of angiosarcomas were retrieved from the archival material of Shands Hospital at the University of Florida, Gainesville, and Jackson Memorial Hospital at the University of Miami, Miami, Florida. These cases were all reviewed and studied using a cytokeratin cocktail (CAM 5.2 and AE1/AE3) and epithelial membrane antigen using standard immunohistochemical techniques. All 33 cases had available material for cytokeratin analysis; however, only 20 cases had enough material for epithelial membrane antigen staining.

Results.—In the 33 cases studied, the age range of the patients was 2 to 88 years (mean, 63 years). There were 23 (70%) men and 10 (30%) women. One (3%) of 33 was cytokeratin-immunoreactive and 2 (10%) of 20 were epithelial membrane antigen-immunoreactive.

Conclusion.—Cytokeratin and epithelial membrane antigen immunoreactivity in angiosarcomas is infrequent but may be encountered. Interpretation of such expression should be done with caution and in conjunction with the characteristic clinical and morphologic features of the tumor as well as the expression of endothelial cell antigens.
Malakoplakia Outside the Urinary Tract
Authors: Yousef George M. , Naghibi Bibi
Published: February 2021

Context.—Malakoplakia is a rare granulomatous disease that occurs commonly in the urinary tract. Histologically, it is defined by sheets of histiocytes (Hansemann cells) with accumulation of granular basophilic periodic acid-Schiff– positive, diastase-resistant inclusions and calcified Michaelis-Gutmann bodies, which are pathognomonic but not necessary for diagnosis. In addition to the urinary tract, malakoplakia has been reported in other organs, including the gastrointestinal tract, central nervous system, female genital tract, and the tongue.

Objectives.—To review the literature of reported sites of malakoplakia outside the urinary tract and their variable clinical presentations, and to discuss the main diagnostic features and differential diagnoses of malakoplakia. The pathogenesis and possible etiologic factors are also presented.

Data Sources.—Data for this work were collected from the published literature, textbooks, and the Internet.

Conclusions.—It is important to be aware of the existence of this entity in abnormal locations. In many situations, malignancy can be mimicked, especially when the lesion is ulcerated and is accompanied by lymph node involvement. Misinterpreting large, rapidly growing nodules of malakoplakia as tumor might lead to overstaging. Pathologists should be also aware of the possibility of malakoplakia coexisting with other lesions, such as tuberculosis and carcinoma, in the same specimen.
Primary Central Nervous System Histiocytic Sarcoma With Relapse to Mediastinum: A Case Report and Review of the Literature
Authors: Cao Ming , Eshoa Camellia , Schultz Christopher , Black Jennifer , Zu Youli , Chang Chung-Che
Published: February 2021

Histiocytic sarcoma is a rare, malignant neoplasm of the lymphohematopoietic system that usually occurs in the skin, lymph node, and intestinal tract. Here we describe a unique case of primary central nervous system histiocytic sarcoma that initially showed an indolent clinical course following local resection and radiotherapy. However, relapse of disease within the mediastinum was noted 3½ years later. Biopsies of the initial brain lesion and subsequent mediastinal recurrence each revealed an identical, diffuse proliferation of histiocytes with expression of CD45, CD68, and CD163 but not pan-cytokeratin, epithelial membrane antigen, CD3, CD15, CD20, CD30, CD43, CD79a, CD138, myeloperoxidase, ALK-1, PAX-5, CAM 5.2, S100, CD1a, or glial fibrillary acidic protein. In the literature, central nervous system histiocytic sarcoma portends a poor prognosis with median survival of 4.5 months. To our knowledge, this case represents the first case of “low-grade” primary central nervous system histiocytic sarcoma with relatively indolent clinical course. A thorough discussion of the differential diagnosis of histiocytic sarcoma and a review of primary central nervous system histiocytic sarcoma are also presented.
Intranodal Palisaded Myofibroblastoma
Authors: Nguyen Thong , Eltorky Mahmoud A.
Published: February 2021

Intranodal palisaded myofibroblastoma (IPM) usually presents as a painless, slow-growing inguinal mass. Our review of 42 cases from 13 publications indicates that two thirds of IPMs occur between the ages of 45 and 55 years, the male-female ratio is 2:1, and there is a lack of ethnic predilection. Grossly, the IPM cut surface shows areas of hemorrhage. Five microscopic features are seen: (a) compressed remnants of lymphoid tissue at the periphery; (b) spindle cells with nuclear palisading; (c) intraparenchymal hemorrhage and erythrocyte extravasation; (d) so-called amianthoid fibers; and (e) intracellular and extracellular fuchsinophilic bodies that stain positive for smooth muscle actin. Immunohistochemically, IPM is positive for smooth muscle actin and cyclin D1 and negative for S100, glial fibrillary acidic protein, CD34, and desmin, and it shows a low proliferative index of Ki-67. Electron microscopy demonstrates features of myofibroblasts and smooth muscle cells. Excellent prognosis is seen after surgical treatment, with an approximately 6% recurrence rate and no malignant transformation.
An In-Depth Look at Leydig Cell Tumor of the Testis
Authors: Al-Agha Osama M. , Axiotis Constantine A.
Published: February 2021

Leydig cell tumor (LCT) is a rare tumor of the male testicular interstitium. This article provides an overview of the major pathologic manifestations of LCT of the testis; patient characteristics; clinical, radiologic, and laboratory features; prognosis; and management. LCTs of the testis are frequently hormonally active, leading to either feminizing or virilizing syndromes. The tumor is usually benign, but malignant variants can occur. The pathologic diagnosis of LCT is usually made based on morphologic characteristics of the tumor cells. The significance of Reinke crystals in the diagnosis of LCT both cytologically and histologically is underscored. Pathologists have to be familiar with the diagnostic histopathologic features, immunohistochemical panel of this tumor, and its principal differential diagnoses to prevent tumor misdiagnosis.
Transbronchial Biopsy Interpretation in the Patient With Diffuse Parenchymal Lung Disease
Authors: Leslie Kevin O. , Gruden James F. , Parish James M. , Scholand Mary Beth
Published: February 2021

Context.—The most common lung tissue samples seen by pathologists worldwide are obtained with the flexible bronchoscope. Specimens taken for examination of diffuse or multifocal parenchymal lung abnormalities pose special challenges for the general surgical pathologist, and these challenges are often compounded by high clinical expectations for accurate and specific diagnosis.

Objective.—To present and discuss the most common histopathologic patterns and diagnostic entities seen in transbronchial biopsy specimens in the setting of diffuse or multifocal lung disease. Specifically, acute lung injury, eosinophilic pneumonia, diffuse alveolar hemorrhage, chronic cellular infiltrates, organizing pneumonia, alveolar proteinosis, sarcoidosis, Wegener granulomatosis, intravenous drug abuse-related microangiopathy, Langerhans cell histiocytosis, and lymphangioleiomyomatosis are presented. Clinical and radiologic context is provided for the more specific diagnostic entities.

Data Sources.—The published literature and experience from a consultation practice.

Conclusions.—The transbronchial biopsy specimen can provide valuable information for clinical management in the setting of diffuse or multifocal lung disease. Computed tomographic scans are useful for selecting appropriate patients to undergo biopsy and in limiting the differential diagnosis. Knowledge of the clinical context, radiologic distribution of abnormalities, and histopathologic patterns is essential. With this information, the surgical pathologist can substantially influence the diagnostic workup and help guide the clinician to an accurate clinical/radiologic/pathologic diagnosis.
Diminished Need for Folate Measurements Among Indigent Populations in the Post Folic Acid Supplementation Era
Authors: Joelson Dean W. , Fiebig Eberhard W. , Wu Alan H. B.
Published: February 2021

Context.—The mandated fortification of processed grains with folic acid in the United States and Canada in 1998 was intended to reduce the incidence of neural tube defects in pregnant women. The incidence of folate deficiency in most populations has declined dramatically since then.

Objective.—To determine the rate of folate deficiency in a cohort of indigent patients, a population among those at highest risk for folate deficiency.

Design.—Using data from 3 years (1997, 2000, and 2004), we examined results of laboratory tests for red blood cell folate ordered at 3 hospitals that predominately service the needs of indigent patients. Folate concentration cutoffs were 160 ng/mL (363.6 nmol/L) and 94 ng/mL (213 nmol/L).

Results.—Using a red blood cell folate cutoff concentration of 160 ng/mL (363.6 nmol/L), the combined incidence of folate deficiency decreased from 4.8% in 1997 to 0.6% in 2004. At a cutoff of 94 ng/mL (213 nmol/L), the incidence went from 0.98% to 0.09% in 1997 and 2004, respectively. Even when the folate concentration was found to be low, the majority of these subjects did not have macrocytosis.

Conclusions.—These data suggest that folate deficiency has become a rare event in the United States, and the utility of routine folate measurements for patients with anemia and/or increased mean corpuscular volume are difficult to justify.