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Allen Gown

Next Generation Immunohistochemistry

Handout (pdf 141 p)

Handout (pdf 36 p)


Immunohistochemistry (IHC) has traditionally been employed in surgical pathology as an ancillary test in the analysis and classification of cancers, based largely upon “cell type” analysis, reflecting the tumor classification system, which has traditionally been based on cell or tissue type (e.g., lung adenocarcinoma, ductal breast carcinoma, rhabdomyosarcoma, etc.).  The availability of an ever-widening array of antibodies to cell- and tissue- specific cytoplasmic proteins, and more recently to organ restricted nuclear transcription factors, has dramatically improved the accuracy and precision of tumor diagnoses.  In this molecular era, however, increasing numbers of tumors are being defined by their underlying molecular alterations such as single point genetic mutations, gene deletions, gene promoter methylation, gene amplification, as well as chromosomal translocations. IHC, a protein-based technique, is able to identify many of these underlying genetic alterations in a number of interesting ways.  Some mutated proteins can be identified by employing mutation-specific monoclonal antibodies, as in the case of the IDH-1 R132H and BRAF V600E mutations.   Other genetic mutations or gene promoter methylation can result in loss of IHC-documented expression of the corresponding protein (e.g., mismatch repair enzymes, INI-1/SMARCB1, E-cadherin).  Additional mutations can result in protein overexpression or complete absence of expression (e.g., p53).  Still other mutations can be identified by protein accumulation in an abnormal compartment within the cell (e.g., nuclear beta-catenin). Chromosomal translocations can be identified by IHC through the identification of a portion of the novel chimeric protein that results from the gene fusions,(e.g., FLI-1 in PNET/Ewings sarcoma; TFE3 in alveolar soft part sarcoma and translocation renal cell carcinomas; ALK in anaplastic large cell lymphoma.) Gene amplification, as in the case of HER2 or MDM2, can be identified by using IHC to identify overexpression of the corresponding protein.  This “Next Generation IHC” (NG-IHC) can often act as a more rapid and inexpensive surrogate for molecular studies, and in some cases provide even more information.  NG-IHC has the additional ability to integrate different genotypic changes which can result in the same phenotypic alterations.  Finally, NG-IHC, can be used to expand and better define selected tumors, such as anaplastic large cell lymphoma and rhabdoid tumor.


Dr. Gown is a pathologist-scientist recognized as one of the world’s leading experts in the diagnostic and research applications of immunohistochemistry (IHC). He is the founder, Medical Director and Chief Pathologist of PhenoPath, a national consultative reference laboratory specializing in IHC, immunofluorescence, flow cytometry, FISH, PCR, and cytogenetics testing. Dr. Gown has developed numerous clinically important monoclonal antibodies used around the world, and continues to be at the forefront of clinical investigative studies employing IHC and other modalities, publishing widely and presenting at national and international conferences. Dr. Gown is a member of the editorial boards of many of the major pathology journals. He is a Clinical Professor of Pathology at the University of British Columbia, Vancouver, BC, and an Affiliate Investigator in the Clinical Research Division of the Fred Hutchinson Cancer Research Center, Seattle, WA. Dr. Gown has contributed extensively to the expanding horizons of immunohistochemistry with well over 290 peer-reviewed publications.

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