Ch.6 Pathology of Lymph Nodes

XI. Non- Hodgkin's lymphoma cont'd

5. Working Formulation was replaced in 1994 with the Revised European American Lymphoma project (REAL) classification, proposed by the International Lymphoma Study Group.
6. This is now being modified by the World Health Organization (WHO)

a. Necessary because purely morphologic Working Formulation classification mixed T and B cell lymphomas together, obscuring the biologic, clinical and therapeutic differences between them, and distorting clinical trials
b. REAL/WHO is a "disease" oriented classsification based on cell lineage and stage of maturation of the presumed normal counterpart. Each entity may have differing grades of aggressiveness
c. Includes immunologic and molecular criteria in addition to purely morphologic criteria of the Working Formulation
d. Greatly expanded the list of entities,and includes leukemias of lymphoid origin
e. Made teaching to medical students (and in fact all physicians) even more difficult than previously
f. Finally, REAL contained a number of "provisional entities" which have undergone further clarification in the upcoming World Health Organization revision.

Table 2: International Lymphoma Study Group Classification (including provisional WHO categories)

B-Cell Neoplasms	T/NK-Cell Lymphoma	Hodgkin's Lymphoma
Precursor B-cell lymphoblastic leukemia/lymphoma	Precursor T cell lymphoblastic leukemia/lymphoma	Lymphocyte predominance, nodular

Peripheral B-cell neoplasms	Peripheral T-cell and NK-cell neoplasms	Classical HL
B-cell CLL/SLL	Predominantly leukemic/disseminated	Lymphocyte rich classical HL
B-cell prolymphocytic leukemia	T-cell prolymphocytic leukemia	Nodular sclerosis
Lymphoplasmacytic lymphoma	T-cell large granular lymphocytic (LGL)	Mixed cellularity
Mantle cell lymphoma	leukemia	Lymphocyte depletion
Follicular lymphoma	NK cell leukemia	Unclassifiable classical HL
Extranodal marginal zone B-cell lymphoma, MALT type (+/- monocytoid B cells)	Adult T-cell leukemia/lymphoma
Splenic marginal zone B-cell lymphoma (+/-villous lymphocytes)	Predominantly nodal
Hairy cell leukemia	Angioimmunoblastic T-cell lymphoma
Diffuse large B-cell lymphoma	Peripheral T-cell lymphoma unspecified
Burkitt lymphoma	Anaplastic large cell lymphoma, T/null-cell
Plasma cell myeloma	Predominantly extranodal
Plasmacytoma	Mycosis fungoides
	Sezary syndrome
	Primary cutaneous (CD30+ T-cell lymphoproliferative disorders)
	Subcutaneous panniculitis-like T-cell lymphoma
	NK/T cell lymphoma, nasal and nasal-type
	Enteropathy-type intestinal T-cell lymphoma
	Hepatosplenic T-cell lymphoma
	gd (gamma/delta)
	ab (alpha/beta)

7. REAL/WHO classification- backbone

a. B cell neoplasms

1) Precursor B cells-related to acute leukemia
2) Peripheral B cell lymphomas- the majority of B cell lymphomas

b T cell and Natural Killer cell neoplasms

1) Precursor T cells
2) Peripheral T cell and NK neoplasms

c Hodgkin's lymphoma

8. B cell neoplasms

a. Precursor B cell lymphoblastic leukemia/lymphoma

1) Frozen at lymphoblast cell stage of antigen independent B cell differentiation- normally restricted to bone marrow
2) Usually present as acute leukemia+/- lymph node involvement
3) Can initially present as node or skin disease, with later progression to bone marrow

b. Peripheral B-cell neoplasms- frozen at various stages of antigen dependent B cell maturation and differentiation

1) Small lymphocytic/CLL- the virgin B cell fresh from the marrow
2) Prolymphocytic leukemia- a more clinically aggressive variant of above
3) Lymphoplasmacytic lymphoma- the primary immune response
4) Mantle cell lymphoma- the mantle region surrounding the follicle
5) Follicular lymphoma- the follicle- grade 1-3
6) Extranodal marginal zone lymphoma- cells at the periphery of the follicle in extranodal sites of lymphoid tissue- Mucosal Associated Lymphoid Tissue- such as G.I. tract
7) Nodal marginal zone lymphoma
8) Splenic marginal zone lymphoma- immunologically distinct
9) Hairy cell leukemia- pre-plasma cell
10) Diffuse large B-cell lymphoma- this breaks the ideal of specific cell stage, but all represent lymphomas with high replication rate
11) Burkitt lymphoma- very aggressive
12) Plasma cell myeloma- diffuse bone marrow proliferation of plasma cells
13) Plasmacytoma- solitary focus of monoclonal plasma cells, with variable risk of progression to myeloma, depending on site

c. Why list separately, if most indolent?

1) Differ in clinical presentation, immunology, therapy, prognosis, molecular pathogenesis, even if all crudely categorized by median survival > two years
2) Examples "indolent" peripheral B

(a). follicular lymphoma- most common type of indolent lymphoma in US, and second most common type lymphoma overall

(1.) Disease of adults >40 (median age 59)
(2.) Usually widely disseminated at diagnosis, with bone marrow involvement
(3.) Will respond to "gentle chemotherapy" but will relapse-cannot be cured short of bone marrow transplant, but overall 5 yr survival 72%
(4.) Benign equivalent is small cleaved cell of germinal center
(5.) Cytology: clumped chromatin and infrequent nucleolus like small lymphocyte, but irregular nuclear profile, with nuclear folds or "cleavages"
(6.) Retain follicular structure, but monotonous accumulation of single cell type
(7.) Over time, additional mutations can occur, producing progression ("transformation") to large cell lymphoma and more aggressive clinical course
(8.) Pathogenesis: due to t(14;18), which upregulates expression of an anti-apoptotic protein Bcl2
(9.) Has characteristic immunophenotype: monoclonal light chain, CD19, CD10, Bcl2 positive, CD5, Bcl1/Cyclin D1 negative

(b). Imitator: Mantle cell lymphoma- 6% lymphomas

Looks like indolent but behaves aggressively
(1.) Disease of adults (median age 63)
(2.) Usually widely disseminated
(3.) Poor response to all attempted therapies, ? curable with transplant-overall 5yr survival 27%
(4.) Benign equivalent is lymphocyte of inner mantle zone
(5.) Cytology similar to cleaved cell, but nuclear irregularities not as prominent
(6.) Nodal infiltration diffuse, or expansion of mantle zone around residual benign follicles
(7.) Large cell progression not frequent
(8.) Pathogenesis due to t(11;14), which upregulates, Bcl1, a cell cycle effector
(9.) Immunophenotype: monoclonal light chain, CD19, CD5, Bcl1 (and Bcl2) positive, CD10 negative

Table X: Indolent B cell lymphomas+imitator

	Follicular Lymphoma (Grade I)	Small lymphocytic lymphoma/CLL	Marginal zone Lymphoma	*Mantle cell Lymphoma*
Frequency (% all lymphomas)	22%	7	8	6
Age of onset-median	59	65	61	63
Stage at Presentation	Stage III/IV (Disseminated)	Stage IV	Stage I	Stage III/IV
Response to Therapy	Good to most treatments, but incurable short of transplant	Similar to Follicular lymphoma	Frequently curable	Poor response to all therapies to date
5 yr survival	72%	51	74	27
Predominant site presentation	Nodal	Marrow/Nodal	Extranodal	Marrow/nodal
Pattern of nodal Infiltration	Follicular	Diffuse	Diffuse	Diffuse or "mantle zone"
Benign cell Equivalent	Germinal center small cleaved cell	Virgin B cell	Marginal zone Lymphocyte	Mantle cell
Dominant cell type	Small cleaved cell in most cases, but can be large cell	Small lymphocytes with round nucleus	Mix of small lymphocytes, plasma cells	Small cell with irregular nucleus, similar to cleaved
Immuno phenotype	Positive: CD19 CD10, Bcl2+ Negative: CD5	Positive: CD19 CD5,CD23 Negative: CD10	Positive: CD19 Bcl2 Negative: CD10, CD5	Positive: CD19 CD5, Bcl2 Negative: CD23, CD10
Molecular Pathogenesis	t(14;18) Bcl2/JH	Trisomy 12	Trisomy 3 t(11;18)	t(11;14) Bcl1/JH

3) Examples aggressive B cell lymphoma

(a.) diffuse large B cell lymphoma-30% NHL

(1.) Disease of adults and children- median age 64
(2.) Limited versus widespread disease 1:1
(3.) Approximately 40% curable with aggressive chemotherapy/ stem cell
transplant- partially predictable by International Prognostic Index
(4.) Benign equivalent- large replicating cells of germinal center and paracortex
(5.) Cytology: Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleoli.
Nucleus larger than that of reactive macrophage, often necrosis; increased mitotic rate
(6.) Diffuse infiltration of lymph node
(7.) Several cytologic subtypes initially felt to have differing clinical behavior. Yielded division into intermediate versus high grade types- now not felt valid or significant.
(8.) Pathogenesis not as clearly defined- several cytogenetic abnormalities associated with large cell lymphoma, but no defining one
(9.) Immunophenotype characterized by monoclonal light chain, CD19 expression, with variable expression of other B cell associated antigens

(b) Burkitt's lymphoma- 3% lymphomas

(1) Disease of adults and children- median age 31
(2) Initially recognized in Africa by Thomas Burkitt- noted association with Epstein Barr
virus infection and localization in jaw
(3) In US, usually presents in ileocecal region of children- 1/3 of all childhood lymphomas
(4) Approximately 40% of adults curable with very aggressive therapy; 70-80% children
(5) Benign equivalent is replicating small noncleaved cell of germinal center: cytology: round to oval nucleus, smaller than that of reactive macrophages with vesicular chromatin and 2-5 nucleoli
(6) Diffuse infiltration of lymph node
(7) Very high mitotic rate, lot of ineffective proliferation; attracts macrophages to phagocytize and produces a "starry sky" pattern at low power
(8) Pathogenesis: t(8;14), producing upregulation of myc oncogene, a cell cytcle regulation gene
(9) Immunophenotype: Monoclonal light chain, CD19, CD10 positive, CD5 negative

9. T cell lymphomas

a. Precursor T cell lymphoblastic lymphoma/leukemia

1) Disease of young teenagers; boys>girls
2) Can present as acute leukemia or mediastinal mass+/- marrow involvement
3) Aggressive lymphoma/leukemia, but curable ~70% with appropriate multiagent chemotherapy
4) Benign equivalent immature T cells of thymus
5) Cytologic features: "Blast cells" of intermediate size with oval to "convoluted" nuclear profiles, fine chromatin and 0-1 nucleolus
(a) Histology: Diffuse infiltration of thymus/adjacent lymph nodes
(b) Pathogenesis unclear, but frequently involves translocation of oncogenes to site of T cell receptor genes, and upregulation of protein production

b. Peripheral T cell lymphomas

1) Predominantly leukemic/disseminated

a) T-cell prolymphocytic leukemia
b) T-cell large granular lymphocytic (LGL) leukemia
c) NK cell leukemia
d) Adult T-cell leukemia/lymphoma

2) Predominantly nodal

a) Angioimmunoblastic T-cell lymphoma
b) Peripheral T-cell lymphoma unspccified
c) Anaplastic large cell lymphoma, T/null-cell

3) Predominantly extranodal

a) Mycosis fungoides
b) Sezary syndrome
c) Primary cutaneous CD30+ T-cell lymphoproliferative disorders
d) Subcutaneous panniculitis-like T-cell lymphoma
e) NK/T cell lymphoma, nasal and nasal-type
f) Enteropathy-type intestinal T-cell lymphoma
g) Hepatosplenic T-cell lymphoma

c. Key points regarding T cell lymphomas

1) Represent 20% all lymphomas
2) Tend to involve extranodal sites like skin, midline facial area, liver more than B cell,
with very characteristic clinical presentations
3) Cytologic features not as predictive of behavior as B cell lymphomas

(a) One of most aggressive looking, anaplastic large cell lymphoma,actually has better prognosis than most indolent B cell lymphomas-77% 5 year survival

4) Most common type in skin, mycosis fungoides, is an indolent lymphoma, similarly incurable, but with long clinical course
5) Most nodal disease is bad, high stage, and poorer response to therapy than B cell lymphomas of all grades
6) Immunophenotypic studies frequently demonstrate

(a) Loss of normal T cell associated antigens
(b) Antigens associated with Natural Killer cell function

7) Pathogenesis: Characteristic cytogenetic findings associated with several types

(a) Anaplastic large cell lymphoma- t(2;5): ALK1 gene
(b) Hepatosplenic T cell lymphoma- Isochromosome 7

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