Transcript Diseases of White Blood Cells(3)

Diseases of White Blood
Cells(3)
Lecturer :Yiran Ni, MD
Department of Pathology
China Three Gorges University
Email:[email protected]
Dec.2012
What we’ve learned
•
•
•
•
Leukopenia;
Reactive leukocytosis;
Lymphadenitis;
General aspects and classification of
neoplastic proliferation of white cell;
• Acute myeloid leukaemia
What we’ve learned
• Myelodysplastic Syndromes
• chronic myeloid leukaemia
Ph chromosome
• histiocytoses
• splenomegaly
Target of this class
• Lymphoid neoplasms
Definition
Lymphoid neoplasms encompass a diverse group of
entities. In many but not all instances, the
phenotype of the neoplastic cell closely resembles
that of a particular stage of normal lymphocyte
differentiation, a feature that is used in the
diagnosis and classification of these disorders.
Definition
• One of the confusing aspects of the lymphoid
neoplasms concerns the use of the descriptive
terms "lymphocytic leukemia and lymphoma.
•
Leukemia is used for lymphoid neoplasms
presenting with widespread involvement of the
bone marrow, usually accompanied by the
presence of large numbers of tumor cells in the
peripheral blood.
Definition
• Lymphoma, on the other hand, is used to describe
proliferations arising as discrete tissue masses.
• Traditionally, these terms were attached to what
were felt to be distinct entities. However, the line
between the "lymphocytic leukemias" and the
"lymphomas" often blurs.
•
Many types of "lymphoma" occasionally present
with a leukemic peripheral blood picture
Definition
• Many types of "lymphoma" occasionally
present with a leukemic peripheral blood
picture accompanied by extensive marrow
involvement, and evolution to "leukemia" is not
unusual during progression of incurable
"lymphomas."
Definition
• Conversely, tumors identical to "leukemias"
sometimes arise as soft tissue masses without
evidence of bone marrow disease.
• Hence, when applied to particular neoplasms, the
terms "leukemia" and "lymphoma" merely
describe the usual tissue distribution of the disease
at the time of clinical presentation.
Lymphoma
Lymphoma is a neoplasm of lymphocytes,
including T and B cells. Primary sites of
lymphoma may be lymphoid tissue or any
organ of the body.
The WHO Classification of the
Lymphoid Neoplasms
1.
2.
3.
4.
Precursor B-cell neoplasms (immature B cells)
Peripheral B-cell neoplasms (mature B cells)
Precursor T-cell neoplasms (immature T cells)
Peripheral T-cell and NK-cell neoplasms (mature
T cells and natural killer cells)
5. Hodgkin lymphoma (Reed-Sternberg cells and
variants).
The WHO Classification of the
Lymphoid Neoplasms
The WHO Classification of the
Lymphoid Neoplasms
The WHO Classification of the
Lymphoid Neoplasms
Classifications
• Within the broad group of lymphomas, Hodgkin
lymphoma is segregated from all other forms,
which constitute the non-Hodgkin lymphomas
(NHL).
• As will be seen, Hodgkin lymphoma is clinically
and histologically distinct from the NHLs.
• In addition, it is treated in a unique fashion,
making the differentiation of Hodgkin lymphoma
and NHL clinically important.
Classifications
• The other important category of lymphoid
neoplasms encompasses the plasma-cell neoplasms,
tumors composed of terminally differentiated B
cells.
• Such tumors most commonly arise in the bone
marrow, only rarely involving lymph nodes or
producing a leukemic peripheral blood picture.
• In addition, as will be seen, much of their pathophysiology is related to the secretion of whole
antibodies or immunoglobulin fragments by the
tumor cells.
Classifications
• The other important category of lymphoid
neoplasms encompasses the plasma-cell neoplasms,
tumors composed of terminally differentiated B
cells.
• Such tumors most commonly arise in the bone
marrow, only rarely involving lymph nodes or
producing a leukemic peripheral blood picture.
• In addition, as will be seen, much of their pathophysiology is related to the secretion of whole
antibodies or immunoglobulin fragments by the
tumor cells.
Classifications
• The clinical presentation of the various lymphoid
neoplasms is dictated by the anatomic distribution
of disease.
• Two-thirds of NHLs and virtually all cases of
Hodgkin lymphoma present with nontender nodal
enlargement (often greater than 2 cm) that can be
localized or generalized.
• The remaining one-third of NHLs arise at
extranodal sites (e.g., skin, stomach, or brain).
Classifications
• In contrast, the leukemic forms (lymphocytic
leukemia) most commonly come to clinical
attention owing to signs and symptoms related to
suppression of normal hematopoiesis by tumor cells
in the bone marrow.
• Lymphocytic leukemias also characteristically
infiltrate and enlarge the spleen and liver.
• Finally, plasma cell neoplasms involving the
skeleton cause local bony destruction and hence
often present with pain due to pathologic fractures.
Our focus will be on the subset of
neoplasms listed below
• Precursor B- and T-cell lymphoblastic
leukemia/lymphoma;
• Small lymphocytic lymphoma/chronic
lymphocytic leukemia;
• Follicular lymphomaMantle cell lymphoma
• Diffuse large B-cell lymphomas;
• Burkitt lymphoma;
• Multiple myeloma and related plasma cell
dyscrasias
Principles(1)
• Before we discuss the specific entities described in the
WHO classification, some important principles
relevant to the lymphoid neoplasms need to be
emphasized.
• 1. Lymphoid neoplasia can be suspected from
the clinical features, but histologic examination
of lymph nodes or other involved tissues is
required for diagnosis.
Principles(2)
• 2. Antigen receptor genes rearrange during
normal B- and T-cell differentiation through a
mechanism that ensures that each developing
lymphocyte makes a single, unique antigen
receptor.
• In most lymphoid neoplasms, antigen receptor
gene rearrangement precedes transformation;
hence, the daughter cells derived from the
malignant progenitor share the same antigen
receptor gene configuration and sequence and
synthesize identical antigen receptor proteins.
Principles(2)
• In contrast, normal immune responses are
polyclonal and thus comprise populations of
lymphocytes expressing many different antigen
receptors. As a result, analyses of antigen receptor
genes and their protein products can be used to
distinguish reactive and malignant lymphoid
proliferations. In addition, each antigen receptor
gene rearrangement produces a unique DNA
sequence that constitutes a highly specific clonal
marker that can be used to detect small numbers of
residual malignant cells after therapy.
Principles(3)
• 3. The vast majority of lymphoid neoplasms
(80% to 85%) are of B-cell origin, most of the
remainder being T-cell tumors; only rarely
are tumors of NK origin encountered.
• Most lymphoid neoplasms resemble some
recognizable stage of B- or T-cell
differentiation, a feature that is used in their
classification.
Principles(4)
• 4. As tumors of the immune system, lymphoid
neoplasms often disrupt normal architecture
and function of the immune system, leading to
immune abnormalities.
• Both a loss of vigilance (as evidenced by
susceptibility to infection) and breakdown of
tolerance (manifested by autoimmunity) can
be seen, sometimes in the same patient.
Principles(4)
• In a further, ironic twist, patients with
inherited or acquired immunodeficiency are
themselves at high risk of developing certain
lymphoid neoplasms, particularly those
caused by oncogenic viruses (e.g., EBV).
Principles(5)
• 5. Neoplastic B and T cells tend to recapitulate
the behavior of their normal counterparts.
• Like normal lymphocytes, transformed B and T
cells tend to home to particular tissue sites,
leading to characteristic patterns of involvement.
• For example, follicular lymphomas proliferate in
the B-cell areas of the lymph node, producing a
nodular or follicular pattern of growth, whereas
T-cell lymphomas typically grow in paracortical
T-cell zones.
Principles(5)
• As is true of their normal counterparts,
lymph node homing of neoplastic
lymphocytes is likely regulated by
expression of particular chemokine
receptors.
• Variable numbers of neoplastic B and T
lymphoid cells also recirculate periodically
through the lymphatics and peripheral blood
to distant sites.
Principles(5)
• Sensitive molecular techniques have shown
that most lymphoid tumors are widely
disseminated at the time of diagnosis. The
most notable exception to this rule is
Hodgkin lymphoma, which is sometimes
restricted to one group of lymph nodes.
Principles(6)
• 6. Hodgkin lymphoma spreads in an orderly
fashion, and as a result staging is of importance in
determining therapy.
• In contrast, the spread of NHL is less predictable,
and as was noted above, most patients are assumed
to have systemic disease at the time of diagnosis.
Hence, staging in particular NHLs provides useful
prognostic information but is generally not as
important in guiding therapy as is the case in
Hodgkin lymphoma.
Precursor B- and T-Cell Neoplasms
(Acute Lymphoblastic
Leukemia/Lymphoma )
General aspects
• Acute lymphoblastic leukemia/lymphoma (ALL)
encompasses a group of neoplasms composed of
immature, precursor B (pre-B) or T (pre-T)
lymphocytes referred to as lymphoblasts.
• The majority (∼85%) of ALLs are precursor B-cell
tumors that typically manifest as childhood acute
"leukemias" with extensive bone marrow and
variable peripheral blood involvement.
General aspects
• Malignant pre-B and pre-T lymphoblasts are also
morphologically indistinguishable, and
subclassification of ALL is thus dependent on
immunophenotyping.
• Because of their morphologic and clinical
similarities, the various forms of ALL will be
considered here together.
General aspects
• Malignant pre-B and pre-T lymphoblasts are also
morphologically indistinguishable, and
subclassification of ALL is thus dependent on
immunophenotyping.
• Because of their morphologic and clinical
similarities, the various forms of ALL will be
considered here together.
General aspects
• Approximately 2500 new cases of ALL are
diagnosed each year in the United States, most cases
occurring in individuals younger than 15 years of
age.
• ALL is almost twice as common in whites as in
nonwhites and is slightly more frequent in boys than
in girls.
• than in children.
General aspects
• The incidence of pre-B ALL is highest at about the
age of 4, perhaps because the number of normal
bone marrow pre-B lymphoblasts (the cell of origin)
peaks in early childhood.
• Similarly, the peak incidence of pre-T ALL is in
adolescence, the age when the thymus reaches its
maximal size.
• Both pre-B and pre-T ALL occur in adults of all
ages, but much less frequently than in children.
Morphology
• Because of different responses to chemotherapeutic
agents, it is of great practical importance to
distinguish ALL from acute myelogenous leukemia
(AML), a neoplasm of immature myeloid cells that
may cause identical signs and symptoms.
• Compared to myeloblasts, lymphoblasts have
condensed chromatin, inconspicuous nucleoli, and
scant agranular cytoplasm.
lymphoblasts have condensed chromatin, inconspicuous
nucleoli, and scant agranular cytoplasm
Morphology
• However, these morphologic distinctions are not
absolute, and definitive diagnosis relies on
detection of B and T lymphocyte-specific markers
with antibodies.
• Histochemical stains can also be helpful, as
lymphoblasts (in contrast to myeloblasts) lack
peroxidase-positive granules and often contain
cytoplasmic aggregates of periodic acid-Schiff
(PAS)-positive material.
Morphology
• As has been noted, ALLs with lymphomatous
presentations are mostly of pre-T cell type.
• Many pre-T ALLs (50% to 70%) are associated
with mediastinal masses stemming from thymic
involvement, and lymphadenopathy and
splenomegaly are also more prevalent in this
subtype.
Morphology
• Regardless of phenotype, the histologic appearance
of ALL is similar.
• Normal tissue architecture is completely effaced by
lymphoblasts having scant cytoplasm anda nuclei
somewhat larger than those of small lymphocytes.
• The nuclear chromatin is delicate and finely
stippled, and nucleoli are either absent or
inconspicuous.
Morphology
• In many cases, the nuclear membrane shows deep
subdivision, imparting a convoluted (lobulated)
appearance.
• In keeping with its aggressive growth, the tumor
shows a high rate of mitosis, and as with other
tumors having a high mitotic rate (e.g., Burkitt
lymphomas), a "starry sky" pattern can be produced
by interspersed benign tingible body macrophages
that have ingested the debris of dying neoplastic
cells.
Immunophenotype
• Immunostaining for terminal
deoxynucleotidyltransferase (TdT), a
specialized DNA polymerase that is
expressed only by pre-B and pre-T
lymphoblasts, is positive in >95% of
cases
Immunophenotype
• Precursor B ALL cells are arrested at stages
preceding surface expression of Ig.
• The leukemic blasts almost always express the
pan B-cell molecules CD19 and CD10.
• In very early pre-B cell ALL, CD19 is the only
B cell-specific marker present.
• Early pre-B ALL is distinguished from late preB ALL by the absence of cytoplasmic IgM
heavy chain (μ chain) in the former.
Immunophenotype
• Precursor T ALL cells are arrested at early
stages of T-cell development.
• In most cases, the cells are CD1+, CD2+, CD5+,
and CD7+.
• Early pre-T cell tumors are usually negative for
surface CD3, CD4, and CD8, whereas late pre-T
cell tumors are positive for these markers.
Origin of lymphoid neoplasms
Cytogenetics and Molecular Genetics
• Approximately 90% of patients with ALL
have numerical or structural changes in the
chromosomes of the leukemic cells.
• Most common is hyperploidy (>50
chromosomes), but also polyploidy, and
t(12;21), t(9;22) (Philadelphia chromosome)
and t(4;11) translocations.
Philadelphia chromosome
Clinical Features
• It should be emphasized that although ALL and
AML are immunophenotypically and
genotypically distinct, they usually present with
very similar clinical features.
• In both diseases, an accumulation of neoplastic
"blast" cells in the bone marrow suppresses
normal hematopoiesis by physical crowding,
competition for growth factors, and other poorly
understood mechanisms.
Clinical Features
• This results in anemia, neutropenia, and
thrombocytopenia, which underlie the major
clinical features of both ALL and AML.
• These common features and those more
characteristic of ALL are listed below:
• 1. Abrupt stormy onset: Patients present
within days to a few weeks of the onset of
symptoms.
Clinical Features
• 2. Symptoms related to depression of normal
marrow function: fatigue due mainly to
anemia; fever, reflecting infections due to
absence of mature leukocytes; bleeding
(petechiae, ecchymoses, epistaxis, gum
bleeding) secondary to thrombocytopenia.
Clinical Features
• 3. Bone pain and tenderness, resulting from
marrow expansion and infiltration of the
subperiosteum.
Clinical Features
• 4. Generalized lymphadenopathy,
splenomegaly, and hepatomegaly caused by
neoplastic infiltration. Each is more common in
ALL than in AML.
• In pre-T ALL presenting in the thymus,
symptoms related to compression of large
mediastinal vessels or airways may be seen.
• Testicular involvement is also common in ALL.
Clinical Features
• Central nervous system manifestations, such as
headache, vomiting, and nerve palsies resulting
from meningeal spread, are also more common
in ALL than in AML.
Prognosis
• Dramatic advances have been made in the
treatment of ALL. With aggressive chemotherapy
(often given together with prophylactic treatment
of the central nervous system), more than 90% of
children with ALL achieve complete remission,
and at least two thirds can be considered cured.
Prognosis
• Several factors have been consistently associated
with a worse prognosis:
• (1) age under 2, possibly because of the strong
association of infantile ALL with translocations
involving the MLL gene on chromosome 11;
• (2) presentation in adolescence or adulthood;
• (3) peripheral blood blast counts greater than
100,000, which may reflect a high tumor burden;
Prognosis
• (4) the presence of unfavorable cytogenetic
aberrations, such as the t(9;22) (the Philadelphia
chromosome). The t(9;22) is present in only 3% of
childhood ALL but up to 25% of adult cases,
which could partially explain the poor outcome in
adults.
Prognosis
• By contrast, favorable prognostic markers include
age of 2 to 10 years, low white count, an early
pre-B phenotype, and hyperploidy or t(12;21).
• Expression profiling shows promise as a means to
identify additional subclasses of ALL of differing
biology and clinical behavior. Allogeneic bone
marrow transplantation also offers hope for those
in poor prognostic categories.
Peripheral B-Cell Neoplasms
Chronic Lymphocytic Leukemia
(CLL)/Small Lymphocytic
Lymphoma (SLL)
Chronic Lymphocytic Leukemia
/Small Lymphocytic Lymphoma
• These two disorders are morphologically,
phenotypically, and genotypically
indistinguishable, differing only in the degree
of peripheral blood lymphocytosis.
• Most patients have sufficient lymphocytosis
to fulfill the diagnostic requirement for CLL
(absolute lymphocyte count >4000 per mm3),
which is the most common leukemia of adults
in the Western world.
Chronic Lymphocytic Leukemia
/Small Lymphocytic Lymphoma
• In contrast, SLL constitutes only 4% of NHL.
CLL/SLL is much less common in Japan and
other Asian countries.
Morphology
• Lymph node architecture is diffusely effaced by a
predominant population of small lymphocytes 6 to
12 μm in diameter containing round to slightly
irregular nuclei with condensed chromatin and scant
cytoplasm.
• These cells are mixed with variable numbers of
larger cells called "prolymphocytes."
Morphology
• In many cases, prolymphocytes gather together
focally to form loose aggregates referred to as
proliferation centers, so called because they
contain relatively large numbers of mitotically
active cells.
• When present, proliferation centers are
pathognomonic for CLL/SLL.
Morphology
• In CLL, the peripheral blood contains increased
numbers of small, round lymphocytes with scant
cytoplasm. These cells are fragile and are frequently
disrupted in the process of making smears,
producing so-called smudge cells.
Morphology
• Involvement of the bone marrow is observed in all
cases of CLL and most cases of SLL, taking the
form of interstitial infiltrates and/or nonparatrabecular aggregates of small lymphocytes.
• Tumor cells usually infiltrate the splenic white and
red pulp and the hepatic portal tracts, although the
extent of involvement varies widely.
Clinical Features
• Most patients present at ages over 50 (median age
60); a male predominance has been noted (M:F
ratio of 2:1).
• Patients with CLL/SLL are often asymptomatic.
When symptoms appear, they are nonspecific and
include easy fatigability, weight loss, and anorexia.
• Generalized lymphadenopathy and hepatosplenomegaly are present in 50% to 60% of the
cases.
Clinical Features
• The total leukocyte count is highly variable.
Patients with SLL and marrow involvement can be
leukopenic, while patients with CLL and heavy
tumor burdens can have leukocyte counts in excess
of 200,000 per mm3.
• A small monoclonal immunoglobulin "spike" is
present in the serum of some patients.
Clinical Features
• CLL/SLL disrupts normal immune function
through uncertain mechanisms.
• Hypogammaglobulinemia is common and
contributes to increased susceptibility to
infections.
Clinical Features
• CLL/SLL disrupts normal immune function through
uncertain mechanisms.
• Hypogammaglobulinemia is common and
contributes to increased susceptibility to infections.
• Conversely, some 10% to 15% of patients develop
autoantibodies directed against red blood cells or
platelets that produce autoimmune hemolytic
anemia or thrombocytopenia.
• The pathogenic IgGs are produced by non-
Prognosis
• The course and prognosis of CLL/SLL are
extremely variable and depend primarily on the
clinical stage.
• Overall, the median survival is 4 to 6 years, but
patients with minimal initial tumor burdens can
survive for 10 years or more.
• The presence of deletions of 11q and 17p
correlates with higher-stage disease and portends
a worse prognosis.
Prognosis
• An additional important factor in patient survival
is the tendency of CLL/SLL to transform to more
aggressive lymphoid neoplasms.
• Most commonly, this takes the form of a
prolymphocytic transformation (15% to 30% of
patients) or a transformation to diffuse large Bcell lymphoma, so-called Richter syndrome
(∼10% of patients).
Prognosis
• Prolymphocytic transformation is marked by
worsening of cytopenias, increasing
splenomegaly, and the appearance in the
peripheral blood of large numbers of
"prolymphocytes," cells with a large nucleus
containing a single prominent, centrally placed,
nucleolus.
• Transformation to diffuse large B-cell lymphoma
is often heralded by the appearance of a rapidly
Prognosis
• Transformation to diffuse large B-cell lymphoma is
often heralded by the appearance of a rapidly
enlarging mass within a lymph node or the spleen.
• These transformations usually stem from tumor
progression, as they retain B-cell phenotypes and
are derived from the same clone as the underlying
CLL/SLL.
• Both prolymphocytic and large-cell transformation
are usually ominous events, most patients surviving
less than 1 year.
Diffuse Large B-Cell Lymphoma
• This important diagnostic category encompasses
a heterogeneous group of tumors that together
constitute about 20% of all NHL and 60% to
70% of aggressive lymphoid neoplasms. There is
a slight male predominance, with a median age
of about 60 years. However, the age range is
wide, and diffuse large B-cell lymphoma
constitutes about 5% of childhood lymphoma.
Morphology
• The common morphologic features that
unite this group of neoplasms are a
relatively large cell size (usually four to five
times the diameter of a small lymphocyte)
and a diffuse pattern of growth.
Morphology
• In other respects, there is a fair degree of
morphologic variation.
• Most commonly, the tumor cells have a round or
oval nucleus that appears vesicular owing to
margination of chromatin at the nuclear
membrane, but large multilobated or cleaved
nuclei are prominent in some cases.
Morphology
• More anaplastic tumors may contain
multinucleated cells with large, inclusionlike
nucleoli that resemble Reed-Sternberg cells
(the tumor cell of Hodgkin disease); in some
difficult cases, immunophenotyping must be
relied on to distinguish these two entities.
Morphology
• Nucleoli may be two to three in number and
located adjacent to the nuclear membrane or
single and centrally placed.
• The cytoplasm is usually moderately
abundant and may be pale or basophilic.
Special Subtypes Associated
with Oncogenic Viruses
• Immunodeficiency-associated large B-cell lymphoma.
These occur in the setting of severe T-cell
immunodeficiency (e.g., end-stage HIV infection, severe
combined immunodeficiency, allogeneic bone marrow
transplantation, and solid organ transplantation).
• The neoplastic B cells are often latently infected with
Epstein-Barr virus, which is thought to play a critical
pathogenic role. Restoration of T-cell immunity may lead
to regression of such EBV-positive proliferations.
Clinical Course and Prognosis
• In contrast to patients with low-grade lymphomas,
who often present with generalized asymptomatic
lymphadenopathy, patients with diffuse large B-cell
lymphoma typically present with a rapidly
enlarging, often symptomatic, mass at a single nodal
or extranodal site.
• Large B-cell lymphomas can arise at virtually any
site. Waldeyer ring, the oropharyngeal lymphoid
tissues that include the tonsils and adenoids, is
involved commonly.
Clinical Course and Prognosis
• Primary or secondary involvement of the liver and
spleen can take the form of large, destructive
masses.
• Extranodal disease can arise within the
gastrointestinal tract, skin, bone, brain, and other
sites.
• Bone marrow involvement usually occurs late in the
disease; rarely a leukemic picture may emerge.
Clinical Course and Prognosis
• As a group, diffuse large B-cell lymphomas are
aggressive tumors that are rapidly fatal if untreated.
• However, with intensive combination
chemotherapy, complete remission can be achieved
in 60% to 80% of patients, and approximately 50%
remain free from disease for several years and may
be considered cured.
• Patients with limited disease fare better than those
with widespread disease or a large, bulky tumor
mass.
Burkitt Lymphoma
• Within this category fall (1) African (endemic)
Burkitt lymphoma, (2) sporadic (nonendemic)
Burkitt lymphoma, and (3) a subset of
aggressive lymphomas occurring in individuals
infected with HIV.
• Burkitt lymphomas occurring in each of these
settings are histologically identical, but some
clinical, genotypic, and virologic differences
exist.
Morphology
• Involved tissues are effaced by a diffuse infiltrate of
intermediate-sized lymphoid cells, 10 to 25 μm in
diameter, containing round or oval nuclei with
coarse chromatin, several nucleoli, and a moderate
amount of faintly basophilic or amphophilic
cytoplasm.
• The nuclear size approximates that of benign
macrophages within the tumor.
Morphology
• A high mitotic index is typical, as is apoptotic
tumor cell death, accounting for the presence of
numerous tissue macrophages with ingested nuclear
debris.
• These benign macrophages are diffusely distributed
among the tumor cells and have abundant clear
cytoplasm, creating a characteristic "starry sky"
pattern.
Clinical Features
• Both the endemic and the sporadic cases are found
largely in children or young adults, accounting for
approximately 30% of childhood NHLs in the
United States.
• Most tumors manifest at extranodal sites.
• Endemic Burkitt lymphoma often presents as a
mass involving the mandible and shows an unusual
predilection for involvement of abdominal viscera,
particularly the kidneys, ovaries, and adrenal glands.
Clinical Features
• In contrast, sporadic Burkitt lymphoma most often
presents as an abdominal mass involving the
ileocecum and peritoneum.
• Involvement of the bone marrow and peripheral
blood is uncommon, especially in endemic cases.
• Burkitt lymphoma is very aggressive but responds
well to short-term, high-dose chemotherapy. Most
children and young adults can be cured, but the
outcome is more guarded in older adults.
Hodgkin Lymphoma
• The term "Hodgkin lymphoma" (HL), previously
known as Hodgkin disease, encompasses a group of
lymphoid neoplasms that differ from NHL in several
respects.
• While 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 the
anatomically contiguous nodes.
General aspects
• It is characterized morphologically by the presence
of distinctive neoplastic giant cells called ReedSternberg cells that induce the accumulation of
reactive lymphocytes, histiocytes (macrophages),
and granulocytes.
• The neoplastic Reed-Sternberg cells typically make
up a minor fraction (1% to 5%) of the total tumor
cell mass, making HL more difficult to study than
typical NHLs.
General aspects
• However, it is now clear that in the vast majority of
cases, the neoplastic Reed-Sternberg cells are
derived from germinal center or post-germinal
center B cells, indicating that most HLs are unusual
tumors of B-cell origin
General aspects
• HL accounts for 0.7% of all new cancers in the
United States, with approximately 7400 new cases
reported per year.
• It is one of the most common forms of malignancy
in young adults, with an average age at diagnosis
of 32 years.
• Much progress has been made in the treatment of
this disease in the last several decades, and it is
now curable in most cases.
Classfication
• The WHO classification recognizes five
subtypes of HL:
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Lymphocyte predominance
Classfication
• In the first four subtypes-nodular sclerosis,
mixed cellularity, lymphocyte-rich, and
lymphocyte depletion-the Reed-Sternberg
cells have a similar immunophenotype; as a
result, these subtypes are often lumped
together as classical forms of HL. In
lymphocyte predominance HL, the ReedSternberg cells have a characteristic B-cell
immunophenotype distinct from that of the
classical HL subtypes.
Morphology of R-S cell
• Identification of Reed-Sternberg cells and their
variants is essential for the histologic
diagnosis.
• Diagnostic Reed-Sternberg cells are large
(15 to 45 μm in diameter) and have either
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)
ReedSternberg
cells
Diagnostic Reed-Sternberg cell, with two nuclear lobes,
large inclusion-like nucleoli, and abundant cytoplasm,
surrounded by lymphocytes, macrophages, and an
eosinophil
Morphology of R-S cell
• The cytoplasm is abundant. Several variants of
Reed-Sternberg cells are also recognized.
• Mononuclear variants contain only a single
round or oblong nucleus with a large
inclusionlike nucleolus.
Morphology of R-S cell
• Lacunar cells, seen predominantly in the
nodular sclerosis subtype, have more delicate
folded or multilobate nuclei surrounded by
abundant pale cytoplasm that is often disrupted
during the cutting of sections, leaving the
nucleus sitting in an empty hole (the lacune).
Morphology of R-S cell
• In classical forms of HL, Reed-Sternberg cells
undergo a peculiar form of cell death in which
the cells shrink and become pyknotic, a process
described as "mummification."
• Lymphohistocytic variants (L&H cells) with
polypoid nuclei resembling popcorn kernels,
inconspicuous nucleoli, and moderately
abundant cytoplasm are specific to the
lymphocyte predominance.
Morphology of R-S cell
• The morphologic diagnosis of HL is complicated
by the occasional presence of cells that are similar
or identical in appearance to Reed-Sternberg cells
in other conditions, such as infectious
mononucleosis, solid tissue cancers, and NHL.
• Thus, although Reed-Sternberg cells are
requisite for the diagnosis, they must be present
in an appropriate background of non-neoplastic
inflammatory cells (lymphocytes, plasma cells,
eosinophils).
Clinical features
• The spread of HL is remarkably predictable:
nodal disease first, then splenic disease, hepatic
disease, and finally marrow involvement and
extranodal disease.
• Because of this uniform pattern of spread,
patients with limited disease may be cured with
local radiotherapy.
Clinical features
• For this reason, the staging of HL is not only
predictive of prognosis but also guides the
choice of therapy.
• Staging involves careful physical examination
and several investigative procedures, including
radiologic imaging of the abdomen, pelvis, and
chest and biopsy of the bone marrow.
Clinical features
• Systemic treatment is preferred whenever the
staging is equivocal.
• The presence of constitutional symptoms (fever,
night sweats, and weight loss) is characteristic of
HL but can also be seen in other lymphoid
neoplasms.
Clinical Staging of Hodgkin
and Non-Hodgkin Lymphomas
Morphology of each subtypes
1.
2.
3.
4.
5.
Nodular sclerosis
Mixed cellularity
Lymphocyte-rich
Lymphocyte depletion
Lymphocyte predominance
page 687
Nodular Sclerosis Type
• This is the most common form of HL,
constituting 65% to 70% of cases. It is
characterized morphologically by the presence of
(1) a particular variant of the Reed-Sternberg
cell, the lacunar cell,
• and (2) collagen bands that divide the lymphoid
tissue into circumscribed nodules
Nodular sclerosis HD
Nodular sclerosis HD
Nodular Sclerosis Type
• The fibrosis can be scant or abundant, and the
neoplastic cells are found in a polymorphous
background of small T lymphocytes, eosinophils,
plasma cells, and macrophages.
• Diagnostic Reed-Sternberg cells are less
frequent than in the mixed cellularity and
lymphocyte depletion types.
Nodular Sclerosis Type
• The tumor cells have a characteristic
immunophenotype: positive for CD15 and CD30
and negative for CD45 and B-cell and T-cell
markers.
• As in other forms of HL, involvement of the
spleen, liver, bone marrow, and other organs and
tissues can appear in due course and take the
form of irregular tumor nodules resembling those
present in the nodes.
Nodular Sclerosis Type
• The nodular sclerosis type occurs with equal
frequency in males and females. It has a
propensity to involve the lower cervical,
supraclavicular, and mediastinal lymph nodes of
adolescents or young adults and is only rarely
associated with EBV.
• The prognosis is excellent.
Mixed Cellularity Type
• This form of HL constitutes about 20% to 25%
of cases.
• Lymph node involvement by the mixed
cellularity type takes the form of diffuse
effacement by a heterogeneous cellular
infiltrate, which includes small lymphocytes,
eosinophils, plasma cells, and benign
macrophages admixed with the neoplastic cells
Mixed Cellularity Type
• Diagnostic Reed-Sternberg cells and
mononuclear variants are usually plentiful.
• The immunophenotype is identical to that
observed in the nodular sclerosis type.
• Small lymphocytes in the background are
predominantly T cells, and early nodal disease
preferentially involves paracortical T-cell
zones.
Mixed Cellularity Type
• Mixed cellularity HL is more common in males
and strongly associated with EBV, as the
Reed-Sternberg cells contain EBV genomes
in at least 70% of cases.
• Compared to the lymphocyte predominance
and nodular sclerosis subtypes, it is more
likely to be associated with older age,
systemic symptoms such as night sweats and
weight loss, and advanced tumor stage.
• Nonetheless, the prognosis is very good.
Lymphocyte-Rich Type
• This is an uncommon form of classical HL
in which reactive lymphocytes make up the
vast majority of the cellular infiltrate.
• In most cases, lymph nodes are diffusely
effaced, but vague nodularity due to the
presence of residual B-cell follicles can
sometimes be seen.
Lymphocyte-Rich Type
• This entity is distinguished from the
lymphocyte predominance type by the
presence of frequent mononuclear and
diagnostic Reed-Sternberg cells with the
characteristic CD45-, CD20-, CD15+,
CD30+ immunophenotype.
• It is associated with EBV in about 40% of
cases and also has a very good to excellent
prognosis.
Lymphocyte Depletion Type
• This least common form of HL,
amounting to less than 5% of cases,
is characterized by a paucity of
lymphocytes and a relative
abundance of Reed-Sternberg cells or
their pleomorphic variants.
Lymphocyte Depletion Type
• The phenotype of the tumor cells is
identical to that observed in the nodular
sclerosis and mixed cellularity types.
Phenotyping is critical for the diagnosis,
since most tumors suspected of being
lymphocyte depletion HL actually prove to
be large-cell non-Hodgkin lymphomas.
Lymphocyte Depletion Type
• Lymphocyte depletion HL is observed
predominantly in older patients, HIVpositive individuals, or patients in
nonindustrialized countries and is often
EBV-associated.
• Advanced stage and systemic symptoms are
frequent, and the overall outcome is
somewhat less favorable than with other
subtypes.
Lymphocyte Predominance Type
• This uncommon variant, accounting for
approximately 5% of all cases, is
characterized by nodal effacement by a
nodular infiltrate of small lymphocytes
admixed with variable numbers of benign
histiocytes.
• Typical Reed-Sternberg cells are extremely
difficult to find.
Lymphocyte Predominance Type
• Typical Reed-Sternberg cells are extremely
difficult to find.
• More common are so-called lymphohistiocytic (L&H) variants that have a
delicate, multilobed nucleus resembling a
popcorn kernel ("popcorn cell").
• Other cells such as eosinophils, neutrophils,
and plasma cells are scanty or absent, and
there is little evidence of necrosis or fibrosis.
Lymphocyte Predominance Type
• Multiple features of L&H Reed-Sternberg
variants point to an origin from germinal center
B cells.
• In contrast to other forms of HL, L&H variants
express B-cell markers (e.g., CD20) and the
germinal center-specific transcription factor
BCL6.
Lymphocyte Predominance Type
• The nodular pattern of nodal effacement is due
to the presence of expanded B-cell follicles,
which are populated not only with L&H
variants, but also with numerous reactive B
cells.
• Finally, in 3% to 5% of cases the lymphocyte
predominance type transforms to diffuse large
B-cell lymphoma. EBV is not associated with
this form of HL.
Lymphocyte Predominance Type
• A majority of patients are males, usually
younger than 35 years of age, who typically
present with cervical or axillary
lymphadenopathy.
• Mediastinal and bone marrow involvement is
rare.
• In some series, this form of HL is more likely to
recur than the classical subtypes, but the
prognosis is excellent.
Etiology and Pathogenesis of HL
• The origin of the neoplastic Reed-Sternberg
cells of classical HL has historically been
extremely controversial, in large part
because these cells fail to express many
markers found on normal lymphocytes.
Etiology and Pathogenesis of HL
• This issue was settled only recently through elegant
studies relying on the microdissection and analysis
of single isolated Reed-Sternberg cells and variants.
• These studies have shown that within most
individual cases, all Reed-Sternberg cells harbor
identical rearranged immunoglobulin genes that
show evidence of somatic hypermutation,
establishing the cell of origin as a germinal center
or post-germinal center B cell.
Etiology and Pathogenesis of HL
• In a small proportion of cases (1% to 2%), ReedSternberg cells do not have immunoglobulin genes
in the germ line configuration and instead have Tcell receptor rearrangements, suggesting that HL
arises in rare instances from transformed T cells.
• Although of B-cell origin in the large majority of
cases, Reed-Sternberg cells fail to express many
genes that are normally turned on in germinal
center or post-germinal center B cells, including the
immunoglobulin genes themselves.
Etiology and Pathogenesis of HL
• One important clue to study the factors that
contribute to Reed-Sternberg cells
transformation is the frequent presence of
EBV episomes in the Reed-Sternberg cells of
many cases of mixed cellularity HL.
• Importantly, the configuration of the EBV
DNA is the same in all tumor cells within a
given case, indicating that infection occurs
before cellular transformation.
Etiology and Pathogenesis of HL
• The characteristic accumulation of
reactive cells occurs in response to
cytokines secreted by the ReedSternberg cells, such as IL-5, IL-6, IL-13,
tumor necrosis factor (TNF), and GMCSF.
• Once attracted by cytokines, the reactive
infiltrate in turn supports the growth and
survival of tumor cells.
Clinical Course
• HL, like NHL, usually presents with a
painless enlargement of lymph nodes.
Although the distinction between HL and
NHL can be made only by examination of
a lymph node biopsy, several clinical
features favor the diagnosis of HL .
Distinction between HL and NHL
Clinical Course
• Younger patients with the more favorable
histologic types tend to present with stage I or II
disease and are usually free from systemic
manifestations.
• Patients with disseminated disease (stages III and
IV) or the mixed cellularity or lymphocyte
depletion subtype are more likely to have
systemic symptoms such as night sweats and
weight loss.
Clinical Course
• One rare paraneoplastic symptom specific to HL
is pain in involved lymph nodes on consumption
of alcohol.
• Cutaneous anergy resulting from depressed cellmediated immunity is seen in most cases. The
basis for immune dysfunction is not understood,
but it tends to persist even in successfully treated
patients, possibly indicating that HL arises in the
background of an underlying immune
abnormality.
Clinical Course
• With current treatment protocols, tumor
stage rather than histologic type is the
most important prognostic variable.
• The cure rate of patients with stages I and
IIA is close to 90%.
• Even with advanced disease (stages IVA
and IVB), 60% to 70% 5-year disease-free
survival is obtained.
Clinical Course
• Progress in the treatment of HL has created a
new set of problems. Long-term survivors of
chemotherapy and radiotherapy have an
increased risk of developing second cancers.
• Myelodysplastic syndromes, acute
myelogenous leukemia (AML), and lung
cancer lead the list of second malignancies,
but also included are NHL, breast cancer,
gastric cancer, sarcoma, and malignant
melanoma.
Clinical Course
• The risk of breast cancer is particularly high in
females treated with radiation to the chest
during adolescence, and the risk of other solid
tumors also seems to correlate with
radiotherapy, whereas alkylating
chemotherapeutic drugs appear to be
responsible for the increased risk of acute
myelogenous leukemia and myelodysplasia.
Clinical Course
• Non-neoplastic complications of radiotherapy
include pulmonary fibrosis and accelerated
atherosclerosis.
• New combinations of chemotherapeutic drugs
and more judicious use of radiotherapy may
avoid these complications and yet be equally
curative.
Key points in this class
Hodgkin’s lymphoma
histological subtype of HL
R-S cell, mirror image cell, Hodgkin's cell
Non Hodgkin’s lymphoma
principle of histological classification of NHL
Starry-sky, Burrkit’s lymphoma
Distinction between HL and NHL
Clinical Staging of Hodgkin and Non-Hodgkin
Lymphomas