Hodgkin lymphoma is a type of lymphoma characterized by the presence of Reed-Sternberg cells. It was first described in 1832 and can now be successfully treated with radiation or chemotherapy. The malignant cell is a B cell that has lost expression of normal B cell markers. Molecular changes contribute to uncontrolled growth and proliferation. Risk factors include EBV infection, HIV, and family history. Histologically, Reed-Sternberg cells are identified within an inflammatory background. Staging involves PET scans, bone marrow biopsy, and the Ann Arbor system. Treatment involves chemotherapy such as ABVD or radiation therapy to involved sites.

2. Hodgkin lymphoma
BY Dr Maleeha

3. • It was named after Thomas Hodgkin who first
described it in 1832.
• Dorothy Reed and Carl Sternberg first described the
malignant cells of Hodgkin lymphoma call Reed
Sternberg cells.
• Hodgkin lymphoma was the first cancer which could
be successfully treated by radiation therapy and also
by combination chemotherapy
• Hodgkin lymphoma (HL) is a aggressive B-cell
lymphoma.
INTRODUCTION

4. Hodgkin disease
Hodgkin lymphoma
Type of malignant lymphoma in which Reed-Sternberg cells are present in
a characterstic background of reactive inflammatory cells of various types,
accompanied by fibrosis of variable degree.
( except NLPHL)
4

5. Epidemiology
5

6. Pathogenesis
Cell of origin
The malignant lymphocyte in cHL is known as the Hodgkin
and Reed–Sternberg (HRS) cell.
• The demonstration of clonal rearrangements of the
immunoglobulin heavy- and light-chain loci has
confirmed their B-cell origin.
• Furthermore, the presence of somatic hypermutation
within the immunoglobulin heavy and light chain loci
suggest that HRS cell are derived from B lymphocytes.

8. So why they do not have typical B cell
marker???
• HRS cells have lost most of the
normal B-cell lineage gene
expression program through
numerous aberrant genetic
mechanisms, such as genetic
silencing at B-cell gene promoter
regions.

9. MOLECULAR PATHOGENESIS
Genes involved in normal B-lymphocyte growth and
differentiation are suppressed in HRS cells.
Signalling pathways contribute to the malignant
phenotype of HRS cells including the following:
1. HRS cells show constitutive activation of the NF-κB
pathway, which is associated with apoptosis resistance.
2. 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.

10. 3 HRS cells have been shown to have
deacetylated histones (H3), increased
H3K27 trimethylation and DNA
methylation patterns, leading to silencing
of tumor-suppressor genes and the
extinction of the normal B-lymphocyte
expression profile.
4 Mutations in β2M(house keeping gene)

11. ROLE OF EBV
This likely represents a mechanism by
which the HRS cell bypasses the need for
a functional B-cell receptor by using EBV-
encoded proteins. EBV infection and
expression of latent EBV-associated
proteins (LMP1) is also associated with
activation of NF-κB as well as JAK/STAT
pathways.

12. A possible model of pathogenesis
germinal
centre
B cell
transforming
event(s)
loss of apoptosis
RS cell
inflammatory
response
EBV?
cytokines
12

13. Risk Factors
• No clear risk factors, several implicated
• EBV (pathogen or passenger)
• HIV
• woodworking, farming
• rare familial aggregations
• First degree relatives have five fold increase in risk for
Hodgkin lymphoma.
• Associated with EBV infection mainly with mixed cellularity
type.
• High socio economic status.
• Prolonged use of of human growth hormone.
• men > women
• whites > blacks > Asians
13

14. HISTOLOGICAL FEATURES
• An accurate histological diagnosis of cHL is
made by recognizing the morphological and
immuno phenotypic characteristics of the HRS
cell within the appropriate cellular background.
• Systematic immuno histochemical evaluation
of both the tumour cell compartment (HRS
cells and its variants) and the associated
cellular background is important

15. Reed Sternberg cell
Common feature of ALL Hodgkin Lymphomas.
• Large cells ( 20-50 um in diameter) with classically binucleate
or bilobed central nucleus each with a large acidophilic central
nucleoli (mirror image) surrounded by a clear halo. “owl’s eye
appearance”
• Variants: mononuclear (Hodgkin’s cell), lacunar cell, L/H cell.
• Requirement of Reed-Sternberg cell for initial diagnosis is
“absolute”(less strict for LPHL or recurrent disease)
• Classic Reed-Sternberg cell:
+ CD15, CD30, CD25
– CD45, pan-B, S-100, keratin, EMA
High level of circulating tumor DNA detected in most cases and
suggestive of higher proliferatiom rate of tumor cells
15

16. Reed-Sternberg cell
16

17. Cytokines (such as IL-5, IL-10, IL-13, and
TGF-β) and chemokines (such as TARC, MDC,
IP-10, and CCL28) are secreted by Reed-
Sternberg cells.
They lead to florid accumulation of reactive
cells in tissues involved by classical HL.
These reactive cells produce factors that
support the growth and survival of the
tumor cells and further modify the reactive
cell response.
17

18. lacunar cell
(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)
RS Cell variants
18

19. Lymph node, nodular-sclerosing Hodgkin lymphoma. (A) Clusters of Reed-Sternberg
cells and variants react with anti-CD15. (B) Reed-Sternberg cells in the same case show
negative results for CD45 (leukocyte common antigen), in contrast to positive
surrounding small lymphocytes.
A
B
19

20. 2008 WHO Classification of Hodgkin
Lymphoma
20

21. Nodular Lymphocyte predominant
Hodgkin lymphoma(NLPHL)
• <5% of Hodgkin lymphoma
• Mainly involves cervical, axillary or mediastinal
• L&H cells or Popcorn cells are seen
• Positive for CD20, 45, CD79a, Bcl-6, J-chain, and PAX-5. EMA positive
in 50% cases.
• Negative for CD15, 30.
• Differential Diagnosis: Well differentiated lymphocytic lymphoma,
mononucleosis, malignant melanoma,, progressive transformation of
germinal centers
21

22. 22
•Small lymphocytes predominate in the reactive component in
both types and are intermixed with varying numbers of
histiocytes. Eosinophils, neutrophils, and “diagnostic” or
“classic” RS cells are rare. In fact, the diagnosis of NLPHL is
doubtful if diagnostic RS cells are found easily; the number of
such cells should be fewer than one per histologic section.
•In NLPHL, RS cells are conspicuous with folded, multilobed
nucleus and smaller nucleoli(“popcorn nuclei”).
•In the nodular subtype of LPHL, there is almost total
obliteration of the nodal architecture by a vaguely nodular
process.
•LPHL nodules are composed of small, round lymphocytes with
varying numbers of epithelioid histiocytes which gives them a
mottled appearance. L&H variants of RS cells may be
numerous and are principally seen in the nodules.

23. • Hodgkin lymphoma, lymphocyte predominance type. Numerous mature-
looking lymphocytes surround scattered, large, pale-staining
lymphohistiocytic variants (“popcorn” cells).
23

24. • An attenuated rim of residual normal node (top) is often present in
nodular NLPHL. The vaguely nodular growth pattern and compressed
adjacent normal node seen at low magnification are features highly
suggestive of Nodular NLPHL.
24

25. Classical hodgkin

26. 1. Nodular Sclerosis
• Most common type diagnosed
• About 70%
• Lacunar cells seen
• CD15, 30 positive
• EBV negative
• Only subtype without a male predominance
• Seen in younger patients with stage I-II disease.
• Differential diagnosis: Large cell Non Hodgkin lymphoma, carcinoma,
germ cell tumour and thymoma.
26

27. The classic histopathologic criteria for NSHL are
(a) prominent nodularity
(b) presence of lacunar RS cell variants, and
(c) birefringent broad collagen bands
• Nodal architecture is obliterated by relatively large nodules of tumor
partly or totally encircled by dense connective tissue bands that are
birefringent when viewed under polarized light.
27

28. LACUNAR VARIANT RS CELL : These variants possess large, multilobated, or
irregular nuclei with finely dispersed chromatin; nucleoli are usually small.
The cytoplasm of lacunar cells retracts when fixed in formalin, so the
nuclei gives the appearance of cells that lie with empty spaces between
them. (lacunae)
28

29. • Hodgkin lymphoma, nodular sclerosis type. A low-power view shows well-
defined bands of pink, acellular collagen that subdivide the tumor into
nodules 29

30. 2. Mixed Cellularity
• Constitutes about 20%
• More than 50% present as stage III or IV disease
• Biphasic incidence, peaking in young adults and again in adults
older than 55
• CD15, 30, EBV positive
• Presents in advanced stages
• Tendency to involve spleen, bone marrow.
• Differential diagnosis: Some cases of MCHL display an interfollicular
growth pattern. Such cases may be difficult to distinguish from peripheral
T-cell lymphomas. Lennert’s lymphoma (diffuse mixed T-cell ML with
excessive histiocytes). Diffuse follicular lymphoma.
30

31. Lymph node, mixed-cellularity Hodgkin lymphoma disease. Diagnostic Reed-
Sternberg cells are usually found without difficulty in mixed-cellularity
Hodgkin lymphoma. The reactive component consists of small, round
lymphocytes, histiocytes, plasma cells, and eosinophils,
31

32. 3. Lymphocyte Depleted
• Constitutes <1%
• Worst prognosis of all subtypes
• Older males, rare in children
• Present as febrile illness with
pancytopenia, hepatomegaly, and no
peripheral lymphadenopathy
• Advanced stage, Stage IV
• The biologic hallmark of LDHL is a
collapse of cell-mediated immunity,
HIV infection
• RS cells CD15+, CD30+; most EBV+
• Differential Diagnosis: Large cell Non-
Hodgkin’s lymphoma. Nodular
sclerosis HL
32

33. 4. Lymphocyte-Rich
• RS cells CD15+, CD30+; 40% EBV+
• App 5% of cases
• M > F
• Tends to be seen in older adults
• This is an uncommon form of classical HL
• Reactive lymphocytes make up the vast majority of the cellular infiltrate.
In most cases, involved lymph nodes are diffusely effaced, but vague
nodularity due to the presence of residual B-cell follicles is sometimes
seen.
• Differential Diagnosis: This entity is distinguished from the lymphocyte
predominance type by the presence of frequent mononuclear variants and
diagnostic Reed-Sternberg cells with a “classical” immuno phenotypic
profile.
• Very good to excellent prognosis.
33

34. Frequent mononuclear and diagnostic RS cells; background infiltrate
rich in lymphocytes.
34

35. 35

36. CLINICAL FEATURES
• Hodgkin lymphoma arises in a single node or chain of nodes
and spreads first to anatomically contiguous lymphoid tissue.
• Visceral involvement by hodgkin lymphoma may be secondary
to extension from adjacent lymph nodes.
• Hematogenous spread occurs to liver or multiple bony sites.
• Mechanism of spleen involvement is unclear but all patients
with hepatic and bone involvement are associated with
splenic involvement.
36

37. • Most common presentation is asymptomatic lymph node
enlargement, typically in the neck.
• Cervical lymph nodes are involved in 80% cases.
• Mediastinal involvement is seen in about 50% cases. They
produce symptoms like chest pain, cough and dyspnoea.
• Infra diaphrgamatic involvement is seen in 5% cases and
usually seen with older patients.
• Other less common symptoms are :
Pruritis, alcohol induced pain over involved lymphnodes,
nephrotic syndrome, erythema nodosum, cerebellar
degeneration, immune hemolytic anaemia,
thrombocytopenia, hypercalcemia.
37

38. B symptoms
• About 33 % present with B symptoms overall
• Only 15-20% of stage I-III have B symptoms like
1. Fever(>38^C)
• May first present as fever of unknown origin
• Fever persists for days to weeks followed by afebrile intervals and then
recurrence.
• This pattern is called Pel Ebstein fever.
2. recurrent Drenching night sweats
3. Weight loss (>10% in 6 months)
38

39. 39

40. Diagnostic workup
40

41. 41

42. Peripheral Blood
• The peripheral blood shows non -specific abnormalities.
• There may be anaemia, either normocytic normochromic or less often,
hypochromic microcytic.
• Rouleaux formation is often increased as is the erythrocyte sedimentation
rate.
• Some patients have neutrophilia, eosinophilia or thrombocytosis
• Occasional patients have lymphocytosis.
• Lymphopenia is common, with severe lymphopenia being seen in patients
with advanced disease or with unfavourable histological categories.

43. • Anaemia, leucopenia and pancytopenia are common in patients
with bone marrow infiltration
• The neoplastic cells of classical Hodgkin lymphoma rarely if ever
circulate in the peripheral blood; occasional instances of this
phenomenon have been reported but not in recent decades and
the diagnosis of the cases reported might therefore be doubted.
• In multivariate analysis an increased WBC and a reduced
lymphocyte count are of prognostic significance

44. Bone Marrow Biopsy
44

45. • The demonstration of
infiltration requires
trephine biopsy
• Detection rate is higher
with bilateral biopsy or
single large biopsy
• Diagnostic cells are
rarely present in films
of aspirate.
• BM infiltration is more
likely with B symptoms,
stage 3 & 4,anemai.

46. Bone marrow trephine biopsy from a patient with
stage IV classical Hodgkin lymphoma demonstrates
diagnostic Reed-Sternberg and Hodgkin cells

47. PET SCAN
47

48. Spread
• Generally a well behaved spread of disease through contiguous LN
groups, (especially NS and LP); <5% show non-contiguous spread
• May have direct extension into perinodal tissue.
• 85% of Stage I/II disease are above diaphragm.
• Spleen: if >400g, almost always positive.
• Liver: if positive, spleen and retroperitoneal LN’s are also positive.
48

49. Ann Arbor Staging System
• Stage I: Single lymph node region (I) or single extralymphatic organ or
site (IE)
• Stage II: > 2 lymph node regions on same side of diaphragm (II) or with
limited, contiguous extra lymphatic tissue involvement (IIE)
• Stage III: both sides of diaphragm involved, may include spleen (IIIS) or
local tissue involvement (IIIE)
• Stage IV: multiple/disseminated foci involved with > 1 extra lymphatic
organs (i.e. bone marrow)
(A) or (B) designates absence/presence of “B” symptoms
*(E) Localized, solitary involvement of extra lymphatic tissue, excluding
liver and bone marrow 49

50. Stage I Stage II Stage III Stage IV
Staging of lymphoma
A: absence of B symptoms
B: fever, night sweats, weight loss
50

51. Management
chemotherapy Radiotherapy

52. Chemotherapy
Regimen Medication Regimen Medication
1. ABVD
(US)
•ADRIAMYCIN
•BLEOMYCIN
•VINBLASTINE
•DACARBAZINE
2. STANFORD V
(NEW)
•ADRIAMYCIN
•BLEOMYCIN
•VINBLASTINE
•VINCRISTINE
•PREDNISONE
•MECHLORETHAMINE
ETOPOSIDE
3. MOPP •Mechlorethamine
• Vincristine
•Procarbazine
• Prednisone
4. BEACOPP
(EUROPE)
•BLEOMYCIN
•ETOPOSIDE
•ADRIAMYCIN
•CYCLOPHOSPHAMIDE
•ONCOVIN
•PROCARBAZINE
•PREDNISONE
52

53. Radiotherapy
• Radiation therapy is the most effective single thrapeutic agent for treating
Hodgkin lymphoma.
• The main objective of radiation in Hodgkin lymphoma is to treat involved
and contiguous field.
• Radiotherapy can be given by
1. 2D planning
2. 3D planning
3. IFRT(involved field radio therapy)
• Involved field radiotherapy is the most commonly used technique at
present. It targets a smaller area rather than a classical extended field.
53

54. Novel agents
• One of the single most effective new anti-HL therapies emerge is
brentuximab vedotin (BV)
• BV is an antibody–drug conjugate, which consists of an anti-CD30
antibody conjugated to an antimicrotubule agent (monomethyl auristatin
E (MMAE)). .
• Other agents that have shown promise in cHL include the
immunomodulatory drug lenalidomide, the histone deacetylase inhibitors
(e.g. panobinostat) and the anti-PD-1 antibody nivolumab.

55. LATE EFFECTS/COMPLICATIONS
• Due to the high cure rates achieved by the treatment of both early stage and advanced stage
cHL, patients treated for cHL are at risk of numerous late toxicities related to treatment.
• During the first 10 years after diagnosis, most deaths are the result of relapse, however, after
this period most deaths are a result of late effects of treatment.
• For early-stage disease, the cause of death for the majority of patients overall is related to
treatment rather than cHL.
• The chronic toxicity profile of cHL treatment depends on numerous factors, including the
intensity of chemotherapy regimen, types of chemotherapeutic agents to which the patient is
exposed, site of radiotherapy fields and age of patient at treatment.

56. Secondary solid organ malignancy
• Patients treated for HL have an approximately 3 fold increased risk of solid organ malignancy
• The most common secondary malignancies are ;
breast
lung
gastrointestinal tract cancers
• Radiotherapy increases the risk of secondary solid organ malignancy at exposed sites, whereas
chemotherapy has a more complex association with secondary solid organ malignancy, resulting in an
increased risk of some types (e.g. colorectal carcinoma associated with procarbazine use), but also acting
to abrogate the risk of others (e.g. reduction of breast cancer risk in patients receiving radiotherapy
through reducing ovarian function and inducing premature menopause).
• One of the most potent determinants of the risk of developing a secondary solid organ malignancy is the
age at which the patient received treatment

57. Secondary myeloid malignancy
• The risk of secondary MDS/AML is approximately 1% or less with ABVD,
but may be up to 4% with escalated BEACOPP.
Cardiovascular disease
• Patients treated for cHL are at an increased risk of late cardiovascular
disease. This is contributed to by exposure of the heart to radiotherapy, as
well as treatment with anthracycline based chemotherapy regimens. The
latency of coronary artery disease as a result of radiotherapy is
approximately 10 years. Importantly, concomitant cardiovascular risk
factors including hypertension, hypercholesterolemia and smoking all
compound this risk and should be aggressively managed.

58. Infertility
• Women (regardless of age) receiving escalated BEACOPP have severely reduced
ovarian reserve and significantly higher rates of sustained amenorrhea post
treatment.
• Women over the age of 30 treated with BEACOPP regimens have a 50% rate of
sustained amenorrhea (4 years) post treatment and those over 35 treated with
escalated BEACOPP have a less than 5% rate of return to a regular menstrual cycle.
• For male patients,sperm storage can usually be offered before treatment.

59. CASE PRESENTATION OF
HODGKIN’S LYMPHOMA

60. History
• • Female patient, 12years old, presented on 10/2009 .
• • The condition started 2 weeks ago with sever diffuse abdominal pain, abdominal distention ,
absolute constipation so patient sought medical advice and was diagnosed as acute intestinal
obstruction.
• Urgent exploration done with intestinal mass found and completely excised moderate to high grade
fever mainly by night, partially responding to medical treatment.
• • The condition was associated with small right neck swelling of lemon size surgical removal of
which showed a non malignant nature.
• On 5/2010, patient developed multiple painless neck swellings with gradual onset progressive
course associated with night fever and weight loss - no drenching night sweating.
• • Surgical removal of cervical swelling was done and patient was referred to us.
• • No manifestation of other system affection was apparent.

61. Examination & Workup
Lymphatic system:
• Right upper deep cervical LN about 3*2 cm
• Multiple small left upper deep cervical LNs the largest one about 1 cm in diameter
• RT axillary LN about 1,5 cm in diameter in the apical group
• All of the above described lymph nodes are firm to rubbery in consistency, non
tender, freely mobile and with normal overlying skin
• No other enlarged LN groups
Laboratory workup:
ESR: 1st hr 25
Imaging Workup:
CT neck : Multiple bilateral upper and lower deep cervical LNs the largest one on RT
side about 3*2.5 cm, the largest one on the left side about 1 *1 cm
US axillae: Multiple bilateral axillary LNs the largest one on the RT side about 1.6*0.8
cm most of them show loss of the central hilum mostly pathological LNs
Echo: FS 36 with MR grade1
Pulmonary Function Test : Free
Pathology report
Suggestive of Hodgkin lymphoma, nodular lymphocytic predominant type with tumor
cells positive for CD20
Bone marrow biopsy Free

62. Management
Final Diagnosis :
Hodgkin lymphoma, nodular lymphocytic predominant type stage 2B, non bulky disease
Treatment plan:
4 courses of ABVD /COEP then IFRTH 25 gy/17 settings on neck and axillae
Evaluation after 2 courses:
CT neck : multiple enlarged cervical LNs the largest one about 1cm
Axillae US: RT LN with eccenteric hilum largest 1cm
Evaluation after another 2 courses and IFRTH:
CT neck : multiple enlarged cervical LNs the largest one about 1cm.
Axillae US: RT LN with eccenteric hilum largest one about 1 cm.
Other imaging investigations, Echo, PFT, BMB were free

63. Prospective Approach
• What is the current situation?
• - Patient finished treatment on 11-2010 -
Patient is in CR up till now and on follow up
for 2,5 years now
• What is the future plan ?
• - Patient is under regular follow up in our
outpatient clinic