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Best Practices in Immunohistochemistry in Surgical Pathology and Cytopathology.

This special section on diagnostic immunohistochemistry (IHC) consists of a series of 10 articles from the first Chinese American Pathologists Association (CAPA) diagnostic pathology course, Best Practices in Immunohistochemistry in Surgical Pathology and Cytopathology, which took place in Flushing, New York, August 22-24, 2015. The CAPA was founded in 2003 and today has more than 700 active members who are practicing pathologists or pathologists in training in North America. We wholeheartedly thank Philip T. Cagle, MD, editor-in-chief, and the editorial board of the Archives of Pathology & Laboratory Medicine for giving us the exceptional opportunity to publish this 2-part special section. We would also like to take this opportunity to sincerely thank the CAPA Executive Committee, all of the course faculty, and the contributors to this special section.

Each part of this special section comprises 5 articles. These 10 articles are largely derived from the CAPA course materials and specifically designed to be practical and concise, with a format of example-based presentation and discussion. Most articles begin with a set of specific examples that mimic real practice scenarios, then their related differential diagnosis, followed by step-by-step illustrations showing how to apply the most effective and specific IHC panels in these challenging circumstances.

One of the most frequent and important applications of diagnostic IHC is to assist in working up an undifferentiated neoplasm/tumor of uncertain primary site on fine-needle aspiration and small tissue biopsy specimens. The first article uses 7 challenging yet representative examples to comprehensively review some diagnostic strategies and algorithms; to update many recently described diagnostic markers, such as von Hippel-Lindau tumor suppressor gene protein (pVHL), paired box gene (PAX) 8, ETS-related gene (ERG), sal-like protein 4 (SALL4), sex-determining region Y box (SOX) 10, NK3 homeobox 1 (NKX3.1), discovered on GIST1 (DOG1), and Merkel cell polyomavirus (McPyV); and to refine the diagnostic IHC panels frequently used in daily practice.

The second article focuses on papillary and nonpapillary breast lesions and their differential diagnosis; the diagnostic and prognostic IHC markers for triple-negative breast cancers, such as proline glutamic acid and leucine-rich protein (PELP1), GATA-binding protein 3 (GATA3), and androgen receptor (AR); and an example with aberrant expression of breast markers in lung adenocarcinoma. Six interesting examples, 7 informative tables, and 10 figures are provided to illustrate the useful diagnostic pearls. Noteworthy exceptions are also highlighted as potential diagnostic pitfalls.

The next article focuses on gynecologic pathology. Four examples and 6 tables are used to show the practical applications of several IHC markers for gynecologic diseases. Specifically, the authors discuss the values and pitfalls of using p16 and Ki67 for squamous lesions of the cervix, vagina, and vulva; IHC markers for endometrial adenocarcinoma subtyping; the IHC profiles of various stromal tumors of the uterus; and the usefulness of hydroxyl-delta-5-steroid dehydrogenase (HSD3B1), human leukocyte antigen G (HLA-G), GATA3, human placental lactogen (hPL), and p63 for gestational trophoblastic diseases. The article also delineates the application of many recently introduced IHC markers, such as (1) loss of expression of PAX2 in invasive and in situ endocervical adenocarcinomas, (2) strong and diffuse nuclear expression of cyclin D1 in high-grade endometrial stromal sarcomas, (3) expression of hepatocyte nuclear factor 1[beta] (HNF-1[beta]) and napsin A in clear cell carcinomas of the uterus and ovary, (4) forkhead box protein L2 (FOXL2) and steroidogenic factor 1 (SF1) as sensitive and specific markers for sex cord and stromal tumors, and (5) loss of expression of p57 in complete hydatidiform moles.

The first part of this special section concludes with 2 articles on soft tissue and skin lesions. The fourth article illustrates the diagnostic pearls and pitfalls of adipocytic tumors (lipomatous neoplasms), spindle cell tumors, epithelioid soft tumors, tumors with myxoid stroma, and small round cell tumors. It is noteworthy that conventional osteosarcoma (~10%), parosteal osteosarcoma (>85%), and undifferentiated high-grade pleomorphic sarcoma of bone (~17%) may be positive for mouse double minute 2 homolog (MDM2) by fluorescence in situ hybridization

(FISH) but negative for MDM2 by IHC, whereas pleomorphic rhabdomyosarcoma, malignant peripheral nerve sheath tumor, and myxofibrosarcoma may be positive for MDM2 by IHC but negative for MpM2 by FISH. It also summarizes the useful clinical, morphologic, and molecular/IHC features of various epithelioid soft tissue tumors. Many recently reported diagnostic markers are described in this article, such as (1) signal transducer and activator of transcription 6 (STAT6) as the most sensitive and specific IHC marker for solitary fibrous tumor; (2) loss of antihistone H3 acetyl K27 trimethylation (H3K27) nuclear expression in 50% of malignant peripheral nerve sheath tumors, particularly in high-grade malignant peripheral nerve sheath tumors; (3) mucin 4 (MUC4) expression in low-grade fibromyxoid sarcomas and sclerosing epithelioid fibrosarcomas; and (4) nuclear expression of calmodulin binding transcription activator 1 (CAMTA1) in epithelioid hemangioendotheliomas.

The fifth article concentrates on skin and superficial soft tissue cluster of differentiation (CD) 34+ spindle cell lesions. Four examples are used to highlight the differential diagnosis of cellular digital fibroma, superficial [CD34.sup.+] fibroblastic tumor, spindle cell lipoma (low-fat type), and plaquelike [CD34.sup.+] dermal fibroma.

The second part of this special section begins with a very comprehensive, example-based review of the commonly used and emerging IHC markers for the neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas. The IHC markers of increasing clinical use are special AT-rich sequence-binding protein 2 (SATB2) and cadherin-17 (CDH17) for gastrointestinal lineage, glypican-3 (GPC3) and heat shock protein 70 (HSP70) for liver malignancy (versus benign lesions), and the 4-marker panel of pVHL, maspin, S100P, and insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) for pancreatic and biliary tract malignancy. The authors also summarize the relatively specific markers for differentiating the site of origin of metastatic well-differentiated neuroendocrine tumors, including thyroid transcription factor 1 (TTF-1) for lung; caudal type homeobox 2 (CDX-2) for small intestine and appendix; SATB2 for rectum, colon, and appendix; CDH17 for small intestine, appendix, and rectum; and islet-1 and PAX8 (polyclonal) for pancreas, duodenum, and rectum.

The seventh article recommends, when possible, a panel of cytokeratin (CK) 7, carbonic anhydrase IX (CA IX), CD117, human melanoma black 45 (HMB-45), [alpha]-methylacyl coenzyme A racemase (AMACR), and transcription factor E3 and transcription factor EB (TFE3/TFEB) for classifying renal epithelial tumors; CK20, p53, and CD44 for bladder urothelial carcinoma versus reactive urothelium; p63, NKX 3.1, GATA3, high-molecular-weight CK, prostein (P501S), and prostate-specific antigen (PSA) for prostatic adenocarcinoma versus (bladder) urothelial carcinoma; and a-fetoprotein (AFP), [beta]-human chorionic gonadotropin ([beta]hCG), glypican-3 (GPC3), octamer-binding transcription factor 4 (OCT4), CD117, and CD30 for testicular germ cell tumors.

Four common yet challenging instances of thoracic pathology are discussed in the eighth article. The authors report that adenocarcinomas and squamous cell carcinomas of the lung could be effectively differentiated using TTF-1 (SPT24 clone with lower specificity, and 8G7G3/1 clone with higher specificity), napsin A, CK5/6, p40 (high specificity), p63 (low specificity), and CK903/34[beta]E12; malignant mesothelioma and reactive mesothelium using p53, epithelial membrane antigen (EMA), desmin, glucose transporter 1 (GLUT1, high sensitivity), IMP3 (high sensitivity), and loss of nuclear staining of BRCA1-associated protein 1 (BAP1, high specificity); carcinoid tumor, atypical carcinoid tumor, small cell lung carcinoma, and large cell neuroendocrine carcinoma using chromogranin, synaptophysin, CD56, TTF1, and Ki67; and sclerosing pneumocytoma (formerly pulmonary sclerosing hemangioma) and its mimickers using TTF-1 (staining both surface and round cells) and AE1/AE3 (staining surface cells only).

The ninth article showcases 13 uncommon tumors of the head and neck region. The noteworthy or emerging markers mentioned in this review include S100, mammaglobin, vimentin, EMA, and balanced translocation t(12;15)(p13;q25) for mammary-analog secretory carcinoma; microphthalmia-associated transcription factor (MITF) and SOX10 for mucosal melanoma; diffusely positive p40 and p63 for basaloid squamous cell carcinoma; p63, Epstein-Barr virus-encoded small RNA (EBER), and latent membrane protein 1 (LMP-1) for nasopharyngeal carcinoma; loss of parafibromin, galectin3 overexpression, increased Ki-67 index, and expression of protein gene product 9.5 (PGP9.5) for parathyroid carcinoma (versus adenoma); and EMA, CK, and CD117 labeling epithelial cells and p63, smooth muscle actin (SMA), and S100 labeling myoepithelial cells for epithelial-myoepithelial carcinoma.

Finally, the tenth article provides a CD5- and CD10-based algorithm to better define mature B-cell lymphomas, although the 2 IHC markers by themselves are not very specific. Moreover, a panel of CD19, CD45, CD56, and CD117 is recommended to identify plasma cell differentiation in B-cell lymphomas, whereas CD138 is always positive in a group of aggressive B-cell lymphomas with plasmablastic features. Furthermore, the authors elegantly compare and contrast the IHC and flow cytometric features of plasmablastic plasma cell myeloma, plasmablastic lymphoma, primary effusion lymphoma, and anaplastic lymphoma kinase 1 (ALK1) and large B-cell lymphoma.

In summary, these 10 example-based articles on best practices in IHC provide a practical review and update, share some useful diagnostic strategies and algorithms, and emphasize some important diagnostic pitfalls. The summary tables and exemplary figures may be particularly helpful and handy when working up a case with uncommon histologic features and unexpected and/or conflicting IHC results. As always, implementing best practices would not be possible without a good understanding of the diagnostic sensitivity, specificity, and staining pattern of each IHC marker in association with morphologic features and clinical-radiologic findings. A small IHC panel is more likely to provide more accurate and useful diagnostic information than a single IHC marker. DNA or RNA in situ hybridization and molecular tests should be considered when dealing with a challenging case.

Please Note: Illustration(s) are not available due to copyright restrictions.

Accepted for publication February 27, 2017.

From the Department of Pathology, University Medical Center of Princeton, Plainsboro, New Jersey (Dr Zhang); the Department of Chemical Biology, Ernest Mario School of Pharmacy, Piscataway, New Jersey (Dr Zhang); the Department of Pathology, Rutgers University, Newark, New Jersey (Dr Zhang); and the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania (Dr Lin).

The authors have no relevant financial interests in the products or companies described in this article.

doi: 10.5858/arpa.2017-0084-ED

Reprints: Fan Lin, MD, PhD, Department of Laboratory Medicine, Geisinger Medical Center, 100 N Academy Ave, MC 19-20, Danville, PA 17822 (email:

Lanjing Zhang, MD, MS; Fan Lin, MD, PhD

Lanjing Zhang, MD

Lanjing "L.J." Zhang, MD, MS, is the gastrointestinal and liver pathology director at University Medical Center of Princeton at Plainsboro, New Jersey;an associate member of Rutgers Cancer Institute of New Jersey;and an adjunct professor of chemical biology at Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey. He also regularly teaches cancer molecular biology at Princeton University, Princeton, New Jersey, and mentors graduate students from Rutgers School of Public Health, Piscataway, New Jersey. Supported by the advisory committee, he founded and chairs the annual Princeton Integrated Pathology Symposium, which attracts more than 120 pathologists and trainees each year. His research and clinical interest is focused on gastrointestinal and breast pathology, particularly the clinical epidemiology and carcinogenesis of colorectal and breast cancers. His recent work also concerns genomic meta-analysis and data science. Dr Zhang has published more than 40 peer-reviewed articles, has mentored more than 10 undergraduate and graduate students, and is a co-principal investigator of a Rutgers University Initiative for Multidisciplinary Research Teams grant. He was a recipient of a resident subspecialty grant from the American Society of Clinical Pathology and several unrestricted educational grants. His editorial experiences include serving as executive editor-in-chief of American Journal of Digestive Disease, associate editor of Journal of Clinical and Translational Hepatology, section editor of Stem Cell Investigation, and academic editor of PLoS One, and editorial board membership on Medicine, Scientific Reports, Experimental Hematology and Oncology, Gastrointestinal Endoscopy, and North American Journal of Medicine and Science. He serves on the International Expert Panel of the National Medical Research Council of Singapore after having been an ad hoc grant reviewer with them for 8 years. He has also reviewed grant proposals for the Center for the Advancement of Science in Space (National Aeronautics and Space Administration) and for the National Science Foundation of China. Dr Zhang serves as an associate editor for the Archives of Pathology & Laboratory Medicine.

Fan Lin, MD

Fan Lin, MD, PhD, is a deputy editor-in-chief of the Archives of Pathology & Laboratory Medicine and the director of anatomic pathology at Geisinger Health System (Danville, Pennsylvania). He received his MD from Fujian Medical University (Fuzhou, the People's Republic of China) and his PhD in biological sciences from the University of North Texas (Denton). He completed anatomic pathology/ clinical pathology residency training at the University of Chicago Hospital in 1999, followed by 1 year of cytopathology fellowship training at MD Anderson Cancer Center in Houston, Texas. He has authored more than 80 articles in peer-reviewed pathology journals and more than 20 book chapters, and has presented more than 175 posters/platform presentations at pathology society meetings. He leads the Geisinger anatomic pathology group in making contributions to the field of immunohistochemistry, including publishing the second edition of Handbook of Practical Immunohistochemistry-Frequently Asked Questions and its free companion immunohistochemistry Web site ( and contributing 2 special issues on immunohistochemistry updates to the Archives of Pathology & Laboratory Medicine in 2014 and 2015. Dr Lin is a reviewer for many pathology journals. He is the former president of the Chinese American Pathologists Association (CAPA) (2015-2016) and was one of the co-organizers for the first CAPA diagnostic pathology course in Flushing, New York, in August, 2015.
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Title Annotation:Special Section-First Chinese American Pathologists Association Diagnostic Pathology Course, Part I
Author:Zhang, Lanjing; Lin, Fan
Publication:Archives of Pathology & Laboratory Medicine
Date:Aug 1, 2017
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