Lymphocyte Disorders
Acute Lymphoblastic Leukemia (ALL):
ALL has a lot of the same characteristics as AML (anemia, thrombocytopenia, and granulocytopenia). The obvious main difference is cell lineage. ALL is also most commonly associated with childhood leukemia; whereas, AML tends to be a more adult disease. Pediatric cases have a better prognosis than adult cases of ALL. At presentation, about 50% of patients will have an increased WBC count. ≥20% lymphoid blasts in the bone marrow is diagnostic.
The FAB classification for ALL, based mostly on morphology, has been mostly abandoned and ALL is now classified using immunophenotype and genetics. In the WHO classification system, there are basically two main categories, precursor B-cell, and precursor T-cell. Woohoo it’s pretty straightforward! The main requirement is the cells must be lymphoblastic or very early in development, hence the precursor in front of the B-cell or T-cell. So, the immunophenotype is used to distinguish between precursor B-cells and precursor T-cells, and the genetic testing further classifies the ALL to guide treatment.
How do you know if a B-cell is in a blast stage or very immature? B-cells express different antigens based on their maturity. Typically, the presence of TdT is the best indicator.
| Type of B-cell | TdT | CD19 | CD20 | CD10 (CALLA)* | Cytoplasmic mu | Surface Ig |
| Early pre-B | + | +/- | - | +/- | - | - |
| Pre-B | + | + | + | + | + | - |
| Mature B-cell | - | + | + | - | - | + |
Vocabulary Note
CD10 and CALLA (common acute lymphoblastic leukemia antigen) are the same cell surface marker, it has multiple names.
Once a case of ALL has been confirmed to be precursor B-cell ALL, cytogenetics and other molecular tests will further sub-classify the ALL.
Perspective Note
CD which stands for cluster of differentiation are cell surface molecules used to identify cell types. Cell surface molecules can have a number of different functions and are not restricted to any one function. There are hundreds of CD markers and they are commonly used in flow cytometry to identify various conditions especially cancer types.
TdT (terminal deoxynucleotidyl transferase) is a DNA polymerase strongly associated with precursor B-cells and precursor T-cells. It is often used to distinguish ALL from AML because its presence in AML is rare.
About 75-85% of ALL is of the precursor B-cell type and 15-25% is of the precursor T-cell variety. The surface antigen TdT is also present on precursor T-cells, so be aware of this! CD10/CALLA is also present on about 10% of precursor T-cell ALL cases, so it is not unique to precursor B-cells.
CD markers that are indicative of precursor T-cells are CD7, CD2, and CD5. T-cell antigens stay with the T-cell into maturity, so for immature T-cells, the absence of CD4 and CD8 is something to look for because they will only be on mature T-cells.
| Type of T-cell | TdT | CD7 | CD5 | CD2 | CD4 | CD8 | TCR (T-cell receptor) |
| Early thymocyte* | + | + | +/- | +/- | - | - | - |
| Common thymocyte | + | + | + | + | + | + | - |
| Mature T-cell | - | + | + | + | Either CD4 or CD8 | Either CD4 or CD8 | + |
*a thymocyte is a T-cell still residing in the thymus
The main takeaway is it is important to be able to distinguish immature B-cells from mature B-cells, immature T-cells from mature T-cells, and B-cells from T-cells. This table outlines the most important for differentiation.
| Mature T-cells | CD4 or CD8 |
| Unique to T-cells | CD2, CD3, CD7 |
| Mature B-cells | surface immunoglobulin (Ig) |
| Unique to B-cells | CD19, CD20 |
| T-cells and B-cells | CD10/CALLA, TdT |
Study Tip
Simplify the cell markers to more easily remember them
| Mature T | 4,8 |
| Unique T | 2,3,7 |
| Mature B | sIg |
| Unique B | 19,20 |
| T/B | 10/CALLA, TdT |
Burkitt’s Leukemia/Lymphoma:
Burkitt’s leukemia/lymphoma is a unique condition because morphologically it appears lymphoblastic but immunophenotypically it more closely represents a mature B-cell. Burkitt’s is associated with HIV and Epstein Barr virus. It is known to effect the jaw and abdominal areas. Cellular vacuolization is a common morphological trait. It is also associated with a t(8:14) genetic translocation.
Perspective Note
Leukemia versus lymphoma:
Leukemia and lymphomas have a lot in common. The main differences are leukemias are associated with the blood and bone marrow; whereas, lymphomas are associated with the lymph nodes and extramedullary sites. However, many leukemias can eventually effect lymph nodes and extramedullary sites, and many lymphomas can effect the bone marrow and peripheral blood. There can be gray areas.
Chronic Lymphocytic Leukemia (CLL):
CLL is associated with a proliferation of mature B-cell or T-cell lymphocytes in the bone marrow and peripheral blood. CLL can present with anemia, neutropenia, thrombocytopenia, as well as splenomegaly, hepatomegaly, and enlarged lymph nodes (lymphadenopathy). CLL can also present with hypogammaglobulinemia from the suppression of all classes of Ig that leaves the patient more susceptible to bacterial and viral infections. Autoimmune disease can also present and lead to the coagulation condition idiopathic thrombocytopenic purpura (ITP) (antibodies to platelets) or autoimmune hemolytic anemia (antibodies to red cells). Key morphologic features include hyper condensed chromatin that gives a soccer ball like appearance. Smudge cells, which are broken cells, are also a common peripheral smear finding.
Key diagnostics for CLL are a highly increased lymphocyte count on the peripheral smear, increased lymphocytes in the bone marrow (usually ≥30% lymphocytosis), genetic abnormalities such as trisomy 12, and symptoms listed above. CLL usually effects people over 50 years old.
Hairy cell leukemia:
Hairy cell leukemia is characterized by mature B-cell lymphocytes with irregular hair-like projections. These cells will be positive for the stain tartrate resistant acid phosphatase (TRAP). Hairy cell leukemia can present with pancytopenia and splenomegaly.
Lymphomas:
Hodgkin lymphoma:
The lymphomas are basically lymphocytic proliferations of the lymph nodes. Symptoms of Hodgkin lymphoma can include enlarged lymph nodes, splenomegaly, and hepatomegaly amongst others. The most important lab diagnostic is the presence of Reed Sternberg cells which will be found in the lymph node or tissue biopsy, not the peripheral blood or bone marrow. Reed Sternberg cells have an owl eye appearance. Hodgkin lymphoma has a good prognosis.
Nerdy Note
Hodgkin lymphoma is named after the British doctor Thomas Hodgkin (1798-1866). Hodgkin described the condition as benign in 1832 and it wasn’t until 1865 that the British doctor Samuel Wilks described it as malignant and named it in honor of Thomas Hodgkin.
Non-Hodgkin Lymphoma (NHL):
Non-Hodgkin lymphoma is the basket of the rest of the lymphomas other than Hodgkin lymphoma. The lymph node is a complex organ that houses B-cells and T-cells of varying maturation in specific compartments. Each of these cell groups can go haywire. Some of the lymphomas are named after the compartment of the lymph node where the cells normally reside, e.g. follicular lymphoma and mantle cell lymphoma (both mature B-cell lymphomas). NHL’s are predominantly mature B-cell (85-90%) and mature T-cell/Natural killer cell (10-15%).
A common type of T-cell NHL is cutaneous T-cell lymphoma. NHL’s can effect the skin also. Two common types of cutaneous T-cell lymphoma are mycosis fungoides and Sezary syndrome.
Plasma cell disorders:
Monoclonal gammopathy of undetermined significance (MGUS):
This can be the precursor to more serious plasma cell disorders. MGUS is associated with a small “M-spike.” An M-spike is basically a large amount of monoclonal antibody, indicating over-proliferation of a cloned plasma cell usually detected with protein electrophoresis. MGUS can lead to plasma cell disorders like multiple myeloma, or things like NHL and CLL.
Multiple myeloma:
Multiple myeloma is one of many conditions characterized by an over proliferation of plasma cells. Plasma cells? Aren’t those of lymphoid origin? Yes, technically a myeloma is defined as a malignant tumor of the bone marrow. Most of the time when the prefix myelo- is used it’s referring to myeloid cell lines (granulocytes, RBCs, platelets) but in this case it’s lymphocytes. Don’t get tripped up by this! Make sure you know multiple myeloma involves plasma cells. What does the multiple refer to? Multiple in this sense refers to multiple different areas of bone. This disease has a tendency to spread and be in multiple areas. The three main characteristics of multiple myeloma are: over proliferation of plasma cells in the bone marrow, over production of monoclonal antibody, and the breaking down of bone.
Typical findings in multiple myeloma include rouleaux on the peripheral blood smear due to increased IgG or IgA serum protein. Anemia and even pancytopenia can present in multiple myeloma due to the malignant plasma cell colonies.
Bence-Jones proteinuria (free light chains in the urine) can also be present in multiple myeloma. An over-proliferation of immunoglobulin usually results in excess free light chains and these won’t be detected in the blood, so urine electrophoresis is necessary for detection. These excess free light chains can cause kidney damage and contribute to renal failure in patients with multiple myeloma.
Waldenstrom’s Macroglobulinemia:
Waldenstrom’s macroglobulinemia is a rare malignant lymphoproliferative disorder where small lymphocytes exhibit plasma cell differentiation and produce excess amounts of IgM. An IgM spike with a plasma cell disorder is a strong indication of Waldenstrom’s macroglobulinemia! The condition can present with anemia, lymphadenopathy, organomegaly, and even things like increased coagulation tests (PT and APTT) because the excess IgM can interfere with platelets and blood clotting proteins. Bence Jones protein in the urine can also be seen here.