Pathology of Lymphomas Flashcards
Tumor grade in lymphoma
Matters more in lymphomas than for some other malignancies
- lymphomas are essentially metastatic in nature
- treatment is very heavily dependent upon chemo and radiation –> not amenable to surgery
- high grade tumors are more susceptible to treatment
- –> replicate very quickly - cell division is a vulnerable time and drugs are most effective
- –> often diverge more from normal cells - have a better chance of killing the tumor cells and not healthy cells
- if treatment fails, usually a poor prognosis
Tumor stage in lymphoma
Stage 1 = single location
Stage 2 = multiple sites, same side of the diaphragm
Stage 3 = multiple sites, both sides of the diaphragm
Stage 4 = diffuse involvement of non-lymphoid organs
Tumor staging techniques
- Biopsy/resection methods
- needed to establish diagnosis
- differential may include other malignancies or inflammatory conditions - Radiology
- Clinical findings
- Blood
- CSF
Hodgkin Lymphoma
Neoplastic proliferation of Reed Sternberg cells = large B cells with multilobed nuclei + prominent nucleoli (owl eyed nuclei) –> positive for CD15 + CD30
RS cells secrete cytokines
- occasionally results in B symptoms = night sweats, fevers, chills, weight loss
- attract reactive lymphocytes, plasma cells, macrophages and eosinophils
- may lead to fibrosis
Reactive inflammatory cells make up a bulk of the tumor and form the basis for classification of HL
Less often widely disseminated as compared to Non-Hodgkins lymphomas –> pattern of spread closer to carcinoma (travels to adjacent areas)
Hodgkin Lymphoma - Morphology
Reed Sternberg cells = minority of cells
- mostly germinal center or post-germinal center B cells
- big, prominent nuclei + nucleolus (owl eye)
- lots of cytoplasm
Reactive infiltrate = majority of cells
- lymphocytes, plasma cells, eosinophils, etc –> often predominates
- limits the utility of flow cytometry/molecular studies
Hodgkin Lymphoma - Subtypes
Classical = regular RS cells
- different subtypes within this category
- CD15+/CD30+
- EBV + often –> depends on subtype
- prognosis depends on subtype
Non-classical = popcorn RS cell
- lymphocyte predominant subtype
- CD15-, CD30-, EBV-
- prognosis generally good
Subtypes of classical Hodgkins Lymphoma
- Nodular sclerosing = most common
- classic presentation is an enlarging cervical or mediastinal lymph node in a young adult, usually female
- lymph node is divided by bands of sclerosis
- RS cells are present in lake like spaces = lacunar cells
- rare EBV association - Lymphocyte rich = EBV+ 40% of time
- best prognosis of all types - Mixed cellularity = EBV + 70% of time
- Often associated with abundant eosinophils –> RS cells produce IL-5 - Lymphocyte depleted = EBV 90% of time
- most aggressive of all the types
- seen in elderly and HIV positive patients
*Generally, as ratio of RS:lymphocytes increases = rate of EBV+ increases and prognosis decreases
Hodgkins vs. Non-Hodgkins
Localization
- Hodgkins = localized
- NHL = disseminated/diffuse
Spread
- Hodgkins = contiguous
- NHL = non-continguous
Extranodal presentation
- Hodgkins = rare
- NHL = common
B symptoms
- Hodgkins = marked
- NHL = usually mild/absent
Diffuse Large B Cell Lymphoma
Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
- most common form of NHL
- Clinically aggressive = high grade
Arises sporadically or from transformation of a low grade lymphoma (eg follicular lymphoma)
Presents in late adulthood as an enlarging lymph node of an extranodal mass –> can arise anywhere in the body
DLBCL - Morphology
- diffuse pattern of growth
- large cells ~5x normal lymphocyte diameter
- may be hard to correctly identify
- –> may resemble hodgkins
- –> may resemble non-lymphomatous malignancy
DLBCL - Immuno and Molecular
Express mature B cell immunomarkers
- flow cytometry may not be useful –> cells die quickly
Heterogeneous molecular abnormalities
- BCL6
- t(14:18) (Bcl2)
- ** these mutations are mutually exclusive
- may derive from several different unidentified precursor lesions with DLBCL as a common morphologic endpoint
DLBCL - Viral associated subtypes
Immunodeficiency-associated
- HIV/bone marrow transplant
- EBV driven
Primary effusion lymphoma = occupies pleural space between chest wall and lung
- HHV8 association
- don’t express B or T cell markers = hard to recognize –> IgH gene arrangement
Burkitt Lymphoma
Neoplastic proliferation of intermediate sized B cells (CD20+)
- associated with EBV
- classically presents as an extranodal mass in a young adult or child
3 major epidemiologic types
- Endemic (African) - practically all EBV
- –> usually involves jaw - Sporadic form - minority EBV
- –> usually involves the abdomen - HIV-minority EBV
* **subtypes are histologically identical but the clinical picture differs
Burkitt Lymphoma - Morphology
- medium sized cells with moderate cytoplasm
- high rate of apoptosis –> macrophages with dead cells = “starry sky”
- extremely high rate of mitosis –> virtually all cells are in cycle (Ki67 ~100%)
- often presents as a rapidly growing on mass –> depending on location may be an emergency
Burkitt Lymphoma - Immuno and Molecular
Mature B cells –> usually not Bcl2
High rate of mitosis –> extremely high Ki67
All forms have c-MYC translocation (chromosome 8)
- over expression of c-myc oncogene promotes cell growth
- t(8;14) = most common –> translocation of c-myc to the IgH locus on chrom 14
- t(2;8) = Ig kappa
- t(8;22) - Ig lambda
Follicular lymphoma
Neoplastic proliferation of small B cells (CD20+) that form follicle like nodule
- germinal center B cells
- presents in late adulthood with painless lymphadenopathy
- may transform to more aggressive lymphoma
Driven by t(14;18)
- BCL2 on chromosome 18 translocates to the IgH locus on chromosome 14 –> results in overexpression of Bcl2 = inhibits apoptosis
Follicular lymphoma - morphology
- lymph nodes, spleen, marrow, liver
- nodular aggregates of cells (resemble follicles)
- cells
- –> centrocytes = small cells, irregular nuclear contours and little cytoplasm (usually majority)
- –> centroblasts = bigger cells with nucleoli and more cytopasm
Follicular lymphoma - immunophenotypes
Mature B cell markers
Distinguished from reactive follicular hyperplasia by:
- disruption of nomral lymph node architechture –> maintained in follicular hyperplasia
- lack of tingible body macrophages in germinal centers –> present in follicular hyperplasia (eat dead B cells)
- Bcl2 expression in follicles –> not expressed in follicular hyperplasia
- monoclonality –> follicular hyperplasia is polyclonal
Follicular lymphoma - transformation
Normal follicular center cells undergo somatic hypermutuation - so do follicular lymphomas
- 30-50% transform eventually, usually to DLBCL –> presents as an enlarging lymph node
Follicular lymphoma - Tx
Reserved for patients who are symptomatic
- involves low dose chemo or rituximab
Marginal zone lymphoma
Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone
- marginal zone is formed by post germinal center memory B cells
Occurs in lymph nodes/spleen, but often extranodal
- mucosal associated lymphoid tissue = MALToma or MALT lymphoma (e.g. in GI)
- often associated with chronic inflammatory states such as hashimotos, sjogren syndrome or h. pylori
- may regress if cause of inflammation is fixed
Marginal zone lymphoma - Morphology
- moderate cytoplasm
- fairly normal looking on a cell by cell basis
- may invade epithelial structures = lymphoepithelial lesion
Marginal zone lymphoma - immuno and molecular
No specific markers –> diagnosis of exclusion
Mantle cell lymphoma
Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
- presents in late adulthood with painless lymphadenopathy
Driven by t(11;14)
- cyclin C1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
- overexpression of cyclin D1 promotes G1/S transition in the cell cycle –> facilitates neoplastic proliferation
Mature T or NK cell Lymphomas
Important subtypes
- adult T cell leukemia/lymphoma
- anaplastic large-cell lymphoma
- extranodal NK/T cell lymphoma
- mycosis fungoides/szary syndrome
- peripheral T cell lymphoma NOS
Adult T cell lymphoma
Neoplastic proliferation of mature CD4+ T cells
- associated with HTLV1 –> viral material present in tumor cells
- most commonly seen in japan and the carribean
Tumor cells with cloverleaf multilobulated nuclei
Adult T cell lymphoma - clinical features
- rash
- generalized lymphadenopathy with hepatosplenomegaly
- lytic bone lesions with hypercalcemia
Anaplastic large cell lymphoma
Often involves soft tissue
Large anaplastic cells
- clusters around vessels and lymphatics
- may mimic carcinoma
ALK constitutively activated –> similarly appearing tumors that are ALK-negative have a different behavior
Extranodal NK/T cell lymphoma
Destructive mass often of the nasopharynx
- can be skin or testis occassionally
Invades vessels –> causes ischemic necrosis
Strong association with EBV
- identical EBV material within all neoplastic cells of a given tumor
Mycosis Fungoides/Sezary Syndrome
Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin –> produces a local skin rash, plaques and nodules
- aggregates of neoplastic cells in the epidermis = pautrier microabscesses
Cells can spread to involve the blood –> produces Sezary syndrome
- characteristic lymphocytes with cerebriform nuclei are seen on blood smear
Peripheral T cell Lymphoma NOS
Heterogeneous collection of several T cell lymphomas that don’t fit into other categories
- effacement of lymph node architecture
- pleomorphic malignant cells
- also non-neoplastic reactive cells
- mature T cell immunophenotype
Plasma cell neoplasia - Types
MGUS Plasmacytoma Multiple myeloma Disease related to overproduction of Ig - Primary amyloidosis - Heavy-chain disease - Waldenstrom macroglobulinemia
MGUS
Monoclonal gammopathy of uncertain significance
- asymptomatic elevated monoclonal paraprotein (Ig/Ig light chain) component in blood = monoclonal protein –> m protein
- lacks criteria for any of the other more serious diagnoses
- pre-neoplastic condition, relatively common
- coverts to myeloma at ~1% per year
Smoldering Myeloma
Elevated marrow plasma cells (>10%)
Serum M component at myeloma levels
Asymptomatic
- no bone lesions
- no anemia, hypercalcemia, or renal insufficiency
Plasma cell myeloma
AKA plasmacytoma
- marrow-based lesion
- increased marrow plasma cells, even away from lesion
- elevated M component
- may be solitary or multiple
Multiple myeloma
Malignant proliferation of plasma cells in the bone marrow –> even away from lesions
- most common primary malignancy of bone
- multipe plasmacytomas
- normal and abnormal plasma cell forms
- multiple molecular defects reported
- chromosomes 1, 11 and 14 most often involved
Monoclonal Ig Deposition Disease
Primary Amyloidosis- light chains (usually gamma) deposited as amyloid
- Many, but not all, associated with MM
Heavy chain disease
- Deposit in tissues (not as amyloid) and may cause dysfunction
Waldenstrom macroglobulinemia- high IgM levels –> hyperviscosity of blood
Hairy cell leukemia
Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes
- cells are positive for tartrate resistant acid phosphatase (TRAP)
Clinical features
- suppression of other marrow elements with fibrosis –> anemias, infections
- “dry tap” on bone marrow aspiration –> due to marrow fibrosis
- splenomegaly –> due to accumulation of hairy cells in red pulp
- lymphadenopathy usually absent
Cells with hairlike projections
Langerhans cell histiocytosis
Neopastic proliferation of Langerhans cells
- multifocal –> bone, liver spleen, skin, lung = aggressive
- unisystem –> bone
- pulmonary –> usually adult smokers, may be reactive
Langerhans cell histiocytosis - Morphology
- langerhans cells = histiocytes with deeply grooved nuclei and abundant cytoplasm (coffee bean)
- birbeck granules on electron microscopy = tennis rackets
- immunostain for S100 and CD1a
Post transplant lymphoproliferative disorders
Immune system normally plays a role in cancer surveillance/prevention
Transplantation requires suppression of immune system in order to not reject the allograft
- This allows tumors to develop at a higher-than-normal rate
- Lymphoproliferative disorders and skin cancers are the two biggest types
B-cell neoplasms driven by EBV
Typically risk of malignancy is roughtly proportional to the degree of immune suppression
In early stages, you can try to treat this by reducing immune suppression
- May lead to trouble with rejection
Summary of translocations
t(8;14) Burkitt lymphoma
Other translocations involving c-MYC (8)
t(14;18) Follicular lymphoma
t(11;14) Mantle cell lymphoma
Translocations involving ALK (2)- ALCL
Summary of viral associations
EBV- Hodgkin, DLBCL (immune-deficiency), Burkitt, extranodal NK/T, PTLD
HTLV- Adult T-cell lymphoma
HHV8- DLBCL (primary effusion)
