Module 6 Path

Front 1

Define lymphoma.

Back 1

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

Front 2

What areas do leukemias involve?

Back 2

Peripheral blood and BM, but may spread to lymphoid organs

Front 3

The majority of lymphomas present with...?

Back 3

lymphadenopathy
-- 1/3 arise in extranodal sites such as GI (MALT lymphoma)

Front 4

Two major lymphoma categories?

Back 4

1. Hodgkin

2. Non-Hodgkin

These two are morphologically, immunophenotypically, and clinically distinct

Front 5

Non-Hodgkin lymphomas and maturation?

Back 5

They relate to normal stages of B or T cell maturation
-- distinct morphology
-- distinct immunophenotype

Front 6

The Dx of lymphoma requires...?

Back 6

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

Front 7

What are the steps involved in the Dx of lymphoma?

Back 7

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

Front 8

Morphology of Non-Hodgkin lymphoma (NHL)?

Back 8

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

Front 9

Immunophemotype of NHL?

Back 9

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

Front 10

Genotype/cytogenetics of NHL?

Back 10

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

Front 11

Major lymphoma classifications of NHL?

Back 11

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

Front 12

What is the basis of the Working Formulation for clinical usage classification of NHL?

Back 12

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

Front 13

What are the three "clinical grades" of NHL.

Back 13

Low grade
Intermediate grade
High grade

Front 14

Describe low grade NHL

Back 14

-- 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

Front 15

Describe intermediate grade NHL.

Back 15

-- 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

Front 16

Describe high grade NHL.

Back 16

-- large proliferative fraction

1. lymphoma, large cell, immunoblastic

2. lymphoma, lymphoblastic

3. lymphoma, small noncleaved cell (SNC)

Front 17

What are the difficulties with the WHO classification?

Back 17

1. Not distinct disease entities

2. Some of the more recently recognized lymphomas (mantle cell, MALT) are not included in the classification

Front 18

What is the revised European-American Classification of Lymphoid Neoplasms (REAL)?

Back 18

1. well defined "real" diseases

2. distinct clinicopathological entities based on a combination of:
-- morphology
-- immunophenotype
-- cytogenetic and molecular studies
-- biological behavior

Front 19

Which classification is preferred for NHL?

Back 19

Currently the WHO classification is preferred (based on similar principles as its predecessor, REAL)

Front 20

List the WHO B cell neoplasms.

Back 20

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

Front 21

List the WHO T cell neoplasms.

Back 21

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

Front 22

How are NHLs categorized?

Back 22

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

Front 23

Clinical presentation of follicular lymphoma (FL)?

Back 23

MOST COMMON NHL in the U.S.

Median age 50-60yrs

Males = females

Generalized painless lymphadenopathy

Front 24

FL morphology?

Back 24

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

Front 25

FL immunophenotype

Back 25

B cell (CD19+, CD20+)
-- CD10(+)

Monoclonal kappa or lambda light chain

BCL2 protein +

Front 26

FL genotype?

Back 26

t(14;18)(q32;q31)

BCL2 rearrangement

Front 27

FL classification?

Back 27

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

Front 28

FL staging?

Back 28

Most present w/ advanced stage (75% at stage IV)

Front 29

FL pathogenesis?

Back 29

BCL-2 gene rearrangement t(14;18)
-- leads to BCL-2 overexpression
-- BCL-2 inhibits apoptosis
-- prolinged survival of follicle center cells

Front 30

FL clinical course?

Back 30

Median survival or 7-9 yrs

NOT cured by therapy

30-50% progress to diffuse large cell lymphoma
-- median survival <1yr

Front 31

Describe diffuse large cell B cell lymphoma.

Back 31

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

Front 32

Clinical presentation of small lymphocytic lymphoma (SLL)?

Back 32

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

Front 33

SLL morphology?

Back 33

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

Front 34

Clinical presentation of Burkitt lymphoma?

Back 34

30% of childhood NHL

A subset of lymphomas occurring in HIV infected

Most tumors manifest at extranodal sites

Front 35

Two major clinical types of Burkitt lymphoma?

Back 35

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

Front 36

Burkitt lymphoma morphology?

Back 36

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

Front 37

Burkitt lymphoma immunophenotype?

Back 37

B-cell (CD19+, CD20+)
-- monoclonal kappa or lambda light chain
-- CD10(+)
-- BCL2(-)

Front 38

Burkitt lymphoma classification?

Back 38

WORKING FORMULATION
high grade lymphoma, small noncleaved cell type

Front 39

Burkitt lymphoma staging?

Back 39

variable stage at presentation

Front 40

Burkitt lymphoma pathogenesis

Back 40

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

Front 41

Burkitt lymphoma clinical course?

Back 41

highly aggressive

curable w/ aggressive therapy

Front 42

What is MALT lymphoma?

Back 42

Presents as extranodal disease in mucosa associated lymphoid tissue

Assoc w/ chronic inflammatory disorders
-- H.pylori gastritis
-- Autoimmune diseases: Sjogren, Hashimoto thyroiditis

Front 43

MALT lymphoma clinical presentation?

Back 43

Extranodal
-- stomach (most common)
-- salivary gland
-- lung
-- orbit
-- skin

Front 44

MALT lymphoma morphology?

Back 44

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

Front 45

MALT lymphoma immunophenotype?

Back 45

B-cell (CD19+, CD20+)
-- monoclonal surface Ig
-- CD5(-), CD10(-)

Front 46

MALT lymphoma classification?

Back 46

Not in Working Formulation (low grade)

Recognized in REAL classification

Front 47

MALT lymphoma staging?

Back 47

usually localized

Front 48

MALT lymphoma etiology?

Back 48

Gastric MALToma associated w/ H.pylori infection

Front 49

MALT lymphoma clinical course?

Back 49

Indolent

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

May transform to higher grade, large cell lymphoma

Front 50

What is Mycosis Fungoides (MF)/Sezary Syndrome?

Back 50

A mature T-cell lymphoma arising in the skin

Front 51

Mycosis Fungoides (MF)/Sezary Syndrome clinical features?

Back 51

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

Front 52

Mycosis Fungoides (MF)/Sezary Syndrome morphology?

Back 52

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

Front 53

Mycosis Fungoides (MF)/Sezary Syndrome immunophenotype?

Back 53

Mature helper T cells (CD4+, CD3+)

Front 54

Clinical features of Hodgkin lymphoma?

Back 54

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

Front 55

Hodgkin lymphoma morphology?

Back 55

1. Reed-Sternberg cells

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

3. inflammatory background
-- histiocytes
-- plasma cells
-- eosinophils

Front 56

Hodgkin lymphoma classification?

Back 56

1. lymphocyte predominance HL (LPHL)

2. classic HL
-- nodular sclerosis (NS)
-- lymphocyte rich (LR)
-- mixed cellularity (MC)
-- lymphocyte depleted (LD)

Front 57

Hodgkin lymphoma immunophenotype?

Back 57

L&H cells
-- LCA+, CD20+

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

Rule out NHL, carcinoma, melanoma

Front 58

Hodgkin lymphoma staging?

Back 58

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

Front 59

Hodgkin lymphoma etiology?

Back 59

Unknown cell of origin

Infectious/viral etiology

EBV viral genome found in many cases

Immunodeficiency (congenital and acquired)