MATURE LYMPHOID

NEOPLASMS
Review: Morphologic and Immunophenotypic
Features of Normal Lymph Nodes

• Lymphoid organs serve as sites

of antigen recognition, antigen
processing, and lymphopoiesis.
• Histologic components of a
lymph node include cortex,
paracortex, medullary cords,
and sinuses.
• Respiratory and Digestive
Tracts: Mucosa- Associated
Lymphoid Tissue (MALT)
Review: Cortex

• Immediately below the capsule

• Most superficial portion of the lymph node with primary and secondary follicles.
• Primary Follicles
– microscopic aggregates of small naive B lymphocytes
– Express CD19 and CD20 and are frequently CD51
• Secondary Follicles
– best visualized by immunohistochemical stains such as CD21
Review:
Cortex
Review:
Cortex
Review: Paracortex

• Occupies the area separating the follicles and extends toward

medullary cords.
• Generates immunocompetent t cells and is occupied predominantly
by t cells, interdigitating dendritic cells (antigen-presenting cells),
and high-endothelial venules.
• Specialized vessels serving as a gate of entry for lymphocytes from
peripheral blood into lymph nodes
• T cells: CD3, CD5, CD2, and CD7
• Both CD4+ and CD8+ T lymphocytes are seen in paracortex
 Review: Medulla and Sinuses

MEDULLA
• represents the innermost portion of the
lymph node surrounding the hilum
• composed of medullary cords with
plasma cells and medullary sinuses.
SINUSES
• filtration of lymphatic fluid through
lymph nodes is accomplished via
afferent lymphatics communicating with
a subcapsular sinus
• subcapsular sinus drains into cortical
sinuses, which run through the cortex
and empty to medullary sinuses.
Lymphoma
• Recapitulate specific stages of normal lymphoid differentiation
• Based on a combination of biologic features such as morphology,
immunophenotype, molecular genetic characteristics and clinical
information.
• Most cases develop in previously healthy individuals
• Strongest risk factor: Altered immune function as seen in
immunocompromised patients or individuals with autoimmune
diseases
• Viral and bacterial infections: higher risk
 • Lymphadenopathy, lymph node enlargement,
can occur in benign/reactive and malignant
conditions.
• Can affect any compartment of a lymph node
and present as expansion of normal nodal
structures.
Reactive • Reactive hyperplasias are classified into several
Lymphadenopathies patterns:
1. Follicular
2. Paracortical
3. Sinusoidal
4. Mixed
 FOLLICULAR PATTERN
• Most common form of reactive
lymphadenopathies.
• Frequently seen in lymph nodes
and tonsils of children and
adolescents as a reaction to
infections
• In adults, it occurs in association
with infections, autoimmune
disorders (rheumatoid arthritis,
systemic lupus erythematosus),
syphilis, and early human
immunodeficiency virus (HIV)
infection.
 PARACORTICAL PATTERN

• Associated with viral infections

(e.g., infectious
mononucleosis) and drug
reactions
• Also seen in patients with
chronic skin diseases
(dermatopathic
lymphadenopathy)
 • Expanded subcapsular,
cortical, and medullary
sinuses
• May be completely filled
with histiocytes showing
abundant cytoplasm, a
SINUSOIDAL small oval nucleus with
PATTERN inconspicuous
nucleolus, and delicate
chromatin
• Numerous malignant
lesions show
predilection for sinuses
LYMPHOMAS
• Most cases develop in previously healthy individuals
• Strongest risk factor: altered immune function as seen in
immunocompromised patients or individuals with autoimmune
diseases
• Viral and bacterial infections: higher risk
• Exposure to chemicals and herbicides: predispose to lymphoid
neoplasms
• Numerous types of lymphoma are distinguished based on
morphology, immunophenotype, molecular genetics, and clinical and
laboratory characteristics.
MATURE B CELL
LYMPHOMAS
 • Derived from various stages of
B cell differentiation.
• All B cell lymphomas produce
MATURE B monoclonal light chain
CELL immunoglobulins, clonal
immunoglobulin gene
LYMPHOMAS rearrangements, or both
• Follicular lymphoma and
diffuse large B cell lymphoma
(DLBCL): most common
subtypes of B cell lymphoma
 Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma

• Characterized by accumulation of small lymphoid cells in peripheral blood,

bone marrow, and lymphoid organs
• Unknown exact cell origin
• The diagnosis of CLL/SLL is based on the predominant site of involvement.
• CLL presents mostly in peripheral blood and bone marrow.
• SLL primarily involves lymph nodes and other lymphoid organs.
Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
• CLL: Small lymphoid cells with a
characteristically coarse chromatin
(“soccer-ball pattern”), absent or
inconspicuous nucleoli, and scant
cytoplasm.
• FAB Morphologic Classification of
CLL consisting of two major types:
1. Typical CLL (.90% small mature
lymphocytes and ,10%
prolymphocytes)
2. Atypical CLL category
Chronic Lymphocytic Leukemia

• SMUDGE CELLS
– Represents disintegrated
lymphoid cells
– Helpful in dx of CLL
because these cells are not
often seen in other
subtypes
 • Diagnosed based on a sustained increase in the
monoclonal B lymphocytes with CLL
immunophenotype which is equal or greater than
5000/uL
• Expression of CD19, CD20, and CD23, with
CLL Diagnosis and aberrant expression of CD5.
Immunophenotype • Expression of kappa or lambda light chains
• CD23 and LEF1 (lymphoid-enhancer-binding
factor 1) expression and the absence of FMC7,
cyclin D1, and SOX11 distinguish CLL/SLL from
mantle cell lymphoma.
 CLL Clinical Features and
Prognosis
• Generally affects older adults
• Most patients are asymptomatic at diagnosis.
• First indication: incidental finding of lymphocytosis on a
routine CBC in a blood count ordered for a different reason.
• 55% of CLL patients: mutated IGVH, indolent disease, and a
median survival time of 24 years
• Patients with unmutated IGVH: aggressive disease and a
median survival of approximately 8 years
• FISH: presence of chromosomal abnormalities, del13q14.3,
del11q22-23, trisomy 12, and del17p13.
• 5% of patients with CLL/SLL develop a high-grade diffuse
large B cell lymphoma (called Richter syndrome) with a
survival of less than 1 year.
 Prolymphocytic
Leukemia
• Rare mature lymphoid leukemia
that can be derived from B or T
cells
• Diagnosis requires that more than
55% of circulating lymphoid cells
have the morphology of a
prolymphocyte
• Pathognomonic cell of B cell PLL
is a prolymphocyte of medium
size with round nucleus,
moderately abundant cytoplasm,
and distinct “punched-out”
nucleolus
Prolymphocytic Leukemia

B Cell PLL
– PB: white blood cell count frequently in excess of 100 X 10^9/L
– BM: interstitial and/or nodular proliferation of prolymphocytes
– B Cell PLL: positive for pan–B cell markers CD20, CD19, CD22, and FMC7.
T cell PLL
– Neoplastic cells seen in peripheral blood films are small to medium size, with round or
irregular nuclei, the latter resembling Sézary cells.
– T prolymphocytes are positive for T cell markers such as CD3, CD2, and CD5.
– In contrast to many T cell lymphomas, T cell PLL is positive for CD7 antigen
– Most commonly CD4 antigen is expressed
 • Disease of the elderly (mean age: 70 years old)
• Overall prognosis is poor (median survival: 3 years for
Prolymphocytic B cell
Leukemia • T cell PLL : aggressive with median survival of 1 year
Clinical when conventional chemotherapies are used.
– Addition of Alemtazumab (monoclonal Ab therapy
Features and against CD52)
Prognosis • Improved tx response and survival of patients
with T cell PLL
 Hairy Cell Leukemia

• Small B lymphocytes with abundant cytoplasm and fine (“hairy”)

cytoplasmic projections
• Cells are found predominantly in bone marrow and the red pulp
of the spleen.
• BM: interstitial and are composed of small to medium-sized
lymphoid cells with abundant cytoplasm
• Neoplastic cells display an oval or indented nucleus, abundant
cytoplasm, and fine, hairlike cytoplasmic projections
• strong positivity for
• B cell markers (CD19, CD20, CD22) coupled with bright
expression of CD11c, CD25, CD103, tartrate-resistant acid
phosphatase, DBA-44, CD123, and annexin A1.
• CD123 and annexin A1 are the most specific markers for
classic hairy cell leukemia
• postulated cell of origin is the peripheral B cell of post–germinal center
stage (memory B cell).
 Rare lymphoproliferative disorder
occurring in middle-aged individuals
Hairy Cell
Leukemia Median age: 55 years old
Clinical
Features Splenomegaly and pancytopenia
and
Prognosis Conventional Lymphoma therapy is
not effective
 Mantle Cell Lymphoma

• Lymphoproliferative disorder characterized by

medium-sized lymphoid cells with irregular nuclear
outlines derived from the follicular mantle zone.
• Main site of presentation: lymph nodes
• LN show a replacement of normal nodal architecture
with a diffuse proliferation of monotonous, medium-
sized lymphoid cells with irregular nuclear outlines
• Lymph nodes demonstrate a vaguely nodular pattern
or partial preservation of nodal architecture with a
prominent thickening of mantle zones
 Mantle Cell Lymphoma Immunophenotype

• Pan–b cell markers (CD19, CD20) and high-density clonal

surface light chains.
• Coexpression of cd5 antigen
• Absent CD23 antigen
• In contrast to CLL/SLL, the expression of CD20 and light
chains is strong, and there is immunoreactivity for cyclin D1
and SOX11.
• Cyclin d1 (BCL1): expressed through its translocation to the
immunoglobulin heavy chain gene, t(11;14)
 Mantle Cell Lymphoma Clinical
Features and Prognosis

• Aggressive lymphoproliferative disorder

• Median survival time of 3 to 5 years.
• Most patients present with dissiminated diseases
• Incurable with currently available chemotherapy
• Stem cell transplantation: successful in some patients
Follicular Lymphoma

• originates from germinal center B cells and in

most cases recapitulates follicular architecture.
• Numerous closely spaced follicles replace the
normal nodal architecture
• Pan–B cell markers (CD19, CD20) are present
coexpression of CD10, BCL6, and clonal surface
immunoglobulin.
• Neoplastic cells express BCL2 protein
– Responsible for the decreased sensitivity of lymphoma
cells to apoptosis and allows the accumulation of
neoplastic lymphocytes
– Due to the t(14;18)(q32;q21)
– Seen in 95% of cases
 Follicular Lymphoma
Clinical Features and Prognosis

• Median age: 59 years old

• Most patients present with disseminated diseases
• BM involvement in 50% of cases
• Course is indolent in grade 1-2, while more aggressive in grade 3
cases
• Treated with Doxorubicin (Adriamycin) based regimens
 Extranodal Marginal Zone Lymphoma of
Mucosa- Associated Lymphoid Tissue

Three subtypes of Marginal Zone Lymphoma

1. Nodal
2. Extranodal (MALT lymphoma)
–The neoplastic proliferation is usually heterogeneous,
encompassing small and medium-sized lymphocytes, plasma
cells, and scattered large lymphoid cells.
–MALT lymphoma is frequently associated with autoimmune
conditions (e.g., Sjögren syndrome, Hashimoto thyroiditis) or
infections (Helicobacter pylori gastritis or hepatitis C)
3. Splenic
 Extranodal • Neoplastic population is composed of a mixture of
Marginal Zone medium- sized lymphocytes, plasma cells, and
occasional large lymphoid cells.
Lymphoma of • Predominance of medium-sized marginal zone cells
Mucosa- with irregular nuclei
Associated • Characteristic feature: presence of so-called
Lymphoid lymphoepithelial lesions, representing the invasion of
Tissue the neoplastic lymphocytes into the glandular
epithelium
• Neoplastic cells of marginal zone lymphoma express
CD20, CD19, and monoclonal immunoglobulin chains.
CD5 and CD10 are absent.
• Cd43 antigen is coexpressed in 30% of cases
Extranodal
Marginal Zone
Lymphoma of
Mucosa-
Associated
Lymphoid
Tissue
Extranodal Marginal Zone Lymphoma of
Mucosa- Associated Lymphoid Tissue

• Approximately 30% of cases show a translocation involving

apoptosis-inhibitor gene API2 and the MLT gene, the
t(11;18)(q21;q21)
• Gastrointestinal tract is the most common site for extranodal
marginal zone lymphoma
• Lung, thyroid, ocular adnexa, and breast are other primary sites of
involvement
• In cases of gastric MALT lymphoma positive for H. Pylori, the
antibiotic treatment of the infection may induce a remission of the
associated lymphoma.
 • Characterized by a monoclonal proliferation of terminally
differentiated B cells
• Present as a localized or disseminated process most commonly
involving bone marrow and bone.
• Plasma cell myeloma
– Multifocal accumulation of malignant plasma cells in bone marrow
Plasma Cell presenting as lytic bone lesions
• Monoclonal immunoglobulin produced by neoplastic plasma cells is
Neoplasms detected in serum, urine, or both (monoclonal gammopathy)
• Monoclonal gammopathy of undetermined significance (MGUS)
– Encompass the entire patient population with clonal serum
immunoglobulin and only mild marrow plasmacytosis
• Plasmacytoma
– Localized form of plasma cell neoplasm, may present as a solitary
bone lesion or involve an extraosseous or extramedullary site,
most commonly the nasopharynx, oropharynx, or sinuses
 • Plasma cell myeloma is characterized by marked bone
marrow plasmacytosis
• Large aggregates and sheets of plasma cells, frequently
with cytologic atypia, are present and often constitute
more than 30% of marrow cellularity
• Plasma cell leukemia
– Reserved for cases with more than 20% circulating plasma cells
Plasma Cell or plasma cell counts exceeding 2 X 10^9/L.
• Pan–b cell markers CD19 and CD20 and surface
Neoplasms immunoglobulin chains are usually absent
• Plasma cells are positive for CD138 (syndecan-1), high-
density CD38 antigen, and monoclonal cytoplasmic
immunoglobulins
• Monoclona proteins (IgG or IgA or isolated clonal light
chains
– Are secreted by the neoplastic plasma cells and are seen in
serum and urine as monoclonal spikes
Plasma Cell Neoplasms Clinical Features and
Prognosis

• Plasma cell myeloma is a disease of older individuals (median age, 70 years).

• Bone pain and pathologic fractures
• Renal insufficiency
• Cytopenias
• Depressed normal immunoglobulin levels
• Amyloidosis
• Rapidly progressive course, and the median survival is 3 years.
• Patients with more than 50% bone marrow plasma cells, associated renal
failure, and severe anemia have a shorter survival than patients with fewer
than 20% plasma cells and preserved renal function
• Patients with bone and extraosseous plasmacytomas are younger and
respond favorably to local radiation therapy.
Plasma Cell
Neoplasms
 Diffuse Large B cell Lymphoma

• Significantly larger than normal lymphocytes

• Diffuse histologic growth pattern
• Differ significantly in cytologic appearance and immunophenotype
• One of the most common lymphomas, accounting for 30% to 40% of all non-
Hodgkin lymphoma cases
• DLBCL not otherwise specified diffuse proliferation of large lymphoid cells replacing
normal nodal architecture. Cells are at least twice the size of normal small
lymphocytes and show single or multiple nucleoli and ample cytoplasm
• Pan–b cell antigens are expressed
• CD5, CD10, BCL6, CD30, and CD138 can be present
 Diffuse
Large B
cell
Lymphoma
Diffuse Large B cell Lymphoma Clinical
Features and Prognosis

• Can be seen in children and young adults

• Presents as a localized disease involving a group of lymph nodes.
• Can also be seen in extra nodal sites, including the gastrointestinal
tract, central nervous system, bone, and serous effusions.
• Aggressive neoplasm with a proliferation rate frequently exceeding
40%
• Prognosis depends on a variety of clinical parameters, such as
patient age, the extent of disease, and the site of involvement
 • characterized by
medium- sized, highly
proliferating lymphoid
cells with basophilic
vacuolated cytoplasm
3 variants:
– Endemic
Burkitt – Sporadic
– Immunodeficiency
Lymphoma associated
• Lymphoid proliferation
is diffuse and at low
magnification shows a
prominent “starry sky”
pattern imparted by
numerous tangible-
body macrophages
 Burkitt Lymphoma Immunophenotype

• Reflects germinal center origin

• CD19, CD20, CD10, and BCL6 antigens are present
• BCL2 is absent
• Hallmark of Burkitt lymphoma is a High Proliferation Rate.
– Linked to the constitutive expression of MYC gene (cell cycle
gatekeeping gene) secondary to its translocation under the promoter of
immunoglobulin heavy or light chain genes [t(8;14), t(2;8), or t(8;22)].
– This translocation is pathognomonic for burkitt lymphoma, and its
demonstration is required for a definitive diagnosis.
Burkitt Lymphoma Clinical Features and Prognosis

• Medical emergency: due to its high proliferation rate

• Endemic form presents in young children (4 to 7 years of age), most
commonly as a jawbone mass
• Sporadic variant, seen in the United States and Europe, occurs in children
and young adults most commonly as an abdominal mass
• Immunodeficiency-associated Burkitt Lymphoma presents most often as
nodal disease.
• Occurs predominantly in HIV-positive patients
• Involves the central nervous system, bone marrow, and peripheral blood
(Burkitt leukemia).
• Epstein-Barr virus (EBV) is present in a proportion of patients
 Mature T Cell and
Natural Killer Cell Lymphomas
 Mature T Cell and Natural Killer Cell
Lymphomas

• Much less common than B cell neoplasms

• Account for approximately 10% of all lymphomas.
• Significant morphologic and cytologic variability
• Immunophenotypic features are not as specific as those seen
in B cell malignancies.
• Integration of morphologic, immunophenotypic, cytogenetic,
molecular, and clinical information
 Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides
• most common cutaneous lymphoma
• composed of small to medium-sized lymphoid
cells with irregular nuclear outlines (cerebriform
nuclei)
• predilection for the epidermis (epidermotropism)
and dermis and may spread to regional lymph
nodes
Sézary syndrome
• presents as a disseminated disease with
widespread skin involvement (erythroderma),
lymphadenopathy, and circulating lymphoma
cells (Sézary cells with characteristic
cerebriform nuclei)
 Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides
• Pautrier microabscesses
• aggregates of neoplastic lymphocytes in epidermis
• expression of pan–T cell markers CD3, CD5, and CD2 is seen along with CD4
antigen
• absence of CD7 antigen.
Sézary syndrome
• disseminated disease with leukemic presentation and skin and lymph node
involvement
• both morphologic and immunophenotypic evaluations are performed in order to
demonstrate at least 1000 Sézary cells/mL, a CD4-to-CD8 ratio of more than 10
and an aberrant immunophenotype.
 Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides
• Incidence increases with age
• Average age: 55-60 years old
• Survival of patients with early-stage disease is excellent,
• 10-year disease-specific survival was reported as 97% to 98%

Sézary syndrome
• is an aggressive lymphoma with a low (10% to 20%) 5-year survival rate
 Peripheral T Cell Lymphoma, Unspecified

• Comprises a morphologically heterogeneous group of lymphomas with

mature T cell phenotype.
• Cytologic features are variable with medium-sized to large cells with atypical
and occasionally pleomorphic nuclei
• Derived from CD4+ T cells and retain this immunophenotype.
• Variable loss of pan–T cell antigens, including CD7, is seen
• Aggressive disease occurring predominantly in older adults (average age of
60 years)
• Generalized lymphadenopathy and a variety of constitutional symptoms,
such as fever, night sweats, weight loss, and pancytopenia
• Approx. 40%: 3-year survival rate
Anaplastic Large Cell Lymphoma

• Characterized by large atypical cells with pleomorphic nuclei and

abundant cytoplasm.
• One of the most common lymphomas in the pediatric population
(10% to 15% of childhood lymphomas)
• Significant fibrosis is present: may resemble Classical Hodgkin
Lymphoma
• proportion of cells are large with abundant cytoplasm and
pleomorphic, eccentric, kidney-shaped nuclei, so-called hallmark
cells
 Anaplastic Large Cell Lymphoma

• CD30 antigen and ALK1 protein- defining features

• Pan–T cell markers (CD3, CD7, CD5) are often absent
• CD4 and CD2- most commonly expressed T cell lineage–associated
antigens
• Most important prognostic feature is the expression of ALK-1 protein.
• ALK-1+ disease has a favorable prognosis, whereas ALK-1– disease shows
survival rates more comparable to those of peripheral T cell lymphoma,
unspecified
 Hodgkin Lymphoma

2 BROAD CATEGORIES:
1. Nodular lymphocyte-predominant Hodgkin lymphoma
– B cell neoplasm composed of relatively rare neoplastic
cells (lymphocytic/histiocytic or “popcorn” cells)
scattered within nodules of reactive lymphocytes
– normal architecture of a lymph node is replaced by a
nodular proliferation of small lymphocytes and scattered
lymphocytic/histiocytic or popcorn cells, the latter being
the neoplastic cells of nodular lymphocyte-predominant
Hodgkin lymphoma
– CD20 antigen, BCL6, and immunoglobulin chains
– Most patients are males in their thirties and present with
localized peripheral lymphadenopathy.
– prognosis is excellent, with survival rates of 80% to
90%
 Hodgkin Lymphoma

2 BROAD CATEGORIES:
2.Classical Hodgkin Lymphoma
– comprises a heterogeneous group of
lymphoid neoplasms derived from the
germinal center
– presence of relatively few diagnostic
neoplastic cells, Reed-Sternberg cells, in a
rich reactive background
– Bimodal age distribution (between 15 and
34 years and older than 54 years)
– Divided into 4 subtypes
Classical Hodgkin Lymphoma

Reed-Sternberg cells
– present in all subtypes of
classical Hodgkin lymphoma
– Large with a bilobed nucleus or
two nuclei with prominent
eosinophilic nucleoli and
abundant cytoplasm
– Pathognomonic for the
diagnosis
 Classical Hodgkin Lymphoma

Variants of Neoplastic cells

– Hodgkin Cells
• large mononuclear lymphoid cells with an oval nucleus, thick nuclear membrane,
distinct eosinophilic nucleolus, and abundant cytoplasm.
– Mummified cells
• degenerated or apoptotic cells with a pyknotic nucleus and condensed cytoplasm
– Lacunar cells
• occur predominantly in the nodular sclerosis variant of classical Hodgkin lymphoma and
are characterized by a lobated nucleus and artifactual retraction of cytoplasm
secondary to formalin fixation. Because of this artifact, the cells appear to be situated in
a clear space
 • CD30+ in all cases and CD15+ in approximately 80% of
cases
• Cell marker CD20 is weak to absent
• CD45 antigen is absent
• Frequency of EBV infection depends on the subtype of
Classical classical Hodgkin lymphoma
• Disease of young adults with a peak incidence at 15 to 35
Hodgkin years except Lymphocyte-rich variant
Lymphoma • Mostly peripheral lymph nodes are involved, except in the
nodular sclerosis variant, which often shows mediastinal
lymphadenopathy.
• Cure rates are 80% to 90%,
• Nodular Sclerosis Subtype: Best prognosis
• Lymphocyte-depleted Hodgkin lymphoma: Most
Aggressive
• Treated with a combination of chemotherapy and
radiotherapy
Subtypes of Classical Hodgkin Lymphoma

a. Nodular Sclerosis Classical Hodgkin Lymphoma

– Presence of broad collagen bands transecting the lymph node and thickening of
nodal capsule
– most common subtype of classical Hodgkin lymphoma, accounting for 70% of cases.
– frequency of immunohistochemically demonstrable EBV infection is lowest in this
variant
b. Mixed Cellularity Classical Hodgkin Lymphoma.
– Reed-Sternberg cells and their variants are scattered among the diffuse background
composed of small lymphocytes, histiocytes, eosinophils, neutrophils, and plasma
cells
– Lacunar cells are absent
– Approximately 20% of classical Hodgkin
– An association with EBV infection is seen in 75% of cases.
 Subtypes of Classical Hodgkin Lymphoma

c. Lymphocyte-Rich Classical Hodgkin Lymphoma.

– Scattered mononuclear Hodgkin and Reed-Sternberg cells are seen together with a
vaguely nodular background of small lymphocytes
– Background cellularity: less heterogeneous.
d. Lymphocyte-Depleted Classical Hodgkin Lymphoma.
– Uncommon variant of classical Hodgkin lymphoma occurring predominantly in
immunodeficient patients
– Paucity of reactive background, and neoplastic Reed-Sternberg cells and their
variants are much more frequent
– Neoplastic cells show evidence of EBV infection
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