Chapter 13: Hodgkin's Lymphoma

Question 1

What is Hodgkin lymphoma (HL)?

Answer 1

encompasses a group of lymphoid neoplasms that differ from NHL in
several respects ( Table 13-7 ).

Question 2

What is the difference between NHLs vs HL with regards to the site?

Answer 2

• NHLs frequently occur at extranodal sites and spread in an unpredictable fashion,
• HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues.

​

Question 3

What is the reason why staging of HL is much more important in guiding therapy than it is in NHL?

Answer 3

HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues.

​

Question 4

What is the distinctive morphologic features of HL?

Answer 4

characterized by the presence of neoplastic giant cells called Reed-Sternberg cells.

These cells
release factors that induce the accumulation of reactive lymphocytes, macrophages, and
granulocytes, which typically make up greater than 90% of the tumor cellularity. In the vast
majority of HLs, the neoplastic Reed-Sternberg cells are derived from germinal center or postgerminal
center B cells.

Question 5

What is Reed-Sternberg cells?

Answer 5

. These cells

• *release factors that induce** the accumulation of reactive lymphocytes, macrophages, and
• *granulocytes,** which typically make up greater than 90% of the tumor cellularity.

In the vast
majority of HLs, the neoplastic Reed-Sternberg cells are derived from germinal center or postgerminal
center B cells.

Question 6

In the vast
majority of HLs, the neoplastic Reed-Sternberg cells are derived from what?

Answer 6

germinal center or postgerminal
center B cells.

Question 7

TABLE 13-7 – Differences between Hodgkin and Non-Hodgkin Lymphomas

Answer 7

Hodgkin Lymphoma

• More often localized to a single axial group of nodes
  (cervical, mediastinal, para-aortic)
• Orderly spread by contiguity
• Mesenteric nodes and Waldeyer ring rarely involved
• Extra-nodal presentation rare

​

Non-Hodgkin Lymphoma

• More frequent involvement of multiple peripheral nodes
• Noncontiguous spread
• Waldeyer ring and mesenteric nodes commonly involved
• Extra-nodal presentation common

Question 8

What is the epidemiology of Hodgkin lymphoma?

Answer 8

accounts for 0.7% of all new cancers in the United States; there are about 8000 new cases each year.

Question 9

What is the average age of diagnosis in Hodgkin’s lymphoma?

Answer 9

The average age at diagnosis is 32 years.

It is one of the most
common cancers of young adults and adolescents, butalso occurs in the aged.

It was the first
human cancer to be successfully treated with radiation therapy and chemotherapy, and is
curable in most cases.

Question 10

Classification.
The WHO classification recognizes five subtypes of HL:

Answer 10

1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Lymphocyte predominance

Question 11

In what subtypes of Hodgkin’s lymphoma the Reed-Sternberg cells have a similar immunophenotype?

Answer 11

In the first four subtypes—

1. nodular sclerosis,
2. mixed cellularity,
3. lymphocyte-rich,
4. and lymphocyte depletion—.

These subtypes are often lumped together as classical forms of HL.

NMDR

Question 12

In the remaining subtype, lymphocyte predominance, the Reed-Sternberg cells have a distinctive B-cell immunophenotype that differs
from that of the “classical” types.

Question 13

What is essential in the diagnosis of Hodgkin’s lymphoma?

Answer 13

Identification of Reed-Sternberg cells and their variants is essential for the diagnosis.

Question 14

Diagnostic Reed-Sternberg cells are what?

Answer 14

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) (
Fig. 13-24A ).

The cytoplasm is abundant.

Question 15

Several Reed-Sternberg cell variants are also
recognized.

What are these?

Answer 15

• Mononuclear variants
• Lymphohistocytic variants (L&H cells)
• classical forms of HL, Reed-Sternberg cells

Question 16

Describe the mononuclear variant of Reed-Sternberg cell

Answer 16

• contain a single nucleus with a large inclusion-like nucleolus ( Fig. 13-24B ).
• Lacunar cells (seen in the nodular sclerosis subtype) 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) ( Fig.

Question 17

Describe the classical forms of HL, Reed-Sternberg cells ?

Answer 17

undergo a peculiar form of cell death
in which the cells shrink and become pyknotic, a process described as “mummification.”

Question 18

What is “mummification.”

Answer 18

a process undergo a peculiar form of cell death
in which the cells shrink and become pyknotic,

Question 19

Describe the Lymphohistocytic variants (L&H cells).

Answer 19

with polypoid nuclei, inconspicuous nucleoli, and
moderately abundant cytoplasm are characteristic of the lymphocyte predominance subtype (
Fig. 13-24D ).

Question 20

What other conditions that HL must be distinguished from resemblingReed-Sternberg
cells can be seen?

Answer 20

• infectious mononucleosis,
• solid-tissue cancers,
• and large-cell NHLs.

Question 21

Where does the diagnosis of HL depends on?

Answer 21

the identification of Reed-Sternberg cells in a typical

prominent background of non-neoplastic inflammatory cells.

The Reed-Sternberg cells of HL also have a characteristic immunohistochemical profile.

Question 22

What is Nodular Sclerosis subtype of Hodgkin’s Lymphoma?

Answer 22

• most common form of HL,
• constituting 65% to 70% of cases.

Question 23

What is the characterisitc of Nodular Sclerosis subtype of Hodgkin’s Lymphoma?

Answer 23

• presence of lacunar variant Reed-Sternberg cells and
• the deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules ( Fig. 13-25 ).
• 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.

Question 24

What is the characteristic immunophenotype of Reed- Sternberg cells in this and other “classical” HL subtypes in Nodular Sclerosis subtype?

Answer 24

• positive for PAX5 (a B-cell transcription factor),
• CD15, and
• CD30,
• and negative for other:
  
  • ​ B-cell markers,
  • T-cell markers, and
  • CD45 (leukocyte common antigen).

Question 25

What is the course of the disease of Nodular Sclerosis subtype of HL?

Answer 25

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.

This subtype is uncommonly associated with EBV.

Question 26

What subtype of HL is uncommonly associated with EBV?

Answer 26

Nodular Sclerosis

Question 27

What age predominance does nodular sclerosis type has?

Answer 27

equal frequency in males and females.

Question 28

The nodular sclerosis type of HL has a propensity to involve what locations?

Answer 28

• lower cervical,
• supraclavicular, and
• mediastinal lymph nodes of adolescents or young adults.

Question 29

What is the prognosis of nodular sclerosis type of HL ?

Answer 29

The prognosis is excellent.

Question 30

What is the Mixed-Cellularity Type of HL?

Answer 30

• constitutes about 20% to 25% of cases.
• 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

( Fig. 13-26 ).

Question 31

To what age is Mixed-cellularity HL is more common?

Answer 31

males.

Question 32

What is the distinguishing feature of Mixed Cellularity type of HL compared to lymphocyte predominance and sclerosis subtype?

Answer 32

it is more likely to be associated with older age,

Question 33

What are the clinical symptoms of Mixed Cellulearity Type of HL?

Answer 33

systemic symptoms such as night sweats and weight loss, and advanced tumor stage.

Nonetheless, the
overall prognosis is very good.

Question 34

What is the Lymphocyte-Rich Type of HL?

Answer 34

• 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.

Question 35

How do you distinguish Lymphocyte-Rich Type of HL from the lymphocyte predominance

Answer 35

type by the presence of frequent mononuclear variants and diagnostic Reed-Sternberg cells
with a “classical” immunophenotypic profile.

It is associated with EBV in about 40% of cases
and has a very good to excellent prognosis

Question 36

What is the Lymphocyte Depletion Type of HL?

​

Answer 36

• least common form of HL,
• amounting to less than 5% of cases.
• It is characterized by a paucity of lymphocytes and a relative abundance of Reed-Sternberg cells or their pleomorphic variants.
• The immunophenotype of the Reed- Sternberg cells is identical to that seen in other classical types of HL

Question 37

Why is Immunophenotyping essential in the Lymphocyte Depletion Type of HL

Answer 37

since most tumors suspected of being lymphocyte depletion HL actually prove to be
large-cell NHLs.

Question 38

Lymphocyte depletion HL occurs predominantly to what age?

Answer 38

• elderly,
• in HIV+ individuals of any age,
• and in nonindustrialized countries.

Question 39

What is the overall outcome in Lymphocyte Depletion Type of HL?

Answer 39

Advanced stage and systemic symptoms are frequent, and the overall outcome is somewhat less favorable than in the other subtypes.

The Reed-Sternberg cells are infected with EBV in over 90% of cases.

Question 40

What is the Lymphocyte Predominance Type of HL?

Answer 40

• uncommon “nonclassical” variant of HL
• accounts for about 5% of cases.
• Involved nodes are effaced by a nodular infiltrate of small lymphocytes admixed with variable numbers of macrophages ( Fig. 13-27 ).
• “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.

Question 41

In contrast to the Reed-Sternberg cells found in classical forms of HL, L&H variants of Lymphocyte Predominance Type ?

Answer 41

L&H variants express
B-cell markers typical of germinal-center B cells, such as CD20 and BCL6, and are
usually negative for CD15 and CD30.

Question 42

What is the typical nodular pattern of growth in Lymphocyte Predominance Type ?

Answer 42

The typical nodular pattern of growth is due to the
presence of expanded B-cell follicles, which arepopulated with L&H variants, numerous
reactive B cells, and follicular dendritic cells.

Question 43

What does the IgH genes of the L&H variants show?

Answer 43

evidence of ongoing somatic hypermutation, a modification that occurs only in germinalcenter
B cells

.

Question 44

In the Lymphocyte Predominance Type, in 3% to 5% of cases transforms into what?

Answer 44

tumor resembling diffuse large B-cell lymphoma.

Question 45

EBV is associated in the Lymphocyte Predominance Type.

TRUE OR FALSE

Answer 45

FALSE

EBV is not associated with this subtype.

Question 46

Answer 46

FIGURE 13-24 Reed-Sternberg cells and variants.

• A, Diagnostic Reed-Sternberg cell, with

two nuclear lobes, large inclusion-like nucleoli, and abundant cytoplasm, surrounded by
lymphocytes, macrophages, and an eosinophil.

B, Reed-Sternberg cell, mononuclear
variant

• . C, Reed-Sternberg cell, lacunar variant. This variant has a folded or multilobated

nucleus and lies within a open space, which is an artifact created by disruption of the
cytoplasm during tissue sectioning.

• D, Reed-Sternberg cell, lymphohistiocytic variant.

Several such variants with multiply infolded nuclear membranes, small nucleoli, fine
chromatin, and abundant pale cytoplasm are present.

Question 47

TABLE 13-8 – Subtypes of Hodgkin Lymphoma​

Nodular
sclerosis

Answer 47

Morphology:

• Frequent lacunar cells and occasional diagnostic RS cells;
• background infiltrate composed of T lymphocytes, eosinophils, macrophages, and plasma cells;
• fibrous bands dividing cellular areas into nodules. RS cells CD15+, CD30+; usually EBV

Typical Clinical Features

• Most common subtype;
• usually stage I or II disease;
• frequent mediastinal involvement;
• equal occurrence in males and
  females (F = M),
• most patients young adults

and Immunophenotype Typical Clinical Features

Question 48

TABLE 13-8 – Subtypes of Hodgkin Lymphoma​

Mixed
cellularity

Answer 48

Morphology and Immunophenotype

• Frequent mononuclear and diagnostic RS cells;
• background infiltrate rich in T lymphocytes, eosinophils, macrophages, plasma cells;
• RS cells CD15+, CD30+; 70% EBV+

Typical Clinical Features

• More than 50% present as stage III or IV disease; M greater than F;
• biphasic incidence, peaking in young adults and again in adults older than 55

Question 49

TABLE 13-8 – Subtypes of Hodgkin Lymphoma​

Lymphocyte
rich

Answer 49

Morphology and Immunophenotype

• Frequent mononuclear and diagnostic RS cells;
• background infiltrate rich in T lymphocytes;
• RS cells CD15+, CD30+; 40% EBV+

Typical Clinical Features

• Uncommon;
• M greater than F;
• tends to be seen in older adults

Question 50

TABLE 13-8 – Subtypes of Hodgkin Lymphoma​

Lymphocyte
depletion

Answer 50

Morphology and Immunophenotype

• Reticular variant:
• Frequent diagnostic RS cells and variants and a paucity of backgroundreactive cells;
• RS cells CD15+, CD30+;
• most EBV+

Typical Clinical Features

• Uncommon;
• more common in older males, HIV-infected individuals, and in developing countries;
• often presents with advanced disease

Question 51

TABLE 13-8 – Subtypes of Hodgkin Lymphoma​

Lymphocyte
predominance

Answer 51

Morphology and Immunophenotype

• Frequent L&H (popcorn cell) variants in a background of follicular dendritic cells and reactive B cells;
• RS cells CD20+, CD15-, C30-;
• EBV

Typical Clinical Features

• Uncommon;
• young males with cervical or axillary lymphadenopathy;
• mediastinal

Question 52

Answer 52

FIGURE 13-25 Hodgkin lymphoma, nodular sclerosis type. A low-power view shows welldefined
bands of pink, acellular collagen that subdivide the tumor into nodules.

Question 53

Answer 53

FIGURE 13-26 Hodgkin lymphoma, mixed-cellularity type. A diagnostic, binucleate Reed-
Sternberg cell is surrounded by reactive cells, including eosinophils (bright red cytoplasm),
lymphocytes, and histiocytes

Question 54

Answer 54

FIGURE 13-27 Hodgkin lymphoma, lymphocyte predominance type. Numerous maturelooking
lymphocytes surround scattered, large, pale-staining lymphohistiocytic variants
(“popcorn” cells).

Question 55

Where did the origin of the neoplastic Reed-Sternberg cells of classical HL come from?

Answer 55

. In the vast majority of cases, the **Ig genes of Reed-Sternberg cells have undergone
both V(D)J recombinatio**n and**somatic hypermutation,**establishing**an origin from a germinal
center or post-germinal-center B cell.**[50]

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. **

The cause of this wholesale reprogramming of gene expression has yet to be fully
explained.

Question 56

What is the Molecular Pathogenesis of classical Hodgkin’s lymphoma?

Answer 56

Activation of the transcription factor NF- κB is a common event in classical HL

. NF-κB is
activated either by EBV infection or by some other mechanism and turns on genes that promote
lymphocyte survival and proliferation.

EBV+ tumor cells express latent membrane protein-1
(LMP-1), aprotein encoded by the EBV genome that transmits signalsthatup-regulate NF-κB.

Activation of NF-κB also occurs in EBV - tumors, in some instances as a result of acquired
mutations in IκB, [52] a negative regulator of NF-κB.

It is hypothesized that activation of NF-κB
by EBV or other mechanisms rescues “crippled” germinal-center B cells that cannot express Igs
from apoptosis, setting the stage for the acquisition of other unknown mutations that collaborate
to produce ReedSternberg cells.

Little is known about the basis for the morphology of Reed- Sternberg cells and variants, but it is intriguing that EBV-infected B cells resembling
ReedSternberg cellsare found in thelymph nodes of individuals with infectious mononucleosis strongly suggesting that EBV-encoded proteins play a part in the remarkable metamorphosis of
B cells into Reed-Sternberg cells.

Question 57

The florid accumulation of reactive cells in tissues involved by classical HL occurs in response
to a wide variety of cytokines such as ___________and chemokines_______that are secreted by Reed-Sternberg cells. [53]

Answer 57

• cytokines: (such as IL-5, IL-10, IL-13, and TGF-β)
• chemokines (such as TARC, MDC, IP-10, and CCL28)

Once

attracted, the reactive cells produce factors that support the growth and survival of the tumor
cells and further modify the reactive cell response.

For example, eosinophils and T cells
express ligands that activate the CD30 and CD40 receptors found on Reed-Sternberg cells,
producing signals that up-regulate NF-κB.

Other examples of “cross-talk” between Reed-
Sternberg cells and surrounding reactive cells are provided in Figure 13-28 .

Answer 58

FIGURE 13-28 Proposed signals mediating “cross-talk” between Reed-Sternberg cells and
surrounding normal cells in classical forms of Hodgkin lymphoma. CD30L, CD30 ligand;
bFGF, basic fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating
factor; HGF, hepatocyte growth factor (binds to the c-MET receptor); TGFβ, transforming
growth factor β; TNFβ, tumor necrosis factor β (lymphotoxin); Tc, CD8+ cytotoxic T cell; TH1
and TH2, CD4+ T helper cell subsets