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.

• 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 accompanied by

extensive marrow involvement, and evolution to

"leukemia" is not unusual during progression of

incurable "lymphomas." 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.

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

accompanied by extensive marrow involvement,

and evolution to "leukemia" is not unusual during

progression of incurable "lymphomas."

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.

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. Precursor B-cell neoplasms (immature B cells)

2. Peripheral B-cell neoplasms (mature B cells)

3. Precursor T-cell neoplasms (immature T cells)

4. 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

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 patho-physiology 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

• Hodgkin lymphoma.

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

• 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 pre-B 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 non-paratrabecular 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 hepato-splenomegaly 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-neoplastic, self-reactive B cells rather than tumor cells,1\ suggesting a systemic defect in immune regulation.

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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 B-cell 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 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.19

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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 Reed-Sternberg 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 Reed-Sternberg 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)

Reed-Sternberg

cells

Diagnostic Reed-Sternberg cell, with two nuclear lobes, large inclusion-like nucleoli, and abundant cytoplasm, surrounded by lymphocytes, macrophages, and an eosinophil

• 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.


• 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).


• 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.


• 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.

• 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 features

Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas

Morphology of each subtypes

page 687

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

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


• 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.


• 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.


• 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.


• 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 HL is observed predominantly in older patients, HIV-positive 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.


• Typical Reed-Sternberg cells are extremely difficult to find.

• More common are so-called lympho-histiocytic (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.


• 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.


• 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.


• 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%), Reed-Sternberg

cells do not have immunoglobulin genes in the germ line configuration and instead have T-cell 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.


• 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.


• The characteristic accumulation of reactive cells occurs in response to cytokines secreted by the Reed-Sternberg cells, such as IL-5, IL-6, IL-13, tumor necrosis factor (TNF), and GM-CSF.

• 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 cell-mediated 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

diseases of white blood cells(3)

Documents

terms leukemia

soft tissue masses

discrete tissue masses

particular neoplasms

extensive marrow involvement

usual tissue distribution

lymphocytic leukemias

time of clinical presentation