Malignant Lymphomas Donald Innes, M.D. Hodgkin Lymphoma ... · 1 Malignant Lymphomas Donald Innes, M.D. with special thanks to John Cousar, M.D. Hodgkin Lymphoma and Non-Hodgkin Lymphomas

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Malignant Lymphomas Donald Innes, M.D.

with special thanks to John Cousar, M.D.

Hodgkin Lymphoma and Non-Hodgkin Lymphomas

I. Overview of the Lymphoid System:

1. The lymphoid system consists of circulating T and B lymphocytes and the

lymphoid organs, including lymph nodes, thymus, spleen, tonsils, and

adenoids. Less well-organized lymphoid tissue is also present in the

gastrointestinal tract and lung (referred to as Mucosal Associated Lymphoid

Tissue, or MALT), marrow and skin.

2. Lymphopoiesis: Lymphocytes are derived from marrow stem cells. T-

lymphocytes undergo differentiation and maturation in the thymus and then

migrate to peripheral lymphoid tissue (nodes, spleen, etc.), and function as T-

helper (CD4+) or T-suppressor (CD8+) cells. B-lymphocytes develop in the

marrow, and likewise migrate to specific B-cell compartments of peripheral

lymphoid tissue. The effector cell, and most differentiated cell of the B-cell

system, is the plasma cell, which produces immunoglobulin. The maturation

and differentiation of T and B cells are associated with changes in the DNA of

the cells (which can be detected by molecular genetic techniques) and sequential

gain and loss of surface and cytoplasmic antigens (which can be detected by

monoclonal antibodies using flow cytometry or immunohistochemistry).

3. Lymph Nodes: The major function of

lymph nodes is to detect and inactivate foreign

antigens arriving via lymphatics. Lymph nodes

are principally located to receive lymph from

those organs in major contact with the

environment (i.e. skin, respiratory tract,

gastrointestinal tract). Lymph nodes are

encapsulated, and are organized into B and T

cell subcompartments. In the cortex of the

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node are spherical aggregates of lymphoid cells called primary follicles, which are B-

cell domains. With antigenic stimulation, primary follicles develop germinal or

follicular centers composed of follicular center cells. Surrounding the follicular

center is a cuff or mantle of small B-cells which have not been challenged by

antigen. The paracortex of the node is a T-cell dependent area.

4. Spleen: The spleen consists of a filtering component, the red pulp, and a lymphoid

component, the white pulp. The white pulp is organized into B-cell domains similar

to the follicles of nodes and T-dependent areas, the periarteriolar lymphoid sheath.

5. Mucosa-Associated Lymphoid Tissue: Extranodal specialized lymphoid tissue

present in the GI tract, lung, and other sites is termed Mucosa-Associated Lymphoid

Tissue, or MALT, and is composed of lymphocytes that provide mucosal immunity.

II. Malignant Lymphomas:

1. Lymphomas are malignancies which arise from lymphocytes residing in lymphoid

tissue outside of the marrow (i.e. lymph nodes, spleen, etc.). Lymphomas are broadly

separated into Hodgkin lymphoma (identified in part by its neoplastic cell – the

Reed-Sternberg cell), and all other types of lymphomas referred to as non-Hodgkin

lymphomas. There are no recognized benign neoplasms of the hematopoietic-

lymphoid system.

2. Important Features of Malignant Lymphomas:

Lymphomas are clonal. There is abundant immunologic and karyotypic

evidence indicating these neoplasms contain clonal expansions of a single

functional subpopulation.

The cause of most lymphomas is generally unknown.

There are major clinicopathologic differences between childhood and adult

lymphomas. The great majority of non-Hodgkin lymphoma occurring in

children are of high histologic grade, and are clinically aggressive. Low-

grade lymphomas are rare in children. Non-Hodgkin lymphomas of adults

may be either low or high-grade.

Prognosis is closely correlated with histologic grade of the neoplasm. For

example, follicular lymphoma grade 1-2, (composed predominantly of

dormant, non-dividing B-cells, called centrocytes) is a low-grade neoplasm,

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while diffuse large B-cell lymphoma (composed predominantly of larger,

more rapidly dividing B-cell) is a higher-grade process.

III. Classification of Non-Hodgkin Lymphomas (NHLs):

1. NHLs are heterogeneous (much more so than Hodgkin Lymphoma), and can

develop as a result of malignant transformation at any stage of B and T cell

differentiation. Therefore, NHLs are broadly grouped into B or T cell types. In

this country, B cell NHLs are much more common than T cell types. The

classification system most widely used for NHLs is the 2008 World Health

Organization Classification (W.H.O.)]. It is not necessary that you memorize

this system in its entirety, but it is important that you understand several

principles of classification of NHLs:

NHLs are classified on the basis of the morphologic, immunologic,

cytogenetic, and molecular genetic similarity of the predominant

neoplastic cell to the various stages of B and T cell differentiation.

For example, the lymphoma that is comprised predominantly of

centrocytes (small cleaved cells) of the follicular (germinal) center is

called a follicular lymphoma. It is a B-cell neoplasm that

morphologically and immunologically resembles the cell of origin

(i.e. centrocyte).

When classification is based on the cell of origin, distinct

clinicopathologic entities emerge which better predict prognosis and

facilitate therapy.

In general, NHLs in which the predominant cell is small and

dormant-appearing tend to be more indolent than those in which

the predominant cell is a transformed lymphocyte, and are more

aggressive.

Site of the primary disease (i.e. node vs. spleen vs. gastrointestinal

tract vs skin, etc.) is important.

Currently, the most widely used classification system is the 2008

W.H.O. system. A listing of the W.H.O. lymphomas is shown in

Table 1 on the next page.

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2008 World Health Organization Classification of B cell, T cell, Hodgkin Lymphoma, Histiocytic/Dendritic Cell Neoplasms, and Post-Transplant Lymphoproliferative Disorders (Swerdlow SH et al editors)

PrecursorLymphoidNeoplasms

B lymphoblastic leukemia / lymphoma NOS B lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities T lymphoblastic leukemia / lymphoma

MatureB‐CellNeoplasms

Chronic lymphocytic leukemia / small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia Heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type Nodal marginal zone lymphoma Follicular lymphoma Primary cutaneous follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma, NOS (T-cell / histiocyte-rich type; primary CNS type ; primary leg skin type & EBV+ elderly type) Diffuse large B-cell lymphoma with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma associated with HHV8+ Castleman disease Primary effusion lymphoma Burkitt lymphoma B cell lymphoma, unclassifiable, Burkitt-like B cell lymphoma, unclassifiable, Hodgkin lymphoma-like

MatureT‐Cell&NK‐CellNeoplasms

T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK-cells.

Aggressive NK-cell leukemia Systemic EBV+ T-cell lymphoproliferative disorder of childhood Hydroa vacciniforme-like lymphoma Adult T-cell lymphoma/leukemia Extranodal T-cell/NK-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepato-splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorder Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, ALK+ type Anaplastic large cell lymphoma, ALK- type

Hodgkinlymphoma(Hodgkindisease)

Nodular lymphocyte-predominant Hodgkin lymphomas

Classic Hodgkin lymphomas Nodular sclerosis Hodgkin lymphoma Lymphocyte-rich classic Hodgkin lymphoma Mixed cellularity Hodgkin lymphoma Lymphocyte depletion Hodgkin lymphoma

Post‐TransplantLymphoproliferativeDisorders(PTLD)

Plasmacytic hyperplasia Infectious mononucleosis like PTLD Polymorphic PTLD Monomorphic PTLD (B & T/NK cell types) Classic HD type PTLD

HistiocyticandDendriticCellNeoplasms

Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumor Indeterminate dendritic cell sarcoma Disseminated juvenile xanthogranuloma

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IV. Diagnosis of Lymphomas:

1. Clinical Information: Age, symptoms, distribution of disease,

organomegaly, and lab data are often useful in determining the type of

neoplasm and the extent of disease.

2. Morphologic Evaluation: Most lymphomas are very distinctive on

histologic sections, and are actually recognizable at a glance (by the

experienced eye).

3. Immunophenotypic Analysis: The cell lineage of most lymphomas can be

determined by immunologic techniques using monoclonal antibodies and

flow cytometry (requires viable cell suspensions) or immunoperoxidase

techniques (can be performed on frozen or fixed paraffin embedded tissue).

Clonality can also be detected in B-cell neoplasms by immunoglobulin light

chain restriction (presence of single light chain type on the surface or in the

cytoplasm of neoplastic cells).

4. Karyotypic and Molecular Techniques: Certain lymphomas have

characteristic chromosomal abnormalities (i.e. follicular lymphomas often

demonstrate a 14;18 translocation). Clonality and lineage can be determined

using molecular techniques for immunoglobulin or T-cell receptor

rearrangements.

V. B-cell Non-Hodgkin Lymphomas (B-NHL):

1. Introduction: B-NHLs are the most common group of lymphomas in

Western countries (85-90% of all non-Hodgkin lymphomas), and the

frequency of these malignancies has dramatically increased over the last 20

years.

2. Important Features of B-NHLs:

All B-NHLs demonstrate clonal rearrangement of the

immunoglobulin gene, detectable by Southern blot or PCR.

Most B-NHLs express monotypic immunoglobulin which is easily

detectable on the cell surface (with flow cytometry), or in the cell

cytoplasm (immunohistochemistry), or occasionally as a monoclonal

protein in the serum.

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The B-lineage of many B-NHLs can be accurately and simply

determined by histopathologic features such as follicular nodulation,

plasmacytic differentiation, and other morphologic features.

3. Common B-NHL:

Follicular Lymphoma (FL): Follicular

lymphoma is a common type of NHL, and

occurs almost exclusively in adults: Most

patients present with peripheral or

retroperitoneal adenopathy and the disease is

often widespread at diagnosis. The cell of

origin of the tumor is a B follicular center cell.

The most important histopathologic feature

is effacement of nodal architecture by a

proliferation of neoplastic follicular nodules.

Most follicular lymphomas are composed

predominantly of centrocytes (Grade 1), or

mixtures of centrocytes and centroblasts

(Grade 2). Rarely FLs are made up of

predominantly centroblasts (Grade 3).

Grade 1 and 2 FLs are considered low-grade

tumors, and Grade 3 is more aggressive. The

characteristic immunophenotype of FL is

CD20+ (pan B-cell), CD10+, and abundant

monotypic surface immunoglobulin.

Approximately 90% of FLs will demonstrate a t(14;18). This translocation

juxtaposes the BCL-2 oncogene to the Ig heavy chain locus on chromosome 14

leading to the overexpression of Bcl-2 protein which blocks apoptotic cell death.

B-Small Lymphocytic Lymphoma (B-SLL): B-SLL typically occurs in older

adults. In addition to adenopathy, many patients will have a leukemic blood

picture, which is identical to B-chronic lymphocytic leukemia. In fact, this

neoplasm is now referred to as Chronic Lymphocytic Leukemia/Small Lymphocytic

Lymphoma. Involved lymph nodes show diffuse effacement by a proliferation of

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small lymphocytes with round nuclei and dense chromatin. This neoplasm is

considered to be low-grade. Phenotypically, the neoplastic cells of B-SLL express

weak CD20, CD5, CD23, and weak surface immunoglobulin.

Low-grade B-cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT

Lymphoma): MALT lymphomas are usually low-grade lymphomas of adults

that arise in extranodal lymphoid tissue, especially the GI tract and lung. The

lymphoid tissue in which MALT lymphomas arise may be a normal constituent of

the site of origin (for example, Peyer’s patches of the small intestine), or may be

acquired as part of an autoimmune disorder (for example, Hashimoto thyroiditis) or

infection (for example, H. pylori-associated chronic gastritis).

Mantle Cell Lymphoma (MCL): Mantle cell lymphoma

occurs in adults and is a clinically aggressive neoplasm,

although the histologic appearance is low grade. Involved

nodes usually show a diffuse effacement by a very

homogenous population of small lymphoid cells with

virtually no large cells. Phenotypically, the neoplastic cell is

CD 20+ and SIg+. Like B-SLL, the tumor cells co-express

CD5 but unlike B-SLL usually do not express CD 23. A

characteristic t(11;14)(q13;q32) translocation is seen and

involves the immunoglobulin heavy chain genes and the

CYCLIN D1 (a.k.a. BCL-1) gene, which leads to the

overexpression of CYCLIN D1. The CYCLIN D1 protein

can be detected by immunohistochemistry.

Diffuse Large B-cell Lymphoma (DLBCL): DLBCL is

the most common type of NHL that occurs in adults, and

rarely in children. Morphologically, it is a diffuse

proliferation of large

neoplastic B-lymphoid cells. Within this group of

lymphomas, there have been a variety of subtypes

recognized. Most cases are CD20+, and express surface

immunoglobulin. This neoplasm behaves in an

aggressive fashion.

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Burkitt Lymphoma (BL): BL is a highly aggressive lymphoma that

occurs in children as well as adults, and often presents in extra-nodal

sites, such as the jaws, distal ileum and ovaries. It is endemic in young

children in Africa, and sporadic in children of all ages in the U.S.A.

Morphologically, it demonstrates a diffuse proliferation of small

noncleaved cells with a very high mitotic rate, and a background of

“starry sky” macrophages. Epstein-Barr virus is thought to play an

important role in the pathogenesis of BL, especially the endemic form.

Phenotypically, the neoplastic cells are CD20+, CD10+, and surface

immunoglobulin positive. All cases have a translocation of the MYC gene

on chromosome 8 to the Ig heavy chain on chromosome 14, or, less

commonly, to the light chain loci on chromosome 2 or 22.

VI. T-cell Lymphomas:

1. Introduction: Only 10-15% of lymphomas in Western countries are T-cell origin.

Despite their relative rarity, T-cell lymphomas are important because they are

difficult to diagnose, tend to be more aggressive than most B-cell lymphomas, can

occur in young patients, and may be associated with paraneoplastic syndromes

such as hypercalcemia, hypergammaglobulinemia, and erythrophagocytosis.

2. Classification of T-cell Neoplasms: T-cell neoplasms are broadly classified

according to the anatomic compartment from which they arise, and their level of

maturity. Immature or precursor T-cell neoplasms arise in the marrow (T-

lymphoblastic leukemia), or in the thymus (T-lymphoblastic lymphoma). T-cell

lymphomas arising in other sites as a group are called peripheral (peripheral to the

thymus) T-cell lymphomas, and they arise in lymph nodes or extranodal sites

(skin, lung, nasopharynx, intestine, liver, spleen). In addition, some T-cell

lymphomas are classified according to histologic features (anaplastic large cell

lymphoma, angioimmunoblastic T-cell lymphoma).

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3. Specific T-cell Neoplasms:

T-lymphoblastic

Lymphoma (T-LL): TLLs often

present as a rapidly growing anterior

mediastinal mass in young patients,

most often male, who may have

respiratory or cardiovascular

compromise and pleural or pericardial

effusions. These lymphomas

disseminate rapidly to the marrow, peripheral blood, and regional lymph

nodes, and, therefore, at that stage, closely resemble T-lymphoblastic

leukemias. The tumor cells have a blastic appearance which a high nuclear

to cytoplasmic ratio, finely dispersed chromatin, and inconspicuous nucleoli.

Thymic tissue is effaced by a diffuse growth of these monomorphic tumor

cells that have a high mitotic rate, and invade the capsule. The tumor cells

mark immunophenotypically as immature T-cells.

Mycosis Fungoides (MF): Mycosis fungoides is a tumor of small, skin-

based T-cells, predominantly of the CD4+ subset that occurs in adults. MF

produces a band-like superficial dermal infiltrate adjacent to, and invading

the epidermis (epidermotropism) with formation of small collections of

lymphocytes in the epidermis (Pautrier’s microabscess). The lymphocytes

are small and have a characteristic folded, cerebriform nucleus.

Peripheral T-cell Lymphoma (PTCL): PTCL is usually a nodal disease of

adults, and encompasses a variety of morphological variants. Most patients

have advanced stage disease with constitutional symptoms and paraneoplastic

features such as eosinophilia, and hemophagocytosis may be seen. Most cases

demonstrate a T-phenotype with loss or aberrant expression of pan T-cell

antigens.

VII. Hodgkin Lymphoma (HL):

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1. Introduction: In 1832, Thomas Hodgkin was the first to report that

lymphadenopathy could occur as a primary disorder, rather than secondary

to infection or carcinoma. Three decades later, primary diseases of the

lymph node well called Hodgkin Disease, in honor of Dr. Hodgkin’s

important observation. Between 1898 and 1902, Dorothy Reed and Carl

Sternberg described the histologic features of HL, including the diagnostic

dysplastic Reed-Sternberg (RS) cell that bears their names.

2. General Features of Hodgkin Lymphoma: HL represents 30% of all

lymphomas. HL is separated from NHL for several reasons. 1) The

cellular composition of HL is unique in that the neoplastic cell (Reed-

Sternberg cell) accounts for only a minority of the tumor mass, most

of which is reactive inflammatory cells. Thus the general principles for

the histopathologic diagnosis of HL differ from NHL. 2) The clinical

features and response to therapy of HL differ from those of NHLs. HL

mostly affects young adults (15-35 years) but also occurs in older adults

(>50 years). The spread of HL is nonrandom, with dissemination via

lymphatics to contiguous lymph node groups including the spleen.

Prognosis in large part is related to stage of disease. Limited stage

disease (stage I or II) has a better prognosis than advanced stage disease

(stage III or IV). In addition, asymptomatic patients (A) fare better than

those with B symptoms – fever, night sweats or weight loss >10% of

body weight. The therapy for HL is usually determined by the stage of

disease, as well as histopathologic subtype, and includes radiotherapy, and

specific combination chemotherapy. Long-term survival is usually quite

good.

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3. Diagnostic Criteria: HL typically

effaces nodal architecture, forming a mass

of characteristic reactive inflammatory

cells with an admixed smaller population

of large dysplastic RS cells. The RS cell

is a large binucleate cell with dispersed

chromatin, inclusion-like macronucleoli,

and abundant eosinophilic cytoplasm. For

diagnostic purposes, recognition of the

characteristic inflammatory component is

just as important as identifying the RS cell. Although the histologic features of HL

are often diagnostic, “RS-like” cells may be seen in reactive conditions such as

infectious mononucleosis and other lymphomas. Immunologic studies are useful in

confirming the diagnosis, as classical RS cells have a characteristic

immunophenotype: LeuM1 (CD15)+, Ki-1 (CD30)+ and leukocyte common antigen

[(LCA) CD45–]. It is now known that the RS cells of almost all types of classical

HL are of B-lineage. However, in contrast to normal B-cells, the RS cells of classical

HL show a global shut down of the B-cell transcription program. Thus, markers of

B-lineage, such as CD 20 or surface Ig, are usually not expressed by classical RS

cells.

4. Classification: The W.H.O. Classification recognizes two major

categories of HL: Classical HL and nodular lymphocyte predominant HL.

These two categories differ with respect to morphologic appearance,

clinical behavior and immunophenotype. There are four types of classical

HL that are distinguished by the pattern of nodal infiltration, the mixture

of reactive cells, and the number and appearance of RS cells. The four

types of HL include nodular sclerosis, lymphocyte -rich, mixed cellularity,

and lymphocyte depleted.

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Nodular Sclerosis (NS): NSHL is the most

common type of HL. It occurs most often in

young adults, and is the only type of HL that

affects females more than males. Patients usually

present with cervical adenopathy and/or a

mediastinal mass. Histologic features include

capsular fibrosis, and dense bands of connective

tissue that efface nodal architecture and give a

nodular appearance. The nodules often contain

numerous inflammatory cells and scattered RS

cells. Most RS cells have a lacunar appearance

where the cytoplasm retracts against the nucleus,

giving the appearance of a hole or lacuna.

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Mixed Cellularity (MC): MCHL is the second most common type. The most

common presentation is a symptomatic (fever, weight loss, night sweats) middle-aged

to elderly male. The prognosis is intermediate. Typically, nodal architecture is

completely effaced with numerous inflammatory cells (lymphocytes, histocytes,

eosinophils, and plasma cells) and a readily identifiable RS-cells including

“diagnostic” binucleate forms.

Lymphocyte Depletion (LD): LDHL is uncommon, representing <5% of HL. Most

patients have fever and peripheral blood cytopenias. Generally, there is little

peripheral and more abdominal adenopathy. As the name implies, lymphocytes are

fewer in number, and RS cells may predominate over the reactive component. RS

cells vary from diagnostic to bizarre, multinucleated cells that may have sarcomatous

appearance.

Lymphocyte – rich (LR): LPHL is rare and mimics LPHL but has an

immunophenotype of classical HL.

NOTE: NSHL, MCHL, LRHL, and LDHL subtypes of HL are grouped together as

classical Hodgkin Lymphoma, as RS cells have the characteristic immunophenotype

(CD 45-, CD 15+, CD 30+) described above.

Lymphocyte Predominance (LP): LPHL represents 5-10% of all HL cases.

Patients typically are asymptomatic young males with cervical or axillary

adenopathy. The prognosis is excellent. Histologically, the predominant cell is a

small lymphocyte. RS cells are few in number, and have a folded, vesiculated

nucleus with less prominent nucleoli than seen in other types of HL. These RS cells

are sometimes called “popcorn cells” based on this morphology.

NOTE: LPHL has a characteristic immunophenotype (CD 45+, CD 15-, CD 30-,

CD20+) that is different from “classical HL”, and molecular genetic studies have

shown a B-cell origin for LPHL. In contrast to classical HL, the neoplastic cells of

LPHL express B-lineage markers, such as CD 20.