lymphoma : malignancy of lymphocytes lymphocytes b-cells t-cells nk-cells (natural killer cells)
TRANSCRIPT
Lymphoma : Malignancy of Lymphocytes
Lymphocytes B-cells
T-cells
NK-cells (Natural Killer Cells)
Definition The term "malignancy" refers to cancerous
cells that have the ability to invade and destroy tissues, and / or to metastasize to other sites in the body. There may also be changes to the physiology of the organism.
Malignant cells tend to have fast, uncontrolled growth due to changes in their genetic makeup.
A malignant clone is a clone of cell that have genomic changes that leads to the malignant state.
However not all genomic changes result in malignant clones.
Clonal evolution is the further changes in the genome which may result in
progression of disease
relapse after treatment
resistence to standard therapy.
Lymphomas
10-20 new case per 100,000 per year
Deaths 8 per 100,000 per year
Commonest: Diffuse Large B-cell lymphoma
Follicular lymphoma
CLL
Mantle cell lymphoma
Rappaport Lymphoma Classification 1966
Well-differentiated diffuse lymphocytic lymphoma Poorly differentiated diffuse lymphocytic lymphoma
Well differentiated nodular lymphocytic lymphomaPoorly differentiated nodular lymphocytic lymphoma
Nodular Histiocytic lymphoma (= large cell lymphoma)Diffuse Histiocytic lymphoma (=large cell lymphoma)
Mixed cell lymphoma
MORPHOLOGY ONLY
Non-Hodgkin’s lymphoma
Lukes and Collins USA Dorfman
Kiel (Lennert) Germany
WHO Geneva UK
Hodgkin’s lymphoma
Lukes-Butler
Rye Nodular sclerotic Lymphocyte predominent Mixed cellularity Lymphocyte depleted
Lukes and Collins (1974)
I. Unidentified Cell Type
II. T-cells Mycosis fungoides and Sezary, convoluted lymphocyte Immunoblastic sarcoma of T-cells.
III. B-cells Small lymphocytic Plasmacytoid lymphocyte Follicular center cell (FCC types; follicular, diffuse, follicular and diffuse, sclerotic) small cleaved large cleaved small non-cleaved Large non-cleaved Immunoblastic
IV Histiocytic type
V Unclassifiable
Updated Kiel
B- cell
Low Grade Lymphocytic-
CLL, prolymphocytic,hairy cell lymphoma Lymphoplasmacytic/lymphoplasmactoid
Medium Grade Plasmacytic Centrocytic Centroblastic/centroblastic
High Grade Centroblastic Immunoblastic Large cell anaplastic Burkitt’s lymphoma Lymphoblastic
Rare types
T-cell
Lymphocytic
CLL, prolymphocytic Lymphoepitheloid
Angioimmunoblastic T-zone Pleomorphic small cell Pleomorphic medium and large
Immunoblastic Large cell naplastic
Lymphoblastic
Rare types
Working Formulation
Low Grade Malignant Lymphoma, small lymphocytic (chronic lymphocytic leukemia) Malignant Lymphoma, follicular, predominantly small cleaved cell Malignant Lymphoma, follicular, mixed (small cleaved and large cell)
Intermediate grade Malignant Lymphoma, follicular, predominantly large cell Malignant Lymphoma, diffuse, small cleaved cell Malignant Lymphoma, diffuse, mixed small and large cell Malignant Lymphoma, diffuse, large cell
High grade Malignant Lymphoma, large cell, immunoblastic Malignant Lymphoma, lymphoblastic Malignant Lymphoma, small non-cleaved cells (Burkitt's lymphoma)
Miscellaneous Composite Mycosis fungoides Histiocytic Extramedullary plasmacytoma Unclassifiable
Immunophenotyping
Cytogenetics
Normal Karyotype
t(9:22)
Philadelphia
chromosome
Fluorescent In Situ Hybridisation (FISH)
The Revised European American Lymphoma Classification (REAL) 1994
I. Precursor B-cell neoplasm:
Precursor B-lymphoblastic leukemia/lymphoma II. Mature (peripheral) B-cell neoplasms
B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) Hairy cell leuekmia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone lymphoma (+/- monocytoid B-cells) Follicle center lymphoma, follicular, Mantle cell lymphoma Diffuse large cell B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/Burkitt's cell leukemia
T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm:
Precursor T-lymphoblastic lymphoma/leukemia II. Mature (peripheral) T cell and NK-cell neoplasms
T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary's syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T cell lymphoma, not otherwise characterized Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma, T/null cell, primary systemic type
Hodgkin lymphoma (Hodgkin Lymphoma) Nodular lymphocyte predominance Hodgkin's lymphoma Classical Hodgkin's lymphoma Nodular sclerosis Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma
WHO classification 2002 Mature B cell neoplasms
Chronic lymphocytic leukemia/Small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia) Hairy cell leukemia Splenic marginal zone lymphoma Extranodal marginal zone B cell lymphoma, also called MALT lymphoma Nodal marginal zone B cell lymphoma (NMZL) Follicular lymphoma Mantle cell lymphoma Diffuse large B cell lymphoma Mediastinal (thymic) large B cell lymphoma Intravascular large B cell lymphoma Primary effusion lymphoma Burkitt lymphoma/leukemia
Mature T cell and natural killer (NK) cell neoplasms T cell prolymphocytic leukemia T cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T cell leukemia/lymphoma Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T cell lymphoma Hepatosplenic T cell lymphoma Blastic NK cell lymphoma Mycosis fungoides / Sezary syndrome Primary cutaneous CD30-positive T cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Angioimmunoblastic T cell lymphoma Peripheral T cell lymphoma, unspecified Anaplastic large cell lymphoma
Hodgkin lymphoma Classical Hodgkin lymphomas: Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depleted or not depleted Nodular lymphocyte-predominant Hodgkin lymphoma
Immunodeficiency-associated lymphoproliferative disorders Associated with a primary immune disorder Associated with the Human Immunodeficiency Virus (HIV) Post-transplant Associated with methotrexate therapy Primary central nervous system lymphoma occurs most often in immuno-compromised patients, in particular those with AIDS, but it can occur in the immunocompetent as well. It has a
poor prognosis, particularly in those with AIDS. Treatment can consist of corticosteroids, radiotherapy, and chemotherapy, often with methotrexate.
WHO Classification 2008
98 lymphoma entities
Burkitt’s Lymphoma
Endemic Sporadic
c-myc oncogene
Regulator of 15% of genes, some of which are involved in cell replication.
Chronic Lymphocytic LeukemiaSmall lymphocytic lymphoma
CD20 weak
IgM weak
FMC7 neg
CD5 pos
CD 23 pos
CD 38 prognostic marker
ZAP-70 prognostic marker
CLL Staging Stage 0 (LOW RISK)
Lymphocytosis >5,000/mm3
without adenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged spleen),
anemia (low red blood cells), or thrombocytopenia (low platelets).
Stage I (INTERMEDIATE RISK)
lymphadenopathy
Stage II (INTERMEDIATE RISK)
hepatomegaly or splenomegaly with or without lymphadenopathy
Stage III (HIGH RISK)
Hb < 11.0 g/dL,
Stage IV (HIGH RISK)
low platelets < 100,00/mcL
FISH
17 p- 32 mths 11q- 79 mths Normal 111 mths Trisomy 12 114 mths 13q- 133 mths 6q- Good prognosis 14q32 Poor prognosis
Low-risk CLL People in this group are often diagnosed based on a high lymphocyte count in the blood but otherwise have normal blood counts and do not have enlarged lymph nodes or organs. The prognosis (outlook) for people in this group is often very good, with long survival expected.
Most people can be observed with careful and frequent follow-up exams. Treatment is considered if there are signs that the leukemia is progressing or if a person develops bothersome symptoms. When needed, initial treatment is usually chemotherapy (chemo) often combined with a monoclonal antibody targeting CD20 like rituximab (Rituxan).
Patients with high-risk CLL (stages III and IV) are more likely to need immediate treatment.
When treatment is needed, there are many options. What treatment is used will depend on factors like the patient's health, possible side effects, the reason treatment is needed, and any need for a rapid response. Commonly used treatments include:
■FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
■Bendamustine (sometimes with rituximab)
■FR: fludarabine and rituximab
■CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
■CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
■Chlorambucil
■PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
■Alemtuzumab (Campath) Anti-CD52
■Fludarabine (alone)
Prolymphocytic leukemia
FMC7 pos
Lymph node
Mantle cell lymphoma
CD5 +ve
MC treatment
CHOP (hyper VCAD)
Proteosome inhibitors
Stem cll transplant
Follicular lymphoma
WelI differentiated germinal centre lymphoma
CD 5 –ve
CD 10 +ve
Bcl-2
Lymphoma staging
Ann Arbor
A No symptoms B Symptoms Sweats, Unexplained fever
Weight loss
FL treatment
CLL type combinations
FMDR Fludarabine
Mitoxanthrone
Dexamethasone
Rituxamab
Diffuse Large B-cell Lymphoma
30% - 40% lymphomas
Poorly Differentiated Germinal Centre Lymphoma Bcl-6 +ve (Chr 3q.27) (Myc, Bcl-2, cyclin D2, CyclinD3,MUM-1)
Poorly differentiated non-germinal centre lymphomas
May be cured by CHOP cyclophosphamide adriamycin vincristine prednisone
Marginal cell lymphomas
Mucosa-associated lymphoid tissue MALT-oma
Splenic marginal zone lymphoma
Nodal marginal zone lymphoma
Gastric MALTOMA
Helicobactor pylori nearly always present.
Virulence factor CagA may be required for the continued growth of the lymphoma
Japanese have shown triple antibiotic therapy for H. pylori will result in regression of the lymphoma.
(amoxicillin, clarithromycin, omeprazole)
Other Maltomas
Associated with Autoimmune Disease
Thyroid Maltoma with Hashimoto’s thyroiditis
Lacrimal and Salivary gland Maltoma associated with
Sjrogen’s disease.
MALT FISH PANEL
t(11;18) in gastric Maltoma
t(14,18) in lacrimal/salivary gland Maltoma
t(3;14) in thyroid Maltoma
t(1;14) in lymph node marginal zone lymphomas
Hairy cell leukemia
B memory cell Red pulp of spleen Often bone marrow
Tartrate-resistent acid phosphatase positive CD103 positive CD11c, CD25 DBA-44 positive in paraffin sections
Cures with α-interferon adenosine-deaminase inhibitors deoxycorfomycin 2-chlorodeoxyadenosine
Immunoglobulin Secreting Disorders Primarily bone marrow diseases
1. Lymphoplasmacytic lymphoma
Waldenstom’s Macroglobulinaemia
IgM > Hyperviscosity
MYD-88 L265P mutation 2013
2. Plasma cell IgG, IgA, (IgD, IgE rare)
Plasma cell disorder WHO 20081. M-protein < 30g/L
<10% plasma cells No symptoms = MGUS Monoclonal gammopathy of uncertain significance
2. M-protein > 30g/L
and/or >10% plasma cells No symptoms = Smouldering multiple myeloma
3. M-protein
and/or clonal plasma cells Symptoms CRAB hypercalcaemia renal impairment anaemia bone lesions = Multiple myeloma
Cytogenetics
Hyperdiploid or not hyperdiploid Translocations Cyclin D1 and Cyclin D3 Good
Cyclin D2 Poor
Treatment of Myeloma
Bortezomib, cyclophosphamide, dexamethasone
Thalidomide
PSCT
T-cell Large Granular Lymphocytic Leukemia
T 8 lymphoproliferative disorder.
Indolent.
Sometimes associated with rheumatoid arthritis. In RA patients is due to chronic inflammation involving T8-cells
May cause severe neutropenia due to cytotoxic action on neutrophils
Diagnosed by T-cell receptor gene rearrangement studies.
T-cell Prolymphocytic Leukemia
Spleen, lymph nodes, liver , skin ,effusions
Survival < 1 yr
Adult T-cell leukemia-lymphoma
Endemic: Central Africa, South-west Japan, Carribean
Vertical transmission of HTLV-1
sexual promiscuity
drug addicts
Leukemia, lymph nodes, abdominal, skin and bone marrow with
hypercalcemia
Survival < 1 yr.
Mycoses fungoides
Enteropathy-associated T-cell lymphoma
Associated with refractory coeliac disease Patient is positive for HLA-DQ2 or DQ8 Associated dermatitis herpatiformis and
hyposplenism.
Aggressive T lymphoma with poor prognosis
Peripheral T-cell lymphomas (NOS)
Lymph node , bone marrow, liver, spleen,
Other organs
Low 5 year survival rate
Anaplastic Large cell LymphomaALK-positive
Immunophenotype CD30, ALK Cytogenetics t(2;5)
Hodgkin’s Lymphoma
CD30, CD15 PAX-5
Virus associated Lymphomas
EBV Burkitt’s lymphoma
Nasal type NK cell lymphoma
Post-transplant lymphoproliferative disorders
AIDS associated lymphomas
Some classical type Hodgkin’s disease
HTLV-1
HHV-8 Causes multicentric Castleman’s disease
Case Studies
Mr. JC 67 yrs Kaitaia March 2009 1 month of feeling tired. Hb 139 WCC 156 Pl 77
Bone marrow : high grade lymphoma cells
CSF: Clear
Flow cytometry :CD19, CD20 , CD22 +ve CD10, CD 5 Lambda light chain FISH, c-myc bcl-2 bcl-6 all detected
Received CHOP, methotrexate, etopiside
Remission in June 2009
September 2009 Headache, drowsiness
CSF relapse Died
“Burkitt-like Lymphoma”
Heterogenous population of large cells
New Classification 2008
“B-cell lymphoma, unclassifiable, with
features between DLBCL and Burkitt
lymphoma”
AH. From Kaitaia
Long standing CLL. Blood film changes
55 yr old man presents with cervical lymphadenopathy
Hb 149 WCC 12.9 7.0x109 /L Pl 166
Cervical lymph node biopsy June 2012
Lymphocytes CD 19 CD20 weak CD5, CD 23 pos Lamba light chain weak CD 38 pos
FISH Trisomy 12