Pathology of Lymph Nodes

DR.dr. Fairuz Quzwain, SpPA, M.Kes

Anatomical organization
š  The anatomic organization of the lymphoid immune system
divided into two major functional regions:
●  The primary immune organs, sites of initial maturation -->
immune competent cells:
•  B cells- bone marrow
•  T cells- thymus
●  The secondary immune organs, sites of antigen driven
replication and differentiation into committed effector cells
•  Lymph nodes
•  Spleen
•  Mucosal Associated Lymphoid System (MALT)- lymphoid
cells lining the respiratory and gastrointestinal tracts
•  Everywhere else
š  The lymph nodes, in their totality, represent the largest secondary
organ, and the major site of lymphoid pathology
 Lymph node anatomy

š To recognize
lymph node
pathology,
one has to
be familiar
with normal
lymph node
anatomy
and cytology
Lymph node histology
 Lymphocyte homing
š  After initial maturation in the primary š  The site of T cell homing is the
immune organs, "virgin" B and T paracortex
lymphocytes --> peripheral blood --> š  The separation of B and T lymphocytes
home to specific sites within the lymph not absolute,
node (and the other secondary š  Both cell types present throughout
organs), lymph node, necessary for coordinated
lymphoid immune response.
š  The sites of B cell homing include:
●  The primary and secondary
follicles of cortex-the sites of
•  antigen presentation
•  proliferation and
differentiation in response to
same
●  The medullary cords -->plasma
cells aggregate--> release their
immunoglobulins into the efferent
lymph
Overview of the lymphoid
immune system
š Lymphocytes evolve from pluripotent stem cells --> two
major functional cell types:
●  B lymphocytes, comprising the humoral immune -->

production of antibodies
●  T lymphocytes, comprising the cellular immune

system, -->
•  Direct killing of foreign or intracellularly infected
cells, cytotoxic T cells
•  Fine control of the immune response through the
secretion of cytokines, helper and suppressor T
cells.
Lymphocyte recirculation
š Normal lymphocytes recirculate, passing from blood -->
lymph nodes --> efferent lymphatics
●  Allows constant surveillance for the presence of the

antigen for which the lymphocyte has a unique and

specific receptor on it's surface.
š If antigen not present, lymphocytes leave the node and
recirculate
š Virgin lymphocytes have a finite lifespan, numbered in
weeks, unless they come in contact with antigen
š Lymphadenopathy can be defined as LNs
that are abnormal in size, consistency or
number
š Lymphadenopathy : localized if only one
group of LN is involved, limited if 2-3
groups of LN are involved and generalized
if more than three noncontiguous groups are
involved.
š  Lymphadenopathy occur when the number
of white blood cells inside them has
increased in response to an infection or
other illness. The number of disease-
fighting cells builds rapidly, causing
pressure and swelling inside lymph nodes.
š can be the site of infectious, immune and neoplastic
disease, the latter either primary or metastatic
š The clinical manifestations of diseases of the lymph nodes
are:
●  Local enlargement, tender on nontender, +/_

●  Compression of adjacent structures +/_

●  Release of cytokines producing "systemic" symptoms

of fever, weight loss and night sweats

š Infectious organisms can stimulate the same acute, chronic
or granulomatous reactions in the draining lymph nodes as
they characteristically stimulate at other sites
A doctor should be consulted when certain symptoms are
present. These include:
š Nodes that are swollen for more than two weeks
š Night sweats
š Weight loss
š Long-lasting fever Fatigue
š Nodes that are hard, fixed to the skin, or growing rapidly
š Swollen nodes close to the collarbone or lower part of the
neck. Swollen nodes in this area often indicate a cancerous
condition
š Red or inflamed skin over swollen nodes
š Difficulty breathing
Pathology of lymphadenopathy
š Infections
š Reactive hyperplasias
š Sarcoidosis
š Metastatic tumors
š Malignant lymphomas
●  Non-Hodgkin’s lymphoma-NHL

●  Hodgkin’s lymphoma
Infections
●  Bacterial
•  Acute inflammation, abscess formation
●  Granulomatous, caseous and noncaseous
●  Diagnosis by culture, serologies, and/or special stains
Reactive hyperplasias
š  Exaggerations of normal histology.
●  Expansion of all regions or selective expansion
●  Some types characteristic of certain diseases, but most not
š  Follicular hyperplasia- increase in number and size of germinal centers,
spread into paracortex, medullary areas
●  Collagen vascular diseases
●  Systemic toxoplasmosis
●  Syphillis
š  Interfollicular hyperplasia- paracortex
●  Skin diseases
●  Viral infections
●  Drug reactions
š  Sinus histiocytosis- expansion of the medullary sinus histiocytes-
●  Adjacent cancer
●  Infections
Metastatic tumors
š Metastatic tumors spread to the lymph nodes primarily via
lymphatic drainage from adjacent solid organs
š Primary neoplasms of the lymph nodes are all malignant
š They are divided into malignant non-Hodgkin's
lymphomas (NHL), and Hodgkin lymphoma
Malignant lymphomas

š Malignancies of the lymphoid system which primarily

manifest themselves outside the bone marrow (lymph
nodes, Spleen, M.A.L.T, Anywhere
(Lymphomas outside lymph nodes and spleen are referred
to as extranodal lymphomas)
š They are divided into malignant non-Hodgkin's
lymphomas (NHL), and Hodgkin lymphoma
š Approximately 40, 000 cases per year, 20,000 deaths
š NHL's are more common, and can be simply divided into
indolent, or slow growing types, and aggressive types
š Malignant lymphomas represent clonal malignancies in
which mutational events have caused the majority of
progeny cells to freeze at a single stage of normal
lymphocyte differentiation
●  Lymphomas frozen at a stage associated with high

replication --> aggressive lymphomas;

●  Lymphomas frozen at stages associated with

recirculation or final function --> indolent lymphomas

š The diagnosis of malignant lymphomas is based on the
microscopic recognition of the dominant cytologic cell
type, supplemented by immunologic and molecular
techniques
š The treatment and prognosis of lymphomas are based on
●  The dominant cell type (and it's inherent biologic

behavior),
●  The extent of spread (Stage)

●  The underlying health of the patient

š All of the previous statements are complicated by the fact

that indolent lymphomas can further mutate and
transform to aggressive types
š Hodgkin lymphoma is a less common nodal disease
whose diagnosis is based on the detection of a
characteristic cell, the Reed Sternberg cell, in the
appropriate histologic setting
š There are several (five) histologic subtypes, but prognosis
is based primarily on extent of disease
š Hodgkin lymphoma is a more curable disease than non-
Hodgkin lymphomas
š Now watch me confuse this relatively straightforward
information with the details.
 Cell types I
š  Small lymphocytes
●  Small round dark blue dots. Round
nucleus, clumped chromatin, small or
absent nucleolus.
●  The dullest looking cells hiding the
greatest level of functional
heterogeneity.
●  Locations:
•  Can be T or B cell, virgin
•  B cells- primary follicles,
(unexposed to antigen) or
mantle zone of secondary
differentiated effector/memory cell.
follicles, medullary cords
•  Most likely lineage, B or T,
•  T cells- paracortex, minor
guessed by location within the
population within germinal
node, but lineage and state of
center.
differentiation must be confirmed
by immunologic/molecular ●  Kinetically, clumped
techniques chromatin tells us that the cell is
not proliferating- not activated
to enter the cell cycle and
replicate
 Cell types 2:Follicular (germinal)
center cells
š  Replicating and post-replicating B cells ●  Small cleaved cells-
●  Noncleaved cells, small and large •  Nonreplicating population
•  Replicating populations- •  Post mitotic memory or plasma
expanding antigen responsive cell precursors
cells. •  Clumped chromatin
•  Round nuclei but larger than •  Irregular folded and cleaved
resting small lymphocyte nuclear profiles
•  Open or vesicular chromatin
•  Recognizable nucleoli.
–  Nucleus clear -->genetic
material unwound for
replication.
•  Size, large or small compared
nucleus of macrophage.
Reactive germinal center
MZ

LZ

DZ
 Cytology of lymph node 3
š  Immunoblasts
●  Replicating large cells found
outside the germinal centers.
●  May be of B or T cell type
●  Have nuclear characteristics of
replicating lymphocytes-
•  Vesicular chromatin
•  Nucleoli
š  Accessory cells
●  Antigen processing cells
•  Interdigitating reticulin cells- T cell
paracortex
•  Dendritic reticulin cells- B cell germinal
centers
•  Process and present antigen to B and T
lymphocytes
•  Invisible in normal lymph node
●  Macrophages (histiocytes)-
•  Phagoctytic cells of lymph node
•  Tingible body macrophages of germinal
centers
•  Medullary and subcapsular sinus
macrophages-
•  Abundant pale cytoplasm
•  Oval nucleus, single small nucleolus
Clinical presentation
š  Enlarging mass(es), typically painless, at sites of nodal tissue
š  Compression, infiltration of hollow organs
●  Pain, obstruction, perforation
š  Interference with normal organ function-
●  Solid organ infiltration- kidneys, liver, bone marrow
š  Systemic symptoms
●  Fever
●  Night sweats
●  Weight loss
š  If marrow infiltrated, can have leukemic component
 WorkingFormulation for
•  Low grade
Clinical Usage •  ML, small lymphocytic
•  ML, follicular small cleaved cell
š  From 1982-1994, the classification used •  ML, follicular, mixed small and large
in the United States cell
š  Based on:
•  Intermediate grade:
●  The observed clinical history of
1200 patients classified according to •  ML, follicular, large cell
the terminology to right •  ML, diffuse, small cleaved cell
●  Microsopic examination alone, •  ML, diffuse, mixed small and large cell
•  ML, diffuse, large cell
utilizing
•  Loss of normal nodal •  High grade
architecture
•  The dominant cytologic cell •  ML, immunoblastic
type observed under the •  ML, lymphoblastic
•  ML, small non-cleaved cell (Burkitt's vs
microscope
non-Burkitt's)
•  Presence or absence of
"follicularity" - mimicking of •  Miscellaneous (mycosis fungoides,
normal lymphoid follicle true histiocytic, etc.)
formation
B-Cell Neoplasms
•Precursor B-cell lymphoblastic
leukemia/lymphoma
Peripheral B-cell neoplasms
•B-cell CLL/SLL
•B-cell prolymphocytic leukemia •T-cell prolymphocytic leukemia
•Lymphoplasmacytic lymphoma •T-cell large granular lymphocytic
•Mantle cell lymphoma
•Follicular lymphoma
•Extranodal marginal zone B-
cell lymphoma, MALT type (+/-
monocytoid B cells)
•Nodal marginal zone B-cell
lymphoma (+/-monocytoid B
cells)
•Splenic marginal zone B-cell
lymphoma (+/-villous
lymphocytes)
•Hairy cell leukemia
•Diffuse large B-cell lymphoma •Sezary syndrome
•Burkitt lymphoma
•Plasma cell myeloma
•Plasmacytoma
T/NK-Cell Neoplasms Hodgkin's Lymphoma
•Precursor T cell lymphoblastic •Lymphocyte predominance,
leukemia/lymphoma nodular
Peripheral T-cell and NK-cell •Classical HL
neoplasms
Predominantly •Lymphocyte rich classical HL
leukemic/disseminated
•Nodular sclerosis
•Mixed cellularity
(LGL) leukemia
•NK cell leukemia •Lymphocyte depletion
•Adult T-cell leukemia/lymphoma •Unclassifiable classical HL
Predominantly nodal
•Angioimmunoblastic T-cell
lymphoma
•Peripheral T-cell lymphoma
unspecified
•Anaplastic large cell lymphoma,
T/null-cell
Predominantly extranodal
•Mycosis fungoides
•Primary cutaneous (CD30+ T-cell
lymphoproliferative disorders)
•Subcutaneous panniculitis-like T-
cell lymphoma
•NK/T cell lymphoma, nasal and
nasal-type
•Enteropathy-type intestinal T-cell
lymphoma
•Hepatosplenic T-cell lymphoma
g/d (gamma/delta)
a/b (alpha/beta)
REAL/WHO classification-
backbone
š B cell neoplasms
●  Precursor B cells-related to acute leukemia
●  Peripheral B cell lymphomas- the majority of B
cell lymphomas
š T cell and Natural Killer cell neoplasms
●  Precursor T cells
●  Peripheral T cell and NK neoplasms
š Hodgkin’s lymphoma
Frequency of lymphomas
B cell neoplasms- Precursor B
š Precursor B cell lymphoblastic leukemia/lymphoma
●  Frozen at lymphoblast cell stage of antigen

independent B cell differentiation- normally restricted

to bone marrow
●  Usually present as acute leukemia +/- lymph node

involvement
●  Can initially present as node or skin disease, with later

progression to bone marrow

●  Treated as acute leukemia

•  80% cure rate in children

•  20-30% in adults because of "bad" cytogenetics:
frequent presence of Philadelphia chromosome
t(9;22)
 Peripheral B-cell lymphomas
š Lymphomas frozen at various stages of antigen dependent B cell maturation and
differentiation

Peripheral B-cell neoplasms
š  Frozen at various stages of antigen dependent B cell maturation and
differentiation
●  Small lymphocytic/CLL- the virgin B cell fresh from the marrow
●  Prolymphocytic leukemia- a more clinically aggressive variant of above
●  Lymphoplasmacytic lymphoma- the primary immune response
●  Mantle cell lymphoma- the mantle region surrounding the follicle
●  Follicular lymphoma- the follicle- grades 1-3
●  Extranodal marginal zone lymphoma- cells at the periphery of the follicle in
extranodal sites of lymphoid tissue- Mucosal Associated Lymphoid tissue-
such as G.I. tract
●  Nodal marginal zone lymphoma
●  Splenic marginal zone lymphoma- immunologically distinct
●  Hairy cell leukemia- pre-plasma cell
●  Diffuse large B-cell lymphoma- this breaks the ideal of specific cell stage
but all represent lymphomas with high replication rate
●  Burkitt lymphoma- very aggressive
●  Plasma cell myeloma- diffuse bone marrow proliferation of plasma cells
●  Plasmacytoma- solitary focus of monoclonal plasma cells, with variable
risk of progression to myeloma, depending on site
 Burkitt's lymphoma
š  Clinical š  Pathogenesis:
●  3% lymphomas ●  t(8;14), producing upregulation of
●  Disease of adults and children- myc oncogene, a cell cycle
median age 31 regulation gene
●  Initially recognized in Africa by
Thomas Burkitt
•  Association with Epstein Barr
virus infection
•  Localization in jaw
●  In US, usually presents in ileocecal
region of children
●  1/3 of all childhood lymphomas
●  Earlier eras, very aggressive and
rapidly fatal
•  Now, ~70-80% children curable
•  40% of adults
 Burkitt's lymphoma
š  Pathology
●  Benign equivalent is replicating small
noncleaved cell of germinal center:
●  Diffuse infiltration of lymph node
●  Very high mitotic rate, lot of
ineffective proliferation;
●  Attracts macrophages to
phagocytize> starry sky pattern at
low power
●  Cytology: round nucleus, smaller
than that of reactive macrophage
●  Vesicular chromatin and 2-5 nucleoli
●  Immunophenotype:
•  Positive: Monoclonal light chain,
CD19, CD10
•  Negative: CD5
Mantle cell lymphoma
š  Clinical
●  6% lymphomas
●  Disease of adults (median
age 63)
●  Usually widely disseminated
●  Poor response to all
attempted therapies,
●  ? curable with transplant
●  5yr survival 27%

š  Pathogenesis
●  Due to t(11;14)
●  Upregulates Bcl1 (cyclin
D1), a cell cycle regulator
 Mantle cell lymphoma
š  Pathology/Diagnosis
●  Benign equivalent is lymphocyte of
inner mantle zone
●  Cytology similar to cleaved cell, but
nuclear irregularities not as
prominent
●  Nodal infiltration diffuse, vaguely
nodular or "mantle zone" around
residual benign follicles
●  Large cell progression infrequent
●  Immunophenotype:
•  Positive: monoclonal light
chain, CD19, CD5, Bcl1 (and
Bcl2)
•  Negative CD10, CD23

Follicular lymphoma
Mantle cell lymphoma

CyclinD1

Bcl2
 Table X: Indolent B cell lymphomas
Follicular Marginal zone Small lymphocytic Mantle cell
Lymphoma Lymphoma lymphoma/CLL Lymphoma
(Grade I)
Frequency (% 22% 8 7 6
all lymphomas
Age of onset 59 61 65 63
median
Stage at Stage III/IV Stage I Stage IV Stage III/IV
Presentation Disseminated
Response to Good to most Frequently Similar to Poor response to
Therapy treatments, curable Follicular all therapies
but incurable lymphoma to date
short of
transplant
5 yr survival 72% 74% 51% 27%

Predominant site Nodal Extranodal Marrow/nodal Nodal

presentation
Pattern of nodal Follicular Diffuse Diffuse Diffuse,
Infiltration nodular
or
“mantle zone”
Benign cell Germinal Marginal zone Virgin B cell Mantle cell
Equivalent center Lymphocyte
small cleaved
cell
Dominant cell Small cleaved Mix of small Small Small cell
type cell in most lymphocytes, lymphocytes with irregular
cases, but can plasma cells with round nucleus,
be large cell nucleus similar to
cleaved
Immunopheno Positive: CD19 Positive: Positive: Positive:
-type CD10, Bcl2+ CD19, Bcl2 CD19, CD5 CD19, CD5,
Negative: CD5- Negative: CD23 Bcl2
CD10, CD5 Negative: Negative:
CD10 CD10
Molecular t(14;18) Trisomy 3 Trisomy 12 t(11;14)
Pathogenesis Bcl2/JH Bcl1/JH
 T cell lymphomas-Precursor T
š  Clinical
●  Disease of teenagers; boys>girls

●  Can present as acute leukemia or mediastinal mass+/- marrow

involvement
●  Aggressive lymphoma/leukemia, but curable: ~70% with

appropriate multiagent chemotherapy

š  Pathogenesis
●  No single gene culprit, but frequently involve translocation of

(onco)genes to site of T cell receptor genes, --> upregulation of

proteins
 T cell lymphomas-Precursor T
š  Pathology
●  Benign equivalent
immature T cells of
thymus
●  Histology: Diffuse
infiltration of thymus/
adjacent lymph nodes
●  Cytology: “Blast cells”
of intermediate size with
oval to “convoluted”
nuclear profiles, fine
chromatin and 0-1
nucleolus
●  Again need immunology
to distinguish from pre-B
Peripheral T cell lymphomas
š  Predominantly leukemic/ š  Predominantly extranodal
disseminated
●  Mycosis fungoides
●  T-cell prolymphocytic
●  Sezary syndrome
leukemia
●  Primary cutaneous CD30+ T-
●  T-cell large granular
cell lymphoproliferative
lymphocytic (LGL) leukemia
disorders
●  NK cell leukemia
●  Subcutaneous panniculitis-
●  Adult T-cell leukemia/ like T-cell lymphoma
lymphoma
●  NK/T cell lymphoma, nasal
and nasal-type
š  Predominantly nodal ●  Enteropathy-type intestinal T-
●  Angioimmunoblastic T-cell cell lymphoma
lymphoma ●  Hepatosplenic T-cell
●  Peripheral T-cell lymphoma lymphoma
unspecified
●  Anaplastic large cell
lymphoma, T/null-cell
 Key points regarding T cell
lymphomas
š  Clinical
●  Represent 20% all lymphomas
●  More often extranodal than B
•  Can involve skin, midline facial
area, liver
•  Very characteristic clinical
presentations
●  Most diseases bad: high stage,
and poorer response to therapy
than B cell lymphomas of all
grades
š  Pathogenesis:
●  Characteristic cytogenetic findings
associated with several types
•  Anaplastic large cell
lymphoma- t(2;5): ALK1 gene
•  Hepatosplenic T cell
lymphoma- Isochromosome 7
š  Pathology
●  Cytologic features not as predictive of
behavior as B cell lymphomas
•  Anaplastic large cell lymphoma
--> better prognosis than most
indolent B cell lymphomas- 77% 5
year survival
•  Mycosis fungoides, indolent
cutaneous lymphoma, incurable, but
with long clinical course
●  Immunophenotypic studies frequently
demonstrate
•  Loss of normal T cell associated
antigens
•  Antigens associated with Natural
Killer cell function
•  Immunology absolutely necessary to
recognize
Ancillary diagnostic studies
š  Use of immunologic/molecular techniques
š  Malignant lymphomas reproduce the immunobiology of their
benign counterparts
š  This reproduction may be aberrant, and hence distinguishable
from normal
š  Expression, normal and aberrant can be used to:
●  Determine lineage, B versus T versus NK

●  Detect clonality

●  Suspect malignancy- loss or aberrant expression of

expected antigens
●  Recognize characteristic patterns of antigenic expression

associated with certain subtypes of lymphoma

Normal lymphoid maturation
š  Requires two major activities
●  The production of a unique
antigenic receptor on it's
surface
●  The expression of several
surface proteins necessary for
antigen recognition, cell
activation, cell-cell
communication.
●  Antigen receptors are
generated through the process
of "genetic rearrangement"- the
random selection and
juxtaposition of discontinuous
genetic segments encoding the
antigen receptor genes
●  B cells
•  Immunoglobulin receptor
composed of two heavy
and two light chains
–  Select specific heavy
chain antigen
recognition sequence
–  Select only one of two
light chains, kappa or
lambda
●  T cells
•  Select one of two
heterodimeric receptors
–  Alpha/Beta
heterodimer T cell
receptor
–  Gamma/Delta
heterodimer T cell
receptor
Normal lymphoid maturation
š  Requires two major activities
●  The production of a unique antigenic receptor on it's surface
●  The expression of several surface proteins necessary for antigen
recognition, cell activation, cell-cell communication.
š  Antigen receptors are generated through the process of "genetic
rearrangement"- the random selection and then juxtaposition of
discontinuous genetic segments encoding the antigen receptor genes
●  B cells
•  Immunoglobulin receptor composed of two heavy chains and
two light chains
–  Select specific heavy chain gene sequences
–  Select only one of two light chains, kappa or lambda
●  T cells
•  Select one of two heterodimeric receptors
–  Alpha/Beta heterodimer T cell receptor
–  Gamma/Delta heterodimer T cell receptor
Antigen receptor selection- B cell
Surface antigen production
š  Immune cells require numerous surface molecules for
effective immune response, cell-cell communication and
regulation
š  Classified into B cell associated, T cell associated, activation
associated, cytokine receptors
š  Expression occurs in an orderly sequence in lymphoid
maturation
š  Antibodies to these molecules cataloged thru the CD -
clusters of differentiation - numerical system
●  Initially developed to characterize monoclonal antibodies

detecting proteins whose function was unknown .

●  Now up to CD166. You'll only be tested on 1-130 though

(- a joke for you paranoid types.)

B cell antigen expression
T cell antigen expression
Immunologic Techniques
š  Flow cytometry-automated
fluorescent microscopy
š  Immunohistochemistry- in situ
immunologic detection through
the use of enzyme substrate
color deposition
š  Both utilize monoclonal
antibodies to detect clonality
and unique antigenic patterns
Immunologic Techniques
š Flow cytometry-automated fluorescent microscopy
š Immunohistochemistry- in situ detection through the use of
enzyme substrate color deposition
š Examples
●  B cell small lymphocytic lymphoma-

•  Monoclonal light chain, CD19, CD20, CD5, CD23

positive, CD10 negative
●  B cell follicular lymphoma-

•  Monoclonal light chain, CD19, CD20, CD10

positive, CD5 negative

Molecular techniques
š Detection of antigen receptor clonality
š Detection of unique cytogenetic
rearrangements/translocations
š Examples
●  Clonal gene rearrangement by Southern blot
●  Bcl2/JH rearrangement by polymerase chain
reaction

Clinical presentation
š Enlarging mass(es), typically painless, at sites of nodal
tissue
š Obstruction, ulceration of hollow organs- pain, perforation
š Interference with normal organ function-
●  Solid organ infiltration- kidneys, liver, bone marrow
š Systemic symptoms
●  Fever
●  Night sweats
●  Weight loss
š If marrow infiltrated, can have leukemic component
Clinical staging of lymphomas
š  Defines extent of disease; determines therapy and prognosis
š  Based on physical, radiologic examination, bone marrow biopsy and
aspiration
š  Ann Arbor Staging system
š  B symptoms- fever, weight loss > 10% body weight, night sweats
Staging table
Prognosis
š International prognostic index
●  Aggressive lymphomas
š Cytogenetics
š Oncogenes
 Hodgkin's lymphoma
š  Less common than NHL; ~
10,000 cases per year
š  Age incidence bimodal, with one
peak in late adolescence, young
adulthood, second peak
beginning in sixth decade
●  Bimodal curve shifts to

younger ages in poorer

countries
š  Unlike NHL, HL diagnosed by
the presence of a minor cellular
component, the Reed-
Sternberg cell, found in the
appropriate microscopic cellular
background
Hodgkin's lymphoma
classification
Rye Classification REAL/WHO Classification

Lymphocyte predominant-5% Lymphocyte predominance,

nodular
Nodular sclerosis-70%

Mixed cellularity-20% Classical HL

Lymphocyte depleted-5% Lymphocyte rich classical HL

Nodular sclerosis

Mixed cellularity

Lymphocyte depletion

Unclassifiable classical HL
 Hodgkin's Histologic subtypes
š  Are characteristic patterns of
involvement, and characteristic
variants of Reed Sternberg cell
associated with different subtypes
š  Nodular sclerosing HL
●  Most common type Hodgkin's
lymphoma in US/Europe
●  Usually presents in the anterior
mediastinum and neck of young
adult females
●  Characterized by fibrotic capsule
and bands subdividing tissue and
●  Lacunar variant Reed Sternberg
cell
 Histologic
subtypes 2
š  Lymphocyte predominant
●  Usually presents with limited disease in the
neck of young adults
●  Associated with L and H (lymphocytic and
histiocytic) or "popcorn cell" variant RS cell
š  Mixed cellularity
●  More extensive disease
●  Older patients than NS and LP
●  More R-S cells, eosinophils, plasma cells
●  Mononuclear variant R-S cells
●  Inherently more aggressive disease
š  Lymphocyte depleted
●  Often presents in retroperitoneum, older
patients
●  Accompanied by loss lymphocytes,
sclerosis and pleomorphic RS cell variants
●  Also more aggressive disease
Ancillary studies
š  Ancillary immunologic studies assist the dx of Hodgkins' lymphoma
š  Distinguish HL from
●  Immunoblast reactions

●  Unusual variants of NHL

š  CD15 and CD30 antigens in golgi and on cell membrane of R-S cells
most useful
Patterns of spread
š Hodgkin's lymphoma spreads contiguously via
lymphatics
š Staging as in NHL- may or may not include
laparotomy/splenectomy

Pathobiology
š  The etiology of HL is still unknown
š  The lineage of the R-S cell was also obscure until recently
š  The mixed cellular infiltrate, unusual large cells, clustered familial
cases, and early evidence of immune dysfunction suggest an infectious
etiology+/- an inherited predisposition
š  In approximately 30% of cases, Epstein Barr virus found within the RS
cells
š  Molecular studies, utilizing single cell dissection and PCR based
sequencing of the antigen receptor genes indicate that the R-S cell in
the majority of cases is an altered B cell.
š  Thus HL is a type of B cell lymphoma, but with a very different
biology from the other types of B cell lymphoma
š  Still deserves a separate category in the classification system
Molecular information
š  The molecular abnormalities within the different types of
R-S variants effect the expression of lineage associated antigens
●  L and H cells of lymphocyte predominant HL express B cell

antigens, and are clonal proliferations of this cell type

●  RS cells of other types may express T cell, B cell and macrophage

associated antigens, but usually fail to express antigen receptors

•  At the molecular level, show B cell gene rearrangements with out of
frame mutations or.
•  Mutations in transcription/translation systems so no antigen receptor
proteins transported to surface
The End!
Additional figures
Reed Sternberg cells
Large cells