Pictures in a bone marrow exhibition
Susan J. Leclair, PhD, CLS (NCA) Chancellor Professor, Department of Medical Laboratory Science, University of Massachusetts is a laboratory scientist and senior associate at the UMass Center for Molecular Diagnostics. Her observations and analyses are familiar to us through her contributions to the MPN-NET patient support list and Patient Power.
Most of us are somewhat familiar with blood lab results, our CBCs, but still baffled by the pathology reports on our blood marrow biopsies.
It’s not surprising. In his classic Morphology of the Blood and Marrow in Clinical Practice, Dr. Richard Silver, commenting tongue in cheek on identification of various blood stem cells, observed, “….It is difficult if not impossible to distinguish one stem cell from another. The names finally assigned to these cells often depend upon the more mature cells accompanying them, the location in which they are observed and on the name, rank and bias of the examiner.”
Still, since the bone marrow biopsy is a such a standard — and painful — feature of our MPN diagnostics, we thought it would useful to have some sense of what the hematopathologist sees looking at our BMB slides.
For help, we turned to Dr. Leclair who graciously agreed to share some slides and thoughts on bone marrow biopsy and blood morphology.
by Susan J. Leclair, PhD, CLS (NCA)
Some basic rules:
1. Aspirates are good to identify individual cells and to evaluate the qualitative morphology of the cells. But, in the making of a smear (as the name implies), the internal structure of a 3-dimensional specimen is flattened and spread out so you really can’t say much about structure.
2. Biopsies are good to evaluate architecture. Are the cells grouped together or are they spread across? Do they touch each other or interact with collagen, etc.?
3. Are the cells present in adequate numbers and do they mature in a proper fashion? Since each stage of development should result from a mitotic division, then the numbers 1-2-4-8-16-32 would be logical if you were evaluating how many blasts and then promyelocytes, etc. are present.
4. As cells mature, they change their size and shape. Red cells increase in the amount of hemoglobin present, while their nucleus becomes smaller, etc. So you want to know if the cells are maturing correctly.
5. There should be a mixture of blood cells, structural cells (osteoblasts and osteoclasts) and compounds such as collagen present. What you don’t want are surprise cells that don’t belong there. In addition, there should be some related cells such as mast cells which belong in the marrow but are not part of the structure nor of the blood cells.
6. Morphology tells you a lot but additional tests are always necessary.
Reviewing a Sample Bone Marrow Report:
Sample taken from the right posterior iliac crest biopsy.
Here are some phrases you might run across in a BMB report and some relevant notes.
“The biopsy and aspirate smear are adequate for evaluation, with an overall cellularity of 80%.”
Cellularity should max out at around 50% or so as one reaches full adulthood. A high cellularity typically suggests that the marrow is having a hard time trying to keep up with demand or has lost control of the numbers of cells that are needed.
“The myeloid maturation is complete, but shifted to the left.”
Sadly, the traditional counter used to keep track of the numbers of various white cells in the traditional/manual differential has the immature cells on the left side of the keyboard. Thus, one had to “shift your fingers to the left” to count immature forms. So a shift to the left is a short hand version of saying that the “1-2-4-8-16” increase in cells is not being followed. There might be 4 blasts, 8 promyelocytes but only 8 myelocytes (when they should be 16), etc.
“The erythroid maturation shows dysplastic features, including nuclear/cytoplasmic asynchrony, nuclear irregularity, and late stage mitotic activity.”
“Plasia” means cells or numbers of cells. “dys” means abnormal. So dysplastic features means that the cells look abnormal. As red cells mature, they get smaller and the nucleus gets darker and tighter. The cytoplasm starts out as deep blue (mostly from RNA) and gradually breaks down the RNA and gets so filled with hemoglobin that the color turns red.
This dance – the decreasing size of the nucleus and the increasing hemoglobinization is called nuclear cytoplasmic synchrony. When there is Asynchrony, it means that these actions are not happening at the same time. You can have an immature nucleus with a mature looking cytoplasm or a mature nucleus with an immature cytoplasm. The nucleus is essentially round throughout the early maturation process but sometimes that roundness is lost. Irregularity can be oval or stretched or having scallop-like edges, etc. So those two findings would suggest that the red cells are not capable of making cells in any number. And, even when they are made, they have lost a good deal of quality and probably won’t last 120 days.
Mitosis is supposed to stop when the hemoglobin content reaches a specific point. Late stage mitotic activity suggests that it is taking longer than it should to reach that concentration or mitosis is continuing to happen even when it should no longer be.
“Megakaryocytes are increased in numbers, with dysplastic features including hypo- lobulated micromegakaryocytes and cluster formation.“
Megakaryocytes make platelets by budding off pieces of their cytoplasm.If they are small, they will make fewer platelets.
If they are increased in number, then they are also under some stress to make more platelets, except they can’t since they are smaller than they should be.
“Blasts comprise -5°% of marrow cellularity on differential count and by CD34 staining.”
Typically you should have less than 4% blasts (usually meaning myeloblasts, the precursor cell for neutrophils). So there is an ever so slight – could be nothing – increase here.
“An iron stain on the biopsy shows markedly reduced stainable storage iron.”
There should always be some iron storage in the bone marrow, ready both for every day incorporation into hemoglobin and white cells but also to help you recover quickly from some blood loss – for example a blood donation.
If you don’t have any visible iron, then you have 1) no abililty to recover quickly and 2)probably not enough iron to make the hemoglobin and white cell enzymes that you need.
“Reticulin stain shows normal to slightly increased reticulin network.”
Reticulum is a form of support tissue.
It is not as cross linked or thick as collagen or fibrosis but increases in it can cause a change in the environment of the marrow which could affect the way the cells function.
Flow Cytometry Report
“By flow cytometry analysis, atypical granulocytes are seen. However, CD34+ cells could not be accurately evaluated. Overall, the findings are not entirely specific; a myeloid dysplastic process is suspected. Other possible causes include nutritional or drug/toxic effect. Correlation with cytogenetics analysis is recommended.”
CD34 is a marker found on highly immature cells such as stem cells and some blasts. So this is only saying “cells are weird but I don’t know why”.
“Smears are hypo-cellular, without spicules and maybe hemodiluted. Due to platelet clumps, assessment of CD34 positive non lymphoid blasts is difficult. Maturing granulocytic cells are noted to express CD14, which is abnormal.”
On spicules: The essential structure of the bone marrow is similar to that of a honeycomb with the developing cells as the honey and the supportive materials (blood vessels, nerves, tissue cells, etc.) serving as the three-dimensional comb. When withdrawn from the body, these pieces of the honeycomb are called spicules and their presence signifiies that the specimen is of good quality. Absence of spicules makes one wonder if one got enough bone marrow cells to do a thorough examination.
Hemodilution means that there is a lot of blood while might have contaminated the specimen and
washed out some cells. CD14 is a marker that will react to the presence of bacterial cell walls so it is a primary defense against bacterial infection. This is one of the last functions of the fully mature cells so to find it on immature cells suggests that the cells are not maturing in a normal fashion and some functionality is probably lost.
“Here is a marrow that is essentially confusing and not immediately diagnostic. “
Cells are having issue with normal maturation and development and that usually happens in either the acute and chronic leukemias but also in a situation called myelodysplasia which was first described by the presence of funny-looking (myelodysplastic cells.)
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