Hodgkin's lymphoma is characterized by the presence of Reed-Sternberg cells. It is classified into five subtypes based on the microscopic appearance of the malignant cells and reactive cells present. The subtypes include nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte depletion, and lymphocyte predominance. Reed-Sternberg cells have origins from B cells but fail to express most B cell markers. Diagnosis involves lymph node biopsy and staging involves imaging and laboratory tests to determine extent of disease.

1. HODGKIN’S LYMPHOMA

2. HISTORY
 Thomas Hodgkin (17 August 1798 – 5 April 1866), British
physician and pathologist - 1832, in a paper titled ”On Some
Morbid Appearances of the Absorbent Glands and Spleen”.
 Theodor Langhans and WS Greenfield first described the
microscopic characteristics of Hodgkin's lymphoma in 1872
and 1878.
 In 1898 and 1902, respectively, Carl Sternberg and Dorothy
Reed independently described the cytogenetic features of the
malignant cells of Hodgkin's lymphoma.
Thomas Hodgkin

3. INTRODUCTION
 Hodgkin lymphoma (HL) is characterized by the presence of neoplastic giant cells called Reed-
Sternberg cells and encompasses a group of lymphoid neoplasms that differ from NHL in several
respects.
Hodgkin Lymphoma Non-Hodgkin Lymphoma
More often localized to a single axial group of nodes
(cervical, mediastinal, para-aortic)
More frequent involvement of multiple peripheral
nodes
Orderly spread by contiguity Noncontiguous spread
Mesenteric nodes and Waldeyer ring rarely involved Waldeyer ring and mesenteric nodes commonly
involved
Extra-nodal presentation rare Extra-nodal presentation common

4. EPIDEMIOLOGY
 0.7% of all new cancers in the United States.
 Based on Globocan 2012 data :
 Average age at diagnosis - 32 years.
 It is one of the most common cancers of young
adults and adolescents, but also occurs in the aged.
“Bimodal peaks”
 Men > Women.
INCIDENCE
Indian males
- 5,677 per
100,000
2,938 per
100,000 in
Indian
females
MORTALITY
2,938 males
per 100,000
died
1,404 per
100,000
females died

5. RISK FACTORS
First degree relatives have five fold increase in risk for Hodgkins Disease.
Associated with EBV infection mainly with mixed cellularity type.
Associated with Infectious Mononucleosis. Incidence is about 2.55 times
higher
High socio economic status.
Patients with reduced immunity, for example, AIDS

6. PATHOGENESIS

7. EBV infection
NF-kB
activate
s
promotes
Lymphocyte survival &
proliferation
EBV+ tumor cells
express
Latent Membrane Protein-1
Upregulates NF-kB
EBV tumors
Acquired loss of function
mutation in IkB or A20
Upregulates NF-kB
Activation of NF-kB (Nuclear Factor-kappa-light chain enhancer of activated B
cells
Rescues “crippled” germinal centre B cells (cant produce Ig) from
APOPTOSIS
+ Other unknown
mutations
Produce Reed-Sternberg cells

8. Reed-Sternberg
cells
secrete
CYTOKINES – eg. IL-5, IL-10, M-
CSF
CHEMOKINES – eg.
Eotaxin
Others – eg. Immunomodulatory Factor
Galectin-1
Florid accumulation of REACTIVE Cells in tissues involved
cHL
Produce factors that support the growth and survival of the tumor
cells and further modify the reactive cell response.

9. Proposed signals mediating
“cross-talk” between Reed-
Sternberg cells and
surrounding normal cells in
classical forms of Hodgkin
lymphoma.

10. REED-STERNBERG CELLS
 The Ig genes of Reed-Sternberg cells have undergone both V(D)J recombination and somatic
hypermutation, establishing an origin from a germinal center or post-germinal-center B cell.
 Despite having the genetic signature of a B cell, the Reed-Sternberg cells of classical HL fail to express most
B cell–specific genes, including the Ig genes.
 Aneuploid and possess diverse clonal chromosomal aberrations.
 Copy number gains in the REL proto-oncogene on chromosome 2p are particularly common and may
contribute to increases in NF-κB activity.

11. RS CELLS - MORPHOLOGY
 Large cells (≥45 μm in diameter) with
multiple nuclei or a single nucleus with
multiple nuclear lobes, each with a large
inclusion-like nucleolus about the size of
a small lymphocyte (5–7 μm in
diameter).
 Abundant cytoplasm.
 Classic RS cells:
+ CD15, CD30, PAX5 (a B-cell
transcription factor)
- CD45, other B cells and T cell markers.

12. Classic RS cell showing
two nuclear lobes, large
inclusion-like nucleoli, and
abundant cytoplasm,
surrounded by lymphocytes,
macrophages, and an
eosinophil.
Mononuclear variants
contain a single
nucleus with a large
inclusion-like
nucleolus
Lacunar cells have more
delicate, folded, or
multilobate nuclei and
abundant pale cytoplasm
that is often disrupted
during the cutting of
sections, leaving the
nucleus sitting in an
empty hole (a lacuna)
Lymphohistocytic
variants (L&H cells) or
“popcorn cells” -with
polypoid nuclei,
inconspicuous nucleoli,
and moderately
abundant cytoplasm
 Mixed cellularity
& Lymphocyte
rich subtypes
 Nodular Sclerosis subtype
 Lymphocyte
predominant
subtype

13. ARP CLASSIFICATION
(1934)
•Localised (Sclerosing)
•Generalised (Cellular)
•Sarcomatous
GALL & MALLORY
(1942)
•Hodgkin’s Lymphoma
•Hodgkin’s Sarcoma
JACKSON AND PARKER
(1947)
•Paragranuloma
•Granuloma
•Sarcoma
SMETANA AND
COHEN’S ADDITION
(1956)
•Paragranuloma
•Granuloma
•Nodular Sclerosis
•Sarcoma
EARLY CLASSIFICATIONS

14. EARLY CLASSIFICATIONS
RAPPORT (1956)
• Nodular
• Diffuse
LUKES
(1963)
• Lymphocytic & Histiocytic
• Nodular
• Diffuse
• Mixed Cellularity
• Nodular Sclerosis
• Diffuse Fibrosis Reticular
LUKES – BUTLER
(1966)
• lymphocyte-predominant
• nodular sclerosing
• mixed cellularity
• lymphocyte-depleted.

15. REAL CLASSIFICATION
 1994.
 Separated the nodular lymphocyte-predominant (NLP) subtype from so-called classic HL based on the
immunophenotypic and genotypic differences.
 The REAL classification of HL was carried forward to the 2001 WHO classification of HL and the 2008
WHO classification.

16. WHO CLASSIFICATION
 2016
 The WHO classification recognizes five
subtypes of HL
Nodular Sclerosis
Mixed Cellularity
Lymphocyte - rich
Lymphocyte depletion
Lymphocyte predominance

17. NODULAR SCLEROSIS TYPE
 Most common form of HL - 65% to 70% of cases.
 Males = Females.
 Uncommonly associated with EBV.
 As in other forms of HL, involvement of the spleen, liver, bone marrow, and other organs and tissues can
appear in due course in the form of irregular tumor nodules resembling those seen in lymph nodes.
 It has a propensity to involve the lower cervical, supraclavicular, and mediastinal lymph nodes of
adolescents or young adults.
 Excellent prognosis.

18. • Characterized by the presence of lacunar
variant Reed-Sternberg cells and the
deposition of collagen in bands that
divide involved lymph nodes into
circumscribed nodules.
• The fibrosis may be scant or abundant.
• The Reed-Sternberg cells are found in a
polymorphous background of T cells,
eosinophils, plasma cells and
macrophages.
• Diagnostic Reed-Sternberg cells are
often uncommon.
• Positive for PAX5, CD15, and CD30, and
negative for other B-cell markers, T-cell
markers, and CD45.
A low-power view shows well-defined bands of pink, acellular
collagen that subdivide the tumor into nodules.

19. There are numerous scattered large cells with a surrounding prominent clear space
surrounding the nucleus, an artefact of formalin fixation. These are the lacunar
cells characteristic for the nodular sclerosis type of Hodgkin lymphoma.

20. MIXED CELLULARITY TYPE
 ~20% to 25% of cases.
 Mixed-cellularity HL is more common in males.
 More frequent in HIV patients and in developing countries
 More likely to be associated with older age, systemic symptoms such as night sweats and weight loss,
and advanced tumor stage.
 Overall prognosis is very good.

21.  Involved lymph nodes are diffusely effaced by a
heterogeneous cellular infiltrate, which includes
T cells, eosinophils, plasma cells, and benign
macrophages admixed with Reed-Sternberg
cells.
 Diagnostic ReedSternberg cells and
mononuclear variants are usually plentiful.
 The Reed-Sternberg cells are infected with EBV
in about 70% of cases.
 The immunophenotype is identical to that
observed in the nodular sclerosis type:
• Positive for PAX5, CD15, and CD30, and
• negative for other B-cell markers, T-cell
markers, and CD45.
A diagnostic, binucleate Reed-Sternberg cell is
surrounded by eosinophils, lymphocytes, and
histiocytes.

22. LYMPHOCYTE-RICH TYPE
 Uncommon form (5%) of classical HL and is associated with EBV in about 40% of cases .
 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.
 This entity is distinguished from the lymphocyte predominance type by the presence of frequent
mononuclear variants and diagnostic Reed-Sternberg cells with a “classical” immunophenotypic profile.
 Very good to excellent prognosis.

23. Lymphocyte-rich classical Hodgkin lymphoma (LRCHL), nodular variant, involving lymph node. The
nodules are composed of many small lymphocytes and scattered Hodgkin and Reed-Sternberg
(HRS) cells

24. LYMPHOCYTE DEPLETION TYPE
 Least common form of HL, amounting to less than 5% of cases.
 The Reed-Sternberg cells are infected with EBV in over 90% of cases.
 Occurs predominantly in the elderly, in HIV+ individuals of any age, and in nonindustrialized countries.
 The immunophenotype of the Reed-Sternberg cells is identical to that seen in other classical types of HL.
Immunophenotyping is essential, since most tumors suspected of being lymphocyte depletion HL
actually prove to be large-cell NHLs.
 Lymphocyte depletion HL Advanced stage and systemic symptoms are frequent, and the overall
outcome is somewhat less favorable than in the other subtypes.

25. It is characterized by a paucity of lymphocytes and a relative abundance of
Reed-Sternberg cells or their pleomorphic variants.

26. LYMPHOCYTE PREDOMINANCE TYPE
 Uncommon “nonclassical” variant of HL - accounts for about 5% of cases.
 EBV is not associated with this subtype.
 More common in males, usually younger than 35 years of age,
 Patients typically present with cervical or axillary lymphadenopathy. Mediastinal and bone marrow
involvement is rare.
 In 3% to 5% of cases, this type transforms into a tumor resembling diffuse large B-cell lymphoma.
 Prognosis is excellent.

27. • Involved nodes are effaced by a nodular
infiltrate of small lymphocytes admixed with
variable numbers of macrophages.
• “Classical” Reed-Sternberg cells are usually
difficult to find.
• Instead, this tumor contains so-called L&H
(lymphocytic and histiocytic) variants, which
have a multilobed nucleus resembling a
popcorn kernel (“popcorn cell”).
• Eosinophils and plasma cells are usually scant or
absent.
Numerous mature-looking lymphocytes surround
scattered,
large, pale-staining lymphocytic and histiocytic variants
(“popcorn” cells).

28. CLINICAL FEATURE
 HL most commonly
present as painless
lymphadenopathy.
 Enlarged, painless,
rubbery, non-
erythematous, nontender
lymph nodes are the
hallmark of the disease.

29.  Patients with the nodular sclerosis or lymphocyte predominance types tend to present with stage I–II
disease and are usually free of systemic manifestations.
 Patients with disseminated disease (stages III–IV) or the mixed-cellularity or lymphocyte depletion
subtypes are more likely to have constitutional symptoms, such as fever, night sweats, and weight
loss.
 Cutaneous anergy resulting from depressed cell-mediated immunity is seen in most cases.
 The mix of factors released from Reed-Sternberg cells suppress TH1 immune responses and may
contribute to immune dysregulation.

30. SPREAD
 Cervical, supraclavicular and axillary lymphadenopathy are the most commonly involved first.
 Generally a well behaved spread of disease through contiguous LN groups, (especially NS and LP);
 <5% show non-contiguous spread
Nodal
disease
Splenic
disease
Hepatic
disease
Bone
marrow
Other
tissues

31. STAGING – ANN ARBOR CLASSIFICATION
Involvement of a
single lymph node
region (I) or a
single extra-
lymphatic organ or
site (IE).
Involvement of two or more
lymph node regions on the
same side of the diaphragm
alone (II) or localized
involvement of an extra-
lymphatic organ or site (IIE).
Involvement of lymph
node regions on both
sides of the diaphragm
without (III) or with (IIIE)
localized involvement of
an extra-lymphatic
Diffuse involvement of
one or more extra-
lymphatic organs or
sites with or without
lymphatic involvement.

32. INVESTIGATIONS
DIAGNOSIS
• LN – FNAC
• LN- BIOPSY
STAGING
• Chest X ray
• CT – Chest, Abd, Pelvis
• MRI, PET
• LP- CNS signs
OTHER LAB TESTS
• CBC – Anemia, High TLC
(Eosinophilia)
• LDH – high
• ESR – high
For classifying SUBTYPES – Immunophenotyping, Flow Cytometry,
FISH
Poor Prognostic
Factors