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59 Cards in this Set

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Define lymphoma.
Clonal (neoplastic) lymphoproliferative disorders primarily involving solid lymphoid organs
-- lymph nodes
-- spleen
-- tonsil
-- thymus

May also arise from lymphocytes/lymphoid tissue in extranodal sites other than the spleen, tonsil, and thymus
-- skin
-- lung
-- GI tract

May secondarily involve peripheral blood and BM
What areas do leukemias involve?
Peripheral blood and BM, but may spread to lymphoid organs
The majority of lymphomas present with...?
lymphadenopathy
-- 1/3 arise in extranodal sites such as GI (MALT lymphoma)
Two major lymphoma categories?
1. Hodgkin

2. Non-Hodgkin

These two are morphologically, immunophenotypically, and clinically distinct
Non-Hodgkin lymphomas and maturation?
They relate to normal stages of B or T cell maturation
-- distinct morphology
-- distinct immunophenotype
The Dx of lymphoma requires...?
1. Histologic evaluation of biopsy material

2. Immunophenotyping of biopsy material is helpful

3. Molecular diagnostic analysis may be required to
-- demonstrate clonality OR
-- detect distinct genetic lesion
What are the steps involved in the Dx of lymphoma?
1. Biopsy of lymphoid tissue
Algorithm:
-- Benign vs. malignant
-- lymphoid vs. non-lymphoid malignancy (carcinoma, melanoma)
-- Hodgkin vs. Non-Hodgkin Lymphoma
-- Subtype of lymphoma (classification) based on cell type, anatomic compartment, immunophenotype

2. Clinical staging
-- Evaluation of peripheral blood and BM
-- Radiologic studies

3. Prognostic index
-- classification
-- stage
-- age
-- LDH
Morphology of Non-Hodgkin lymphoma (NHL)?
1. Lymphoid infiltrate w/ loss of normal architecture

2. Abnormal growth patterns
-- nodular OR
-- diffuse

3. Cellular composition
-- homogeneity
-- size
-- nuclear shape

**Features that favor a reactive process include preservation of the normal architecture and cellular heterogeneity
Immunophemotype of NHL?
1. B or T cell lineage

2. Monoclonal
-- kappa/lambda Ig light chain

3. Abnormal phenotype
-- ex: CD5 (T cell marker) positive B lymphocytes in CLL/SLL
Genotype/cytogenetics of NHL?
1. Clonality
-- Ig/T-cell receptor gene rearrangement

2. Cytogenetic aberration
-- t(14;18)(q32;q21) BCL-2 Follicular lymphoma

-- t(8;14)(q24;q32) C-MYC Burkitt lymphoma

-- t(11;18)(q21;q21) MALT-1 MALT lymphoma

-- t(11;14)(q13;q32) CYCLIN D1 Mantle cell lymphoma
Major lymphoma classifications of NHL?
1. Morphology (Rappaport) 1966

2. Cell lineage and differentiation (Kiel; Lukes-Collins) 1974

3. Clinical features (Working Formulation) 1982

4. Combination of morphology, immunophenotype, genetics, and clinical features (REAL/WHO) 1994/2001
What is the basis of the Working Formulation for clinical usage classification of NHL?
1. Separates lymphomas into three major clinical prognostic groups or "clinical grades"

2. Within each group further sub-classification was based on:
-- pattern of growth --> nodular or diffuse
-- size of cells --> small, large, mixed small and large
-- proliferative rate
What are the three "clinical grades" of NHL.
Low grade
Intermediate grade
High grade
Describe low grade NHL
-- Predominantly small lymphocytes
-- nodular growth pattern

1. lymphoma, small lymphocytic

2. lymphoma, follicular, predominantly small cleaved cell

3. lymphoma, follicular, mixed small celaved and large cell
Describe intermediate grade NHL.
-- predominantly large lymphocyte
-- diffuse growth

1. lymphoma, follicular, predominantly large cell

2. lymphoma, diffuse, small cleaved cell

3. lymphoma, diffuse, mixed small and large cell

4. lymphoma, diffuse, large cell
Describe high grade NHL.
-- large proliferative fraction

1. lymphoma, large cell, immunoblastic

2. lymphoma, lymphoblastic

3. lymphoma, small noncleaved cell (SNC)
What are the difficulties with the WHO classification?
1. Not distinct disease entities

2. Some of the more recently recognized lymphomas (mantle cell, MALT) are not included in the classification
What is the revised European-American Classification of Lymphoid Neoplasms (REAL)?
1. well defined "real" diseases

2. distinct clinicopathological entities based on a combination of:
-- morphology
-- immunophenotype
-- cytogenetic and molecular studies
-- biological behavior
Which classification is preferred for NHL?
Currently the WHO classification is preferred (based on similar principles as its predecessor, REAL)
List the WHO B cell neoplasms.
PRECURSOR B-CELL NEOPLASMS
1. B-lymphoblastic leukemia/lymphoma**

MATURE B-CELL NEOPLASMS
1. B-cell CLL/SLL*
2. Hairy cell leukemia
3. Extranodal marginal zone lymphoma (MALT lymphoma)
4. Follicular lymphoma*
5. Plasma cell myeloma
6. Diffuse large B-cell lymphoma*
7. Burkitt lymphoma*

*most common in adults
**most common in children
List the WHO T cell neoplasms.
PRECURSOR T-CELL NEOPLASMS
1. T-precursor lymphoblastic leukemia/lymphoma**

MATURE T-CELL AND NK-CELL NEOPLASMS
1. mycosis fungoides/Sezary syndrome

**more common in children
How are NHLs categorized?
Based on LINEAGE, they are divided into two major categories:
1. B-cell lymphomas
2. T/NK-cell lymphomas

Based on DIFFERENTIATION STAGE, the above are further divided into:
1. B- or T-precursor lymphoblastic leukemia/lymphoma (ALL/LBL)
2. Peripheral or mature B- or T-cell lymphomas
Clinical presentation of follicular lymphoma (FL)?
MOST COMMON NHL in the U.S.

Median age 50-60yrs

Males = females

Generalized painless lymphadenopathy
FL morphology?
Closely resembles the normal germinal center of lymphoid follicles
-- effacement of normal nodal architecture
-- nodular (follcicular) growth pattern; may be diffuse or both nodular and diffuse

Composed of mixture of follicle center cells
--centroblasts (large non-cleaved cells)
-- centrocytes (small cleaved cells)

Lack apoptosis/tingible body macrophages
FL immunophenotype
B cell (CD19+, CD20+)
-- CD10(+)

Monoclonal kappa or lambda light chain

BCL2 protein +
FL genotype?
t(14;18)(q32;q31)

BCL2 rearrangement
FL classification?
WORKING FORMULATION
1. Low grade
-- follicular, predominantly small cleaved cell
-- follicular, mixed small cleaved and large cell

2. Intermediate grade
-- follicular, predominantly large cell
-- diffuse, mixed small and large cell
-- diffuse, large cell

REAL/WHO CLASSIFICATION
-- follicular lymphoma, nodular and/or diffuse
-- Grades I, II and III based on number of large cells present
-- most are low grade (I-II) at presentation
FL staging?
Most present w/ advanced stage (75% at stage IV)
FL pathogenesis?
BCL-2 gene rearrangement t(14;18)
-- leads to BCL-2 overexpression
-- BCL-2 inhibits apoptosis
-- prolinged survival of follicle center cells
FL clinical course?
Median survival or 7-9 yrs

NOT cured by therapy

30-50% progress to diffuse large cell lymphoma
-- median survival <1yr
Describe diffuse large cell B cell lymphoma.
Heterogeneous group of tumor composed of a predominance of large lymphocytes w/ dispersed (vesicular) chromatin and prominent nucleoli
-- represents 30-40% NHLs

Some transformed from a lower grade lymphoma
-- ex: follicular lymphoma

Also forms a subset of lymphomas occuring in HIV infected individuals

Aggressive by may be curable
Clinical presentation of small lymphocytic lymphoma (SLL)?
Overlap btwn CLL and SLL
-- morphologically and immunophenotypically and genotypically indistinguishable
-- primarily differ in degree of peripheral blood lymphocytosis at presentation

CLL: peripheral blood or BM involvement, but may have or develop lymphadenopathy

SLL: primarily affects lymphoid tissues but may involve BM and peripheral blood
SLL morphology?
Diffuse (NOT follicular) effacement by a monotonous infiltrate of small lymphocytes

Small round (non-cleaved) lymphoctes

Pseudonodules "growth center": prolymphocytes, paraimmunoblasts

Features of low grade lymphoma
-- low mitotic activity
-- absence of necrosis
Clinical presentation of Burkitt lymphoma?
30% of childhood NHL

A subset of lymphomas occurring in HIV infected

Most tumors manifest at extranodal sites
Two major clinical types of Burkitt lymphoma?
1. African (endemic)
-- Tropical equatorial Africa and New Guinea
-- median age 7 yrs
-- maxilla, mandible, ovaries, kidneys

2. Non-African (sporadic)
-- non-endemic areas
-- median age 11 yrs
-- Ileocecum, peritoneum
Burkitt lymphoma morphology?
Loss of normal architecture
-- diffuse lymphoid infiltrate

Medium size cells w/ dispersed (vesicular) chromatin and prominent nucleoli
-- round nuclei (small noncleaved cells)
-- moderately abundant blue cytoplasm

Admixed benign (tingible body) macrophages -- "starry sky" appearance

High mitotic activity
Burkitt lymphoma immunophenotype?
B-cell (CD19+, CD20+)
-- monoclonal kappa or lambda light chain
-- CD10(+)
-- BCL2(-)
Burkitt lymphoma classification?
WORKING FORMULATION
high grade lymphoma, small noncleaved cell type
Burkitt lymphoma staging?
variable stage at presentation
Burkitt lymphoma pathogenesis
C-MYC (8q24) translocation: t(8;14), t(8;22) or t(8;2)

EBV related
-- African --> EBV genome present in 95% of the cases
-- Non-African --> EBV genome present in 15% of the cases
Burkitt lymphoma clinical course?
highly aggressive

curable w/ aggressive therapy
What is MALT lymphoma?
Presents as extranodal disease in mucosa associated lymphoid tissue

Assoc w/ chronic inflammatory disorders
-- H.pylori gastritis
-- Autoimmune diseases: Sjogren, Hashimoto thyroiditis
MALT lymphoma clinical presentation?
Extranodal
-- stomach (most common)
-- salivary gland
-- lung
-- orbit
-- skin
MALT lymphoma morphology?
Infiltrate of:
-- centrocyte-like cells
-- monocytoid B-cells
-- plasma cells

Reactive germinal centers

Lymphoepithelial lesions
-- lymphocytes infilt and destroy epith of crypts, ducts, and glands
MALT lymphoma immunophenotype?
B-cell (CD19+, CD20+)
-- monoclonal surface Ig
-- CD5(-), CD10(-)
MALT lymphoma classification?
Not in Working Formulation (low grade)

Recognized in REAL classification
MALT lymphoma staging?
usually localized
MALT lymphoma etiology?
Gastric MALToma associated w/ H.pylori infection
MALT lymphoma clinical course?
Indolent

Potential cure by :
-- antimicrobial therapy
-- surgical excision
-- radiation

May transform to higher grade, large cell lymphoma
What is Mycosis Fungoides (MF)/Sezary Syndrome?
A mature T-cell lymphoma arising in the skin
Mycosis Fungoides (MF)/Sezary Syndrome clinical features?
Most common cutateous T-cell lymphoma
-- indolent, waxing, waning 8-9yrs
-- progressive skin lesions from skin rash to plaques, and to tumor stages

Involvement of peripheral blood: Sezary Syndrome
Mycosis Fungoides (MF)/Sezary Syndrome morphology?
lymphoid infiltrate composed of:
-- small and large cells w/ "cerebriform" nuclei in the epidermis (epidermotropism and Pautrier's abscesses)
-- AND in the upper dermis

Circulating Sezary cells w/ cerebriform nuclei
Mycosis Fungoides (MF)/Sezary Syndrome immunophenotype?
Mature helper T cells (CD4+, CD3+)
Clinical features of Hodgkin lymphoma?
20-30% of all lymphomas in the U.S.

Bimodal age incidence:
-- 15 to 45 yrs
-- >50 yrs

Cervical lymphadenopathy or mediastinal mass
-- spread via contiguous LNs
-- "B" symptoms
Hodgkin lymphoma morphology?
1. Reed-Sternberg cells

2. Reed-Sternberg cell variants
-- mononuclear
-- lacunar cell
-- lymphocytic and histiocytic (L&H)

3. inflammatory background
-- histiocytes
-- plasma cells
-- eosinophils
Hodgkin lymphoma classification?
1. lymphocyte predominance HL (LPHL)

2. classic HL
-- nodular sclerosis (NS)
-- lymphocyte rich (LR)
-- mixed cellularity (MC)
-- lymphocyte depleted (LD)
Hodgkin lymphoma immunophenotype?
L&H cells
-- LCA+, CD20+

RS cells and variants:
-- LCA-, CD30+, CD15+, CD20-

Rule out NHL, carcinoma, melanoma
Hodgkin lymphoma staging?
Ann Arbor staging system

STAGE I:
-- single lymph node region OR
-- single extra-lymphatic site (Ie)

STAGE II:
-- 2 or more lymph node regions on the same side of the diaphragm OR
-- involvement of limited contiguous extra-lymphatic site (IIe)

STAGE III:
-- lymph node regions of both sides of the diaphragm, which may involve spleen, AND/OR
-- limited contiguous extra-lymphatic site (IIIe)

STAGE IV:
-- multiple or disseminated foci of involvement of 1 or more extralymphatic organs (liver, BM) OR
-- tissues w/ or w/o lymphatic involvement
Hodgkin lymphoma etiology?
Unknown cell of origin

Infectious/viral etiology

EBV viral genome found in many cases

Immunodeficiency (congenital and acquired)