Hodgkin Lymphoma is a type of lymphoma that is highly curable. It most commonly affects young adults and presents with slow growing lymph node enlargement. There are two main types - classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment involves chemotherapy, with or without radiation therapy, depending on the stage and risk factors. Prognosis and treatment are determined by staging tests and prognostic scoring systems. New treatments involving immunotherapy are showing promise for relapsed or refractory cases.

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)