This post is a sidebar to the CLP May 2014 feature on Hematology Testing

Karen P. Mann, MD, PhD, Emory University Medical Center

Karen P. Mann, MD, PhD, Emory University Medical Center

Laboratory testing for hematological disorders ranges from highly automated routine laboratory tests such as complete blood count and automated differential to cutting-edge technologies that are performed in a minority of CLIA-certified high complexity laboratories and require a significant amount of professional oversight and interpretation of test results. In between are complex tests that have been used for decades, such as flow cytometric immunophenotyping, cytogenetic analysis, and fluorescence in situ hybridization (FISH). “As you go from low complexity to cutting-edge technologies, challenges increase for a number of reasons,” says Karen P. Mann, MD, PhD, professor and director of the hematopathology section in the department of pathology and laboratory medicine at Emory University Medical Center, Atlanta.

For the majority of molecular tests, no reporting standard exists. “This makes it difficult to compare results from one laboratory to another,” says Mann, who is also the chair of the American Society of Hematology (ASH) scientific committee on hematopathology and clinical laboratory hematology. “This has been addressed in molecular monitoring of chronic myeloid leukemia with the development of an international standard, but has not yet been addressed in other tests.”

In addition, multiple new somatic mutations have been identified in hematopoietic malignancies in the last few years. “Although there is high enthusiasm among some clinicians for adding new testing, there is no consensus on which ones should be included,” Mann reports. In addition, “Although there is a lot of excitement about next-generation sequencing, there are no standard bioinformatics pipelines, and the need for HIPAA-compliant storage of ‘big data’ is only now being addressed.”

Regarding care settings, Mann says a major weakness of non-hospital care settings is rapid delivery of a specimen for accurate testing. One example would be a platelet aggregation study, where the sample should be delivered to the laboratory within 1 to 2 hours. Access to consultation with medical directors of laboratories may also vary among academic hospitals, community hospitals, and reference laboratories.


Genomic testing, which is becoming increasingly common for inherited and acquired disorders, is among the emerging practices and technologies to which the ASH committee expects to bring improvement. Others include next-generation sequencing (NGS) and single nucleotide polymorphism/copy number (SNP/CN) microarray testing. “This type of approach has become cost-effective as the methodologies are improved and optimized,” Mann says. Testing for copy number abnormalities by SNP/CN array is already being utilized in a subset of hematolymphoid malignancies.

“This technique can be cheaper than large FISH panels and can detect small, but clinically significant, abnormalities that would be missed by FISH,” Mann says. For acquired disorders, NGS can be used to evaluate somatic mutations that can help subclassify disease, guide targeted therapy, and help provide prognostic information.

As the cost, speed, and accuracy of sequencing improve, it will become cost-effective to perform exome sequencing and eventually whole genome sequencing. “Currently, NGS, as implemented in many laboratories, is excellent for detecting somatic mutations, weaker for insertions and deletions (especially large insertions and deletions), and poor for detection of balanced translocations,” Mann reports. As the technologies continue to improve, with decreased cost, increased read lengths, and the use of whole transcriptome shotgun sequencing (RNA-Seq) and other approaches, these issues will be addressed.

Hematopoietic diseases will increasingly be classified by underlying pathobiology, and physicians will be able to combine knowledge of a patient’s tumor mutation status with pharmacogenomics studies to allow direct targeting of tumors using patient-specific doses.

Regarding molecular technologies, the ASH committee believes that they should be incorporated into routine practice as evidence arises that testing for specific mutations will improve patient care by precisely subclassifying disorders, and guiding targeted therapy or providing important prognostic information. “The cost as compared to other modalities should be considered,” Mann notes.


Many issues in genomic testing are not yet fully resolved. “The bioinformatic tools and instruments were originally developed for research and may not conform to HIPAA requirements,” Mann points out. Different software tools must be used in many cases to analyze data accurately, requiring some understanding of bioinformatics.

Additionally, there is a lack of well-curated clinical-grade databases of human genetic sequences. “The large genetic databases were created by researchers and have errors,” Mann says. When these are detected, there is not a mechanism to correct the data. Storage of large amounts of data generated by genomic technology is a major and expensive challenge. HIPAA-compliant solutions need to become affordable and easily available to the laboratory. And finally, there are ongoing issues with reimbursement for molecular testing on both the technical and professional sides.