hodgkin lymphoma

1. Hodgkin Lymphoma
By NUWAYEZU JEAN BOSCO

2. Introduction
• Hodgkin lymphoma (HL) is an aggressive B-cell lymphoma, and one
of the most curable of all haematological malignancies.
• Today more than 80% of patients with newly diagnosed HL can now
expect to be cured of their disease.

3. • The incidence of HL varies with economic status and geographic
location.
• It can affect all age groups but is most common in young adults.
• In developed countries it is associated with a bimodal age of onset
distribution, with an early, larger, peak occurring in young adults
aged between 20 and 40 years and a second, smaller, peak
occurring in those over 55 years.
• In developing countries, the disease predominantly occurs in
childhood, with the incidence decreasing with age.
• Overall, men are affected slightly more frequently than women (1.3 :
1).

4. Classification
Classic hodgkin lymphoma (cHL):
95%
Nodular Lymphocyte Predominant
Hodgkin lymphoma ( NLPHL): 5%

5. Classical Hodgkin Lymphoma
Classic owl’s eye appearance (
binucleate
HRS cell with two mirror-image nuclei)
• The malignant cell in cHL, the Hodgkin Reed- Sternberg
(HRS) cell, is a large(20–50 μm), bi- lobed cell with two
or more nuclei with eosinophilic nucleoli.
• HRS cells are derived from germinal center B
lymphocytes, but lack a B- cell receptor and several B- cell
associated genes and proteins.
• HRS express CD30, CD15 and PAX-5.
• Other B- cell markers are typically reduced or absent
including CD20, CD19, and transcription factors OCT-2
and BOB1
• HRS cells account for the minority of cells in affected lymph nodes and are surrounded
by a background of mixed inflammatory cells including B- and T- cells, plasma cells,
eosinophils, neutrophils, macrophages, and fibroblasts.

6. • Classic Hodgkin lymphoma is further subdivided into 4 histopathological
subtype:
Nodular sclerosis, 70%
Mixed cellularity 20-25%
Lymphocyte-rich, 5%
Lymphocyte-depleted <1%

7. Popcorn cell or LP cell
• The malignant cells in NLPHL are
large with folded nuclei and multiple
nucleoli (also known as “popcorn”
cells) in a nodular background
consisting of expanded follicular
dendritic cell meshworks and small
B-lymphocytes.
• LP cells are typically CD30 and CD15
negative, with CD19+,CD20+,CD45+,and
CD79a+
Nodular Lymphocyte Predominant Hodgkin lymphoma

8. Malignant cell in Classic hodgkin
lymphoma (cHL)
Malignant cell in Nodular Lymphocyte Predominant Hodgkin lymphoma (
NLPHL)
Pathogenesis

9. Molecular pathogenesis
• HRS cells show constitutive activation of the NF-κB pathway, which is associated
with apoptosis resistance.
• The basis for constitutive NF-κB activation in at least a proportion of cases is the
result of inactivating mutations in TNFAIP3 and NFKBIA, which encode inhibitors
of the NF-κB pathway.
• Other mechanisms of NF-κB over-activity include genomic amplification of REL,
expression and stimulation of CD40 by HRS cells and EBV infection of HRS cells
(resulting in LMP-1 expression, which can mimic activation of CD40).
• Epstein-Barr virus (EBV)−positive Reed-Sternberg (RS) cells are found in
approximately 40% of patients with HL ,mostly in cases of mixed cellularity classic
HL (MCCHL) and lymphocyte-depleted classic HL (LDCHL),

10. • The JAK-STAT signalling pathway is overactive in HRS cells, resulting in
uncontrolled growth and proliferation.
• Mechanisms of JAK-STAT over-activity include chromosomal gains at 9p24 (which
includes the JAK2 locus) and inactivating mutations in PTPN1 (leading to
increased phosphorylation of JAK-STAT pathway members).
• HRS cells have been shown to have deacetylated histones (H3), increased
H3K27 trimethylation and DNA methylation patterns, leading to silencing of
tumour-suppressor genes and the extinction of the normal B-lymphocyte
expression profile.
• HRS cells escape antitumor immune responses via inhibition of PD-1-expressing immune
cells, such as cytotoxic T cells, due to overexpression of the PD-1 ligands PD-L1 and PD-L2.

11. Molecular Pathogenesis of cHL

12. Risk factors
• EBV infection(mixed cellularity and LD subtypes)
• Immunocompromised status: HIV , immunosuppression due to solid organ or
hematopoietic stem cell transplantation (SCT), or who are treated with
immunosuppressive medications( EBV associated disease)
• Autoimmune diseases: SLE, RA, sarcoidosis
• The risk of developing cHL is higher among relatives of patients with cHL, and specific HLA
haplotypes (HLA-A1) are associated with a higher risk.
• In identical twins, the risk of HL is increased approximately 100-fold.
• NS subtype, is associated with factors indicative of a high standard of living, including
small family size

13. Clinical presentation
• Lymphadenopathy that commonly shows a slow progressive growth over months
• The most frequent site of lymphadenopathy is in the cervical and supraclavicular
nodal regions but other sites may be involved too
• Lymphadenopathy can cause compression to vital organ and may present as
Cough, chest pain and superior vena cava syndrome ( mediastinal)
• cHL is a highly inflammatory tumour and may be associated with numerous
systemic symptoms including classic B symptoms, itch and alcohol-induced
lymph node pain

14. Diagnosis
• An accurate histological diagnosis of cHL is made by recognizing the
morphological and immunophenotypic characteristics of the HRS cell
within the appropriate cellular background
• Excision biopsy( prefered) or image guided core niddle biopsy if no
accessible peripheral lymphadenopathy for adequate tissue diagnosis

15. WORK UP
• CBC
• Renal and liver function tests – usually performed as a baseline before
chemotherapy and as a screen for hepatic dysfunction as a result of cHL
• Erythrocyte sedimentation rate (ESR) commonly is elevated and is prognostic in
early stage disease.
• Lactate dehydrogenase (LDH) is rarely elevated except in patients with extensive,
advanced-stage disease
• HIV serology
• Echocardiogram/nuclear medicine assessment of cardiac function

16. Staging and risk stratification
• Staging should be performed with [18F]fluorodeoxyglucose (FDG) positron
emission tomography/computerized tomography (PET/CT) scanning.
• PET/CT improves the accuracy of staging compared with CT scans alone
and is the preferred imaging modality in cHL.
• Recent studies have demonstrated a high sensitivity of PET/CT for bony
involvement.
• Therefore, bone marrow biopsies are not necessary as part of the initial
staging procedures for most patients with cHL younger than 60 years.

17. Cotswold-Modified Ann Arbor Staging System for Hodgkin
Lymphoma

18. • HL patients have traditionally been divided into two distinct prognostic
groups according to clinical stage at diagnosis:
Early-stage disease, accounting for 45% of newly diagnosed patients,
Advanced-stage disease, accounting for 55% of newly diagnosed
patients.
• Early stage disease refers to Ann Arbor stage I or II.
• Advanced stage Disease refers to any patient with Ann Arbor stage III or IV.

19. • Early stage I or II HL is considered “favorable” if it is limited to an area
above the diaphragm and is not associated with other risk factors.
• Early stage I or II HL is considered “unfavorable” in the presence of other
risk factors related to age, tumor burden, ESR, and number of involved
nodal areas

20. Prognostic Factors in Early and Advanced-Stage Hodgkin
Lymphoma

21. RISK STRATIFICATION FOR ADVANCED DISEASE
IPS of 0, 1 or 2 :low-risk
IPS 3–7 : high-risk

22. Management of classical HL
• cHL is treated with chemotherapy with or without radiotherapy
• Chemotherapy alone is associated with a higher risk of relapse (4% to 8%)
but likely has less long-term toxicity compared with combined modality
treatment.
• Most widely used initial chemotherapy regimens are:
• ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine)
• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide,
vincristine, procarbazine, and prednisolone)

23. Treatment Approach According to Prognostic Group

24. PET-adapted therapy
• In addition to stratifying therapy based on early- or advanced stage
disease and the presence or absence of baseline risk factors,
patients may also be stratified by their early response to therapy.
• This is based on the fact that the prognosis is worse for those with residual
disease on PET scan after 2 cycles of Chemotherapy

25. Deauville score for the standardized reporting of
PET scans in lymphoma.

26. Early-stage disease
• PET scan is performed after 2 to 3 cycles of ABVD, decision for further
cycles of chemotherapy and/or radiotherapy depending on the response
• This aim to offer escalated therapy to those patients with suboptimal initial
disease response, whilst sparing those patients with good early disease
control to potentially unnecessary further treatment/toxicity

27. Advanced disease
• Commence treatment with ABVD in all patients and then intensify
treatment to escalated BEACOPP if interim PET appearance is
unfavourable. Or,
• Commence treatment with escalated BEACOPP and subsequently de-
intensify treatment to ABVD (or a reduced number of cycles of escalated
BEACOPP) if interim PET is favourable. Or,
• Stratify patients based on IPS upfront to decide between ABVD or
escalated BEACOPP as frontline therapy. Treatment is then intensified or
de-intensified to the alternative regimen, based on interim PET scan.

28. Treatment of Relapse/refractory disease
• Salvage chemtherapy followed by Autologous stem cell transplantation
• Commonly used Salvage chemotherapy regimen include:
ICE (ifosfamide, carboplatin, etoposide)( most common)
ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin)
DHAP (dexamethasone, cytarabine, cisplatin).
• Brentuximab vedotin: anti CD 30
• Nivolumab and Pembrolizumab: anti PD1
• Allogenic stem cell transplantation for relapsed cases post ASCT

29. Treatment of NLPHL
Early stage(I or II)
• Radiotherapy alone is associated with excellent outcomes.
• Observation may be considered after complete surgical excision of single node.
• Combined modality therapy (chemoradiotherapy) is often used in those with B-symptoms or
risk factors for poorer outcomes
Treatment – advanced stage (III–IV)
• Chemotherapy with a variety of regimens is used including “cHL-type” (e.g. ABVD) as well as
“NHL-type” (e.g. CVP/CHOP).
• Rituximab is usually incorporated into these regimens (due to CD20 expression on tumour cells
and its observed activity as a single-agent)