Category Archives: Lymphoma

Methods to establish monoclonality

Methods to establish monoclonality

•    Immunohistochemistry

•    Flow cytometry

•    Molecular techniques (eg. PCR)

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Waldenstrom Macroglobulinemia

Waldenstrom Macroglobulinemia

Lymphoplasmacytic Lymphoma

 

Also known as Waldenstrom Macroglobulinemia

 

Monoclonal IgM serum paraprotein

Hyperviscosity symptoms

 

Morphology

Mixture of cells

Small lymphocytes

Plasmacytoid lymphocytes

Plasma cells

Dutcher bodies

 

Immunophenotype

CD19, CD20, CD22, CD79a

CD38

Surface IgM

 

Molecular Genetics

Heavy chain of immunoglobulin rearranged

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Hairy Cell Leukemia

Hairy Cell Leukemia

 

Males

Middle age

Pancytopenia

Splenomegaly often

Heptaomegaly

NO lymphadenopathy commonly

 

Spleen

Bloody lakes of red pulp infiltration by neoplastic cells

 

Peripheral Blood

Medium sized cells

Circumferential hairy projections

 

Bone Marrow Aspirate

Dry Tap – as neoplastic cells are difficult to aspirate due to reticulin

 

 

Immunophenotype

CD19, CD20, CD22, CD79a

CD11c, CD25, CD103, Cyclin D1

Molecular Genetics

Heavy Immunoglobulin chain rearrangements

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Small Lymphocytic Lymphoma

Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia Small Lymphocytic Lymphoma

 

Patients usually asymptomatic.

Many different presentations including fatigue, absolute lymphocytosis, hepatosplenomegaly, anemia, lymphadenopathy.

 

Morphology

Small lymphocytes

Occasional mixed large lymphocytes termed prolymphocytes

Proliferation centers composed of paraimmunoblasts and prolymphocytes

 

Peripheral Blood

Small cells with no nucleoli and clumped chromatin

 

Immunophenotype

CD19, CD20, CD22, CD23, CD79a

CD5

 

Molecular Genetics

Trisomy 12

Deletions

Somatic hypermutation

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Lymphoma Follicular

Follicular Lymphoma

 

Non-Hodgkin’s Lymphoma

Most common non-hodgkin’s lymphoma

45% of adult lymphomas

 

Patients middle age

Widespread peripheral and central lymphadenopathy

Bone marrow involved in less than half of cases

 

Morphology

Cells appear as normal germinal center B cells

Follicular pattern – closely packed follicles

Follicles contain either cleaved centrocytes or large centroblasts

 

Also exists a diffuse pattern that will stain in a follicular pattern

 

Grading Follicular Lymphoma

Grade 1 : 0 to 5 centroblasts per high power field

Grade 2 : 6 to 15 centroblasts per high power field

Grade 3 : > 15 centroblasts per high power field

 

Immunophenotype

CD19, CD20, CD22, CD79a, CD10, BCL-2, BCL-6

 

Molecular Genetics

Translocation t(14;18)(q32;q21)

BCL-2 rearrangement leading to BCL-2 overexpression and inhibition of apoptosis

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Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia

Small Lymphocytic Lymphoma

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma are the same disease but differ in the extent of malignant white blood cells in the peripheral blood (lymphocytosis).

Chronic Lymphocytic Leukemia

4000 per mm3

Diagnostic requirement for Chronic Lymphocytic Leukemia is an absolute lymphocyte count of greater than 4000 per mm3.

Most common leukemia in Western world

Less common in Asia

Average age is 60

Males more common than females

Patients often asymptomatic

Nonspecific symptoms: fatigue, anorexia, weight loss

Half of cases have lymphadenopathy

Half of cases have hepatosplenomegaly

1/10 of patients have autoantibodies to red blood cells and platelets

Chronic Lymphocytic Leukemia often transforms to a more aggressive lymphoid malignancy including:

Prolymphocytic transformation (25% of patients)

Diffuse large B cell lymphoma (10% of patients)

 

Transformation to one of these leads to a survival of less than 1 year

 

Morphology

Diffuse effacement of lymph node by small lymphocytes

Irregular nuclei

Condensed chromatin

Scant cytoplasm

 

Large cells, prolymphocytes, admixed with small lymphocytes – often form aggregates termed proliferation centers containing many mitotically active cells

 

Proliferation centers are diagnostic for Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukemia

 

Peripheral Blood in Chronic Lymphocytic Leukemia

 

Increased numbers of small, round lymphocytes

Scant cytoplasm

Smudge cells – fragile cells that have ruptured during making of smear

 

Bone Marrow in Chronic Lymphocytic Leukemia

Always involved by small lymphocytes

Interstitial infiltrates

Non-paratrabecular aggregates

 

Spleen in Chronic Lymphocytic Leukemia

Involvement of both white and red pulp

 

Liver

Involvement of hepatic portal tracts

 

Immunophenotype

Pan B cell markers CD19, CD20

CD5 (T cell marker)

CD23

Surface immunoglobulin (IgM, IgD)

 

Molecular Genetics

Deletions of 13q12-14

 

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Lymphoma Protocol

Lymphoma Protocol

Lymphoid tissue once received from the surgeon should be examined grossly with touch preparations and/or frozen section being done.

The lymph node is cut in perpendicular sections and submitted into different tubes for specific studies to aid in diagnosis.

Cut lymph node perpendicularly along long axis.

1. Wet touch preparations fixed in formalin or 95% alcohol for hematoxylin and eosin staining

2. Air dried touch preparations (left alone to air dry) for cytogenetics (FISH) or cytochemistry or Giemsa staining

3. Snap freeze (rapidly freezing, in –70 degrees, liquid nitrogen) tissue, small amount (e.g. 0.5 x 0.2 cm), for molecular analysis including genetics, also for immunohistochemistry

4. Fresh tissue in saline for flow cytometry (also small amount of tissue e.g. 0.5 x 0.2 cm)

5. B5 fixative and tissue (e.g. one slice of tissue if have a lot, if not 0.5 x 0.2 cm should suffice). B5 provides high nuclear detail, good for Hodgkin’s lymphoma. Usually done when the patient is young and suspecting Hodgkin’s lymphoma.

B5 is toxic to the environment as it has high levels of mercury. It is also very expensive and molecular studies are not effectively done on B5 fixed tissue.

6. Remaining tissue (all) into formalin (10% neutral buffered) for hematoxylin and eosin staining and immunohistochemistry

Optional (depends on your suspicion)

7. Thin shaved tissue in glutaraldehyde for electron microscopy (must put tissue QUICKLY into glutaraldehyde)

8. Sterile tissue, fresh, for microbiology (e.g. sent for cultures). Can also be used for cytogenetics (e.g. FISH)

 

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Small Cell Lymphoma

Small Cell Lymphoma and Chronic Lymphocytic Leukemia

Appearance in lymph node

Diffuse effacement of lymph node architecture by population of small cells (6-12 um in diameter)

Cells contain small, round, slightly irregular nuclei with condensed chromatin and scant cytoplasm

These cells are mixed with variable numbers of larger cells known as prolymphocytes

Prolymphocytes gather to form loose aggregates known as proliferation centres (which contain large numbers of mitotically active cells) and are pathognomonic for CLL/SLL

Appearance in bone marrow

Observed in all cases of CLL and most cases of SLL

Small lymphocytes are seen to form interstitial infiltrates and/or non-paratrabecular aggregates

Small Cell Lymphoma Immunohistochemistry

CD19/20 +

CD5+

CD21, CD23+

CD43+

CD10-

Cyclin D1-

IgM, or IgM/IgD +

Either kappa or lambda restricted

Prognosis

Patients present over age 50 (median age: 60 y.o.), often asymptomatic

When symptomatic, symptoms are non-specific (fatigue, weight loss, anorexia)

Course and prognosis is variable and dependent on clinical stage

Median survival is between 4-6 years, however some patients with minimal disease survive over 10 years

Presence of 11q and 17p deletions portends a poor prognosis

Transformation to more aggressive neoplasms can occur (eg. prolymphocytic transformation [15-30% of patients] or transformation to DLBCL [10% of patients]) with most patients surviving less than 1 year

Differential diagnosis

Mantle cell lymphoma

Follicular cell lymphoma

Marginal zone lymphoma

Reactive lymph node hyperplasia

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Burkitt

Burkitt lymphoma

Burkitt Lymphoma Pathogenesis

Burkitt lymphoma is caused by the translocation of c-myc (on chromosome 8 ) to immunoglobulin gene locus allowing for upregulation of c-myc (increased transcription and translation). Translocation occurs to IgH locus t(8;14) or light chain locus t(2;8) or t(8;22). This is thought to occur during errors in class switching or during attempted V(D)J joining, or breaks generated during somatic hypermutation of Ig genes.

Additional mutation of p53, MDM, or p16 are needed for malignant transformation.

Burkitt Lymphoma Histology

Tissues involved by Burkitt lymphoma are effaced by a diffuse proliferation of intermediate-sized cells (10 to 25 um diameter; similar to nuclear size of benign macrophages within tumor), containing round or oval nuclei with coarse chromatin, several nucleoli, and a moderate amount of faintly basophilic to amphophilic cytoplasm. There is a high mitotic index and high rate of apoptotic cell death within the tumor. This is a requirement. Tingible body macrophages are diffusely scattered among the tumor cells imparting a “starry sky” appearance to the neoplasm.

Classification in the Working Formulation and the REAL classification

Working Formulation

- Classified under high grade lymphoma (small, noncleaved cells)

REAL Classification

-    Classified as peripheral B-cell neoplasm

References:

Robbins Basic Pathology 7th ed, edited by Vinay Kumar, Ramzi S. Cotran, and Stanley J. Robbins, 873 pp, Philadelphia, Pa, Sounders, 2003.

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Lymphoma Mutations

Lymphoma Mutations

Mantle cell lymphoma mutation:

cyclin D1 translocation [t(11;14]

Follicular lymphoma mutation:

translocation of bcl-2 to IgH heavy chain of immunoglobulin[t(14;18)]

Chronic Myelogenous Leukemia (CML) mutation:

creation of fusion protein bcr-abl from translocation [t(9;22)]

References:

Robbins Basic Pathology 7th ed, edited by Vinay Kumar, Ramzi S. Cotran, and Stanley J. Robbins, 873 pp, Philadelphia, Pa, Sounders, 2003.

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