Last updated on March 19, 2020 at 17:29
We’re entering the topics about haematological malignancies. Before we start, we need to make a few concepts clear first.
The figure above shows the normal haematopoiesis. Based on this figure can we divide the white blood cells into two categories: The myeloid cells, which includes the cell lines on the right, and the lymphoid cells, which includes the cell lines on the left.
There are three major types of haematological malignancies:
- Lymphoid neoplasms – where cancer cells originate from T cells, B cells or NK cells
- Myeloid neoplasms – where cancer cells originate from myeloid progenitor cells
- Histiocytic/dendritic neoplasms – where cancer cells originate from macrophages or dendritic cells
Lymphoid neoplasms may manifest as leukaemias, in which the tumor cells are present in the peripheral blood and bone marrow, or as lymphomas, in which the tumors cells produce masses in lymph nodes or other tissues. The different neoplasms are names according to their usual manifestation. If a certain neoplasm always or almost always forms a lymphoid mass is it called a lymphoma, like Burkitt lymphoma. If a certain neoplasm always or almost always causes tumor cells to be present in the blood is it called a leukaemia, like acute lymphoblastic leukaemia.
The lymphoid neoplasms are classified according to multiple properties:
- Whether they are Hodgkin lymphoma or non-Hodgkin lymphoma
- Whether they originate from T or NK cells or from B cells
- Whether they are aggressive, indolent (not so aggressive) or in-between (“other”)
- Whether they originate from precursor cells (which don’t express CD20) or mature cells (which express CD20)
The classification is best visualized like this:
The bolded boxes are specific names of neoplasms. The non-bolded boxes show the classifications. This list is not conclusive.
As you can see from the figure above are there many lymphoid neoplasms that are classified as “non-Hodgkin lymphoma”. Most (80%) of these originate from B-cells.
Lymphomas may be nodal or extranodal, where “nodal” refers to a lymph node. A lymphoma is nodal if it originates in a lymph node, and primary extranodal if it starts in other lymphoid tissues, like the lymphoid tissues in the GI tract, the skin or in the CNS. A lymphoma can be “secondary” extranodal if it spreads from a lymph node to other tissues.
Aggressive lymphomas have worse prognosis than the indolent ones. They can be considered “high-grade”. They proliferate rapidly and are more frequent in children. Aggressive lymphomas counterintuitively have a higher chance of being treatable.
Indolent lymphomas are much less harmful than the aggressive ones; in some cases they may not even require treatment. They can be considered “low-grade”. These tumors are more frequent in older patients. The tumor cells don’t proliferate much. In most cases are indolent lymphomas uncurable.
Lymphoid neoplasms that affect lymph nodes cause painless and firm lymphadenomegaly. Infiltration of tumor cells into the spleen and liver can cause spleno-and-hepatomegaly as well. Proliferating tumor cells in the bone marrow displace and destroy the normal cells of the bone marrow, which can cause bone marrow failure with anaemia, thrombocytopaenia and neutropenia.
The neutropenia can predispose to systemic infections. Autoimmune haemolytic anaemia may occur in patients with lymphoid neoplasms.
The term B symptoms refer to systemic symptoms of fever, night sweats and weight loss, which are common symptoms in patients with lymphoid neoplasms.
The staging system used for lymphoid neoplasms is called Ann Arbor staging, which works like this:
- Stage I – cancer in a single region, usually one lymph node and the surrounding area
- Stage II – cancer in more lymph node regions, on one side of the diaphragm
- Stage III – cancer in more lymph node regions, on both sides of the diaphragm
- Stage IV – cancer in one or more extralymphatic organs, like the bone marrow, liver or lung
Also, several modifiers are used:
- E – if there is extranodal involvement
- A – if there are no “B symptoms”
- B – if there are B symptoms
- X – larger than 10 cm mass – called “bulky disease”
Now, let’s get to the specific diseases.
Follicular lymphoma (FL) is an indolent, mature, non-Hodgkin B-cell lymphoma. It’s the most common indolent non-Hodgkin lymphoma and the second most common non-Hodgkin lymphoma overall. It mostly affects adults older than 50 years.
It very frequently involves a t(14;18) translocation where the gene BCL2 on the chromosome 18 is fused to the immunoglobulin heavy chain gene (IgH) on chromosome 14. This causes overexpression of the antiapoptotic protein Bcl-2, which contributes to tumor cell survival.
It usually manifests as slowly progressive, painless, generalized lymphadenopathy. The name “follicular” comes from the fact that the neoplastic cells form “neoplastic follicles” in lymph nodes. The histology of follicular lymphoma can be studied in the slide section.
The disease is not curable, and therapy is therefore usually not performed. 40% of cases of FL progress into diffuse large B-cell lymphoma.
Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is an indolent, mature, non-Hodgkin B-cell lymphoma. It’s the most common adult leukaemia and the most frequent lymphoma in Hungary. It also mostly affects adults older than 50 years. It’s called “leukaemia” because tumor cells are found in the blood in 90-100% of cases.
The tumor cells of CLL contains high amounts of Bcl-2, however there is no rearrangement of the BCL2 gene involved. Some evidence suggests that the BCL2 gene is upregulated due to loss of regulatory microRNAs.
Symptoms of CLL include painless lymphadenomegaly and splenomegaly, symptomless leukocytosis and B symptoms. Due to the non-specific symptoms is CLL often an incidental finding, which is discovered during a routine blood test. The liver and bone marrow may also be affected – the bone marrow failure may cause anaemia and thrombocytopaenia. If the CLL is limited to a lymph node is the condition called small lymphocytic lymphoma.
Two types of CLL exist: the prefollicular type and the postfollicular type. The main difference is whether the immunoglobulin heavy chain gene (IgH) has been mutated or not. The differences are summed up here:
|Prefollicular type||Postfollicular type|
|IgH gene status||Not mutated||Mutated|
|Has underwent somatic hypermutation||No||Yes|
|Treatment||More frequently required||Less frequently required|
CLL-cells with unmutated IGHV originate from CD5+ B-Cells prior to SHM, while CLL-cells with mutated IGHV originate from CD5+ B-Cells that passed through and differentiated in Germinal center.
–> The tumours are simply reflecting the stage of maturation/differentiation of the parental B cell.
Source that prefollicular type has not underwent somatic hypermutation and has the worst prognosis: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/89008 and http://www.bloodjournal.org/content/120/24/4802?sso-checked=true
Somatic hypermutation is performed by an enzyme called AID. Cancers that have not underwent somatic hypermutation of the IgH gene have worse prognosis because AID will mutate other genes that could make the tumor cells more aggressive instead of mutating the harmless gene IgH. This is not important to know and is just included to explain the above.
The course and prognosis are extremely variable, but generally good. Many patients live more than 10 years after the diagnosis and die of unrelated causes. The median survival is around 5 years. A small portion of patients with CLL will progress into diffuse large B-cell lymphoma (DLBCL); this transformation is called Richter-transformation.
Treatment may involve simple observation (no treatment, just watching for malignant changes), cytostatic drugs, chemotherapy or drugs that target the CD markers of the tumor cells.
Mantle cell lymphoma
Mantle cell lymphoma (MCL) is a mature, non-Hodgkin B-cell lymphoma belonging to the “other” group. It originates from mantle zone B-cells and mostly affects adult males. It’s associated with lymphadenomegaly and bone marrow infiltration. It affects the peripheral blood in only 20% of cases and is therefore not considered a leukaemia.
It sometimes arises in the gastrointestinal tract, where it manifests as multifocal submucosal nodules that resemble polyps. These can be mistaken for polyps due to other diseases, like familiar adenomatous polyposis, hamartomatous polyps or ulcerative colitis.
MCL involves a t(11;14) translocation where the cyclin D1 gene is fused to the IgH locus. Cyclin D1 is involved in cell proliferation and is overexpressed as a result of this translocation.
It’s an aggressive cancer; the mean survival is 3-5 years.
Marginal zone lymphoma
Marginal zone lymphoma (MZL) is an indolent, mature, non-Hodgkin B cell lymphoma. The name comes from how it develops from marginal zone B-cells. Three subtypes exist:
- Extranodal marginal zone lymphoma – most common type
- Nodal marginal zone lymphoma
- Splenic marginal zone lymphoma – least common type
Extranodal marginal zone lymphoma, also called MALT lymphoma, arises most commonly from lymphoid tissue in organs such as the stomach, salivary glands, intestines, lungs, orbit or breast. They are associated with chronic infection, such as that seen in H. pylori gastritis. They are also associated with autoimmune disorders, like Sjögren’s (MALT lymphoma in the salivary glands).
Nodal marginal zone lymphoma arises in lymph nodes, most commonly cervical lymph nodes. It causes lymphadenopathy.
Splenic marginal zone lymphoma arises in the spleen or bone marrow and causes splenomegaly.
27. Reactive lymph node changes
29. High grade B cell lymphomas (BL, DLBCL). Plasma cell neoplasms