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