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Appendix 2: Current and Emerging Molecular Technologies in Dermatopathology

Garrett T. Desman; Michael Donovan

INTRODUCTION

Since Rudolph Virchow first applied the light microscope to the analysis of tissues, traditional histopathological assessment of cutaneous diseases has largely remained unchanged over the past 150 years.1 The process of immunohistochemistry was invented in the 1940s by Coons, Creech, and Jones and revolutionized the pathologist’s ability to identify cellular protein expression and the subclassification of tumors by various lines of differentiation. With the launch of the Human Genome Project in 1990, scientists were able to map all of the genes of the human genome from both a physical and functional standpoint.2 Since then, an explosion of data has been derived from genomic, epigenomic, transcriptomic, proteomic, lipidomic, and metabolomic (“omics”) technologies.3 Below, we briefly summarize the role of some of these technologies in the current and future practice of dermatopathology (Table A2-1).

TABLE A2-1Current Methodologies for Studying Genomic Alterations
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TABLE A2-1 Current Methodologies for Studying Genomic Alterations
TECHNIQUE RESOLUTION COVERAGE ABERRATIONS DETECTED SENSITIVITY AND OTHER CONSIDERATIONS TAT COST
Karyotype >10 Mbp Whole genome Rearrangements (balanced, unbalanced, gain, loss) Low, requires culture 7-10d Low
aCHG 5-100 kbp Whole genome Rearrangements (unbalanced), gain, loss Medium 7-10d Medium
SNP-array 5 kbp Whole genome Gain, loss, uniparental disomy, mutation Medium 7-10d Medium
FISH >20 kbp Probe-specific Rearrangement (balanced, unbalanced), gain, loss High 1-5d Low
PCR <10 kbp Gene specific Rearrangement (balanced, unbalanced), gain, loss, mutation High 3-7d Low
Sanger sequencing <800 kbp Gene-specific Mutation, indel* Medium 7-10d Low
NGS 1 nt Whole genome Rearrangement (balanced, unbalanced), gain, loss, mutation, indel* High >10d High

Specimen considerations: Karyotype requires fresh material. All other technologies can be applied to FFPE with some considerations.

*Indel - an insertion or deletion of bases in the genome.

KARYOTYPE

A karyotype is the number and appearance of Giemsa-stained chromosomes in the nucleus of eukaryotic cells during arrest in metaphase or prophase by colchicine treatment. Since this technology requires fresh live cells growing in tissue culture, it is rarely used in the field of dermatopathology.4

COMPARATIVE GENOMIC HYBRIDIZATION (CGH) AND FLUORESCENCE IN SITU HYBRIDIZATION (FISH)

FISH is a technique for identifying a specific region within an intact chromosome. While it is particularly useful in the identification of specific chromosomal abnormalities in various tumors, it may also be used to identify germline chromosomal diseases, such as some genodermatoses. It can be performed on fresh, frozen, or paraffin-embedded material. FISH can be used to map loci on specific chromosomes, detect chromosomal rearrangements, document chromosomal gains and losses, as well as reveal more subtle abnormalities, such as small deletions or point mutations. FISH is performed by fixing patient cells to a glass slide followed by heating the sample to denature (separate) the double-stranded DNA. Specific fluorescently labeled DNA probes are then applied. ...

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