Non-Hodgkins Lymphoma

B

cell tumors  T cell tumors  Macrophage tumors

Characteristics to predict growth behavior: NON HODGKINS LYMPHOMA

1. 2. 3.

Pattern of tissue replacement Morphology of cells Extent of organ involvement

1. Tissue replacement: Nodular and Diffuse

 

Nodular lymphoma: Reflect the morphology of lymphoid follicles and composed of B cells Diffuse lymphoma: Reflect the structure of diffuse cortex of lymph nodes and appear as sheets of cells. May be B, T, macrophage origin

2.Cell size: Size of the nuclei of cells of tumors is

important morphological feature. Small cells:- better prognosis Large cells:- poor prognosis Mixed cells:- intermediate prognosis 3. Organ involvement: the more organ involved the poorer prognosis. The Rappaport system of classification: Henry Rappaport in 1956 gave the classification on cancer based on morphology of cells of cancer.

Rappaport System
Topography 1. Nodular or cell 2. Diffuse pattern Cell type
1. Lymphocytic, well differentiated (small) 2. Lymphocytic, poorly differentiated (intermediate) 3. Histiocytic (reticulum cell sarcoma) 4. Mixed histiocytic and lymphocytic (mixed) 5. Undifferentiated (blast) (very large)

B cell tumor
Examples: Chronic lymphocytic leukemia, nodular /diffuse lymphoma, tumors of plasma cells etc. The cells of B cells tumor express:  Cell surface immunoglobulin  Cytoplasmic monoclonal immunoglobulin  Rearranged immunoglobulin genes  Cell surface markers of B-cell lineage  Most B cells tumors arise in - Bone marrow (leukemia) - Germinal center of lymph nodes ( lymphoma)

B cell tumor
Tumor Phenotypic markers Bone marrow origin
CLL ALL Mature B cell, sIg, CD5+

Characteristics

Mature B cells, small lymphocytes, blood involved Large cell, spleen involved, rapid progression. Atypical lymphocytes, germinal center type, Splenomegaly, serum contain IL-2R

Immature B cell, sIg+++, CD+/Lymph node origin Follicular lymphoma Hairy cell leukemia sIg+++, CD5sIg+++, CD5, IL-2R

B-cell Leukemia


2 types- Acute Lymphblastic leukemia - Chronic Lymphocytic leukemia Acute B-cell leukemia Maturation arrest at lymphoid stem cell level in the bone

marrow. May be B or T cell type. B-cell leukemia express- CD19, CD79a, terminaldeoxytransferase (TdT), sIg, CD10 T-cell leukemia express- TdT, CD3, CD7 but no sIg Because the arrested stage of maturation is at the blast cell stage, most of the cell are in cycle, so there is high growth rate. Cancer has rapid course. Clinical response on chemotherapy is good.

B cell tumor

B-cell Leukemias
 Chronic lymphocytic leukemia

Protracted disease consisting of increased small lymphocytes in bone marrow & blood. Lymph node & spleen involvement occur at late stage. Cells express monoclonal sIg, or rearranged Ig genes & Tcell marker CD5. Disease starts at bone marrow, later mature lymphocytes extend from bone marrow to blood and visceral organs

 Hairy cell leukemia:

Appearance of an unusual mononuclear cell in the peripheral blood. Spleenomegaly and decrease in other cellular elements of the blood.

B-cell Leukemias
Hairy cell has the size of normal mononuclear cells and has convoluted cytoplasm Cells have some features of macrophage & represents an immature B-cell type. Cells has monoclonal cytoplasmic & surface Ig & are capable of phagocytosis. Treatment is done with alphainterferon.

Fig: hairy cells

B-cell lymphomas
   

2 forms of lymphoma follicular & diffuse Both contain small and large lymphocytes Found in lymph nodes, spleen & gastrointestinal tract. Follicular center cells:
Lukes & Collins (1971) found that cells of most NHL resembled cells of germinal centers and postulated that these cells represented different stages of the B cell cycle. The shape of the nuclei of the cells of a lymphoma reflected the stage of maturation of the cells. Evolution of B cell lymphoma is associated with progression to more malignant behavior. Small cleaved-large cleaved-small noncleaved-large noncleaved.

B-cell lymphomas

Small noncleaved stage

Activated B cell stage

Large Noncleaved cells immunoblastic

Plasma cell stage

B-cell lymphomas


Nodular lymphoma:It is defined as a lymphoma of follicle center B-cells (centrocytes and centroblasts), which has at least a partially follicular pattern. Diffuse large B-cell lymphoma (DLBL, DLBCL, or DLCL) is a type of aggressive non-Hodgkin lymphoma. It accounts for approximately 40% of lymphomas among adults

B-cell lymphomas
Tissue pattern of lymphoma:
Neoplastic follicles are found throughout the node. Diffuse lymphocytic lymphoma consists of small to medium sized lymphocytes. They do not form follicles and diffusely infiltrate lymph node and spleen structures. Diffuse large cell lymphoma are made of large cells and replace lymphoid organs as sheets of malignant cells.

B-cell lymphomas

B-cell lymphomas Phenotypic markers :

The arrested stage of maturation of B cell lineage can be deduced from Phenotypic expression of Ig produced by B-cell tumors Rearrangement of Ig genes Expression of developmentally related cell surface markers (table)  The major distinguishing feature of B cell tumors is monoclonality the presence or production of only one class of Ig or one light chain type by all cells of tumor .

B-cell lymphomas

-

Test of monoclonality: Immuno-labeling of tissue for kappa

& lambda light chains of Ig is done. If all of the cells contain one light chain type, then it is monoclonality If some cells express the kappa chain and others express lambda chain (60:40 ratio) then it is polyclonality.

Ig gene rearrangement:

Rearrangement of Ig genes may be used to differentiate B cell tumors from others those morphologically resemble B cell tumors. - B cell lymphoma rearrangements can be differentiated from normal polyclonal rearrangement by restriction enzyme digestion.

B-cell lymphomas
-

Polyclonal B cell DNA contains multiple gene arrangement that produce a diffuse, non distinct pattern when labeled with a specific cDNA probe. DNA from clonal proliferation give discret bands. Thus diagnosis of lymphoma within a mixture of polyclonal cells can be made accurately. B cell differentiation markers:

B cell surface markers can be used to evaluate the stage of differentiation of B cell lymphomas and leukemia. Expression of markers of mature B cells is associated with better prognosis and expression of markers of immature B cells with poor prognosis.

B-cell lymphomas
For example: expression of late B cell differentiation marker CD23 and lack of early B cell differentiation markers e.g. CD38 indicate longer disease free survival. The expression of CD markers on B cells frequently disobeys the differentiation pattern. Thus CD21 and CD23 markers of different stages of normal differentiation are found on same tumor cells.  Gene expression profiling: the level of mRNA in tissues may be estimated using cDNA microarray analysis. Approximately 40% patients of good prognosis have a pattern similar to that of germinal center B-cells. 60% patients of poor prognosis have a gene expression pattern similar to activated B cells.

Multiple Myeloma
Many sites (multiple) of masses (-oma) of tumor cell found in bone marrow (myel-) Tumors of plasma cells arise in bone marrow, but the cells do not appear in the blood as in leukemia. The plasma cells contain & secret monoclonal Ig of any classes. Ig do not usually demonstrate antigen binding capacity. Myeloma paraprotein: Homogenous Ig is referred to as myeloma paraprotein. Sera of myeloma patients shows peak paraprotein in 80% cases (myeloma spikes). Degree of elevation of a paraprotein in a patient may be used to monitor therapeutic effects.

Multiple Myeloma


Ig idiotype therapy: Myeloma idiotype serves as a marker for all cells in the myeloma and target of immunotherapy. - In mice model, the immunization of mice with a myeloma idiotype can produce resistance to transplanted myeloma cells bearing the idiotype. -Mechanism for control myeloma cell growth by antibodies to idiotype (opsonization, ADCC). by T cells (specific T suppressor cells or T killers cells to the idiotype)

Multiple Myeloma

  

The main symptom is pain in the bones (ribs and spine) lack of red blood cells (tiredness, weakness, palpitations, and dizziness). weight loss, frequent infections, bone fractures without cause.

Burkitts l

T-cell tumors


Markers- Monoclonal Ab to Tcell population are applied to

define Tcell tumors. -Erosettes (CD2) and TdT are most useful phenotypic markers. Many markers (e.g.CD1,CD5) are not useful because they also appear on non T cell tissue. -Others (CD2, CD4, CD7) are T cell specific markers and define T cell lineage and stages of maturation arrest.  Major features of malignancies - monoclonal nature of malignant cells as compared with normal, polyclonal T cell population.  Phenotypic characterization may be carried out on cell suspension (eg leukemic blood/effusions, frozen tissue sections).

T-cell tumors
Bone marrow origin T-cell ALL T-cell CLL Thymoma Rapid course,poor response to chemotherapy Very rare, worse prognosis Anterior mediastinum, true thymic lymphoma very rare.

Lymph node T-lymphoblastic lymphoma Rare, usually in children, begins in thymus T-cell NHL Rare, diffuse lymhoma,

Macrophage tumors


Tumors consists of space-occupying lesions filled by mature histiocytes with abundant cytoplasm. Normal tissue distribution Circulating monocytes Reticuloendothelial cell Follicular, lymph node cortex Intraepithelial
Bone marrow

Histiocyte type Free histiocytes Fixed histiocytes Dendritic histiocytes Langerhans cells Macrophage stem cells

Putative malignant tumor Monocytic leukemia True histiocytic lymphoma Hand-SchullerChristian disease Letterer-Siwe disease Eosinophilic granuloma

System involved

Bone, spleen, lymph node Skin, lymph node, spleen Bone

The diagnosis of NHL is achieved by conducting a biopsy of one of the swollen glands and will be completed with a study into the extent of the disease (examinations to find out how many lymph node areas have been affected). These examinations will include a blood test, one or more image tests (radiograph, ultrasound, scintigraphy, and MRI scan) and a bone marrow biopsy (biopsy of the hip bone) to assess the condition of the bone marrow.