Lymph Node & Lymphoma Pathology

What is the differential diagnosis for an enlarged lymph node?
Causes of lymphadenopathy include:
1. Reactive (benign)
2. Lymphoma (Hodgkin disease vs. Non-Hodgkin lymphoma)
3. Metastatic disease

Benign reactive lymphadenopathy
-Reaction to an immune stimulus
-Pathologic pattern relates to the type of cell stimulated, but is not specific as to the exact cause.
-Normal nodal architecture is preserved
-Most common cause of enlarged lymph nodes

Possible patterns of benign reactive lymphadenopathy
1. Follicular pattern (B-cell proliferation)
2. Paracortical pattern (T-cell proliferation)
3. Sinus histiocytosis (histiocytic proliferation)

To know about follicles…
-These are the B cell zones, primarily on the periphery of the lymph node
-Primary lymphoid follicle (B cell zone) is getting ready for antigen presentation
-When antigen is actively being presented, you have secondary follicles with germinal centers (look like punched out holes)

Describe follicular hyperplasia.
-Proliferation of B lymphocytes (and T-cells also important)
-Increased need for Ab production
-Enlargement of germinal centers with tingible-body macrophages (clear spaces: eating cells that have gotten signal to die) and increased mitotic activity
E.g. neck nodes in strep throat
**Another term for progression for primary to secondary follicles

Flow cytometry of a normal lymph node
-Mixture of B-cells and T-cells
-B-cells express both kappa and lambda light chains
-T-cells express either CD4 or CD8

Describe paracortical hyperplasia.
-Proliferation of T lymphocytes
-Increased need for cell-mediated immunity
-Expansion of paracortical regions with activated lymphocytes and increased mitotic activity
*E.g. neck nodes in infectious mono
**See histology on slide

Describe sinus histiocytosis.
-Proliferation of macrophages (=histiocytes)
-Stimulation of antigen-presenting cells
-Expansion of subcapsular/medullary sinuses
*E.g. lymph nodes draining a carcinoma
**See histology on slide

What is lymphoma?
Malignant neoplasm of lymphocytes associated with a solid mass or infiltrate
**Remember, leukemia primarily involves blood and bone marrow; lymphoma = tissue and lymph node

Lymphoma epidemiology
-6th most common cancer in U.S.
-74k new lymphoma cases annually in U.S. (65k Non-Hodgkin, 9k Hodgkin)
-21k deaths a year
-1k people worldwide diagnosed with lymphoma every day

Incidence of Non-Hodgkin Lymphoma Worldwide
Highest in U.S., Australia, New Zealand, Europe
*Lowest in Asia, some parts of Africa
-Incidence is rising

Non-Hodgkin Lymphoma: Risk factors
1. Age
2. Infections
3. Immune disorders
4. Toxins
-But most patients have no identifiable risk factor

Non-Hodgkin Lymphoma: Infections
HIV (CD4+ T-cells)
EBV, H. pylori, Hep B, Hep C, Human T-cell leukemia virus type 1 (HTLV-1), HHV-8

Non-Hodgkin Lymphoma: Medical conditions that compromise the immune system
HIV, Autoimmune disease, Use of immune suppressive therapy, Inherited immunodeficiency diseases

Non-Hodgkin Lymphoma: Toxic chemicals
-Pesticides, herbicides, or benzene
-Hair dye use in patients who started to use the dyes before 1980

Lymphoma Pathology Classification Schemes
-Working Formulation (previously)
-World Health Organization (WHO) (mostly used today)

Lymphoma Types: WHO Classification
1. Non-Hodgkin (far more common)
-B-cell (85% in N. America)
-T-cell (15% in N. America)
2. Hodgkin
-B-cell tumor, but we didn’t know this at the time of classification

B-cell malignancies: Cells of origin
Lymphomas arise from different stages of B-cell maturation.
-We name the lymphoma based on where the progenitor cell comes from.

The Working Formulation: grading system
1. Low Grade
-small lymphocytic lymphoma
-follicular small cleaved lymphoma
2. Intermediate Grade
-diffuse large cell lymphoma
3. High Grade
-Burkitt lymphoma
-lymphoblastic lymphoma
*Grade somewhat associated with clinical course

Lymphoma: signs in the lymph node
-Abnormal growth pattern in lymph node: loss of architecture (absence of germinal centers and sinuses)
–Histologic classification: growth pattern: Follicular vs. Diffuse
–Histologic classification: cell size: small (CLL) vs. intermediate vs. large (diffuse large B-cell lymphoma)

Small Lymphocytic Lymphoma (low grade)
-Essentially the same disease as CLL, but based in tissue instead of blood/marrow
-SLL and CLL are both:
1. comprised of small, round lymphocytes
2. have the same immunophenotype
3. occur in older adults
4. indolent but considered incurable
-Mature B-cell: CD19+, CD20+, CD22+, CD23+ — co-express CD5, kappa or gamma light chain (positive for kappa, negative for lambda)
-Cytogenetics important for prognosis: del 13q14 good prognosis, Trisomy 12 poor prognosis, loss of 17p (where p53 is) is always bad

CLL/SLL Peripheral Blood Smear
-Smudge cells

Follicular Lymphoma (low grade)
1. Middle-aged to elderly adults
2. 2nd most common type of NHL
3. Cells resemble normal germinal center cells (cleaved)
4. Mature B-cell immunophenotype
5. Cytogenetics: t(14;18) — BCL2 proto-oncogene translocated downstream of IgH gene regulatory sequences *Review
6. Low grade

Follicular Lymphoma (low grade): histology
Nodules / follicular zones (nodular, not diffuse)
-Small cleaved lymphocytes: convoluted morphology with cells that look dented

Follicular Lymphoma (low grade): flow cytometry
Positive for the kappa light chain but negative for the lambda light chain
-Monoclonal kappa phenotype
-B cells that also express CD10

Clinical progression of follicular lymphoma
1. Indolent course (median survival 10 years)
2. Incurable with conventional chemotherapy
3. Patients typically present with high stage disease (including marrow involvement)
4. May progress to diffuse large cell lymphoma
5. Mature B-cell phenotype
-(CD19+,CD20+,CD22+) CD10+ kappa or lambda light chain

Mantle Cell Lymphoma
-Numerous small lymphocytes (irregular, slightly smaller than histiocyte nucleus) with mixed in pink histiocytes (tissue macrophages)
-You would think this lymphoma would behave well, but it is actually very aggressive
*a reason that the Working Formulation didn’t work

Mantle Cell Lymphoma: Flow Cytometry
-Cells express CD20 and CD5 (like CLL)
-Unlike CLL, there is no CD23 expression
-Also negative for CD10
-All kappa, no lambda

Mantle Cell Lymphoma: Epidemiology
-Occurs in middle aged to elderly adults
-Appears low grade morphologically but acts more like an intermediate grade clinically

Mantle Cell Lymphoma: Flow cytometry, Genes
-Mature B-cell that is CD5+ but CD10- and CD23-
-Associated with diagnostic gene rearrangement t(11;14)
-Cyclin D1 gene (chromosome 11) juxtaposed with immunoglobulin heavy chain gene
-Tumor expresses high levels of Cyclin D1 (shown in immunohistochemistry as brown stains…)

Diffuse Large B-Cell Lymphoma (intermediate grade)
-Most common type of NHL
-Low stage disease can be cured (paradoxical because chemotherapy can differentiate better in high stage disease where cells divide very rapidly)
-Occurs in children and adults
-Can be associated with immune dysfunction (HIV, SCID, BM & organ transplants) *so some patients don’t need chemo
-1/3 of cases extranodal (GI tract, brain)
-Molecular: DLBCL often have an abnormal Bcl-6
-Flow cytometry: CD20+, either kappa or lambda

Burkitt Lymphoma (high grade): epidemiology
Small non-cleaved cell
-Endemic (Africa; >95% EBV genome positive)
-Non-endemic (worldwide: 15-20% EBV positive)
–Predominantly in children

Cytogenetics of Burkitt Lymphoma
-t(8;14) most common, also t(2;8) and t(8;22)
-c-myc proto-oncogene downstream of IgH gene
-closely related to ALL FAB L3
-mature B-cell phenotype

Burkitt Lymphoma: Histology
-“Starry sky” appearance: tingible body macrophages eating tumor (cells = sky, tingible = stars)
-Looks like germinal center: rapidly proliferating area

Burkitt Lymphoma: Cytology
Uniform population of cells with cytoplasmic vacuoles (abnormal feature)

T-cell malignancies: cells of origin
Precursor T-cells go awry
In mediastinal mass in teenager: T-lymphoblastic lymphoma (more T-cell)
In blood, BM: T-lymphoblastic leukemia (more B-cell)

Lymphoblastic Leukemia
-Lymph node correlate of ALL. Both are diseases of children, consists of lymphoblasts with similar phenotypes, are treated similarly.
-Lymphoblastic lymphoma more likely than ALL: to occur in teenagers and present with a mediastinal mass
-Immunophenotype is most often that of an immature T-cell expressing CD3, co-expression CD4 & 8 and TdT.

Hodgkin Lymphoma
1. Characterized by Reed-Sternberg cell, an activated B-cell
2. EBV genome is present about 40% of cases (100% of HIV cases)
3. Peak incidence in 20s, smaller peak at age >50 years (binodal distribution)
-Extranodal involvement unusual
-Spreads along contiguous or adjacent lymph nodes
*Teenager with mediastinal mass and lymphoma = Hodgkin or T-lymphoblastic leukemia lymphoma

Hodgkin Lymphoma Pathology
1. Diagnosis based on finding Reed Sternberg cells
-CD30+, CD15+, CD45-
-Neither flow cytometry nor cytogenetics diagnostic
2. Morphologic subtypes (used to correlate with prognosis): nodular sclerosis (most common), lymphocyte rich, mixed cellularity, lymphocyte depletion

Hodgkin Lymphoma: Immunohistochemical Stain
-Positive for CD15 and CD30
-Negative for CD45

Clinical presentation and treatment of Hodgkin Lymphoma
1. Sx due to growth of lymphocytes forming mass or LAD
2. Systemic symptoms = “B” symptoms
3. If you suspect disease, you need a biopsy

What are “B” symptoms?
Fevers > 38 degrees
Drenching night sweats
Weight loss (>10% over 6 months)

*A symptoms = no symptoms

Natural History and Cure Rate for different grades
1. Low grade (follicular, small lymphocytic) = Many years = Incurable
*Mantle cell: low/intermediate grade
2. Intermediate grade (diffuse large B-cell) = a few years = curable (20 to 80%)
3. High grade (Burkitt, lymphoblastic) = months = curable (>=80%)
*Hodgkin’s Disease is similar to intermediate grades with 60-95% cure

Staging system for lymphomas, particularly useful for Hodgkin’s
I: A single nodal region or extranodal site
II: 2 or more nodal regions
III: Lymphatic involvement on both sides of diaphragm
IV: Liver or bone marrow involvement
Each stage is A or B depending on presence of symptoms
*Info from radiographic studies, bone marrow biopsy

Presentation, Treatment: by grade
Low grade: often asymptomatic, treat
Intermediate: sometimes asymptomatic, R-CHOP +/- XRT
High: Usually asymptomatic, treat similar to lymphoblastic leukemia
*Hodgkin’s: treat with ABVD +/- XRT (X-ray therapy)

R-CHOP
Rituximab, cyclophosphamide, adriamycin, vincristine, prednisone
CHOP = trade names

ABVD
Doxorubicin (trade name adriamycin), bleomycin, vinblastine, dacarbazine

XRT
radiation therapy

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