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For the acute lymphoblastic leukemias, the FAB classification system is outdated.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.