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Expert Pathologists Answer Questions on Molecular Testing and Diagnosis in MDS

Tal Oren, MD, PhD

Hematopathologist
Stamford Hospital
Stamford, Connecticut


Tal Oren, MD, PhD, has no relevant financial relationships to disclose.


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Alexa J. Siddon, MD

Associate Professor, Laboratory Medicine and Pathology
Hematopathology Fellowship Director
Yale School of Medicine
New Haven, Connecticut


Alexa J. Siddon, MD, has no relevant financial relationships to disclose.


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Cecilia Yeung, MD

Associate Professor
Clinical Research Division
Fred Hutchinson Cancer Center
University of Washington
Seattle, Washington


Cecilia Yeung, MD: consultant/advisor/speaker: Twinstrands; researcher: OBI, Sensei.


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Released: November 15, 2022

Key Takeaways

  • Next-generation sequencing plays an important role in the diagnosis of myelodysplastic syndromes and can be performed on both bone marrow and peripheral blood samples.
  • FISH is rarely indicated in the diagnosis of myelodysplastic syndromes.
  • Next-generation sequencing should be considered for patients diagnosed with myelodysplastic syndromes before the availability of that technology.

In this commentary adapted from a discussion among Tal Oren, MD, PhD; Alexa J. Siddon, MD; and Cecilia Yeung, MD, these expert pathologists address important clinical questions from a live symposium about the role of pathology to guide treatment decisions for patients with myelodysplastic syndromes (MDS).

Do you use next-generation sequencing (NGS) upfront when diagnosing patients?

Alexa J. Siddon, MD
In our clinic, the healthcare professionals (HCPs) typically order it if they are ordering a bone marrow biopsy, but NGS is not strictly necessary.

Cecilia Yeung, MD
At our center, we use a diagnostic testing pathway system, in which new tests for myeloid neoplasms or suspected MDS are evaluated yearly by our team of HCPs and a pathologist. Samples from patients with suspected myeloid neoplasms or suspected MDS go directly into this testing pathway. We do still use fluorescence in situ hybridization (FISH), but chromosomal genomic array testing and cytogenetics are definitely part of the panel.

Tal Oren, MD, PhD
I practice at a community hospital and am the sole hematopathologist there. Our oncology team typically defers all decisions about ancillary testing to me. I tend to be a bit stingier about ordering tests than some of the academic centers, but it is a completely different model. 

I try to look at the aspirate morphology the same day the bone marrow biopsy is conducted along with the clinical history and make a decision about how likely I think it is that this patient has a myeloid neoplasm. At that point, I will decide if NGS is warranted. Peripheral blood NGS can be ordered along with bone marrow NGS. The bottom line is that I do not order NGS for every cytopenic patient.

Alexa J. Siddon, MD
Preauthorization for NGS tests and insurance reimbursement has been a struggle for our institution. Thus, there are multiple considerations regarding upfront NGS.

Should FISH be used for analysis of genomic changes in MDS?

Tal Oren, MD, PhD
I never use MDS FISH unless there is karyotypic failure because I have seen discord between the 2 so infrequently that FISH seems to be a waste of resources. That said, FISH is faster than cytogenetic testing. The other scenario where I might also use FISH is when the megakaryocyte morphology indicates del(5q) but the karyotype did not detect it. I would then use FISH to confirm the karyotype result.

Cecilia Yeung, MD
In our clinic at Fred Hutchinson Cancer Center, we have a cytogenetics laboratory that allows us not only in-house karyotyping, but also chromosomal genomic array testing that can provide additional information such as loss of heterozygosity. Our cytogenetics director generally does not recommend FISH, because the price of approximately 5 MDS FISH tests is similar to whole microarray testing, which provides more information. However, MDS FISH is more sensitive if you are tracking a specific marker, but that is not a common scenario and would need to be recommended by our cytogenetics director.

Alexa J. Siddon, MD
I agree with both Dr. Oren and Dr. Yeung. At our clinic, we do both FISH and karyotyping upfront due to efficiency and patient volume. I agree that FISH is a waste of resources and think we should only be using karyotype for most patients.

Can next-generation sequencing be used on peripheral blood in a patient with MDS and evidence of cellular dysplasia?

Cecilia Yeung, MD
Yes, peripheral blood can be used for NGS if the patient has not been treated and there is sufficient tumor burden. Multiple studies have shown that although testing bone marrow is more sensitive, NGS of either peripheral blood or bone marrow can detect key mutations.

If a patient diagnosed with MDS with ring sideroblasts no longer shows ring sideroblasts on follow-up bone marrow analysis, is he or she still eligible for luspatercept?

Cecilia Yeung, MD
I was taught that if the follow-up analysis differs from the original, then do not reclassify and continue using the original result to guide treatment.

Tal Oren, MD, PhD
I learned the same approach. So, in this scenario I do not think the second result would disqualify the patient from receiving treatment. Likewise, if a patient with MDS develops thrombotic progression, that too would not change the classification.

As a follow-up to that, if a patient acquires ring sideroblasts after the initial diagnosis, would he or she be eligible for luspatercept at that point?

Tal Oren, MD, PhD
I think this would raise the question of whether the presence of ring sideroblasts was missed on the initial bone marrow biopsy. I am not aware of patients acquiring ring sideroblasts during therapy. As for the use of luspatercept, that would be up to the oncologist.

Many patients with MDS were diagnosed before NGS became available. If a patient was diagnosed with MDS with ring sideroblasts 10 years ago and an NGS has not been performed, should he or she now be assessed with NGS?

Alexa J. Siddon, MD
I think it would be reasonable to complete the workup now that it is available. Before NGS, the patient’s disease would likely have been classified as refractory anemia vs refractory anemia with excess blasts. Now we have different subtypes of refractory anemia and MDS. With updates to the World Health Organization and International Consensus Classification categories for MDS, NGS results might change treatment choices.

A patient presents with cytopenia and a bone marrow analysis shows dysplasia. A subsequent NGS test shows somatic mutations or SF3B1. Would you diagnose the patient with MDS immediately or wait 6 months to confirm?

Tal Oren, MD, PhD
Technically, a patient needs to demonstrate persistent cytopenias to be definitively diagnosed with MDS, but if you detect an SF3B1 mutation, the patient likely has MDS and it was detected early.

Alexa J. Siddon, MD
Most oncologists typically will not perform a bone marrow analysis until after the patient has been cytopenic for some time.

Your Thoughts? What challenges have you encountered in using pathology testing to help manage patients with MDS? Share a comment in the box below!

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