Hematological malignancies. Welcome to this episode, in which we provide
you with an overview of hematological malignancies such as leukemia and lymphoma. Our aim is
to make this complex topic more comprehensible. So, let’s start with an overview of what
these diseases have in common. Neoplasms of blood cell origin are commonly
caused by gene mutations, which lead to the uncontrolled proliferation of cells. This
includes malignant diseases derived from bone marrow, the site of blood cell formation.
However, the lymphatic system is also an important site for the development of neoplasms, as
lymphocytes migrate and are activated here. Since blood can be found almost everywhere
in the body and a variety of cells are present in blood, the clinical picture of hematological
malignancies is quite diverse. To help make our understanding of this topic
more comprehensible, five major disease groups are distinguishable. These include the groups
of lymphomas and acute leukemias with the two subgroups acute lymphoblastic leukemias
and acute myeloid leukemias. In addition, the myeloproliferative and myelodysplastic
disorders are also hematological malignancies. As a basis for this episode, we would like
to provide an initial overview of the process of hematopoiesis. This introduction will be
followed by a structured overview of the five major disease groups, which can make learning
much easier. In the first part, we will not deliberately go into the various diagnoses,
but will provide an initial overview of the characteristics of each group.
These include: Where are the respective malignancies formed?
From which cells are they derived? And what impact does this have on clinical
findings? Now onto blood cell formation -- or hematopoiesis.
It is initially quite useful to have a brief overview of the process of hematopoiesis.
Hematopoietic stem cells in the bone marrow give rise to lymphoid and myeloid stem cells.
They are the starting points for the two cell lines, which can be clearly differentiated
from one another: the lymphoid and myeloid cell lines.
The lymphoid cell line is comprised of T and B cells. B cells differentiate in the lymph
nodes to plasma cells. The myeloid line shows more diversity. It
simultaneously generates three different cell lines:
Firstly, myeloid stem cells give rise to megakaryocytes, which are the precursors of platelets.
Secondly, several intermediate steps lead to the development of erythrocytes, commonly
termed as red blood cells. Thirdly, myeloid stem cells can also lead
to the production of myeloblasts. They are progenitor cells for granulocytes and monocytes.
After monocytes are formed, they migrate to the tissues and differentiate into macrophages.
For a better overview, all of these cells have been classified into various groups.
The two largest groups are the lymphoid and myeloid cell lines.
Differentiation of these groups is important, as it provides the basis for the classification
of hematological malignancies. Lymphomas and acute lymphoblastic leukemias
can, on the left side, be differentiated from the acute myeloid leukemias, myeloproliferative
and myelodysplastic disorders on the right side. The two groups on the left develop from
the lymphoid cells and the three groups on the right from the myeloid cells.
The word leukemia can sometimes be quite confusing, as there are many different types of leukemias.
Knowing the origin of the word leukemia may help to provide a better understanding of
what exactly is meant. The word leukemia can be basically translated into “white blood“.
This goes back to the German physician Rudolf Virchow, who took a closer look at the blood
of a severely ill patient and noticed some changes.
The blood was initially centrifuged. As a result, the blood was separated into a plasma
fraction and a red cell fraction. There was a thin layer of leukocytes and platelets between
both cell fractions, which is also referred to as the buffy coat.
In the patient’s blood sample, Rudolf Virchow noticed a thickened buffy coat, which was
a white color compared to the red blood cells and plasma. He therefore termed the disease
leukemia. This illustrates how the word leukemia is
a historical term that was initially used descriptively and does not refer to a particular
disease. Nowadays, leukemia is no longer defined by the proliferation of white blood cells
in blood, but by the presence of leukemic cells in the bone marrow.
This was a short overview of how the definition of leukemia has changed over time through
a better understanding, but leukemias now comprise numerous different diagnoses. We
would like to introduce you now to the characteristics of the acute leukemias:
The acute leukemias can be differentiated into two groups, the acute lymphoblastic leukemias
and the acute myeloid leukemias. They principally arise from completely different cells, either
lymphoid or myeloid cells. Both groups are, however, formed in the bone
marrow from the precursors of blood cells and thereby generate similar symptoms. Therefore,
they are grouped under the general term “acute leukemias”.
To illustrate the precursor cell they are derived from, we would like to provide you
with an example from each group. The first example concerns the physiological development
of neutrophils and the second example concerns B cell development.
Now to the first example: Neutrophils belong to the myeloid cell line and are derived from
myeloblasts. The next stages in development after myeloblasts are the promyelocytes, myelocytes,
and metamyelocytes. From the metamyelocyte, a band neutrophil granulocyte is formed in
the bone marrow. This cell matures in the blood to a segmented neutrophil.
Acute myeloid leukemia of neutrophils can develop from precursor cells such as myeloblasts
and promyelocytes, however not from mature cells. This is based on the fact that the
immature cells still have a high replicative potential and thus a high risk of malignant
transformation.
So, now onto the second example, B cells: B cells develop from hematopoietic stem cells,
via the pro-B and the pre-B cells, into immature B cells. The next stage is the mature B cell,
which is flushed out of the bone marrow and migrates to the lymph node.
In the lymph nodes, B cell activation occurs. Activation results in the formation of plasma
cells and memory B cells. Acute lymphoblastic leukemia primarily develops
from precursor cells, analogous to acute myeloid leukemia. However, in this case, it concerns
lymphoid progenitor cells. Now onto the clinical findings associated
with acute leukemias: For starters, a brief summary: Although the acute leukemias can
be separated into two groups according to their precursor cells, symptoms for both groups
still remain similar, because: Neoplastic cells in acute leukemia are unable
to function properly and can replace other cell lines in the bone marrow. The typical
symptoms and risk of acute leukemia can be explained by this replacement.
First, suppression of erythropoiesis leads to anemia.
Second, suppression of thrombopoiesis results in low platelet numbers, which, in turn, leads
to a bleeding tendency. Third, suppression of leukopoiesis results
in a deficiency of functional leukocytes and susceptibility to infection.
Because leukemias originate in the bone marrow, this also means that leukemic cells are not
necessarily detectable in blood, which is often confusing. So, the total number of leukocytes
in blood may be increased in leukemia, as has been described for the origin of the term
leukemia. However, a patient with leukemia can have
a normal or even a decreased number of leukocytes in peripheral blood. Therefore: A normal blood
cell count does not exclude leukemia. As a result, there is a risk that the leukemia
may remain undetected. Thus, as a general rule: Suspected leukemia can only be excluded
by bone marrow aspiration! So let’s briefly introduce the lymphomas.
Like the acute lymphoblastic leukemias, malignant lymphomas originate from the lymphoid cell
line. They can be differentiated from leukemias in regards to their site of origin and the
cells they are derived from. The point of origin for leukemias is usually
the bone marrow. In contrast, lymphomas originate in the lymphatic system, particularly the
lymph nodes and spleen. The cells of origin of acute lymphoblastic
leukemias are, as previously mentioned, the precursor lymphocytes, as indicated by the
triangle here. In lymphomas, the cells of origin are mature
lymphocytes and their activated forms. So we could picture this as a triangle in
the opposite direction. This is, admittedly, a simple concept and
the triangles indicate that there is actually a smooth transition between lymphomas and
the acute lymphoblastic leukemias. The percentage of blasts in the bone marrow is important
for differentiating between cases which transition between lymphomas and lymphoblastic leukemias.
If the blasts exceed a certain value, the disease is classified as lymphoblastic leukemia
and not lymphoma and is treated differently. So, after this basic introduction, let’s
go into the clinical presentation of lymphomas. Lymphomas are frequently associated with so-called
B symptoms. These are fever, night sweats, and weight loss. Because many lymphomas develop
in the lymph nodes, lymph node swelling is a common symptom.
Lymphomas include many different diseases, therefore B symptoms or lymph node swelling
vary between the different types of lymphomas. To summarize the lymphomas: they usually originate
in the lymphatic system from more mature lymphocytes. Clinical variation depends on the type and
location, however B symptoms and lymph node swelling are common.
An interesting but difficult aspect of this topic is the overlap between lymphomas and
acute lymphoblastic leukemias. The differentiation is not always possible
based solely on their clinical presentation, which may be quite similar.
There are three interesting overlaps: First, lymphoma cells, which originate from
the lymph nodes, may enter the bloodstream. This could be described as a leukemic phase
of a lymphoma. Second, certain lymphoma cells may infiltrate
the bone marrow, which could be best described as lymphoma with bone marrow infiltration.
Third, in some cases leukemic cells may migrate to the lymph nodes, resulting in leukemia
with lymph node swelling. These three overlapping variations can be
initially confusing, but if you keep this smooth transition between leukemia and lymphoma
in mind, it will provide a much better understanding of the topic.
Ok, we’ve already accomplished a considerable bit up to now. You already have an overview
of hematopoiesis, the acute leukemias, and lymphomas. Now, we will turn to the myeloid
stem cell disorders: