Hodgkins Lymphoma Flashcards
What is Lymphoma?
class of haematological malignancy involving white blood cells. Form solid tumours in lymphatics and reticuloendothelial system. rarely found in peripheral blood
What are Hodgkin Lymphomas?
Lymphoma of B-cell origin.
Comprise a range of sub-types.
Responsible for ~15% of all lymphoma cases.
~2000 cases per year in UK
What common feature do all Hodgkin Lymphomas have?
Reed-Sternberg cells.
Reed-Sternberg cells.
Derived from B-lymphocytes.
Large cells (~50 microns). , x5 larger than normal
Bi-lobed/ multinucleated cells.
Identifying Reed-Sternberg cells.
Slightly unique clusters of differentiation, so can use immunochemistry to find cells. Much quicker
CD30 and 15 positive.
Do not express antibody.
Rare, two or three in a tissue sample is clinical significant
Where do RS Cells originate?
RS Cells originate from the germinal centres of lymphatic tissue.
Mutations of RS cells
Evidence of having undergone VDJ recombination and somatic hypermutation.
Hypersomatic mutations are believed to cripple the ability of the RS cells to express typical lymphocyte genes.
RS cells however develop hyperactive proinflammatory cascades:
NF-kB and Jak/STAT.
Lymphatic microenvironment may play a role in suppressing apoptosis in these cells!
Clinical Presentation of HL x4
Lymphadenopathy.
Night sweats.
Weight loss.
Symptoms brought about by localised infiltration of tumour
Epidemiology of HL
Accounts for approx. 1 per 200 of all cancer diagnoses in UK.
> 1600 cases per annum.
3rd most common cancer in people 15-29 years old.
> Has bimodal age distribution.
What is the geographical variation in incidence of HL?
Rare in East Asia but common in West Asia.
Aetiology of HL.
Epstein-Barr virus infection.
EBV DNA found in ~90% of HD cases.
> rates vary!
> All cases of HD in HIV patients are EBV positive.
Which EBV specific genes are strongly associated with malignancy? x3
LMP1
LMP2a
EBNA1
Investigation of HL; Specific tests
Lymph node biopsy.
Immunohistochemistry.
Investigation of HL; Non-specific tests.
Full blood count.
Serum lactate dehydrogenase.
Liver function tests.
Lactate Dehydrogenase.
Enzyme used in the reversible conversion of lactate to pyruvate.
Found in trace amounts in health in the blood.
Lactate dehydrogenase is useful as a non-specific tumour marker.
What is the Warburg Effect?
Cancer cells will preferentially convert glucose into lactic acid.
(Anaerobic respiration)
Possible explanations for Warburg Effect? x4
Low oxygen environments in tumours?
Mitochondria defects?
Mitochondria deliberately disabled?
Glycolysis provides more essential intermediaries?
Classification of HD
According to the WHO five types of HD exist.
All, but Nodular lymphocyte predominant, are variants of classical HD and are treated in the same manner.
Nodular Sclerosis Classical HD
Approximately 60-80% of HD falls into this group.
Malignant cells are found in nodules within the affected lymph node.
Recruitment of fibroblasts in lymph nodes. Produces collagen. Replaces cells but performs no functions
Nodular Sclerosis Classical HD histology
Pink cuts through cells is scar tissue
Mixed cellularity classical HD
Accounts for 15-30% of HD.
Most common form in patients with HIV.
R-S cells are found in affected lymph nodes surrounded by varied cell background.
Histology of Mixed cellularity classical HD
Characteristic inflammatory background round tumour
Lymphocyte depleted HD
<1% of HD patients.
Lymph nodes have R-S cells and a hypocellular infiltrate.
Appearance of the pink = fluid caused by inflammation response, acute phase reactant protiens = hypocellular infiltrate
Lymphocyte rich HD
~5% of HD.
Tumour of uniform lymphocytes and Reed-Sternberg cells. No other blood cells
Nodular, lymphocyte predominant HD
A HD but not classically, in which R-S cells are rare or occasionally absent
Characterised by “Popcorn” cells (or lymphocyte-predominant cell).
HD because popcorn cells were thought to be R-S cells historically
Staging of HL
Commonest staging methodology for HD is the Ann Arbor system.
Four stage system.
Each stage can be further subdivided by adding letters:
B categorisation is defined by the presence of B symptoms: fever, night sweats and weight loss.
S means splenic involvement.
E means tissue other than lymphatics involved.
X means large tumour (>10cm)
Splenomegaly in HL
lymphoma cells build up inside your spleen, it makes it swell (enlarge).
Splenic involvement is found in ~30% of HL cases.
Frequency appears to differ based on type of HL
Direct Skin involvement in HL.
Direct tumour involvement is very rare complication in HL.
<1% of cases.
Found in advanced disease.
Usually a very poor
Indirect skin involvement in HL
found in ~30% of patients.
Itching, hives, rash.
May be caused by over production of inflammatory protiens released from lymph nodes and triggering mast cells causing hives and rash
Cause may be paraneoplastic syndrome.
What is paraneoplastic syndrome?
Either caused by chemokine synthesis by tumour or host immune response directed against the tumour.
Paraneoplastic syndrome in HL.
Paraneoplastic syndrome can be responsible for a multitude of atypical symptoms. > Endocrine > Haematological > Skin > Neuronal.
How prognostic features are counted to determine overall prognosis in early HL
Point system (International Prognostic Factors Project).
For stage 1 and 2 disease each of the following is worth 1 point.
> Bulky tumour.
> ESR >50mm/hr.
> >3 sites of involvement.
> B symptoms.
> Extranodal disease.
Prognostic features in advanced HL
Serum albumin <4 g/dl Haemoglobin <105 g/l Male. Age >45 years old. Leucocytosis >15 x109 cells/l Lymphopenia <0.6 x109 cells/l
Management of early HD.
Treatment of early stage is usually using ABVD therapy regime.
Adriamycin, bleomycin, vinblastine and dacarbazine.
Surgery to remove tumour.
Management of advanced HD
Advanced HD treated using BEACOPP:
Bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone.
G-CSF also used.
Why not just 1 drug?
More drugs has better outcome and management
ABVD Therapy
ABVD was developed as the first-line treatment for HL in 1975.
Replaced MOPP protocol which was much more toxic (mustargen!).
Remission rates following ABVD 70-90%.
How is ABVD therapy administered?
Protocol is delivered in monthly cycle.
Drugs are infused via IV on days 1 and 15.
Usually ~6 cycles prescribed.
What does Adriamycin do?
Inhibits topoisomerase II (intercalating poison)
What does Bleomycin do?
Induces dsDNA breaks.
What does Vinblastine do?
Disrupts microtubule formation.
What does Dacarbazine do?
Alkylating agent.
BEACOPP therapy
Preferred protocol for patients with stage 2 and above HL.
Especially in presence of unfavourable risk factors.
Remission induction in ~80% of patients.
How is BEACOPP therapy administered?
Protocol is prescribed over 21 days with 4 cycles in first instance.
What is Etoposide?
Topoisomerase II non-intercalating poison.
What is Cyclophosphamide?
alkylating agent.
What is Procarbazine?
alkylating agent.
What is Prednisone?
Steroid
Myelosuppression
common side-effect of chemotherapy.
Therapeutic role of G-CSF
G-CSF was trialled in 1988 as a method of reversing neutropenia in oncology patients.
Recombinant G-CSF is well tolerated and often prescribed as part of treatment protocols
Prophylactic antimicrobials supportive therapies
Acyclovir: Anti-viral.
Fluconazole: Anti-fungal.
Quinolone antibiotics: Anti-bacterial.
other supportive therapies
Blood products; Red cells, Platelets.
Antiemetic drugs.
refractive lymphoma
a relapse or persistence despite therapies
Brentuximab vedotin.
Anti-CD30 antibody.
Vedotin chemotherapy is conjugated onto antibody.
Complete remission rate of ~30% in refractory lymphoma with tumour reduction seen in almost 100% of patients.
Nivolumab and Pembrolizumab.
Anti-PD1 antibodies.
PD-L1 is overexpressed in RS cells.
