Lymphoma Flashcards
Lymphoma
Overview
Tumors of malignant lymphoid cells
-
Two types:
- Non-Hodgkin’s Lymphoma (NHL)
- Hodgkin’s Lymphoma (HL)
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Categorized by location:
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Nodal ⇒ Lymph nodes
- Present as enlarged non-tender lymph nodes (>2 cm)
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Extra-nodal ⇒ Non-lymphoid organs including bone marrow
- Present w/ symptoms related to the site of involvement
-
Nodal ⇒ Lymph nodes
Non-Hodgkin’s Lymphoma (NHL)
Clinical Presentation
- Lymphadenopathy and/or organomegaly
-
“B” symptoms ⇒ systemic
- Weight loss, fevers, night sweats
-
↑ lactate dehydrogenase (LDH)
- High grade, advanced stage
- Monoclonal proteins in serum and/or urine
Non-Hodgkin’s Lymphoma (NHL)
Subtypes
-
B-cell ⇒ 90%
- Diffuse Large B-Cell Lymphoma ⇒ 31%
- Follicular Lymphoma ⇒ 22%
- Marginal Zone Lymphoma ⇒ 8%
- Small Lymphocytic Lymphoma ⇒ 7%
- Mantle Cell Lymphoma ⇒ 6%
- T/NK-cell ⇒ 10%

NHL Subtypes
B-Cell Stages

B-Cell Carcinomas
Immunophenotypic & Histological Dx

Non-Hodgkin’s Lymphoma (NHL)
Immunophenotype Algorithm

Non-Hodgkin’s Lymphoma (NHL)
Grading
Grading is according to clinical behavior:
- Low grade ⇒ Survival is 5 to 7 years
- Intermediate grade ⇒ Survival is 1 to 3 years
- High grade ⇒ Survival is several months to 1 year

Non-Hodgkin’s Lymphoma (NHL)
Staging
Staging is the same as for HL:
Lugano Staging
The higher the stage, the worse the survival

Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL)
Overview
Lymphoma / leukemia composed of small clonal B-cells
- M > F
- Age > 50 yrs
- Considered low grade, but incurable
-
SLL and CLL are morphologically, phenotypically and genotypically indistinguishable
- Differ only in degree of peripheral blood lymphocytosis
- > 5K peripheral WBC ⇒ CLL
- SLL is widespread at presentation
- SLL is 7% of NHL
- CLL is the most common leukemia in western world
SLL/CLL
Diagnostic Studies
-
Biopsy:
- Mature B-cells are small, round, low grade, with soccer ball appearance
- Smudge cells are pathognomonic ⇒ remnants of cells that lack any identifiable cytoplasmic membrane or nuclear structure
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Flow cytometry:
- ⊕ for CD5, CD19, CD20, CD23, kappa light chain
- ⊖ Cyclin D1
- FISH: Negative

Mantle Cell Lymphoma (MCL)
Overview
Lymphoma of intermediate-sized clonal B-cells
- M > F
- Age > 60 years
- Often disseminated at presentation
- Bone marrow involvement ± leukemic phase
- Intermediate to poor prognosis

MCL
Translocation
t(11;14) (q13;q32) is characteristic of MCL
Juxtaposes cyclin D1 gene on 11q13 next to Ig heavy chain gene on 14q32 ⇒ over-expression of cyclin D1 (cell cycle regulatory protein)
MCL
Diagnostic Studies
-
Biopsy:
- Intermediate sized B-cells found in the mantle zone
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Phenotype:
- ⊕ for CD5, CD19, CD20, lambda light chain, cyclin D1
- ⊖ CD23
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Cytogenetics:
- t(11;14) (q13;q32) is characteristic of MCL

Follicular Lymphoma
Overview
Lymphoma composed of neoplastic cells that resemble the normal germinal center B-cells
- F > M
- Age > 50
- Mimics the follicular architecture of normal lymphoid tissues
- Frequently presents with diffuse lymphadenopathy
- Frequently involves bone marrow ± leukemic phase
- Low-grade
- Long survival (70%) but rarely curable
-
t(14;18) (q32;q21) is characteristic of FL
- Bcl-2 @ 18q21 → IgH @ 14q32 ⇒ Bcl-2 over-expression
- Minority of cases have a rearrangement of 3q27 (Bcl-6)

Follicular Lymphoma
Diagnostic Studies
- LN follicular structure similar to normal without lighter center
- ⊕ CD10, CD19, CD20, kappa light chain
- ⊕ Bcl-2 / Bcl-6
- t(14;18)(q32;q21)

MALT Lymphoma
Overview
Extra-Nodal Marginal Zone Lymphoma
- F > M, Median age 60
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Associate with epithelial sites:
- Stomach - most common
- Small intestine, colon and rectum
- Ocular adnexa
- Skin
- Thyroid
- Lung
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Some are associated with infections:
- Gastric ⇒ H. Pylori
- Ocular ⇒ Chlamydia psittaci
- Small intestine ⇒ Campylobacter jejuni
- Cutaneous ⇒ Borrelia burgdorferi
-
Some are associated with genetic translocations
- Clonal IgH rearrangement

MALT Lymphoma
Diagnostic Studies
⊕ CD20
⊖ for CD10, Bcl-6

Lymphoma
Infectious Agents

Burkitt Lymphoma
Overview
Lymphoma composed of intermediate-sized immature B-cells.
- High mitotic rate
- Numerous admixed MΦ
- High-grade
- Poor survival if not treated aggressively
- Curable if treated with high-dose regimens
Burkitt Lymphoma
Translocations
Translocations involving cMYC locus on 8q24 are characteristic of BL:
t(8;14) (q24;q32) ⇒ MYC/IGH
t(8;22) (q24;q11) ⇒ MYC/LAMBDA
t(2:8) (p11;q24) ⇒ MYC/KAPPA
Burkitt Lymphoma
Diagnostic Studies
- ⊕ Ki-67 (100%)
- ⊕ for CD10, CD19, CD20, kappa light chain
- ⊕ Bcl-6
- ⊖ Bcl-2
- t(8;14) (q24;q32) ⇒ most common
- Starry sky appearance on histology
- ± EBERs (EBV-encoded RNAs)

Endemic
Burkitt Lymphoma
- Children in equatorial Africa and New Guinea
- Head and neck tumors
- ⊕ EBV (100%)
-
Common locations:
- Jaw, facial bones (50%)
- CNS
- Distal ileum/cecum, omentum, gonads, kidneys, long bones, thyroid, salivary glands, breasts, ± bone marrow

Sporadic
Burkitt Lymphoma
- Mostly children and young adults, but also elderly
- ⊕ EBV (30% cases)
-
Common locations:
- CNS
- Distal ileum/cecum, abdomen, gonads, kidneys, breasts, LN, ± bone marrow ± leukemic phase
Immunodeficiency-associated
Burkitt Lymphoma
-
HIV ⊕ patients
- CD4 counts may still be high
- ⊕ EBV (30-40% cases)
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Common locations:
- CNS
- LN, bone marrow ± leukemic phase
Diffuse Large B-Cell Lymphoma
Overview
-
Most common type of NHL
- M > F
- Age > 50, but can occur at all ages
- Often presents as isolated mass
- Extranodal sites are common
- Many have BCL6 (3q27) rearrangements
- Intermediate grade
- Higher cure rate than low grade lymphomas
Diffuse Large B-Cell Lymphoma
Diagnostic Studies
- Large B-cells with cytoplasmic rim
- ⊕ for CD20, Bcl-2, Bcl-6, Ki67 (50%)
- t(3;14)(q27;q32)

Mycosis Fungoides
- Most common type of cutaneous T-cell lymphoma
- ⊕ for CD2, CD3, CD4, CD5, CD7, CD8
- Uncommon subtype: < 1% NHL
-
M > F, Adults / elderly
- Black males have higher risk
-
Indolent course with slow progression
- Patches → plaques → nodular lesions in skin
- Associated w/ Sezary syndrome

Sezary Syndrome
- Erythroderma
- Generalized lymphadenopathy
- Clonally related neoplastic T-cells in the skin, lymph nodes and peripheral blood ⇒ called Sezary cells
- Oncology equivalent of a burn
Anaplastic Large Cell Lymphoma, ALK ⊕
Overview
T-cell lymphoma with variable morphology
- M > F
- Predilection for young patients (< 30 yrs)
- Most common pediatric T-cell lymphoma
- Lymph nodes and extranodal sites (skin is frequent)
- Good prognosis compared to other T-cell NHL or diffuse large B-cell lymphoma

Anaplastic Large Cell Lymphoma (ALCL), ALK ⊕
Genetics
- Rearrangements of ALK gene on 2p23 are characteristic of ALCL, ALK ⊕
- Most common ⇒ t(2;5) (p23;q35)
- ALK is a tyrosine kinase
- Result in over-expression of a fusion tyrosine kinase that is constitutively active

Non-Hodgkin’s Lymphoma (NHL)
Characteristic Genetic Abnormalities

Non-Hodgkin’s Lymphoma (NHL)
Treatment Principles
Almost all lymphomas are sensitive to tx with:
- Chemotherapy
- Radiation therapy
- Immune therapy (monoclonal antibodies)
- Treatment plan often includes combination of above modalities
- Treatment usually requires administration of several cycles given at fixed intervals
Non-Hodgkin’s Lymphoma (NHL)
Common Tx Agents
A common regimen is “R-CHOP”
Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, rituximab
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Alkylators
- Cyclophosphamide, chlorambucil
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Anthracyclines
- Adriamycin
- Corticosteroids
-
Anti-metabolites
- Methotrexate, fludarabine
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Anti-mitotic agents
- Vincristine, vinblastine
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Monoclonal antibodies
- Rituximab (anti-CD20), alemtuzumab (anti-CD52)
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Targeted therapies:
- Venetoclax – Bcl-2 (CLL/SLL)
- Ibrutinib – Bruton’s TK (CLL, MCL)
- Idealisib – PI3K (CLL)
- Tazametostat – EZH2 (FL)
- Selinexor – XPO1 (DLBCL)
- Tafasitamab – CD19 (DLBCL)
Rituximab
MOA

Non-Hodgkin’s Lymphoma (NHL)
Prognosis
-
Higher grade lymphomas:
- Require more aggressive therapy
- Are more likely to be cured than lower grade lymphomas
- Higher incidence of relapse after initial successful treatment of low-grade lymphomas
-
Using optimal combos of tx modalities:
- Many patients with NHL can be cured
- Almost all can experience long-lasting meaningful remissions
- Immediate and long-term side effects are comparable to HL
Hodgkin’s Lymphoma (HL)
Epidemiology
- 30% of all lymphomas
- 0.7% of all new cancers
- ~ 8,500 new cases/year (US)
-
Bi-modal age distribution
- First peak 15-35 years
- Second peak > 55 years
- Male : Female = 2 : 1
Hodgkin’s Lymphoma (HL)
Characteristics
- Group of lymphoid malignancies
- Neoplastic giant cells are the minority (1-5%) of the tumor and are referred to as Reed Sternberg cells
- Non-neoplastic inflammatory cells are the majority (95-99%) of the tumor
Hodgkin’s Lymphoma (HL)
Clinical Features
- Adenopathy without other symptoms
-
Spreads first to anatomically contiguous nodes
- Painless
- Can be associated with splenomegaly and hepatomegaly
- Nodal pain with EtOH intake
- Constitutional symptoms are associated with higher stage disease and certain subtypes:
- Fever ± Night Sweats
- Weight loss, anorexia
- Fatigue
- Intense pruritus (25%)
-
Cutaneous anergy is present in most patients
- Arises in a single node or chain of nodes
- Cervical 60-70%
- Axillary 6-12%
- Mediastinal 6-11%
- Arises in a single node or chain of nodes
Hodgkin’s Lymphoma (HL)
Lab Features
- CBC:
- Normochromic, normocytic anemia
- Neutrophilia
- Eosinophilia
- Lymphopenia with loss of cell-mediated immunity
- Erythrocyte sedimentation rate (ESR) often ↑
- LDH occasionally ↑ (less so than NHL)
Hodgkin’s Lymphoma (HL)
Subtype Classification
-
Classical (95% of cases)
- Characterized by the Reed-Sternberg cell and variants
-
Morphological Subtypes:
- Nodular sclerosis
- Mixed cellularity
- Lymphocyte-rich
- Lymphocyte-depleted
-
Nodular Lymphocyte Predominant (5% of cases)
- Characterized by L&H cell
- Morphological Patterns:
- Nodular
- Nodular with diffuse areas

Classical Hodgkin’s Lymphoma (CHL)
Cytology
-
Reed-Sternberg cell
- Large: 45 microns
- Single nucleus ± multiple lobes OR multinucleated
- Large, eosinophilic, inclusion-like nucleolus
- Abundant cytoplasm
-
Variants
- Mononuclear
- Lacunar

Reed-Sternberg Cells
Immunophenotype
⊕ for CD15, CD30, PAX5
± EBV
⊖ for CD3, CD 20, CD45
⊖ EMA (Epithelial membrane antigen)
Nodular Sclerosis Type
Classical Hodgkin’s Lymphoma (CHL)
- Most common subtype: 70% of cases
- Males = Females
- Frequently adolescents and young adults
- Propensity to involve mediastinal (80%), supraclavicular, cervical lymph nodes
- EBV ⊕ in 10-40% of cases
- Low stage at presentation
- Systemic symptoms (40%)
- Excellent prognosis

Mixed Cellularity Type
Classical Hodgkin’s Lymphoma (CHL)
- Second most common type: 25% of cases
- Males > Females
- Older age
- Peripheral lymph nodes
- Systemic symptoms are common
- Advanced tumor stage at presentation
- EBV ⊕ in 75% cases
- Good prognosis

Role of EBV
Classical Hodgkin’s Lymphoma (CHL)
- EBV plays an etiologic role in HL
- Most frequent in: extremes of life, developing countries, HIV infection, cervical nodes
- EBV can be demonstrated to be present in R-S cells and is clonal
- EBV DNA is the same in all cells of the tumor
-
Type 2 pattern of latency (immuno-stains for viral encoded proteins)
- EBNA1 ⊕, LMP1 ⊕
- EBNA2 ⊖, EBNA3 ⊖
Lymphocyte-rich Type
Classical Hodgkin’s Lymphoma (CHL)
Overview
- Rare: 5% of cases
- Male > Female
- Older patients
- Peripheral nodes commonly involved
- Low stage at presentation
- EBV ⊕ in 40%
- Good to excellent prognosis
Lymphocyte-rich Type
Classical Hodgkin’s Lymphoma (CHL)
Histology
- Vague nodularity
- Residual germinal center elements
- Diagnostic Reed-Sternberg cells and mononuclear variants
- Nodules contain mostly B-cells (CD20 ⊕) and few RS cells (CD20 ⊖)

Lymphocyte-Depleted Type
Classical Hodgkin’s Lymphoma (CHL)
Overview
- Least common form: 2% of cases
- Males > females
- Older patients, HIV⊕ patients
- Advanced stage at presentation
- Systemic symptoms are common (80%)
- Most aggressive form of HL
Lymphocyte-Depleted Type
Classical Hodgkin’s Lymphoma (CHL)
Histology
- Few lymphocytes
- Many Reed-Sternberg cells and pleomorphic variants
- Background of fibrosis
- EBV ⊕ 90% of cases, especially in HIV ⊕ patients

Hodgkin’s Lymphoma (HL)
Spread
Spread of HL is predictable:

Contiguous nodes → Spleen →Liver → Bone marrow and other extranodal sites
Hodgkin’s Lymphoma (HL)
Staging
-
Staging
- Physical exam
- CT w/ contrast
- PET/CT
- ± Bone marrow examination
- Implications:
- Prognosis
- Therapy

Hodgkin’s Lymphoma (HL)
Additional Designations
- A: No symptoms
- B: Weight loss, fever, drenching sweats
-
X: Bulky disease
- > ⅓ widening of mediastinum
- > 10 cm maximum dimension of nodal mass
- E: Involvement of a single extra nodal site, or extension to an extranodal site contiguous or proximal to known nodal site
Hodgkin’s Lymphoma (HL)
Criteria For “B” Symptoms
- Unexplained weight loss of > 10% of body weight during the 6 months before initial staging investigation
- Unexplained, persistent, or recurrent fever with temperatures > 38°C during the previous month
- Recurrent drenching night sweats during the previous month
Hodgkin’s Lymphoma (HL)
Radiation Therapy
- Disease ‘volume’ has to fit within radiation field
- Side effects from radiation vary depending on:
- Size of radiation field (larger = more side effects)
- Sensitive non-diseased organs exposed to radiation (gonads, thyroid, lung, heart)

Radiation Therapy
Long-term Side Effects
-
Secondary Malignancies with latency of 5-10 years
Risk continues to increase for 30 years- Breast (women getting radiation before age 30)
- Lung
- Thyroid
- Sarcomas of soft tissue and bone
- Cardiovascular disease (coronary arteries, pericardial, myocardial)
- Hypothyroidism
- Sterility if gonads in radiation field
Hodgkin’s Lymphoma (HL)
Chemotherapy
Most commonly used in US: “ABVD”
Adriamycin, bleomycin, vinblastine, dacarbazine
- Immediate side effects well-known ⇒ neutropenia, alopecia, nausea
- Sterility can often be avoided with use of modern combination chemotherapy
- Long-term side effects increasingly recognized
- Cardiac (anthracyclines)
- Secondary MDS/AML
Hodgkin’s Lymphoma (HL)
Treatment Considerations
- Both radiation and chemotherapy have limitations and side effects
- At 15 years after dx, risk of death from late effects > risk of death from HL
- Tx needs to be tailored to deliver to least amount of toxicity with the highest likelihood of cure
- Risk-adapted therapy via PET-CT
- Need to consider
- Disease factors (stage, relapse risk)
- Co-morbidities (existing and anticipated)
- Patient preferences
Hodgkin’s vs Non-Hodgkin’s Lymphoma
