bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric CD56+ Anaplastic Large Cell Lymphoma: A Review of the Literature
Authors: Dunphy Cherie H. , DeMello Daphne E. , Gale Gordon B.
Published: February 2021

Context.—Anaplastic large cell lymphomas (ALCLs) are a heterogeneous group of CD30+ large cell lymphomas that, according to the World Health Organization classification, are defined as being of T-cell origin, based on immunophenotype, and/or the finding of a T-cell gene rearrangement by molecular studies. Most cases express cytotoxic granule-associated proteins. Relatively recent data have suggested that some T-cell ALCLs are derived from cytolytic CD4+ cells, γδ T cells, or natural killer–like (CD56+ or CD57+) T cells. We encountered a pediatric case of CD56+, anaplastic lymphoma kinase-positive ALCL of apparent natural killer–like T-cell origin (showing positivity for CD2, cytoplasmic CD3, surface CD3 partial positivity, CD7, CD8, CD56, TIA-1, and granzyme B). The patient had initial lymph node and multiple sites of cutaneous involvement and an aggressive clinical course with multiple recurrences after varying periods of complete remission.

Objective.—To review the current pediatric literature regarding the incidence, differential diagnosis, and clinical course of such cases.

Data Sources.—Relevant articles indexed in PubMed (National Library of Medicine) between 1975 and 2006.

Conclusions.—Our review did not confirm a uniformly aggressive clinical course in pediatric cases of CD56+ ALCLs. Such cases suggest the usefulness of the analysis of CD56-positivity in additional cases of ALCL in an attempt to accrue additional information on this condition. Future accrual of such cases may address whether such cases should be treated more aggressively or with possible targeted therapeutic regimens.
Birt-Hogg-Dubé Syndrome: Clinicopathologic Findings and Genetic Alterations
Authors: Adley Brian P. , Smith Norm D. , Nayar Ritu , Yang Ximing J.
Published: February 2021

Context.—Birt-Hogg-Dubé (BHD) syndrome is a rare clinicopathologic condition transmitted in an autosomal dominant fashion. This complex entity is characterized by cutaneous fibrofolliculomas, kidney tumors, pulmonary cysts, and spontaneous pneumothorax. Recently, the gene possibly responsible for the clinical manifestations of BHD syndrome has been cloned and characterized. The few reviews of BHD syndrome found in the English literature mostly focus on the skin lesions or genetics, with limited information on other pathologic changes, particularly the kidney lesions.

Objective.—To review the literature on this subject with a special emphasis on BHD syndrome-associated renal pathology as well as recent advances in molecular genetic discovery of the BHD syndrome.

Data Sources.—We used all data available after performing a literature search using MEDLINE and searching under the headings “Birt-Hogg-Dubé,” “hybrid oncocytic tumors,” and “folliculin.”

Conclusions.—The presence of BHD syndrome should be investigated in any patient with multiple bilateral kidney tumors, especially if the predominant histologic type is chromophobe renal cell carcinoma or the so-called hybrid oncocytic tumor. The genetic alteration for BHD syndrome has been mapped to chromosome 17p12q11, and the gene in this region has been cloned and believed to be responsible for the BHD syndrome. The function of the BHD product, called folliculin, is still unknown, although it is speculated to be a tumor suppressor gene. Numerous mutations have been described in the BHD gene. Studies are ongoing to determine the relationship between the BHD gene and development of sporadic renal cell carcinoma and other lesions.
Radiation-Associated Extraskeletal Osteosarcoma of the Chest Wall
Authors: Orta Lurmag , Suprun Ulana , Goldfarb Alisan , Bleiweiss Ira , Jaffer Shabnam
Published: February 2021

Radiation-associated sarcoma is a rare but potential complication of radiation therapy. Most reported cases of osteosarcoma of the chest wall following radiation therapy for breast cancer arise from the chest wall skeletal structures. In contrast, few cases of extraskeletal osteosarcomas have been reported. We report a rare example of an extraskeletal osteosarcoma involving the pectoralis major muscle occurring after radiation therapy for breast cancer. Extraskeletal osteosarcomas are rare soft tissue tumors with a high rate of local recurrence and a poor prognosis.
Solitary Fibrous Tumor of the Larynx: A Case Report and Review of the Literature
Authors: Dotto Jorge E. , Ahrens William , Lesnik David J. , Kowalski Diane , Sasaki Clarence , Flynn Stuart
Published: February 2021

Solitary fibrous tumors are relatively rare mesenchymal neoplasms that were originally described as pleural- or peritoneal-based lesions. Although they were considered a form of mesothelioma, subsequent investigation failed to reveal mesothelial differentiation. Characterization of their histologic and immunohistochemical features, as well as identification in a multitude of nonmesothelial-based locations has further served to distinguish these lesions from the more diffuse and aggressive mesothelioma. Reports of solitary fibrous tumor in the larynx are extremely rare. We report a case of solitary fibrous tumor of the larynx in a 38-year-old man.
Key Issues in Reporting Common Cancer Specimens: Problems in Pathologic Staging of Colon Cancer
Authors: Compton Carolyn C.
Published: February 2021

Context.—Standardized pathologic assessment is a quality measure for cancer care.

Objective.—Pathologic staging parameters and the clinically important stage-independent pathologic factors that pathologists find most problematic to evaluate in colorectal cancer resection specimens are reviewed. The objective of this review is to provide practical guidance for the practicing surgical pathologist.

Data Sources.—Published literature related to the TNM staging system for colorectal cancer of the American Joint Committee on Cancer and the International Union Against Cancer and to stage-independent tissue-based prognostic factor evaluation was included in the review.

Study Selection, Data Extraction, and Synthesis.—Published guidelines from authoritative sources and published peer-reviewed data related to colorectal cancer staging and pathologic prognostic factor assessment were included for consideration. The general and site-specific rules of application of the American Joint Committee on Cancer and International Union Against Cancer TNM staging system for the colorectum and the protocol for evaluation of colorectal cancer resection specimens of the Cancer Committee of the College of American Pathologists served as the basis for discussion and amplified with practical advice on specific application.

Conclusions.—Standardization of pathologic evaluation of colorectal cancer resection specimens is essential for optimal patient care and is aided by the use of data-driven guidelines that are easily understood and consistently applied.
The Value of Monitoring Frozen Section–Permanent Section Correlation Data Over Time
Authors: Raab Stephen S. , Tworek Joseph A. , Souers Rhona , Zarbo Richard J.
Published: February 2021

Context.—The effectiveness of the long-term monitoring of errors detected by frozen section–permanent section correlation is unknown.

Objective.—To determine factors important in laboratory improvement in frozen section–permanent section discordant and deferral rates by participation in a multi-institutional continuous quality improvement program.

Design.—Participants in the College of American Pathologists Q-Tracks program self-reported the number of anatomic pathology frozen–permanent section discordant and deferred cases in their laboratories by prospectively performing secondary review of intraoperative consultations. Laboratories participated in the program for 1 to 5 years and reported their data every quarter. We calculated mean and median discordant and deferred case frequencies and used mixed linear modeling to determine if length of participation in the program was associated with improved performance.

Participants.—One hundred seventy-four laboratories self-reported data.

Main Outcome Measures.—Mean frozen–permanent section discordant and deferred diagnostic frequencies and changes in these frequencies over time were measured.

Results.—The mean and median frozen–permanent section discordant frequencies were 1.36% and 0.70%, respectively. The mean and median deferred diagnostic frequencies were 2.35% and 1.20%, respectively. Longer participation in the Q-Tracks program was significantly associated (P = .04) with lower discordant frequencies; 4- or 5-year participation showed a decrease in discordant frequency of 0.99%, whereas 1-year participation showed a decrease in discordant frequency of 0.84%. Longer participation in the Q-Tracks monitor was associated with lower microscopic sampling frequencies for discordant diagnoses (P = .04). Increased length of participation in the Q-Tracks program was significantly associated (P = .04) with lower deferred diagnostic frequencies.

Conclusions.—Long-term monitoring of frozen–permanent section correlation is associated with sustained improvement in performance.
Expression of Transforming Growth Factor β1, β2, and β3 in Chronic, Cancer-Associated, Obstructive Pancreatitis
Authors: Fukumura Yuki , Kumasaka Toshio , Mitani Keiko , Karita Kanae , Suda Koichi
Published: February 2021

Context.—Myofibroblasts are considered to play central roles in pancreatic fibrosis. The potent fibrogenic capacities of transforming growth factor βs (TGF-βs) have been emphasized in vitro and in animal studies. However, the roles of TGF-βs in human chronic pancreatitis have not been fully clarified.

Objective.—To investigate whether expressions of TGF-βs are related to myofibroblast distribution in chronic, cancer-associated, obstructive pancreatitis (COP).

Design.—Histopathologic studies using hematoxylin-eosin and Elastica-Masson trichrome and immunohistochemical studies using antibodies against α-smooth muscle actin (SMA); CD68; TGF-β1, -β2, and -β3; and TGF-β soluble receptor type II were performed in 19 COP cases and 6 controls. By classifying COP tissues into 3 fibrosis phases by the amount of collagen deposits, immunoreactivities for TGF-βs, histopathologic changes, and myofibroblast distribution were examined for each fibrosis phase.

Results.—Six cases were categorized in the early stage of fibrosis, 8 in the intermediate stage, and 5 in the advanced stage. Immunoreactivities for all 3 isoforms of TGF-β were observed in occasional myofibroblasts. In the early and intermediate stages, TGF-β1–expressing macrophages and neutrophils were distributed in the midst of myofibroblasts. TGF-β2 and TGF-β3 expressions were observed in ductal structures, sometimes even in sites where no or few myofibroblasts were seen. TGF-β soluble receptor type II was immunoreactive for myofibroblasts, endothelium, and ductal structures.

Conclusions.—All 3 isoforms of TGF-βs may contribute to fibrosis in COP. Macrophages and neutrophils may be sources of fibrogenic TGF-β1. Infiltration of these cells appears to play an important role in the progression of COP fibrosis.
Neutrophil Volume Distribution Width: A New Automated Hematologic Parameter for Acute Infection
Authors: Chaves Fernando , Tierno Bethany , Xu Dongsheng
Published: February 2021

Context.—The number of band forms and immature neutrophils increases during acute bacterial infection. However, the determination of band counts and other neutrophil morphologic changes, such as the presence of toxic granulation, toxic vacuolization, and Dohle bodies in the cytoplasm, is labor intensive and time consuming, as it requires manual examination by an experienced medical technologist.

Objective.—To investigate the value of the neutrophil volume distribution width (NDW), generated by VCS technology of the Coulter LH 750 hematology analyzer, as an additional predictor of acute infection.

Design.—Total white blood cell count, percentage of neutrophils, and NDW data from 70 patients with positive blood cultures for bacteria and from 35 age-matched control subjects were retrospectively analyzed.

Results.—A significant increase in the NDW was observed in the bacteremic patients compared with the controls (24.7 ± 4.5 vs 19.0 ± 1.5; P < .001). Such increase was observed even in patients with white blood cell counts less than 11 000/μL (23.0 ± 5.6 vs 19.0 ± 1.5; P < .001) or with percentages of neutrophils less than 85% (24.0 ± 4.9 vs 19.0 ± 1.5; P < .001). The more dramatic increases were seen in patients with leukocytosis (25.7 ± 3.2, P < .001) or with neutrophilia (25.9 ± 3.4, P < .001). Using an NDW cutoff of 23, a 100% specificity and a 69% sensitivity were achieved.

Conclusions.—As a quantitative parameter, the NDW has potential for use as an additional indicator for diagnosing acute infection.
Postirradiation Osteosarcoma of the Mandible With Heterologous Differentiation
Authors: Seethala Raja R. , Sturgis Erich M. , Raymond A. Kevin , Deavers Michael T.
Published: February 2021

Heterologous differentiation in osteosarcoma is rare, with only 17 cases previously described in the literature. We report a case of a mandibular osteoblastic osteosarcoma with rhabdomyosarcomatous differentiation in a 45-year-old man who had a history of Hodgkin lymphoma that was treated with chemotherapy and radiation. Radiographs showed a destructive osteoblastic tumor of the mandible that was proven by biopsy to be osteosarcoma. After the patient underwent neoadjuvant chemotherapy, the tumor was resected. It contained a high-grade osteosarcoma composed of osteoblastic and chondroblastic elements that had no definitive response to therapy. Within the center of the lesion was a discrete focus of pleomorphic cells with rhabdomyosarcomatous differentiation that was confirmed by immunohistochemical stains for desmin, myogenin, and myogenic differentiation antigen 1. The patient received additional chemotherapy and radiation therapy but developed lung, brain, and spinal metastases and died 7 months after surgery. To our knowledge, this is the first report of osteosarcoma of the mandible with heterologous differentiation.
Asthma: Pathology and Pathophysiology
Authors: Barrios Roberto J. , Kheradmand Farrah , Batts La Keisha , Corry David B.
Published: February 2021

Context.—Asthma has been defined as a chronic inflammatory disorder of the airways that is associated with recruitment of inflammatory cells and the clinical development of wheezing, shortness of breath, chest tightness, and cough. Asthma is a major public health issue. It affects 5% of the United States population and accounts for 2 million emergency department visits, 470 000 hospitalizations, and 4500 deaths annually.

Objective.—To review the pathophysiology and characteristic pathologic patterns of this disease and discuss the possible mechanisms of production of the lesions.

Data Sources.—We searched the literature using MEDLINE and OVID. We also searched related conference abstracts and bibliographies of selected studies.

Conclusions.—There has been a significant evolution in our understanding of asthma. Specific pathways and mechanisms in recent years have been studied; however, numerous mediators and cell receptors have raised new questions that remain to be answered.
Molecular Classification of Human Cancers Using a 92-Gene Real-Time Quantitative Polymerase Chain Reaction Assay
Authors: Ma Xiao-Jun , Patel Rajesh , Wang Xianqun , Salunga Ranelle , Murage Jaji , Desai Rupal , Tuggle J. Todd , Wang Wei , Chu Shirley , Stecker Kimberly , Raja Rajiv , Robin Howard , Moore Mat , Baunoch David , Sgroi Dennis , Erlander Mark
Published: February 2021

Context.—Correct diagnosis of the tissue origin of a metastatic cancer is the first step in disease management, but it is frequently difficult using standard pathologic methods. Microarray-based gene expression profiling has shown great promise as a new tool to address this challenge.

Objective.—Adoption of microarray technologies in the clinic remains limited. We aimed to bridge this technological gap by developing a real-time quantitative polymerase chain reaction (RT-PCR) assay.

Design.—We constructed a microarray database of 466 frozen and 112 formalin-fixed, paraffin-embedded (FFPE) samples of both primary and metastatic tumors, measuring expression of 22 000 genes. From the microarray database, we used a genetic algorithm to search for gene combinations optimal for multitumor classification. A 92-gene RT-PCR assay was then designed and used to generate a database for 481 frozen and 119 FFPE tumor samples.

Results.—The microarray-based K-nearest neighbor classifier demonstrated 84% accuracy in classifying 39 tumor types via cross-validation and 82% accuracy in predicting 112 independent FFPE samples. We successfully translated the microarray database to the RT-PCR platform, which allowed an overall success rate of 87% in classifying 32 different tumor classes in the validation set of 119 FFPE tumor samples.

Conclusions.—The RT-PCR-based expression assay involving 92 genes represents a powerful tool for accurately and objectively identifying the site of origin for metastatic tumors, especially in the cases of cancer of unknown primary. The assay uses RT-PCR and routine FFPE samples, making it suitable for rapid clinical adoption.
Warthin Tumors Do Not Have Microsatellite Instability and Express Normal DNA Mismatch Repair Proteins
Authors: Hunt Jennifer L.
Published: February 2021

Context.—Warthin tumors are controversial entities with a poorly understood etiology. Although some investigators have suggested a neoplastic origin, others have supported a developmental anomaly. A recent study described the absence of staining for hMLH1 and hMSH2 proteins in the epithelial component of Warthin tumors, suggesting that they arise secondary to defects in the DNA mismatch repair system.

Objective.—To determine if Warthin tumors exhibit evidence of DNA mismatch repair defects.

Design.—Immunostains for hMLH1 and hMSH2 were performed using a standard approach. Microdissection of the epithelial component was followed by DNA extraction from the tissue fragments. Polymerase chain reaction and capillary electrophoresis analyses were performed for the following 5 National Cancer Institute–recommended microsatellites: D2s123, D5s346, D17s250, BAT25, and BAT26.

Patients.—Twelve patients with Warthin tumors were included.

Results.—The immunostains for hMLH1 and hMSH2 showed preserved expression in the nuclei of the epithelial component of all Warthin tumors. No microsatellite instability was detected, and no loss of heterozygosity was seen.

Conclusions.—These results are not concordant with previously reported results showing loss of expression of the hMLH1 and hMSH2 DNA mismatch repair enzymes in the epithelial component of Warthin tumors. Furthermore, no microsatellite instability was detected in the 5 loci tested for each tumor in this series. These data demonstrate that Warthin tumors do not have evidence of DNA mismatch repair defects at the genomic or protein expression level.
Herbal Remedies: Effects on Clinical Laboratory Tests
Authors: Dasgupta Amitava , Bernard David W.
Published: February 2021

Context.—Complementary and alternative medicine (herbal medicines) can affect laboratory test results by several mechanisms.

Objective.—In this review, published reports on effects of herbal remedies on abnormal laboratory test results are summarized and commented on.

Data Sources.—All published reports between 1980 and 2005 with the key words herbal remedies or alternative medicine and clinical laboratory test, clinical chemistry test, or drug-herb interaction were searched through Medline. The authors' own publications were also included. Important results were then synthesized.

Data Synthesis.—Falsely elevated or falsely lowered digoxin levels may be encountered in a patient taking digoxin and the Chinese medicine Chan Su or Dan Shen, owing to direct interference of a component of Chinese medicine with the antibody used in an immunoassay. St John's wort, a popular herbal antidepressant, increases clearance of many drugs, and abnormally low cyclosporine, digoxin, theophylline, or protease inhibitor concentrations may be observed in a patient taking any of these drugs in combination with St John's wort. Abnormal laboratory results may also be encountered owing to altered pathophysiology. Kava-kava, chaparral, and germander cause liver toxicity, and elevated alanine aminotransferase, aspartate aminotransferase, and bilirubin concentrations may be observed in a healthy individual taking such herbal products. An herbal product may be contaminated with a Western drug, and an unexpected drug level (such as phenytoin in a patient who never took phenytoin but took a Chinese herb) may confuse the laboratory staff and the clinician.

Conclusions.—Use of alternative medicines may significantly alter laboratory results, and communication among pathologists, clinical laboratory scientists, and physicians providing care to the patient is important in interpreting these results.
Synchronous Interdigitating Dendritic Cell Sarcoma and B-Cell Small Lymphocytic Lymphoma in a Lymph Node
Authors: Cossu Antonio , Deiana Angelo , Lissia Amelia , Dedola Maria Filomena , Cocco Lucia , Palmieri Giuseppe , Tanda Francesco
Published: February 2021

A gradually enlarging axillary mass in a 79-year-old man was excised. The specimen was processed for light microscopy, immunohistochemical studies, and electron microscopy; gene rearrangement studies were also performed. A diagnosis of an interdigitating dendritic cell tumor of the lymph node and a B-cell small lymphocytic lymphoma occurring in the same anatomic location was made. We found that although rare cases of interdigitating dendritic cell tumor with an associated secondary malignancy have been described in the literature, to our knowledge, this is the first report of interdigitating dendritic cell tumor and synchronous neoplasm diagnosed at the same site. A possible relationship between the 2 disorders is also discussed.
Surgical Pathology—Second Reviews, Institutional Reviews, Audits, and Correlations: What's Out There? Error or Diagnostic Variation?
Authors: Frable William J.
Published: February 2021

Context.—A variety of methodologies have been used to report error rates in surgical pathology within the peer-reviewed medical literature. The media has selectively and superficially reported these error rates creating a climate of disinformation between physicians and the public.

Objectives.—To review the medical literature on diagnostic error in surgical pathology and summarize and compare these data with selected reports in the print and broadcast media.

Design.—A search of the medical literature from the National Library of Medicine database using the heading “Error and Pathology Diagnosis.”

Results.—Three thousand nine hundred ninety-two citations were found, of which 83 directly measured in some manner errors in surgical and cytopathology. Major error rates ranged from 1.5% to 5.7% globally for institutional consults. Error rates were less, 0.26% to 1.2% for global in-house prospective review and 4.0% for in-house and retrospective blinded review. Error rates also varied by anatomic site: skin, institutional consult, 1.4%; prostate, institutional consult, 0.5%; and thyroid, institutional consult, 7.0%. Error rates reported in citations used by the Wall Street Journal were as follows: prostate, Gleason score changed by 1 point, 44% and resultant change in treatment for prostate cancer, 10%; for breast, altered lumpectomy or mastectomy plan, 8%; and diagnosis changed for thyroid lesions, 18%. Errors in second opinion on breast lesions (single pathologist author for the study) fall within the range of global reviews. Errors for second opinions on prostate cancer were principally 81% upgrades in Gleason score for prostate core needle biopsies. However, this resulted in an upgrade of patient risk category in only 10.8% of patients. Data for the article on change in diagnosis of thyroid lesions were incomplete. There appeared to be 3 significant diagnostic errors (4.5%).

Conclusions.—Pathology is not immune to the power of the media to create concern about accuracy of diagnosis in surgical pathology and cytopathology. Detailed analysis of the medical literature cited by the media determines that painting the big picture and hitting the highlights can be profoundly misleading.
Imatinib Resistance: Obstacles and Opportunities
Authors: Litzow Mark R.
Published: February 2021

Objective.—To review the current status of resistance to imatinib mesylate (IM) in patients with chronic myelogenous leukemia, and the obstacles and opportunities presented by the development of this resistance.

Data Sources and Study Selection.—Review of selected studies obtained from a MEDLINE search encompassing the years 1950 to 2004.

Data Extraction and Data Synthesis.—Relevant information from the selected studies was abstracted and summarized.

Conclusions.—The identification of the Philadelphia chromosome and the subsequent discovery that it represents a translocation between the long arms of chromosomes 9 and 22 producing an aberrant tyrosine kinase, known as BCR-ABL1, has catalyzed our understanding and treatment of this hematologic malignancy. An extensive search for molecules to block the aberrant BCR-ABL1 protein resulted in the development of IM as an orally bioavailable agent with remarkable efficacy in producing hematologic, cytogenetic, and molecular remissions. However, follow-up of patients treated with IM has demonstrated that some patients can develop resistance to IM with progression of their leukemia. Multiple mechanisms of resistance have been identified. The dominant mechanism appears to be mutations in the kinase domain of BCR-ABL1, which result in altered affinity of IM for the BCR-ABL1 protein. Recently, small-molecule, combined SRC and ABL1 inhibitors have been developed and entered into clinical trials. These inhibitors appear effective in inhibiting most of the mutant BCR-ABL1 molecules that are resistant to IM. The rapid development of new therapies for treatment of chronic myelogenous leukemia brings the promise that this disorder can be cured or controlled in many patients with oral drugs that have a low toxicity profile.
Evaluation of HER-2/neu Gene Status in Osteosarcoma by Fluorescence In Situ Hybridization and Multiplex and Monoplex Polymerase Chain Reactions
Authors: Willmore-Payne Carlynn , Holden Joseph A. , Zhou Holly , Gupta Dilip , Hirschowitz Sharon , Wittwer Carl T. , Layfield Lester J.
Published: February 2021

Context.—Previous reports suggest that the human epidermal growth factor 2 (HER-2/neu) receptor may be overexpressed in osteosarcoma.

Objective.—To determine whether osteosarcomas have amplifications of the HER-2/neu gene.

Design.—We studied a series of osteosarcomas by fluorescence in situ hybridization (FISH) and by 2 real-time polymerase chain reaction assays that measure the amount of HER-2/neu DNA relative to a control gene. The HER-2/ neu monoplex and multiplex assays were capable of identifying those cases of breast cancer that were known to overexpress HER-2/neu as assessed by FISH. We initially studied 21 cases of osteosarcoma by FISH analysis (using a technique that included a probe for chromosome 17), 11 of which had their HER-2/neu gene amplification status previously reported.

Results.—None of these osteosarcoma cases showed HER-2/neu amplification by our FISH analysis and subsequent quantitative (multiplex) polymerase chain reaction. Apparent expression of HER-2/neu protein was observed in several of the cases but the immunoreactivity was localized to the cytoplasm and was not membranous in character. An additional 35 osteosarcoma specimens were subjected to monoplex polymerase chain reaction analysis, and amplifiable DNA was recovered from 19 specimens (54%). None of these samples had HER-2/neu amplification by monoplex PCR analysis and only one case had membranous immunoreactivity graded as 1+.

Conclusion.—Although a small subset of osteosarcomas had weak noncircumferential membranous immunoreactivity for HER-2/neu protein, no osteosarcomas demonstrated positive (2+ or 3+) immunoreactivity for HER-2/ neu protein and none showed HER-2/neu gene amplification by either FISH or polymerase chain reaction.
β-Catenin Nuclear Expression Correlates With Cyclin D1 Expression in Primary and Metastatic Synovial Sarcoma: A Tissue Microarray Study
Authors: Horvai Andrew E. , Kramer Miranda J. , O'Donnell Richard
Published: February 2021

Context.—The association between aberrant (nuclear) β-catenin expression and cyclin D1 accumulation has been demonstrated in diverse neoplasms. In synovial sarcoma (SS), aberrant β-catenin expression has prognostic relevance, but the association with cyclin D1 has not been established. The SYT-SSX fusion protein, unique to SS, may independently increase cyclin D1.

Objective.—To determine whether nuclear β-catenin is associated with cyclin D1 overexpression in SS and whether primary and metastatic SS differ in the expression of these markers.

Design.—We incorporated 82 tumors initially diagnosed as SS into a tissue array. Fluorescence in situ hybridization with custom probes was used to select t(X;18) positive tumors. Clinical data, tumor type and outcome were tabulated. The tumors were tested for the association between nuclear β-catenin and cyclin D1 immunostaining. Primary and metastatic tumors were compared.

Results.—Fifty-one tumors (41 primary and 10 metastatic) from 43 patients demonstrated t(X;18). Cyclin D1 staining was identified in 21 (59%) primary and 8 (80%) metastatic tumors, respectively, and nuclear β-catenin in 24 (41%) primary and 7 (70%) metastatic tumors, respectively. No significant difference was noted between primary and metastatic tumors with respect to the above markers. The presence of nuclear β-catenin showed a significant association with cyclin D1 expression (P < .001). A small number of cyclin D1 cases were negative for nuclear β-catenin but positive for phosphorylated Akt.

Conclusions.—Increased cyclin D1 in SS may be driven by abnormally expressed β-catenin, similar to other neoplasms. The pattern of expression of these markers is established early during tumorigenesis.
Mucin Profiles in Signet-ring Cell Carcinoma
Authors: Nguyen; Minh D. , Plasil Brian , Wen Ping , Frankel Wendy L.
Published: February 2021

Context.—Signet-ring cell carcinoma (SRCC) is a poorly differentiated mucin-producing adenocarcinoma that may arise from many different organs, but all SRCCs share identical morphology. It is not possible to differentiate sites of origin for metastatic SRCC based on morphology alone. Mucins are high-molecular-weight glycoproteins differentially expressed in glandular epithelia and in adenocarcinomas.

Objective.—To identify mucin profiles of primary and metastatic SRCCs using immunohistochemistry to determine whether mucin staining could help distinguish sites of origin.

Design.—Forty-seven SRCCs, including 38 primary (21 stomach, 11 colorectum, and 6 breast) and 9 metastases from these primary sites were retrieved from archival files. Consecutive tissue sections were immunostained with monoclonal antibodies against MUC1, MUC2, MUC4, MUC5AC (MUC5), and MUC6 on separate slides. Cytoplasmic staining was scored based on proportion of positive tumor cells as follows: 0+ (<5%), 1+ (5%–25%), 2+ (26%–50%), and 3+ (>50%). Mucin profiles were recorded as MUC+, MUCv, and MUC− for consistent, variable, and negative expression, respectively.

Results.—The mucin profiles for gastric, colorectum, and breast SRCCs are MUC1·2·4·5·6v, MUC2·4+/MUC5v/ MUC1·6−, and MUC1+/MUC2·5·6v/MUC4−, respectively. Mucin profiles of metastatic cases shared profiles with their respective primaries.

Conclusions.—Signet-ring cell carcinomas of the stomach, colorectum, and breast have distinct mucin expression patterns that are maintained in metastases. Mucin profiling may be useful to identify the origin of a metastatic SRCC of unknown primary.
Current Prostate Biopsy Interpretation: Criteria for Cancer, Atypical Small Acinar Proliferation, High-Grade Prostatic Intraepithelial Neoplasia, and Use of Immunostains
Authors: Iczkowski Kenneth A.
Published: February 2021

Context.—The past decade has brought major changes in prostate biopsy sampling, interpretation, and reporting.

Objective.—To summarize current information on diagnostic decision making, Gleason grading, “atypical” diagnoses, and use of immunostaining.

Data Sources.—Pertinent literature from 1985 to 2005 is reviewed, emphasizing recent findings.

Conclusions.—Diagnosis begins by evaluating a focus of atypical single-cell layer lined acini according to the 3 minimal diagnostic criteria for cancer: an infiltrative pattern, nuclear enlargement and hyperchromasia, and prominent nucleoli. The Gleason score and linear extent or percent of each core containing cancer should be reported. Atypical small acinar proliferation suspicious for malignancy designates foci that have either qualitative or quantitative limitations in atypia precluding a definite cancer diagnosis. It has about a 3% incidence as an isolated finding. Contemporary studies indicate a 39% predictive value for cancer on repeat biopsy. Isolated high-grade prostatic intraepithelial neoplasia has a 3% to 14% incidence and predicts cancer on repeat biopsy in 23% of cases. Immunostaining for a marker of benign prostate (cytoplasmic keratin 34βE12 or nuclear p63) and a marker of cancer (α-methylacyl coA racemase, clone P504S) may or may not resolve atypical small acinar proliferation diagnoses. Performance of 34βE12 and P504S immunostains resolved 76% of atypical small acinar proliferation diagnoses per consensus of 3 urologic pathologists studied; a technical limitation is preservation of the focus in question on the levels used for immunostaining.
Malignant Solitary Fibrous Tumor of the Kidney: Report of a Case and Comprehensive Review of the Literature
Authors: Fine Samson W. , McCarthy Denis M. , Chan Theresa Y. , Epstein Jonathan I. , Argani Pedram
Published: February 2021

Renal solitary fibrous tumors (SFTs) have been reported infrequently. We report a 76-year-old man with a left renal mass that had previously been shown radiographically to be stable, but was now growing. Grossly, the mass measured 12 cm, was poorly circumscribed, and invaded beyond the renal capsule. Approximately 10% of the neoplasm consisted of haphazardly arranged spindle cells admixed with dense collagenous bands, which is typical of benign SFT. However, the remainder of the mass was composed of pleomorphic, spindled sarcoma cells with frequent mitoses and foci of necrosis. Immunohistochemically, we observed CD34 labeling in the benign SFT component with loss of expression in the sarcomatous component, focal labeling for Bcl-2 protein in both areas, and absence of labeling for cytokeratin, renal cell carcinoma marker, S100 protein, CD117, and muscle markers in both areas. To our knowledge, this is the first reported case of malignant renal SFT, likely representing transformation from a histologically documented benign SFT component.
Paratesticular Papillary Mesothelioma: A Case With Borderline Features
Authors: Cabay Robert J. , Siddiqui Noman H. , Alam Shumyle
Published: February 2021

Most often, mesotheliomas involve the serosal (serous) membranes of the pleura and peritoneum. Sometimes, mesothelial proliferations are identified in other locations. On very rare occasions, a mesothelioma is found within the tunica vaginalis of the paratesticular region. We report a case of papillary mesothelioma of the tunica vaginalis in a 52-year-old man. Although this lesion had papillary structures lined by a single layer of mesothelial cells with predominantly bland nuclear and cytologic features, there was evidence of a minimal presence of mesothelial cells in the underlying stroma. This combination of benign and semimalignant characteristics can make the diagnosis of such a lesion problematic. We think that a diagnosis of “borderline papillary mesothelioma” can be considered for similar mesothelial proliferations to allow for a possible increase in diagnostic accuracy and provide an enhanced informational platform from which patients and clinicians can benefit.
Acquired Pelger-Huët Anomaly in Association With Concomitant Tacrolimus and Mycophenolate Mofetil in a Liver Transplant Patient: A Case Report and Review of the Literature
Authors: Etzell Joan E. , Wang Endi
Published: February 2021

Pelger-Huët anomaly is a congenital or acquired abnormality of neutrophil nuclear segmentation. The acquired form may be a result of a clonal myeloid malignancy, such as myelodysplastic syndrome, or may be a secondary nonclonal change related to a variety of underlying causes, including infections and medications. We report a case of a 56-year-old man who developed acquired Pelger-Huët anomaly following liver transplantation while on the immunosuppressive agents tacrolimus and mycophenolate mofetil. These medications have been reported in association with this abnormality, but usually as a single agent or in combination with other drugs. In our case, the Pelger-Huët anomaly may be the result of the combination of these 2 drugs or mycophenolate alone with subsequent desensitization because resolution of the abnormality occurred after a reduction in mycophenolate mofetil dose, and the abnormality did not recur when mycophenolate mofetil was increased to a dose previously associated with Pelger-Huët anomaly during the time that tacrolimus was discontinued.
Unusual Forms of Immature Sporulating Coccidioides immitis Diagnosed by Fine-Needle Aspiration Biopsy
Authors: Ke Yong , Smith Corey W. , Salaru Gratian , Joho Kim L. , Deen Malik F.
Published: February 2021

Coccidioidomycosis is an endemic infection acquired by inhalation of the spores (arthroconidia) of the thermally dimorphic fungus, Coccidioides immitis. The arthroconidia transform into spherical cells called mature spherules in the lung. Immature spherules and other atypical forms of immature C immitis have rarely been found in vivo. We report on a case that presented unusual forms of immature sporulating C immitis in a fine-needle aspiration specimen. A 36-year-old Chinese woman, living in New Jersey for the past 10 years, presented with fever, night sweats, hemoptysis, and an abnormal chest radiograph approximately 9 months after a brief vacation trip to the Grand Canyon in Arizona. She was treated with antibiotics for 4 weeks without improvement. Subsequent chest computed tomography showed a 3-cm cavitary lesion in the right lower lobe of the lung. Fine-needle aspiration biopsy revealed diverse morphologic forms of a fungus that was confirmed by culture as immature sporulating C immitis.
Differential Expression of Melanocytic Markers in Myoid, Lipomatous, and Vascular Components of Renal Angiomyolipomas
Authors: Roma Andres A. , Magi-Galluzzi Cristina , Zhou Ming
Published: February 2021

Context.—Renal angiomyolipoma is a tumor composed of varying amounts of fat, smooth muscle, and blood vessels. Characteristically, tumor cells express melanocytic markers such as HMB-45 and Melan-A. Recently, several other markers have been described as having excellent diagnostic sensitivity in cutaneous melanocytic lesions.

Objectives.—To compare the sensitivities of 5 melanocytic markers in renal angiomyolipoma and to study the expression patterns of these markers in the 3 different components of angiomyolipoma.

Design.—A tissue microarray of 20 renal angiomyolipomas was constructed. For each case, 3 cores containing fat, blood vessels, and smooth muscle were taken. The tissue microarray was then stained for HMB-45, Melan-A, tyrosinase, NK1-C3, and CD117.

Results.—HMB-45 was positive in 95%, Melan-A in 85%, NK1-C3 in 70%, tyrosinase in 50%, and CD117 in 40% of the cases. All (20/20) were positive for HMB-45 and Melan-A combined. These 5 markers had different sensitivities in the 3 components. HMB-45 was positive in 90%, 85%, and 80% of fat, smooth muscle, and blood vessel components, respectively; Melan-A in 70%, 60%, and 40%; NK1-C3 in 55%, 55%, and 45%; tyrosinase in 30%, 40%, and 10%; and CD117 in 20%, 40%, and 10%, respectively, of these 3 components.

Conclusions.—HMB-45 and Melan-A combined were positive in 100% of the renal angiomyolipomas. We recommend the use of these 2 markers in the workup of this entity, including those with predominantly 1 component. Other melanocytic markers are of limited use. A tissue block comprising predominantly fat or smooth muscle components should be used when performing melanocytic marker immunostain.
Placental Mesenchymal Dysplasia
Authors: Parveen Zahida , Tongson-Ignacio Jane Elaine , Fraser Cory R. , Killeen Jeffery L. , Thompson Karen S.
Published: February 2021

Context.—Placental mesenchymal dysplasia is characterized by placentomegaly and may be mistaken for molar pregnancy both clinically and macroscopically because of the presence of “grapelike vesicles.” It may be associated with a completely normal fetus, a fetus with growth restriction, or a fetus with features of Beckwith-Wiedemann syndrome.

Objective.—To review the etiology, molecular pathology, gross and microscopic features, clinical presentation, complications, and differential diagnosis of placental mesenchymal dysplasia.

Data Sources.—The PubMed and the Medline databases were systematically searched for articles between 1970 and 2006. The following keywords were used: placental mesenchymal dysplasia, mesenchymal hyperplasia, molar pregnancy, pseudomolar pregnancy, Beckwith-Wiedemann syndrome, and placentomegaly. Relevant references from review articles were also searched.

Conclusions.—Placental mesenchymal dysplasia should be considered in the differential diagnosis when the ultrasonographic findings show a cystic placenta. Close attention should be paid to fetal morphology for early recognition of fetal complications and to prevent unnecessary termination of pregnancy in cases associated with a normal fetus.
Agranular CD4+/CD56+ Hematodermic Neoplasm: A Distinct Entity Described in the Recent World Health Organization–European Organization for Research and Treatment of Cancer Classification for Cutaneous Lymphomas
Authors: Niakosari Firouzeh , Sur Monalisa
Published: February 2021

Agranular CD4+/CD56+ hematodermic neoplasm is a distinct form of lymphoma with aggressive behavior and marked predilection for cutaneous involvement. Because of CD56 positivity, natural killer cells were initially suggested as the cell of origin in this tumor. In the recent World Health Organization–European Organization for Research and Treatment of Cancer classification, the term blastic natural killer cell lymphoma has been replaced with CD4+/CD56+ hematodermic neoplasm because of its derivation from a plasmacytoid dendritic cell precursor. Clinicopathologic features, immunohistochemical features, and differential diagnosis of this rare neoplasm with emphasis on the recent World Health Organization–European Organization for Research and Treatment of Cancer classification are discussed.
Claudin-7 Immunohistochemistry in Renal Tumors: A Candidate Marker for Chromophobe Renal Cell Carcinoma Identified by Gene Expression Profiling
Authors: Hornsby Christopher D. , Cohen Cynthia , Amin Mahul B. , Picken Maria M. , Lawson Diane , Yin-Goen Qiqin , Young Andrew N.
Published: February 2021

Context.—The differential diagnosis of eosinophilic renal tumors can be difficult by light microscopy. In particular, chromophobe renal cell carcinoma (RCC) is difficult to distinguish from oncocytoma. This differential diagnosis is important because chromophobe RCC is malignant, whereas oncocytoma is benign. Furthermore, chromophobe RCC has distinct malignant potential and prognosis compared with eosinophilic variants of other RCC subtypes. Immunohistochemistry is useful for distinguishing chromophobe RCC from other subtypes of renal carcinoma, but no expression marker reliably separates chromophobe RCC from oncocytoma.

Objective.—In a previous gene expression microarray analysis of renal tumor subtypes, we found the distal nephron markers claudin-7 and claudin-8 to be overexpressed in chromophobe RCC versus oncocytoma and other tumor subtypes. We have confirmed similar findings in independent microarray data and validated differential claudin-7 protein expression by immunohistochemistry.

Design.—Immunohistochemical analysis of claudin-7 in 36 chromophobe RCCs, 43 oncocytomas, 42 clear cell RCCs, and 29 papillary RCCs.

Results.—Membranous claudin-7 expression was detected in 67% chromophobe RCCs, compared with 0% clear cell RCCs, 28% papillary RCCs, and 26% oncocytomas (P < .001).

Conclusions.—Based on microarray and immunohistochemical data, we propose claudin-7 to be a candidate expression marker for distinguishing chromophobe RCC from other renal tumor subtypes, including the morphologically similar oncocytoma. The clinical utility of claudin-7 should be validated in independent studies of renal tumors, possibly in combination with additional targets in a multiplex immunohistochemical panel.
Yield of Primary and Repeat Induced Sputum Testing forPneumocystis jiroveciin Human Immunodeficiency Virus–Positive and –Negative Patients
Authors: Wang Yihong , Doucette Saryn , Qian Qinfang , Kirby James E.
Published: February 2021

Context.—Induced sputum sampling has an approximate 70% sensitivity for detection of Pneumocystis jiroveci in human immunodeficiency virus (HIV) patients. Bronchoalveolar lavage sampling has greater than 90% sensitivity but is a far more invasive procedure. Therefore, bronchoalveolar lavage testing is often recommended as a follow-up after a negative induced sputum. In HIV-negative patients, the utility of induced sputum testing is still not well defined.

Objective.—To determine whether repeat induced sputum sampling increases diagnostic yield and might thereby reduce the need for follow-up bronchoalveolar lavage sampling. To determine the utility of induced sputum sampling in HIV-negative patients.

Design.—A 2-year retrospective review of the utility of repeat induced sputa testing in patients with previous first and/or second negative induced sputa. Retrospective review of induced sputa detection in HIV-negative patients.

Results.—Repeat testing of induced sputa for Pneumocystic jirovecii did not significantly increase diagnostic yield. Furthermore, in HIV-negative patients, induced sputum testing was diagnostically insensitive.

Conclusions.—Bronchoalveolar lavage testing should be performed initially in HIV-negative patients and after a first negative induced sputum in HIV-positive patients.
Second Messenger Systems in Human Gliomas
Authors: McLendon Roger E. , Turner Kristi , Perkinson Kathryn , Rich Jeremy
Published: February 2021

Context.—Patients with glioblastoma (astrocytoma, World Health Organization grade IV) exhibit 2-year survival rates of less than 20% despite significant advances in therapeutic options available to patients. Epidermal growth factor receptor (EGFR) hyperexpression is one of the most commonly encountered abnormalities in this tumor. However, EGFR expression, amplification, and mutations are poorly predictive of patient survival. Investigators have taken to exploiting the sensitivities of activated downstream targets in the EGFR second messenger pathways to certain inhibitory drugs to downregulate their neoplastic messages promoting cell growth and inhibiting cell death.

Objective.—It is important to both gain some understanding of the functional significance of these pathways and to understand the role the pathologist might play in characterizing the activation status of certain downstream messenger proteins that are targeted in these brain tumor therapies. We have reviewed the literature regarding histologic assays that have been incorporated into trials of these new drugs and report on the methods used to study these proteins and the conclusions of these studies.

Data Sources.—Literature review and primary material from Duke University (Durham, NC) Department of Pathology archives.

Conclusions.—To date, drug trial reports indicate that identification of the presence of the EGFR variant, EGFRvIII, and measurement of the activated downstream targets, phospho-Akt, phospho-S6, and phospho-MAPK, may be useful in predicting sensitivity to some of the EGFR kinase inhibitors. No studies to date have identified prognostic significance related to immunoreactivity status among any of these markers that is independent of histologic grade.