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Hematological Malignancies – Part 2A: FAB Classification and Lymphomas

Hematologic malignancies
Welcome to this episode. So far, we’ve had a look at the different groups of hematological
malignancies. In this part, we will be assigning the most important diagnoses to these groups. Acute leukemia: The classification of acute myeloid leukemias is done according to the FAB classification.
Although it’s an older system, it still remains commonly used.
The term FAB stands for French-American-British and refers to an international team of hematologists
who were involved in its development. The FAB classification system is based on
tumor cell morphology under the microscope. Before we go into the individual diagnoses,
the following can be generally said: The myeloid cell line is composed of many different cell
lines. From the precursor cells of each cell line, hematological malignancies may arise.
This can be from the precursors of granulocytes and monocytes, from megakaryocytes, or from
the precursors of red blood cells. As there are many different cell lines with discrete
morphological features, the FAB classification system for the myeloid malignancies differentiates
more subtypes than for the malignancies of lymphoid origin.
Currently, there are eight groups, which are termed M0 to M7, with M indicating myeloid.
These are the subtypes:… In this episode, we won’t discuss the individual
subtypes in detail. However, here’s a short note for your understanding: The most important
cell lines of myelopoiesis can be found in this classification system. For example, M3,
the acute promyelocytic leukemia, originates from the granulocyte line. This is important
to remember because patients with this leukemia show a severe bleeding tendency. Other acute
myeloid leukemia subtypes based on the FAB classification system are M5, M6, and M7,
or acute monocytic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia,
respectively. The names of the subtypes are a good indication of their origin. Apart from
the FAB classification, there is also the newer WHO classification for acute myeloid
leukemias, which is based on molecular genetic findings. This is a much more abstract approach,
but is advantageous in the sense that molecular changes are tightly associated with the aggressiveness
of disease and treatment options. For the acute lymphoblastic leukemias, the
FAB classification system is outdated. It previously served to differentiate the acute
lymphoblastic leukemias into the following groups: small uniform cells, large varied
cells, and large cells with vacuoles. However, the use of morphology to determine the cellular
origin is a poor criterion. The FAB classification of acute lymphoblastic
leukemias has been replaced by the accurate identification of cells using immunophenotyping.
Cell surface marker expression can be used to differentiate the acute lymphoblastic leukemias
into the B-cell and T-cell leukemias. B-cell leukemias can be subdivided into precursor
B-cell acute lymphoblastic leukemia and mature B-cell acute lymphoblastic leukemia. Precursor
B-cell acute lymphoblastic leukemias can be further distinguished by their immunophenotype
into early pre-B-acute lymphoblastic leukemia or pro-B acute lymphoblastic leukemia, common
acute lymphoblastic leukemia, and pre-B acute lymphoblastic leukemia. The immunophenotype
of cells in acute lymphoblastic leukemia correlates with the stages of normal B cell development.
For comparison, let’s go back to B cell maturation, which was shown in part 1 of this
topic. Here, we can find the pro-B cell, pre-B cell,
and mature B cell. The maturity level of cells from common acute lymphoblastic leukemia lies
between pro-B and pre-B cells. It is termed common because it is the most frequent form
of acute lymphoblastic leukemia, accounting for approximately 50% of cases.
The T-cell acute leukemias are also categorized by their level of cellular maturity. Without
going into too much detail, they are classified into three forms: Early T-acute lymphoblastic
leukemia, intermediate T-acute lymphoblastic leukemia, and mature T-acute lymphoblastic
leukemia. Division into these groups is made according
to specific cell surface markers in flow cytometry. In addition to immunophenotyping, the WHO
classification has also gained importance in classifying acute lymphoblastic leukemias.
Apart from their cells of origin, let’s have a look at some more differentiating features
of acute myeloid versus acute lymphoblastic leukemias. One example is age distribution:
Acute lymphoblastic leukemias mainly occur during childhood, whereas acute myeloid leukemias
occur during adulthood. This age distribution is based on a fundamental difference between
lymphocytes and cells from the myeloid line. T cells and B cells are part of the adaptive
immune system and can react specifically to various pathogens. The foundation of this
specificity is the diversity of antibodies and T cell receptors. But how does this diversity
arise? It is achieved by gene rearrangements during lymphocyte development. The entire
process is termed somatic recombination. Somatic recombination also poses a risk, as the slicing
and merging of DNA can lead to errors. This particular mechanism is the key to understanding
the age distribution of the acute leukemias. The adaptive immune system develops the most
in the first 20 years of life and is the reason why acute lymphoblastic leukemias more commonly
affect children and young adults. In contrast, the development of acute myeloid
leukemias is favored by toxic chemicals like benzene, or ionizing radiation. Because a
certain exposure time is necessary for developing acute myeloid leukemia, it is most commonly
observed in adulthood. So let’s summarize the most important points
of the acute leukemias: The FAB classification can be used to categorize
the acute myeloid leukemias into different subtypes based on morphology. In acute lymphoblastic
leukemia, classification is made according to immunophenotyping and, in particular, the
level of cellular maturity. The WHO classification system is most current and is based on genetic
alterations in leukemic cells. An important difference to remember between
both acute leukemias is the age distribution pattern, with acute lymphoblastic leukemias
being the most common type of malignancy in children, and acute myeloid leukemias being
most commonly observed in adulthood. Now let’s move on to the lymphomas.
Lymphomas are classified into Hodgkin lymphoma and the non-Hodgkin lymphomas. Hodgkin lymphoma
was first described in 1832 by the English physician Thomas Hodgkin. In classical Hodgkin
lymphoma, a hallmark histological feature are Hodgkin and Reed-Sternberg cells. A much
less common form of Hodgkin lymphoma is the nodular lymphocyte-predominant Hodgkin lymphoma,
abbreviated as NLPHL, which accounts for only 5% of all Hodgkin lymphomas.
Hodgkin and Reed-Sternberg cells are not present in non-Hodgkin lymphoma. There was an initial
distinction to the other previously poorly characterized lymphomas, which were grouped
as non-Hodgkin lymphoma. The historical classification into Hodgkin and non-Hodgkin lymphoma is unfortunate,
because non-Hodgkin lymphomas represent a heterogeneous group, often with very different
characteristics. Non-Hodgkin lymphoma can be classified according
to its prognosis into high-grade aggressive non-Hodgkin lymphoma and low-grade indolent
non-Hodgkin lymphoma. In the following, we’ll briefly present
the most important non-Hodgkin lymphomas. The most common non-Hodgkin lymphoma is diffuse
large B-cell lymphoma. It is a high-grade, aggressive form of lymphoma. The second most
common non-Hodgkin lymphoma is follicular lymphoma, which is a low-grade lymphoma.
Multiple myeloma is also considered a low-grade non-Hodgkin lymphoma. The malignantly transformed
cells migrate to the bone marrow, making this a lymphoma with bone marrow infiltration.
Burkitt lymphoma is an aggressive non-Hodgkin lymphoma that is uncommon worldwide. However,
it is endemic in Equatorial Africa and other tropical regions.
Lymphoblastic lymphoma is another aggressive non-Hodgkin lymphoma that is relatively rare.
It is quite special in some respects. In the first part, we mentioned that lymphomas primarily
arise from the mature stages of cell development. However, lymphoblastic lymphoma develops from
the precursor cells of lymphocytes and therefore the same cells as the acute lymphoblastic
leukemias. It is namely a variant of acute lymphoblastic leukemia with peripheral manifestations
such as lymph node swelling. However, there is little bone marrow involvement.
Now on to another disorder that belongs to the indolent non-Hodgkin lymphomas, namely
chronic lymphocytic leukemia. Chronic lymphocytic leukemia may be termed leukemia; but it is
actually a lymphoma because malignant transformation does not occur in the bone marrow, but in
the lymph nodes. The malignantly transformed cells then enter the bloodstream, which is
why chronic lymphocytic leukemia was initially considered a leukemia. But more accurately,
it can be termed a lymphoma with a leukemic phase.
For a deeper understanding of the lymphomas, assigning the diseases to their cells of origin
can be very helpful: Precursor B-cell lymphoblastic lymphoma arises
from pre-B cells. Chronic lymphocytic leukemia arises from mature B cells, but may demonstrate
characteristics of memory B cells. Multiple myeloma arises from plasma cells. Most lymphomas,
however, originate from activated B cells. Examples include follicular lymphoma, diffuse
large B-cell lymphoma, and Burkitt lymphoma. Activated B cells are B cells that have been
activated in the germinal centre, where they pass through several stages.
These activation stages appear to represent a risk for the development of certain lymphomas.
In fact, an interesting mechanism has been identified in recent years that contributes
to the development of these lymphomas. The most likely mechanism is an antibody class
switching, for example, from IgG to IgA expression. Without going into too much detail, a class
switch can only occur if the DNA is cut in the initial stage of switching. Certain regions
of DNA are excised and are joined back together. This process is prone to errors. For example,
genes of growth factors may end up in the antibody region and thereby become upregulated.
So, let’s give you a recap of the previous section. Lymphomas can be classified as either
Hodgkin or non-Hodgkin lymphomas. Non-Hodgkin lymphomas represent a very heterogeneous group
and can be further differentiated into indolent and aggressive lymphomas. The most important
B-cell lymphomas have been briefly presented. For the sake of completeness: We haven’t
listed any examples of the T-cell lymphomas as they are less common than the B-cell lymphomas.

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