(L15) IMED2002 - Lymphoma

Lymphoma: Overview of Lecture

DIAGRAM ON SLIDE 2

Normal Lymphoid Tissue

- Primary and secondary lymphoid organs

- All potential sites of lymphoid malignancy

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Lymph node structure:

- primary and secondary follicles

- Germinal centres

- Mantle zone

- Interfollicular zone

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- Contain T and B cells

Normal Lymphoid Tissue INFO

Lymph node structure:

- primary and secondary follicles

- Germinal centres

- Mantle zone

- Interfollicular zone

- Contain T and B cells

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- germinal centre is where lot of immunoglobulins are produced

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• germinal centres: specialized, transient structures formed within secondary lymphoid organs (lymph nodes, spleen, tonsils) during an immune response.

• The mantle zone is the outer ring of small, mature B lymphocytes surrounding the germinal center within a secondary lymphoid follicle (e.g., in lymph nodes). It consists of B cells pushed out from the center during activation

Malignant Lymphomas

- Leukaemia = blood/BM ; Lymphoma = solid

- Replacement of normal lymphoid tissue by abnormal cells

- WHO classification of lymphoma

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Two main types:

- Non-Hodgkin lymphoma (many sub-types)

- Hodgkin lymphoma

A. Non-Hodgkin Lymphoma (NHL) (Subtypes, Grade)

- NHL: 6th most common cause of cancer death

- Increasing incidence and mortality

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Several subtypes:

- WHO Classification of NHL: B vs T cell origin

- Cells: correlate with morphology and immunology and stage of normal lymphoid cell maturation

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Grade:

- Low: slow growing; indolent (lazy); generally incurable

- High: fast growing; aggressive; potentially curable

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- Stage: extent (amount) of disease. Sites; marrow

- Type, grade and stage all have impact on prognosis

Aetiology and Epidemiology of NHL

Immune suppression:

- Organ transplant

- AIDS

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Viral causes:

- EBV: Burkitt lymphoma

- HTLV-I: Adult T cell leukemia / lymphoma

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Geography:

- Burkitt: tropical Africa

- Adult T cell leukemia / lymphoma: Japan & Caribbean

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Chronic inflammation / antigenic stimulation:

- Helicobacter pylori: MALT lymphoma of stomach

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Age:

- Low grade: rare in young; increase in incidence with age

- Large cell: less age related

Clinical Features of NHL

- Systemic symptoms: Fever; night sweats; weight loss

- Lymphadenopathy

- Hepato-splenomegaly

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Interference with normal organ function:

- Solid organ infiltration:-kidneys, liver, other

- Skin, brain

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- Bone marrow failure

Diagnosis of NHL

Biopsy:

- Obtain tissue of the involved region

- Pathology of involved tissue

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Pathological features:

- Pattern: e.g. nodular; diffuse

- Cell size: small, large

- Cell differentiation: well or poorly differentiated

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Ancillary tests:

- Cell phenotype / lineage: B / T; other antigens

- Genetics: chromosomal rearrangements

Clinical Staging of NHL

- Extent of disease; determines therapy and prognosis

- Based on physical, radiologic examination, BM

- B symptoms: fever, weight loss > 10%, night sweats

CT and MRI Scan: staging

DIAGRAM ON SLIDE 11

PET Scan: staging

- lymphoma with significant involvement over inguinal region

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- PET scan is nuclear medicine scan

- gives information about activity of organs or lesions

- patient injected with glucose (he metions a radioactive dye)

- in other words, sugar is injected, carries radiation

- anything that picks up the most sugars or glucose will emit the most radiation (bright spot)

- all the dots where glucose isnt meant to be is lymphoma

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• this is to fuel the increased number of cells in these areas (which indicates increase cells in the lymph nodes)

Types of non-Hodgkin Lymphoma

Examples of non Hodgkin lymphoma:

- Low grade: Follicular lymphoma

- High grade: Burkitt lymphoma Diffuse large B cell lymphoma

1. Follicular Lymphoma

- 2nd most common type of non Hodgkin lymphoma

- Age: Adults >40 years (median age 60)

- Widely disseminated at diagnosis, incl. BM

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Low grade B cell NHL

- B-cell phenotype: CD20, CD10, BCL2 positive

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Clinical:

- 5-year survival 70-80% (rarely curable)

- Can be indolent

- Can transform to aggressive high-grade NHL

Follicular Lymphoma

- Follicular pattern

- Predominantly small cells

- t(14;18)(q32,q21);IGH/BCL2

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Up-regulates expression of anti- apoptotic protein Bcl-2

- Survival advantage of B cells

- Anti-apoptotic: inhibits programmed cell death

Treatment of Follicular Lymphoma

- Watch and wait if indolent

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Indications to treat:

- Constitutional symptoms; painful lymph nodes

- Anatomic obstruction or organ dysfunction

- Cytopenias: marrow failure

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Options:

- Radiotherapy

- Chemotherapy: Bendamustine regimen

- Antibody-based therapy: anti-CD20 Obinutuzumab

- Combination therapy with antibody + chemotherapy

- Bone marrow transplantation Treatment of Follicular Lymphoma

2. Burkitt Lymphoma

- Described in 1958 by Denis Burkitt

- Tumour cells derived from the germinal centreof lymph nodes

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Aetiology: sporadic and endemic

- African variety: jaw tumor; EBV-driven

- Commonest childhood tumor in sub-Saharan Africa

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- Age: Child or adult; 2% AIDS

- Sites: Jaw, abdominal mass, orbit

- Biology: Rapidly growing

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- description of it is as if you are looking at a starry sky (cell apperance)

Burkitt Lymphoma

Genetics: 90% t(8;14);MYC/IGH

- Translocation of proto-oncogene c- MYC from chromosome 8 to IGH gene on chromosome 14

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Biopsy:

- Monotonous B cell infiltrate

- "starry-sky"; high mitotic rate

- Derived from germinal centre B-cells

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- Treatment: aggressive chemotherapy

- Potentially curable

3. Diffuse Large B-cell lymphoma

- Most common lymphoma: 30% NHL

- Disease of adults: median age 65 years

- Presents with rapidly enlarging masses

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Pathology:

- Diffuse infiltration by large cells (usually B cells)

- Diverse histology; high proliferation rate

Diffuse Large B-cell lymphoma (DLBCL)

Most common form of NHL

Prognosis for DLBCL

Aggressive NHL: International prognostic index (score)

- Age: < 60 vs > 60 years

- Performance status: 0 or 1 vs 2-4

- LDH: <1 or >1x normal

- Disease stage: 1, 2 vs 3, 4

- Extra-nodal involvement: <1 vs >1 site

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Treatment: depends on site/s, stage, age

- Combination chemotherapy + CD20; radiotherapy

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- Radiological monitoring: CT, PET/CT

Treatment of DLBCL

- Mortality if not treated given aggressive disease (watch and wait is not an option)

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Treatment options:

- R-CHOP chemotherapy +/- Radiotherapy

- Combination therapy with antibody + chemotherapy

- Effector cells therapies

- Bispecific Antibodies, CD3xCD20 engagers

- CAR (Chemeric Antigen Receptor) -T cell therapy

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Rx: combination chemotherapy (e.g. CHOP-R)

- Complete remission rates: 70-80%

- Approximately 60% curable

- CAR T-cell or bispecific antibodies in relapse setting

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• CAR T-cell therapy is a revolutionary immunotherapy that engineers a patient’s own T cells to recognize and kill cancer cells. It involves extracting immune cells, modifying them in a lab to target specific cancer proteins, and re-infusing them to treat diseases like lymphoma, leukemia, and myeloma

B. Hodgkin Lymphoma

- Thomas Hodgkin 1798-1866

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Hodgkin lymphoma (Hodgkin's disease) is characterised by the Reed-Sternberg cell:

- Minor cell component with an inflammatory cell background

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Bimodal age incidence:

- Young adults (20-30 yrs) and > 50 yrs

Hodgkin Lymphoma: Clinical Features

Painless, non-tender, rubbery lymph nodes

- Cervical: 60-70%

- Axillary: 10-15%

- May become painful after drinking alcohol

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- Shortness of breath with mediastinal involvement: especially young patients

- Splenomegaly: rare at presentation

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Constitutional symptoms ("B symptoms"):

- Fever (30%; cyclic), pruritis (itch), weight loss

Hodgkin Lymphoma: Other features

FBC: reactive blood count and film features

- Normochromic normocytic anaemia

- Leucocytosis: mild neutrophilia; eosinophilia

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Bone marrow: usually reactive changes

- May be performed as staging procedure

- Rarely involved at presentation

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Reduced cell mediated immunity:

- Loss of immunologically competent T cells

Diagnostic Investigations

DIAGRAM ON SLIDE 26

Hodgkin Lymphoma: Pathology

Diagnosis on histology of lymph node or tissue:

- Reed-Sternberg cell: Large, bi- or multi-nucleate; prominent nucleoli ("owl eye"), Pathognomonic = indicative; characteristic of Hodgkin

- Inflammatory cells: lymphocytes, histiocytes, plasmacells, eosinophils

- Variable fibrosis

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Sub-types based on histology:

- Classified by Pathologist

- Not of major clinical significance

Ancillary Pathology Studies

Immunophenotyping:

- Reed-Sternberg cells express CD15 and CD30 antigens and are CD45 negative

Hodgkin Lymphoma: Staging

- Clinical staging: PET/CT

A: No B (systemic) symptoms

B. "B symptoms" (fever, night sweats, weight loss)

Treatment of Hodgkin Lymphoma

- Potentially curable

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Early stage favourable: Stage 1 and 2

- Combined modality or chemotherapy only: BV-AVD: Brentuximab, doxorubicin, vinblastine and dacarbazine, Involved field radiotherapy

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Advanced disease: stage 3 and 4

- ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine

- More intensive combined chemotherapy

Late Effects of Therapy

Second malignancies:

- 10% at 10 years

- 25% at 30 years

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- Lung cancer (from radiotherapy): most common

- AML (from cumulative dose of akylating agents)

- Breast cancer (radiotherapy to mediastinum / axilla) (Adolescent or young women, Dose-response relation exists)

- Skin cancers

Hodgkin Lymphoma: Prognosis

- Hodgkin lymphoma is a curable malignancy

- Overall cure rate approximately 80%

- Prognosis based on staging and bulk of disease

- Infections: reduced cell-mediated immunity

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Relapsed disease: can be treated

- Autologous bone marrow transplant

- Second malignancies can occur 5%

Hodgkin Lymphoma: summary

- A specific type of lymphoma

- Affects young adults and >50yrs

- Classical pathology: Reed-Sternberg cell

- Potentially curable (>80% cases)

- Chemotherapy, radiotherapy, transplant

- Risk of second cancer: 5%

Summary - Learning Outcomes

DIAGRAM ON SLIDE 34