B15 - Lymphoma and Myeloma

Question 1

lymphoid tissue

Answer 1

• Primary and secondary lymphoid organs
  
  • All potential sites of lymphoid malignancy
  • Lymph node structure
    ○ 1 and 2 degree follicles
    ○ Germinal centres of the lymphoid follicles are well cells get most activated by something in the body - hotspot for where tumours arise
    ○ Mantle zone
    ○ Interfollicular zone
  • Contain T and B cells

Question 2

Reactive lymph nodes

Answer 2

• Follicular hyperplasia - increase in number and size of germinal centres: bacterial infections
  
  • Interfollicular hyperplasia: skin diseases, viral infections, drug reactions
  • Sinus histiocytosis: expansion of the medullary sinus histiocytes: infections (atypical)

Question 3

Follicular hyperplasia

Answer 3

increase in number and size of germinal centres: bacterial infections

Question 4

Interfollicular hyperplasia

Answer 4

skin diseases, viral infections, drug reactions

Question 5

Sinus histiocytosis

Answer 5

expansion of the medullary sinus histiocytes: infections (atypical)

Question 6

Malignant lymphomas

Answer 6

• Leukaemia = blood/BM (but can spread to solid sites. Eg. Acute lymphoblastic leukaemia going to spleen, liver and testicles) ; lymphoma = solid tissue
  
  • Replacement of normal lymphoid tissue by abnormal cells

Question 7

2 main types of malignant lymphomas

Answer 7

○ Non-Hodgkin lymphoma (many sub types) NHL

○ Hodgkin lymphoma

Question 8

○ Non-Hodgkin lymphoma (many sub types) NHL

Answer 8

§ NHL: 6th most common cause of cancer death
§ Increasing incidence and mortality
§ Several subtypes
□ WHO classification of NHL: B vs. T cell
□ Cells: correlate with morphology and immunology and stage of normal lymphoid cell maturation
□ Grade: low vs. high (aggressive)

Question 9

§ Aetiology and epidemiology of NHL - don’t really know

Answer 9

□ Immune suppression
® Organ transplant
® AIDS
® Susceptible
□ Viral causes
® EBV: Burkitt lymphoma in Africa in kids
® HTLV-I: Adult T cell leukemia/lymphoma
□ Geography
® Burkitt: tropical Africa
® Adult T cell leukaemia/lymphoma: Japan and Caribbean
□ Chronic inflammation/antigenic stimulation
® Helicobacter pylori: MALT lymphoma of stomach
® Mucosal associated lymphoid tissue
® Helicobacter stimulates lymphoid cells
® Eradicate the helicobacter and then many patients are adequately treated
□ Age
® Low grade: rare in young; increase in incidence with age
® Large cell: less age related

Question 10

§ Clinical features

of NHL

Answer 10

□ Systemic symptoms
® Fever, night sweats, weight loss
® Abdominal fullness due to enlarged liver or spleen
□ Lymphadenopathy - enlarged lymph nodes
□ Hepato-splenomegaly
□ Interference with normal organ function
® Solid organ infiltration, kidneys, liver, other
® Skin, brain
◊ Strange coloured skin lesion
◊ Problems with cerebral function
□ Bone marrow failure
® Tumour can overtake bone marrow function
® Cause anaemia
® Leukopenia with neutropenia and infections
® Thrombocytopaenia causing bleeding

Question 11

staging of NHL

Answer 11

® Lymphomas involve solid tissue sites - lymphoid cells will flow through lymphatics from one lymphoid site to another
® Staging determines therapy and outcome
® Extent of disease - determines therapy and prognosis
◊ Stage 1 - 1 lump in 1 region
◊ Stage 2 - 2 or more sites but on the same side of the diaphragm
◊ Stage 3 - disease above and below the diagram
◊ Stage 4 - may also involve extra nodal sites such as the bone marrow and the liver
® Obtained via imaging, CT scan, bone marrow examination to determine whether there is bone marrow disease (which would indicate stage 4)
® Radiological imaging: CT or PET scan
◊ lesions
® BM; lumbar puncture
® Based on physical, radiologic examination, BM
® B symptoms: fever, weight loss >10%, night sweats
◊ Implies systemic, whole body involvement by the tumour

Question 12

diagnosing NHL

Answer 12

□ Biopsy: pathology of involved tissue
® Because the lymphomas affect solid tissue sites, a biopsy needs to be taken or a whole lymph node removed
◊ Fixed in formalin and processed into paraphen wax to cut tissue section and stain
◊ Look at the poettern to see if it still resem bles the structure of a normal lymph nodes or if cells have taken over
® Pattern: e.g. nodular / follicular
® Cell size: small, large
◊ Large is generally more aggressive disease
® Cell differentiation: well or poorly differentiated
◊ Do they resemble normal cells
◊ The more they resemble normal the better the outcome
◊ More poorly differentiated is more likely to be aggressive
® Cell phenotype / lineage: B / T; other antigens
® Genetics: chromosomal rearrangements

Question 13

NHL stage 1

Answer 13

1 lump in 1 region

Question 14

NHL stage 2

Answer 14

◊ Stage 2 - 2 or more sites but on the same side of the diaphragm

Question 15

NHL stage 3

Answer 15

◊ Stage 3 - disease above and below the diagram

Question 16

NHL stage 4

Answer 16

◊ Stage 4 - may also involve extra nodal sites such as the bone marrow and the liver

Question 17

3 types of NHL

Answer 17

Follicular lymphoma
® burkitt lymphoma
® Diffuse large B cell lymphoma

Question 18

low grade lymphoma

Answer 18

follicular lymphoma

Question 19

agressive lymphoma

Answer 19

burrito or diffuse large B cell lymphoma

Question 20

® Follicular lymphoma

Answer 20

◊ 2nd most common type of NHL
◊ Age: generally adults >40 years (median age 60)
◊ Widely disseminated at diagnosis, including BM
} 75% of cases involves the bone marrow
◊ Low grade B cell NHL
} CD20, CD10, BCL2 positive
} 5-year survival 70-80% (rarely curable)
} Treatable but not curable
} Can be indolent
– Patients have a long survival
◊ B cell tumour, derived from cells in germinal centre of the lymph node because cell is stimulated by the antigen, chronic stimulation causes genetic abnormality
◊ Follicular pattern
} Round lesions are follicles - not normal lymphoid follicles, each one contains tumour cells
◊ Predominantly small cells
} Small, distorted but resemble a normal cell from the germinal centre
◊ T(14;18)(q32,q21)
◊ On chromosome 14 is where the immunoglobulin heavy chain gene sits, it has crossed over and linked in with the Bcl02 gene, which encodes protein Bcl-2 which gives the cells the ‘do not die’ (anti-apoptotic signal) signal, enabling cells to continue to survive
◊ Which it comes into close proximity to the immunoglobulin heavy chain gene(IGH is up regulated), the do not die signal is more heavily expressed
◊ Cells then have a survival advantage
◊ Because
◊ Up-regulated expression of anti-apoptotic protein Bcl-2
} Survival advantage of B cell
} Anti-apoptotic: inhibits programmed cell death

Question 21

follicular lymphoma can transform to aggressive lymphoma

Answer 21

– ‘watch and wait’
– Treatment will expose the patient to drugs to which the tumour will become resistant
– If at some point, the tumour progresses to more aggressive disease, which happens at around 7 years, they will be resistant to the drugs
– Wait until disease progresses, progressed form is potentially curable

Question 22

follicular lymphoma indications for treatment

Answer 22

} Watch and wait if indolent
} Indications to treat
– Constitutional symptoms, painful lymph nodes
w B symptoms
– Anatomic obstruction or organ dysfunction
– Cytopaenias: marrow failure

Question 23

follicular lymphoma treatment options

Answer 23

– Radiotherapy if it is localised disease
– Chemotherapy: CHOP regimen - if the disease is extensive, uses a number of drugs acronym is CHOP
– Antibody-based therapy: rituximab (anti-CD20) - usually combined with CHOP
– Combination therapy with antibody + chemotherapy
– Transplant options - not early in the disease

Question 24

burrito lymphoma

Answer 24

◊ Described in 1958 by denis burkitt
◊ Germinal centre cell derived lymphoma (like follicular lymphoma but different type of cell)
◊ Age: child or adult, 2% AIDS
◊ Sites: jaw, abdominal mass, orbit

Question 25

burrito lymphoma aiteology

Answer 25

◊ Aetiology: sporadic and endemic
} African variety: jaw tumour, EBV driven (endemic)
} Commonest childhood tumour in sub-saharan Africa
} Sporadic in western population in lymph nodes in abdomen or be behind the eye
} common in older population to be orbital tumour

Question 26

burrkit lymphoma biology

Answer 26

◊ Biology: rapidly growing
} Nearly all cells are actively in cell cycle
} When chemotherapy is done cell all rapidly die because they’re in cell cycle

Question 27

burkitt lymphoma genetics

Answer 27

◊ Genetics: 90% t(8;14) MYC-IGH
} Translocation of proto-oncogene c-MYC from chromosome 8 to IGH gene on chromosome 14
} Up regulation of oncogene

Question 28

burkitt lymphoma biology

Answer 28

} Monotonous B cell infiltrate
} Moderately sized cells with very blue cytoplasm and distinctive vacuoles - white holes in cytoplasm
} “starry sky” - high mitotic rate
– Tissue at low magnification - the tumour cells with while gaps which are the macrophages trying to remove cells that are dying due to very high turnover rate
} Derived from germinal centre B-cells

Question 29

burkitt lymphoma treatment

Answer 29

Treatment: aggressive chemotherapy

◊ Potentially curable - treated aggressively with chemo to try and eradicate

Question 30

® Diffuse large B cell lymphoma

Answer 30

◊ Most common lymphoma - 30% NHL
} Incidence is increasing because it is a disease of older people and our population is aging
◊ Disease of adults: median age 65 years
◊ Presents with rapidly enlarging masses
} May be in the lymph nodes (primary lymphoid tissue) or other lymphoid sites

Question 31

diffuse large B cell lymphoma pathology

Answer 31

} Diffuse infiltration by large cells (usually B cells)
} Diverse histology; high proliferation rate
– Many of the cells are in active cell cycle meaning they will respond well to chemo

Question 32

diffuse large B cell lymphoma treatment

Answer 32

◊ Rx: combination chemotherapy (e.g. CHOP-R)
} Rituximab targeting CD20 molecules generally expressed by these tumours (B cell antigen)
} Complete remission rates: 60-70%
} Approximately 30% curable
} Cure rate is higher in younger patients, older patients suffer side effects of treatment
} Stem cell transplant in younger patients <65
– Very high dose chemotherapy to eradicate all cells in haemopoietic system (bone marrow and lymphoid tissue)
– Replace with new stem cells which will result in reconstitution of haemopoietic system
– Only done when disease relapses

Question 33

prognosis fr NHL

Answer 33

} Aggressive NHL: international prognostic index
– Age: <60 vs >60 years
– Performance status: 0 or 1 vs. 2-4
– LDH: <1x normal vs. >1x normal
w Enzyme lactate dehydrogenase
w In lymphoid and red blood cells
– Disease stage: 1,2 vs. 3,4
w From radiological imaging
– Extra-nodal involvement: <1 vs >1 site
w Sites outside the lymph nodes that are involved
} Assigned 1 point for each bad feature
– The more points, the worse prognosis
} Rx: depends on site, extent, age
– Combination chemotherapy + CD20; DXRT
– Young: stem cell transplant
} Radiological monitoring: CT, PET/CT

Question 34

○ Hodgkin lymphoma

Answer 34

§ Thomas Hodgkin 1798-1866
§ Hodgkin lymphoma (Hodgkin’s disease) is characterised by the Reed-Sternberg cell:
□ Minor cell component found in the appropriate microscopic cellular background
□
□ This cells indicates it MUST be hodgkin lymphoma
□ These cells only make up a subpopulation of the entire enlarged lymph node because there is a big inflammatory cell background - indicates the tumour cell turning on an immune response to try and repress the disease

Question 35

bimodal age incidence of Hodgkins lymphoma

Answer 35

§ Bimodal age incidence:
□ Young adults (20-30 years); >50 years
□ Not extremely common
□ Biology differs between younger and older population

Question 36

clinical features of Hodgkins lymphoma

Answer 36

§ Clinical features
□ Lymphadenopathy
□ Painless, non-tender, rubbery lymph nodes (different from lymph nodes following infection which are sore and cancer that metastasise and go to lymph nodes and are hard)
® Cervical: 60-70% (neck)
® Axillary: 10-15% (under arms)
□ Dyspnoea - mediastinal involvement:
® Young patients (nodular sclerosing subtype) - because they have a mass in the anterior of the chest
® Shortness of breath
□ Splenomegaly: rare at presentation
□ Constitutional symptoms (B):
® Fever (30%; cyclic), pruritis, weight loss, night sweats

Question 37

other features of Hodgkins lymphoma

Answer 37

§ Other features
□ FBC: reactive blood count and film features
® Normochromic normocytic anaemia
® Leucocytosis: mild neutrophilia; mild eosinophilia
® Look like a patient with an infection
□ ESR: elevated
□ Bone marrow: usually reactive changes
® May be performed as staging procedure
® Rarely involved at presentation
® Granulocytic hyperplasia, increase in eosinophils - showing immune response
□ Reduced cell mediated immunity:
® Loss of immunologically competent T cells
® Largely unknown why this happens

Question 38

diagnostic investigations of Hodgkins lymphoma

Answer 38

§ Diagnostic investigations
□ Mass in anterior mediastinum
□ Pathology: lymphoid tissue with thick fibrotic bands

Question 39

pathology of Hodgkins lymphoma

Answer 39

® Chest: CT image showing grey area in anterior chest wall - Hodgkin lymphoma, enlarged lymph nodes against the vertebrae and the aorta
® Top right: pathology of the lesion, follicles and bands of scar tissues (fibrotic bands), nodular sclerosing hodgkin lymphoma, cellular nodular areas contain reed sternberg cell (bottom right)
® Cells in the background are lymphocytes within the lymph node
□ Diagnosis on histology of LN or tissue:
® Reed-sternberg cell: large, bi- or multi-nucleate; prominent nucleoli (“owl eye”)
® Inflammatory cells: lymphocytes, histiocytes, plasma cells, eosinophils
® Variable fibrosis
□ Sub-types based on histology:
® Classified by pathologist - sub classify different pathological appearance
® Not of major clinical significance - staging is more important
□ Ancillary pathology studies
® Immunophenotyping:
◊ Reed-sternberg cells express CD15 and CD30 antigens and are CD45 negative

Question 40

hodgkin lymphoma staging

Answer 40

□ Clinical staging: CT, MRI, PET
® Same clinical staging 1,2,3,4 as non-hodgkin
® A: No B (systemic) symptoms
® B: B symptoms (fever, night sweats, weight loss)

Question 41

hodgkin lymphoma treatment

Answer 41

□ Potentially curable 85-90% cured, especially the younger patients
□ Early stage favourable: stage 1 and 2
® Currently combined modality preferred
◊ Short duration chemotherapy
◊ ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine
◊ Involved field radiotherapy - pointing radiotherapy beams at the site where the disease exists
□ Advanced disease: stage 3 and 4
® More intensive combined chemotherapy
□ Late effects of therapy
® Second malignancies
◊ Lung cancer (from radiotherapy to the chest) - most common
◊ Acute myeloid leukaemia (from cumulative dose of akylating agents)
◊ Breast cancer (DXRT (radiotherapy) to mediastinum / axilla(under the arm))
} Adolescent or young women
} Dose-response relation exists
} Overall risk is 20-50%
} Happens 5-10 years after

Question 42

treatment for stage 1 and 2 Hodgkin lymphoma

Answer 42

® Currently combined modality preferred
◊ Short duration chemotherapy
◊ ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine
◊ Involved field radiotherapy - pointing radiotherapy beams at the site where the disease exists

Question 43

□ treatment Advanced disease: stage 3 and 4 Hodgkin lymphoma

Answer 43

□ Advanced disease: stage 3 and 4

® More intensive combined chemotherapy

Question 44

late effects of therapy Hodgkin lymphoma

Answer 44

® Second malignancies
◊ Lung cancer (from radiotherapy to the chest) - most common
◊ Acute myeloid leukaemia (from cumulative dose of akylating agents)
◊ Breast cancer (DXRT (radiotherapy) to mediastinum / axilla(under the arm))
} Adolescent or young women
} Dose-response relation exists
} Overall risk is 20-50%
} Happens 5-10 years after

Question 45

prognosis hodgkin lymphoma

Answer 45

□ Hodgkin lymphoma is a curable malignancy
□ Overall cure rate approximately 80%
□ Prognosis based on staging and bulk of disease
□ Common presentation usually stage 2 disease in young people
□ Infections: reduced cell-mediated T cell immunity
□ Relapsed disease: difficult to treat
® Autologous bone marrow transplant
◊ Drugs needed to eradicate the Hodgkin lymphoma, but all these drugs would have already been used to try and treat the lymphoma before
® Second malignancies can occur 5%

Question 46

○ Multiple myeloma / myeloma / plasma cell myeloma

Answer 46

§ BM neoplasm of end stage differentiated B cells
□ B cells undergo further differentiation from a lymphocyte to a plasma cell with makes immunoglobulins.
□ If that cell becomes malignant due to genetic abnormality they will look abnormal and will make immunoglobulin
□ Because they are all derived from the same cell (clone) they all make the same immunoglobulin molecule (called a monoclonal immunoglobulin or paraprotein or M protein)
§ Tumour cells produce a monoclonal immunoglobulin: paraprotein or “M protein”
§ Free Ig light chains (Bence Jones proteins): small enough to be cleared in the kidney
§ IgG is most common, but Ig can be any class heavy chain of Ig (e.g. IgA myeloma)
§ Lytic bone lesions: cause pathological fractures
□ Plasma cells eat away at bone and cause pathological fractures
§ Painful tumour, most painful of all blood cancers
§ Renal failure is common
□ Abnormal protein can precipitate in the kidneys and cause acute renal failure
§ Peak age >60 years
§ Clinical problems from organ infiltration by neoplastic plasma cells: especially BM
§ Production of excess Ig (“M protein” or paraprotein)
§ Bleeding from platelet dysfunction (Ig coating)
§ Calcium loss and bone wastage

Question 47

recurrent infections on myeloma

Answer 47

§ Recurrent infections are common:
□ Strep; staph; E. coli
□ Marrow failure and hypo-gammaglobulinaemia
□ May present with pneumonia
□ Paraprotein does not function normally
□ Neoplastic plasma cells are suppressing normal plasma cell production, levels of normal immunoglobulins are low

Question 48

symptoms of myeloma

Answer 48

§ Symptoms
□ Bone pain
□ Bone (pathological) fracture without obvious injury
□ Frequent infections or an infection difficult to overcome (pnuemonia is common presenting feature)
□ Tiredness, shortness of breath (anaemia, leukopenia, thrombocytopaenia)
□ Kidney problems; renal failure
□ Epistaxis (heavy nosebleeds) or easy bruising
□ Drowsiness or confusion (high serum protein)

Question 49

diagnostic tests for myeloma

Answer 49

□ Immunoglobulins (quantitative):
® Total plasma immunoglobulins (Ig): elevated
® Reduced levels of normal immunoglobulins
® Overall increase due to paraprotein
□ Serum protein electrophoresis:
® Identifies and quantifies monoclonal proteins
® Monoclonal protein in the gamma region
◊ “M” spike or paraprotein
® Blood count and film: Hb 100; WCC 3; Plt 100
® Bone marrow examination

Question 50

bone imaging methods for myeloma

Answer 50

§ Other bone imaging methods
□ Skeletal survey: (because it eats bone and makes holes)
® Plain x-rays of skull, long bones and axial skeleton
® Detects “lytic lesions” (local loss bone)
® Includes
◊ Lateral skull
◊ Frontal chest film
◊ Cervical-thoracolumbar spine
◊ Shoulders
◊ Pelvis, femur
® Majority of lesions are sharply defined and lytic
®
® ‘pepper pot skull’ - lesions where plasma cells eat into hard bone and leaches calcium into circulation causing high blood calcium
® Calvarium: top of the skull
□ Magnetic resonance imaging:
® More sensitive than skeletal survey (especially for vertebral disease)
□ CT scan: size of local lesions
□ Radionuclide imaging (bone scan):
® Unable to detect lytic lesions (“cold spot”)
® No new bone formation (“hot spot”)

Question 51

§ Acute renal failure in myeloma

Answer 51

□ Common
□ Large amount of protein cleared in the urine
□ Lambda light chains (Bence Jones protein) are toxic to renal epithelium
□ Amyloid deposits in the glomeruli
□ Hypercalcemia
□ Monitoring serum calcium and renal function is essential
□ Paraprotein (especially the light chains) are toxic to the renal epithelium, get stuck and poison the renal cells causing acute renal failure
□ Monitoring renal function and calcium level (which is toxic to kidneys)

Question 52

management in myeloma

Answer 52

□ Not curable, but patients are living longer
□ Median survival approximately 5 years
□ Therapy
® Hydrations: to prevent myeloma kidney - fluids to prevent acute renal failure
® Alkylating agents: remission in 50-70%
® Bisphosphonates to inhibit bone resorption
® Chemotherapy: melphalan, vincristine, cyclophosphamide
® Immunomodulators: thalidomide, lenalidomide
® Proteasome inhibitors: bortezomib
® Young: autologous stem cell (marrow) transplantation

Question 53

causes of death in myeloma

Answer 53

□ Causes of death
® Renal failure, infections and haemorrhage (less common)
® They will relapse