Precursor B cell neoplasm

§   Precursor B-cell lymphoblsatic leukaemia / lymphoma

Mature B-cell neoplasms (% of B / T cell lymphoma)

§   CLL / SLL (7%)

§   B cell prolymphocuteic leukaemia

§   Lymphoplamacytic lymphoma (1.2%)

§   Splenic marginal zone lymphoma

§   Hairy cell leukaemia

§   Splenic lymphoma / leukaemia unclassifiable

§   Splenic marginal zone lymphoma

§   Plasma cell neoplasms

§   MGUS

§   Solitary plasmacytoma

§   Primary amyloidosis

§   Heavy chain diseases

§   Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)

§   Nodal marginal zone lymphoma (1.8%)

§   Follicular lymphoma (22%)

§   Mantle cell lymphoma (6%)

§   Diffuse large B-cell lymphoma (31%)

§   T-cell / histiocyte rich large B-cell lymphoma

§   Primary diffuse large B-cell lymphoma of the CNS

§   Primary cutaneous diffuse large B-cell lymphoma, leg type

§   EBV positive diffuse large B-cell lymphoma of the elderly

§   Diffuse large B-cell lymphoma associated with chronic inflammation

§   Lymphoid granulomatosis

§   Mediastinal (thymic) large B cell lymphoma (2.4%)

§   Intravascular large B-cell lymphoma

§   ALK positive large B-cell lymphoma 

§   Plasmablastic lymphoma

§   Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease

§   Primary effusion lymphoma

§   Burkitt lymphoma / leukaemia (2.5%)

§   B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma

§   B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma

B-cell proliferations of uncertain malignant potential

§   Lymphomatoid granulomatosis

§   Post-transplant lymphoproliferative disorder, polymorphic

Epidemiology

§   90% of lymphoid neoplasms worldwide

§   4% of all cancer

Aetiology

§   Viruses

§   EBV (100% of endemic Burkitts / 40% of HIV associated cases)

§   HHV8

§   Kaposi sarcoma herpesvirus (KSHV)

§   Bacteria

§   H. Pylori – gastric MALT

§   B. Burgdoferi – cutaneous MALT

Pathophysiology

§   Tends to mimic B-cell maturation

§   Initial maturation occurs in the occurs in bone marrow (cf T cell maturation which occurs in the thymus)

§   Cells undergo heavy chain VDJ gene rearrangement CD10, CD19 expressed at this stage. TdT also expressed at this stage.

§   Cells then rearrange light chains and express CD20 around this time.

§   Surface immunoglobulin is then expressed and CD10 and TdT is then lost

§   The mature and antigen naïve B cell then leaves the marrow to circulate and populate lymphoid organs such as lymph nodes, spleen and MALT.

§   Naïve B cell then recognises an antigen with membrane bound antibody.

§   The B cells then collect in the germinal centres of various lymphoid organs and undergo somatic hypermutation.

§   Higher affinity antibody producing cells can then go on to become plasma cells or memory B cells

1. Precursor lymphoblast

§   Bone marrow

§   CD19+, CD10+, TdT+, cm+

§   Undergo VDJ gene rearrangement and mature into naïve B-cells (heavy chain precedes light chain rearrangement)

2. Naïve B Cells

§   Surface Ig (IgM+ / IgD+), CD5+, CD20+, CD23+

§   Small resting lymphocytes that circulate in the blood - also occupy the primary lymphoid follicles and bone marrow

§   On interacting with antigen mature into mantle cells or B-immunoblast

§   CD5+ cells – CLL (CD23+) or mantle cell (CD23-)

§   50% of B-cell CLL

3. Mantle cell

§   Surface Ig (IgM+ / IgD+), CD5+, CD20+, CD23-

§   Germinal centre

§   Virtually all mantle cell lymphoma

4. Follicular B blast

§   IgM+, BCL6+

§   Germinal centre

§   Burkitt’s lymphoma

5. Centroblast

§   Ig-, CD10+, BCL6+, BCL2-

§   Blast cells of the germinal centre

§   Large proliferating cells with 1-3 nucleoli and a narrow rim of cytoplasm.

§   Ungergoing somatic hyper-mutation of the IGV region

§   Many lack BCL2 expression making them susceptible to apoptosis

§   Express BLC6 which is a nuclear transcription factor expressed by centrocytes and centroblasts but not naïve B cells, mantle cells, memory B cells or plasmacells

§   Large B-cell lymphoma

6. Centrocyte

§   IgM/G+, CD10+, BCL6+

§   Germinal centre

§   Medium sized cells with irregular nuclei, inconspicuous nucleoli and scant cytoplasm

§   Express surface antibody that has undergone somatic hypermutation and may have undergone heavy chain class switch

§   Centrocytes with decreased affinity for antigen rapidly undergo apoptosis whilst those with increase affinity bind to antigen trapped on the processes of FDCs which rescues them from apoptosis and they re-express BCL2

§   Through interactions with FDCs and T cells (eg CD23 and CD40 ligand) they switch off BCL6 expression and differentiate into either memory B cells or plasma cells.

§   Follicular lymphoma thought to be tumour of centroblasts and centrocytes which have t(14;18) chromosomal rearrangement that prevents the normal switching off of BCL2.

7. Marginal zone and monocytoid B cell

§   IgM/G+, IgD-, CD10-, CD5-

§   Have mutations in IGV but have no intraclonal diversity

§   Reside in the follicle marginal zones

§   Round to slightly irregular nuclei, moderately condensed chromatin and moderate pale cytoplasm

§   Marginal zone lymphoma

8. Plasma cell

§   Lack surface immunoglobulin (cytoplasmic IgG/A) and pan B antigens CD20-, CD79a+ CD138+

§   Have mutations in IGV but have no intraclonal diversity

§   Home to bone marrow

§   Myeloma, plasmacytoma

9. Immunoblast

§        Highly proliferative

§        DLBCL

10. Plasmacytoid lymphocyte

§        CIgM+ and CD20+

Genetics

§        Several B-cell malignancies have typical cytogenetic abnormalities

§        t(8;14) / t(2;8) / t(22;8) Burkitt

§        translocation of Ig heavy and light chains to myc oncogene (assoc with proliferation)

§        t(11;14) Mantle cell

§        overexpression of cyclin D1 (assoc with proliferation)

§        t(14;18) Follicular

§        overexpression of BCL-2 (prevents apotosis)

§        All put a proto-oncogene under control of the immunoglobulin promoter on 14q

§        t(11;18) in MALT lymphoma results in a fusion protein which causes over expression of API2 (an antiapoptosis gene)

Lymphoma

Types of lymphoma

Indolent

1. Predominantly disseminated lymphoma/leukaemia

§        BM +/- PB and solid tissue

§        Generally indolent

§   CLL

§   Lymphoplamacytic lymphoma / Waldenstrom’s

§   Hairy cell leukaemia

§   Splenic marginal zone lymphoma

§   Myeloma

2. Primary extranodal lymphomas

§   MALT

§   Less likely to disseminate and tend to disseminate to other extranodal sites rather than lymph nodes or bone marrow.

3. Predominantly nodal – indolent (often present with lymph nodes)

§   Follicular lymphoma I, II, IIIa

§   Mantle cell lymphoma (only recently recognised - worse prognosis than follicular).

4. T cell

§   Sezary / Mycosis fungoides

§   Primary cutaneous anaplastic large cell (ALCL)

Aggressive

1. Nodal or extra nodal - aggressive

§   Diffuse large B-cell

§   (Also primary mediastinal large B-cell lymphoma, primary effusion lymphoma, intravascular lymphoma)

§   Burkitt lymphoma

§   Follicular Stage IIIb

§   Precursor B lymphoblastic

2. T cell

§   Peripheral T cell

§   Systemic anaplastic large cell lymphoma

§   Precusor T lymphoblastic

§   ATLL

Aetiology

§   Immunosuppression

§        HIV

§        Treatment related

§        Autoimmune disease (RA / Sjorgrens)

§        Childhood immunodeficiency (Wiskott-Aldrich / SCID)

§        Infections

§        Bacteria - MALT (H pylori, C. Psittaci, Borrelia)

§        EBV – Burkitts, Nasal T/NK

§        HHV8 – Kaposi’s / Castleman’s

§        HTLV1 – ATLL

§        Hep C ? lymphoplamacytic lymphoma

§        SV40 (simian virus 40) detectable by PCR in 40% of follicular / DLBCL by PCR, contaminent of polio vaccine in 60s, causation not firmly established