Hodgkin Lymphoma

Question 1

What are lymphomas? What are the two types?

Answer 1

Lympohas: group of malignant disorders arising primarily in the lymph nodes
Lymphoma types: Hodgkin and Non-hodgkin. Other rarer types.

Question 2

Hodgkin lyphoma

Answer 2

characterised by lymphadenopathy and presence of Reed Srernberg (RS) cells

Question 3

Hodgkins Lymphoma disease course

Answer 3

• Maligant cells accumulat ein signle lymph node, may eventually spread to other nodes
• May also enter blood stream and infiltrate organs
• outcome of HL patients improved over the last few decades: late effects of disease are more apparent now
• Consdiered curable in majority of cases

Question 4

HL incidence

Answer 4

-Uncommon
- Present at any age
- Annual incidence of HL 3/100,000
- incidence peak in young adults 20-34, further peak observed >70 years of age
- Incidence is currently stable

Question 5

HL Risk factors

Answer 5

• No one single clear-cut causative agent but the following is implicated:
  The Epstein-Barr virus has been identified as being a possible cause of HL.
  Previous NHL
  Hepatitis C
  Exposure to pesticides
  Poor immunity (HIV, post-transplant, rare immunological disorders)
  Higher socioeconomic status and lack of early exposure to infections
  Family history (could be due to inheritance or shared lifestyle factors)
  May be lower risk in alcohol drinkers but not in drinkers who also smoke
  Studies ahoq increased risk of Hodgkin lymphoma for people who are obese
  Many people do not have any identifiable risk factors

Question 6

HL Pathogenesis

Answer 6

• Not fully understood
• RS Cells: central to diagnosis of four classic types (large multi-nucleate cells)
• Mononuclear Hodgkin cells also part of the malignant clone
• Possess mechanisms preventing apoptosis
  -Malignant cells and inflitration of inflammatory cells present
  -RS cell is B-cell lineage showing clonal rearrangement of immunoglobulin genes.

Question 7

HL symptoms

Answer 7

Enlarged painless lymphadenopathy
The nodes often fluctuate in size
Alcohol ingestion may precipitate pain
Itching
Cough or breathlessness
Hepatic and splenic enlargement may occur
Systemic symptoms including fever, weight loss, fatigue and night sweats
Extra nodal disease: lung, skin, CNS and bone marrow involvement may occur
Infection may occur due to defective humoral/cell mediated immunity

Question 8

HL Clinical Features

Answer 8

G

Question 9

what are HL B symptoms? Examples

Answer 9

B symptoms: (named after the B lymphocytes, which are involved in the immune response) are Systemic symptoms of drenching night sweats, unexplained fever >38°C, and weight loss of >10% over 6 months are termed B symptoms and are identified in approximately 25% of patients.

Question 10

HL Clincal Features

Answer 10

• HL can arise in any part of the lymphatic system, more common in: Cervical nodes: 60-70% of patients, Axillary nodes: 10-15% of patients, Inguinal nodes: 6-12% of patients
  -Mediastinal disease: identified in 80% of patients and is more common in nodular sclerosing HL
• peripheral or sub-diaphragmatic lymphadenopathy :more common in mixed-cellularity classical HL.
• Bone marrow involvement: detected in only 5–8% of patients with conventional staging-up to 18% with positron emission tomography (PET)/computerized tomography (CT) staging
• many patients have painless swelling in neck/ armpit / groin
• small proprotion of patients have signs of extra nodal disease at presentation, typically in liver and bone marrow
• Bone marrow infiltration associated with specific symptoms

Question 11

Classification

Answer 11

-Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL)

-Classical Hodgkin Lymphoma (cHL):
Nodular sclerosis classical Hodgkin lymphoma
Mixed- cellularity classical Hodgkin lymphoma
Lymphocyte rich classical Hodgkin lymphoma
Lymphocyte depleted classical Hodgkin lymphoma

Question 12

cHL and NLPHL characteristics

Answer 12

• both types characterised by presence of small number of neoplastic cells in inflammatory background of reactive T cells and eosinophils. Varying amounds of fibrosis present.

Question 13

Diagnosis of HL (NLPHL and CHL typical characteristics for diagnosis)

Answer 13

• histological examination of a lymph node biopsy (microscopy with immunohistochemical staining) - Antibodies include: CD15, CD30, CD20 and CD45.

NLPHL:
RS absent but distinct histological appearance.
Cells having a lymphocytic and histiocytic or ‘popcorn’ appearance – called lymphocyte predominant cell (LP-cell)

The immunophenoytype is more typical for a B cell, being positive for CD20 and immunoglobulin expression.
Cells usually CD45 positive and negative for CD15 and CD30.

CHL:
Divided into 4 subtypes, based on RS morphology and composition of reactive cell infiltrate.
Nodular sclerosing is the most frequent.
CD 20 negative.
CD30 + / CD15 +/-

Question 14

RS cell formation/ action

Answer 14

• derived from germinal centre B cells with mutations of the IgH-variable region segment.
• usually aneuploid with no consistent cytogenetic abnormality.
• secrete cytokines to recruit reactive cells that include IL-5 and transforming growth factor-beta (TGF-beta).
• Clonal Ig gene rearrangements found in majorit of isolated RS cells

Question 15

RS cells - Immunohistochemistry stains results

Answer 15

-positive for CD30 and CD15 but typically negative for CD20 and CD45, which are positive only in neoplastic NLP-HL cells.
- also usually positive for PAX5, CD25, HLA-DR, ICAM-1, Fascin, CD95 (apo-1/fas), TRAF1, CD40, and CD86.

Question 16

RS cell variant examples

Answer 16

-Hodgkin cell, mummified cells, and lacunar cells.
- Hodgkin cells are mononuclear RS-cell variants.

Question 17

NLPHL: LP cells immunohistochemistry stain results

Answer 17

NLPHL: LP cells : usually positive for C020, CD45, EMA, CD79a, CD75, BCL6, BOB.1, OCT2, and J chain.

Question 19

Lab features of HL

Answer 19

Peripheral blood manifestations (non-specific)
Anaemia (normocytic, normochromic)
Eosinophilia frequent
Neutrophilia (one-third of patients)
Low lymphocyte count in advanced disease
Platelets (normal or increased in early-stage disease and low in late-stage disease)
Bone marrow involvement may be detected
Raised ESR and CRP: useful prognostic markers and for monitoring response to treatment
LDH is sometimes raised initially
Abnormal LFT’s and U&E’s
Raised urate levels

Question 20

Staging of Hodgkin Lymphoma (stage 1)

Answer 20

• node involvement in one lymph node area.

Question 21

Staging of Hodgkin Lymphoma (stage 2)

Answer 21

disease involving two or more lymph nodal areas confined to one side of the diaphragm.

Question 22

staging of Hodgkin Lymphoma (stage 3)

Answer 22

disease involving lymph nodes above and below the diaphragm. Splenic disease is included in stage Ill but this has special significance

Question 23

Staging of Hodgkin Lymphoma ( A, B. further staging classifications)

Answer 23

• A is absence and B is presence of one or more of the following: Unexplained fever above 38 degrees celcius, ight sweats, loss of more than 10% body weight within 6 months
• E: Localised extra nodal extension from mass of nodes, doesnt advance stage
  IE- medistinal disease with contiguous spread to the lung/ spinal theca
  IIIs : for patients with lymphy node and splenic involvement - spleen involvement usually seen before widespead haematogenous spread of HL
  Bulky disease: wideneing of mediastinum by more than 1/3 or presence of nodal mass > 10 cm in diameter. This is revelant to therapy at any stage

Question 24

staging of Hodgkin Lymphoma (stage 4)

Answer 24

involvement outside the lymph node areas and refers to diffuse or disseminated disease in the bone marrow, liver and other extra nodal sites

Question 25

Tests and procedures for lymphoma staging ( laboratory and radiology)

Answer 25

Laboratory:
FBC and bone marrow (check for marrow involvement), ESR, LFT’s, LDH, CRP
Radiology:
Chest x-ray: Detects enlarged lymph nodes in the chest
PET scan: Positron Emission Tomography: use of low-dose radioactive glucose to measure the activity of cells in different parts of the body. Important in detecting minimal residual disease
CT scan: Computerised Tomography: uses a small amount of radiation to build up a computerised image of the inside of the body
MRI scan: Magnetic Resonance Imaging: uses magnetism to build up a picture of the body (good at showing up involvement in soft tissues and the CNS)

Question 26

Key recommendations for pre-treatment evaluation

Answer 26

Patients require pre-treatment blood evaluation including HIV serology (1A).
Staging with contrast–enhanced CT of the neck to pelvis is required (1A), although PET/CT is preferable if clinically feasible (1B).
Early stage patients should be classified as favourable or unfavourable (1A).
Advanced stage patients should be assessed to define the Hasenclever/IPS (1A).

For male patients, pre-treatment semen cryopreservation should be offered where possible (1A).

For female patients, pre-treatment review of options with a fertility specialist should be considered (1A).

Question 27

Requirements for a favourable prognosis stage I-II HL

Answer 27

EORTC, European Organisation for the Research and Treatment of Cancer;

GHSG, German Hodgkin Study Group;
Patient must have:
Eortc features: No large mediastinal adenopathy, ESR <50 mm/hr without B sympoms. ESR< 30 mm/hr with B sympoms
- age< or equal to 50 years
- 1-3 lymph node sites involved

GHSG features: No large mediastinal adenopathy, ESR <50 mm/hr without B sympoms. ESR< 30 mm/hr with B symptoms, no extra nodal disease, 1-2 lymph node sites involved

Question 28

Requirements for a unfavourable prognosis stage I-II HL

Answer 28

Erotc: Large mediastinal adenopathy
ESR > 50 mm/hr without B symptoms
ESR> 30 mm/hr with B symptoms, age of less than 50 years, age > 50 years, > or equal to 4 lyph node sites involved

GHSG features: Large mediastinal adenopathy, ESR > or equal to 50 mml/hl without B symptoms, ESR> or equal to mm/he with B symptoms, extranodal disease, > or equal to 3 lymph node sires involved.

Question 29

Hasenclever index ( features of more advanced disease

Answer 29

AKA international prognostic score
7 factors identified based on over 5000 patients who initially recieved chemotherapy:
-Age >45 years
- Male gender
- Serum albumin < 40 g/l
Hb < 105 g/l
Stage 4 disease
Leuococytosis ( WBC 15X10^9/L or above)
Lymphopenia ( <0.6 x 10^9 or < 8% of WBC count)

each factor reduced predicted 5- year freedom from progression rate by ~ 8%

Question 30

HL Treatment

Answer 30

• Dependent on stage and symptoms present
• Radiotherapy:
  A. May be used alone for patients with more localised disease (NLPHL).
  B. role in the elimination of bulky disease that may remain after chemotherapy.
  C. to eliminate painful skeletal, nodal or soft tissue deposits after chemotherapy
• Combination chemotherapy
• Combined modality therapy d: chemotherapy and radiotherapy together at lower doses
  -Stem cell transplantation
  -Supportive measures

Question 31

Radiotherapy : HL. What are the common methods and doses?

Answer 31

• Involved-site radiotherapy (ISRT) :internationally recognised as standard of care for HL treated with combined-modality therapy
• dose for favourable (GHSG) early-stage disease: 20 Gy
• dose for most other indications< 30 Gy, boost to 36–45 Gy may be considered for partial responses
• decision to use or omit radiotherapy in early and advanced-stage HL should be made on the individual risk profile and acceptable balance between toxicity and efficacy

Question 32

Treatment: Chemotherapy

Answer 32

• Cyclical chemotherapy : used for stage III and IV disease and stage I and II patients who have bulky disease, B symptoms or who have relapsed following initial radiotherapy
• Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) most commonly used
• Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone (BEACOPP) may be useful for disease with a poor prognosis (more intensive)

Question 33

Combined modality therapy

Answer 33

-chemotherapy and radiotherapy are used together
-allows short courses of chemotherapy to be combined with reduced levels of radiotherapy

Question 34

How is response to treatment assessed?

Answer 34

Clinical examination
Imaging
Identification of residual masses

Question 35

Response to relapse?

Answer 35

Treatment with alternative combination chemotherapy
Radiotherapy for bulky disease
If second line treatment fails: autologous transplant in people under 65 years of age considered

Question 36

recommendations for treatment management dependening on prognosis ( favourable disease)

Answer 36

Standard of care for patients with early favourable disease is to start with two cycles of ABVD followed by an interim PET scan (1A).

For early favourable disease and a negative interim PET scan, standard of care is a total of 2–3 cycles of ABVD followed by radiotherapy (1A).

For early favourable disease and a negative interim PET scan, it may be appropriate to omit radiotherapy following discussion with a radiation oncologist. These patients should receive a total of three or four cycles of ABVD (1A).

Question 37

recommendations for treatment management dependening on prognosis ( unfavourable disease)

Answer 37

For early unfavourable disease, a standard of care is two cycles of eBEACOPP and two cycles of ABVD followed by a PET. With a positive scan, patients should be offered radiotherapy (1A).

-For early unfavourable disease, an alternative standard is two cycles of ABVD followed by interim PET. If iPET-negative, patients have 1–2 further cycles of ABVD with radiotherapy or complete a total of six cycles of chemotherapy with the last four being AVD without radiotherapy (1A).

-For early-stage disease with a positive PET scan after two cycles of ABVD, consider two cycles of eBEACOPP followed by radiotherapy (1A).

• DS1–3 is considered complete metabolic response (1B).

Question 38

Prognosis

Answer 38

Prognosis depends on stage, age and histology results/type of HL.
Stage 1 or 2 disease: 91 to 94% diagnosed with early stage Hodgkin lymphoma will live for at least 5 years.
Stage 3 or 4 disease: 59 to 90% will live for at least 5 years.

Even after relapse, HL can often be treated successfully again. Cure rates are slightly lower if this happens though although the disease can be kept under control for a long time.

European Organization for Research and Treatment of Cancer (EORTC) – divides limited stage disease (I & II) into favourable and unfavourable groups.
The International Prognostic Score (Hansclever Index) is useful for patients with advanced disease.

Question 39

Late effects of HL disease

Answer 39

Second malignancies (lung and breast cancer are related to radiotherapy, MDS and AML are related to chemotherapy)
Cardiac disease
Endocrine dysfunction
Intestinal problems
Lung damage (usually subclinical)
Psychological problems

Much progress has been made in recent years in the treatment of HL
The results of therapy are extremely good
Attention must be paid to the late effects of treatment