Hematologic Malignancies III Flashcards
What is the recurring theme in B cell malignancies?
translocation of an oncogene to an Ig promoter, results in overexpression of the oncogene
ex: Myc moves to IgH promoter (14q32) region
As a general rule (with exceptions), more aggressive B-cell malignancies arise from ____ and less aggressive malignancies arise from ____.
less mature/differentiated cells (i.e., precursor B cells in bone marrow); more mature and well differentiated cells (i.e., plasma cells and memory B cells)
True or false: malignancies that appear to develop from well differentiated B cells can transform into more aggressive forms.
True
Name a non-morphologic indicator of B cell maturation.
Ig expression: surface IgM on interfollicular, naive B cells; surface IgG on activated perifollicular B cells
Name the immunophenotypic markers of the following key stages of B cell development:
- Precursor B cells (in bone marrow)
- Interfollicular B cells
- Follicular B cells (germinal center centroblasts/centrocytes)
- Perifollicular/fully activated B cells (plasma & memory B cells)
- TdT, CD10, CD19, CD20
- CD19, CD20
- CD10, CD19, CD20
- CD38, CD138
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of chronic lymphocytic leukemia/lymphoma (CLL)?
Clinical: lymphocytosis in older males; high familial incidence
Anatomic: peripheral blood > bone marrow, lymph nodes; in lymph nodes memory B cells in mantle zone (perifollicular area) Micro: smudge cells in peripheral blood - small LCs with little cytoplasm and mature (dense) chromatin; pseudofollicular lymph nodes - collections of slightly larger cells undergoing DNA synthesis/mitosis
What is the immunophenotype and genetic/molecular pathogenesis of chronic lymphocytic leukemia/lymphoma (CLL)?
Immunophenotype: light chain restricted (K or L), CD5+, CD20 weak, Cd23+
Genetics: 80% show FISH abnormalities; del 13q14.3 (good) > trisomy 12 > del 11q22-23, del 17p13 (P53 region-BAD)
What is the clinical course and prognosis of chronic lymphocytic leukemia/lymphoma (CLL)?
chronic (except when it’s not); prognosis: ZAP-70 and CD38 expression is bad; 17p deletion is bad; 13q deletion only is good; >30% smudge cells good; increasing fraction of prolymphocytes is bad
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of mantle cell lymphoma (MCL)?
Clinical: lymphadenopathy and/or lymphocytosis in older males, can resemble CLL at presentation but MCL is more aggressive
Anatomy: lymph nodes > BM/spleen/peripheral blood/GI tract
Micro: smudge cells and small LCs (little cytoplasm) in peripheral blood; lymph nodes with homogenous effacement “starry sky”
*Key difference btw MCL and CLL: no proliferation centers in lymph node in MCL
What is the immunophenotype and genetic/molecular pathogenesis of mantle cell lymphoma (MCL)?
IP: light chain restricted (K or L); CD5+, CD20 strong, CD23-
Genetics: t(11;14)(q13;q32) (IgH; Cyclin D1) always seen by FISH
What is the clinical course and prognosis of mantle cell lymphoma (MCL)?
more aggressive than CLL; key predictor is the Ki-67 immunostain which shows mitotic rate
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of sporadic Burkitt lymphoma?
Clinical: abdominal mass in children or young adults; higher incidence in HIV+ patients
Anatomy: ileo-cecal area/ovaries/kidneys
Micro: memory B cells: intermediate sized with basophilic/vacuolated cytoplasm; lymph nodes with homogenous effacement, high growth and death rate; “starry sky” appearance because of the large cells with clear cytoplasm (macrophages); variation in nucleus size and shape
What is the immunophenotype and genetic/molecular pathogenesis of sporadic Burkitt lymphoma?
IP: normal B cell markers - CD10+, CD19+, CD20+
Genetics: translocation of MYC (8q24) to an Ig promoter - either IgH (14q32) or a light chain - K (2p12) or L (22q11); that is: translocation (8;14), (8;2), or (8;22)
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of endemic Burkitt lymphoma?
Clinical: jaw/facial bone mass in child age 4-7 in p. falciparum malaria endemic area (i.e., Ghana, Papua New Guinea)
Anatomy: jaw/facial bone
Micro: memory B cells, same as sporadic Burkitt’s
What is the immunophenotype and genetic/molecular pathogenesis of endemic Burkitt lymphoma?
IP: same as sporadic Burkitt’s
Genetics: same as sporadic Burkitt’s but EBV positive
Molecular pathogenesis is poorly understood
What is the clinical course and prognosis of sporadic and endemic Burkitt lymphoma?
with treatment can achieve 8 year survival rate, even 30% of high-risk cases (this is outside information to maintain consistency of malignancy information)
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of plasma cell neoplasms (PCN)?
Clinical: common in elderly; can be mild (asx lab findings–MGUS) or severe (multiple lytic bone lesions–plasma cell myeloma) with pain, fractures, and renal failure; labs show inc. total protein and Rouleaux (stacks of RBCs on smear)
Anatomy: BM»_space; peripheral blood
Micro: plasma cells have lots of cytoplasm, eccentric nucleus, clumpy chromatin, large and obvious Golgi (hof) “blue sky clearing” by nucleus; lots of these cells collecting in BM can leave bone lesions (seen radiologically, hence multiple myeloma)
What is the immunophenotype and genetic/molecular pathogenesis of plasma cell neoplasms (PCN)?
IP: CD38+++, CD138+++, CD19-, CD20-; light chain restricted
Genetics: translocation of IgH to various oncogenes in 2/3 of cases; trisomies of odd numbered chromosomes are common
What is the clinical course and prognosis of plasma cell neoplasms (PCN) [differentiated between MGUS and MM]?
MGUS: 1%/year progress to MM
MM: median survival 3-4yrs
Negative predictors: serum beta2 microglobulin; t(4;14) FGFR3; t(14;16) C-MAF; t(14;20) MAFB; del 17p - p53 region
What is IFE?
immunofixation electrophoresis: run lanes of proteins, transfer to support matrix and visualize with reagent stain (either stain most all proteins or only certain Ig proteins); normally will show lanes of smears (polyclonal proteins) but abnormal will show a single band indicating that monoclonal proteins are present
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of follicular lymphoma?
Clinical: lymphadenopathy (big, non-tender lymph nodes) in older patients, can otherwise be asx
Anatomy: germinal centers in lympho nodes; can involve BM and peripheral blood
Micro: cells of variable size, no tingible body macrophages, fewer mitotic figures than normal
What is the immunophenotype and genetic/molecular pathogenesis of follicular lymphoma?
IP: CD19+, CD20+, CD10+, Bcl-2+, Bcl-6+
Genetics: Bcl-2 (18q21) overexpression (failure of B cells to apoptose), often due to translocation of oncogene to IgH promoter region; t(14;18)(q32;q21); many others
What is the clinical course and prognosis of follicular lymphoma?
variable clinical course depending on stage, grade (how many centroblasts are present), and cytogenetics; 30% progress to diffuse large B cell lymphoma
What is the difference between centroblasts and centrocytes?
Centroblasts are larger B cells undergoing somatic hypermutation and class switching in the germinal center. Centrocytes are B cells that have finished their centroblast proliferation; normally would apoptose if not going to be plasma cell but in FL they don't and instead accumulate in the germinal center. Grade of FL: lower = more centrocytes; higher = more centroblasts
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of diffuse large B-cell lymphoma?
Clinical: rapidly growing adenopathy; elderly, 40% with extranodal disease (GI, BM, other)
Anatomy: lymph nodes, germinal centers
Micro: category defined by morphology only; may also correlate with germinal center and post-germinal center B cells
What is the immunophenotype and genetic/molecular pathogenesis of diffuse large B-cell lymphoma?
IP: CD19+, CD20+, CD10+
Genetics: t(v, 3q27)(v, Bcl-6); t(14;18); multiple others
What is the clinical course and prognosis of diffuse large B-cell lymphoma?
depends on stage; predictors include BM involvement and appearance (concordant vs. disconcordant)
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of Hodgkin lymphoma?
Clinical: males age 30-50; 2 major subtypes: Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHD)
Anatomy: localized or diffuse adenopathy, often involvement of cervical, mediastinal, or abdominal lymph nodes, and/or spleen
Micro: Classical - Reed/sternberg cells, diverse background cells (lymphocytes or not), can contain nodular sclerosis pattern; NLPHL - R/S cells are smaller (“popcorn” cells) with less prominent nucleoli, sometimes large, densely staining nuclei with little cytoplasm (“mummified”), mostly background lymphocytes and T cells that surround the R/S cells
What is the immunophenotype and genetic/molecular pathogenesis of Hodgkin lymphoma?
IP: Classical - CD30+, CD15+, Pax5+, CD20- weak; NLPHD - CD30-, CD15-, Pax5+, CD20+
Genetics: not currently useful
*Can’t use flow cytometry because the R/S cells are large and fragile - don’t survive dicing of the lymph node
What is the clinical course and prognosis of Hodgkin lymphoma?
curable with chemo/RT; predictors include stage and histological type; 3-5% of NLPHD progress to diffuse large B cell lymphoma
Describe the origin and appearance of Reed-Sternberg cells, and the major difference between the R/S cells of classical and NLPHD Hodgkin lymphoma.
R/S cells are B cells that don’t die in germinal centers; classical type avoid apoptosis by disabling IgH expression, whereas NLPHD DO express surface Ig and other B cells markers. These large lymphoid cells have mono- or bi-nucleate appearance, huge eosinophilic nucleoli; overall horseshoe shape is likely. Similar cells can be seen in some reactive conditions, such as mononucleosis. However R/S cells can’t be killed due to either: overactive NF-kappaB expression (mutation), EBV, or anti-apoptotic mutations. Likely genetic instability.
True or false: malignancies that appear to develop from well differentiated T cells can transform into more aggressive forms.
False - there is no such correlation with T-cell malignancies
Name the immunophenotypic markers of the following key stages of T cell development:
- Precursor T cells (in bone marrow and thymus)
- Peripheral Lymphoid Tissue T cells
- TdT early, CD3+ (cytoplasmic) later, then CD4+ AND CD8+
- CD3+ (surface), CD4+ OR CD8+
* CD7+ throughout
Name the immunophenotypic markers of gamma/delta T cells and NK cells.
gamma/delta T cells: CD3+ (surface); CD4-, CD8+/-, CD7-
NK cells: CD3+ (cytoplasmic)
How can clonality of a T cell malignancy be demonstrated?
PCR-based studies of the TCR gene
What is the best way to IP diagnose mycosis fungoides?
it’s a malignancy of T cells that express CD4+ and other antigens like CD3+, but usually not the complete package of 4/5 normal T cell antigens; finding T cells that lack 1 or more T cell antigens is one way to diagnose
What is the clinical presentation, anatomic distribution of proliferation, and microscopic appearance of mycosis fungoides?
Clinical: patchy red, flat skin lesions that can progress to ulcers; usually presents in elderly
Anatomy: lymphocytes invade mostly epidermis, can also involve bloodstream (Sezary syndrome) and lymph nodes, spleen, liver
Micro: CD4+ T cells, normal sized with indented nuclei; malignant clusters of lymphocytes are called Pautrier micro-abscesses (though they are not really abscesses)
What is the immunophenotype and genetic/molecular pathogenesis of mycosis fungoides?
IP: CD3+, CD4+, CD5+
Genetics: clonal rearrangement of the TCR gene - major distinction between this and some kind of chronic inflammatory/reactive condition, because they will be polyclonal TCR and the malignancy will be monoclonal
Describe peripheral T cell lymphoma, NOS.
diffuse lymphadenopathy, B symptoms (fever, night sweats, weight loss), paraneoplastic features (eosinophilia, pruritis, hemolytic anemia); usually doesn’t involve blood stream; expanded paracortex and abnormal architecture in lymph nodes, OR paracortical clusters of epitheloid histiocytes
IP: loss of 1/more of CD3+, CD5+, CD7+, CD4+ OR CD8+; can also be a double positive (CD4+/CD8+)
Genetics: complex karyotype with multiple chromosomal gains/losses, no real pattern; course is aggressive
Excess CD10+ (along with CD3+ and CD4+) on cells in paracortex of lymph nodes is a finding of what type of T cell lymphoma?
Angioimmunoblastic T cell lymphoma
Which of the following is a typical morphologic feature for CLL cells?
Monomorphic appearance (they all look the same)
Size 2-3 times that of a red cell
Prominent nucleoli
Large amounts of cytoplasm
Many cytoplasmic granules
Monomorphic appearance
- cells do not grow to be very big, compared to blasts
- prominent nucleoli are typical of cells that are rapidly proliferating
- not much cytoplasm
- *also look out for SMUDGE CELLS in CLL**
If you see lymphocytosis and smudge cells and suspect CLL, what test will you order to follow up?
Immunophenotype (light chain restricted (K or L), CD5+, CD20 weak, Cd23+)
What is the difference between CLL and SLL?
CLL is mostly involving peripheral blood
SLL is mostly involving lymph nodes
Monoclonal plasma cells express which one of these? IgG IgM kappa light chains kappa or lambda light chains lambda light chains
kappa or lambda light chains. One or the other but not both.
You find that your pt has increased serum protein. What is going to be your follow-up?
Serum protein electrophoresis to determine the oligoclonality of the protein. Monoclonal protein may be cause to suspect neoplasia. Could also be monoclonal gammopathy of uncertain significance (MGUS)!
Describe to me in rich, vivid detail what a reed-sternberg cell looks like and which malignancy it is associated with.
They look like a pair of testicles, but the testicles are red. The red testicles are the two ends of the horse-shoe shaped nucleolus. Also, the nucleoli are fucking huge. Like as big as a regular lymphocyte’s face. And by face, I mean nucleus.
Hodgkin Lymphoma.
Which of these features would favor a Dx of Mantle Cell lymphoma instead of CLL/SLL?
Lots of “smudge cells” in peripheral blood
Expression of only kappa light chain, not lambda
Surface CD20 expression
Very little cytoplasm
Expression of Cyclin D1 under the control of the IgH (Ig heavy chain) promotor
Expression of Cyclin D1 under the control of the IgH (Ig heavy chain) promotor
Which is more aggressive and why, mantle cell lymphoma or CLL/SLL?
Mantle cell lymphoma. Because it is found in less mature B cells.
What is the anatomical entity most affected by mantle cell lymphoma?
lymph node. presents as lymphadenopathy
CD5 is found on what two subtypes of WBC?
Both B cells (IgM secreting) and T cells
Let’s say there is a translocation that results in the anti-apoptotic gene Bcl-2 to be planted next to an IgH promotor. What do you expect to see on a lymph node biopsy under the scope?
germinal center proliferation beyond the norm
Name the most common mutated gene in follicular lymphona.
Bcl-2 overexpression
What happened to Reed-Sternberg cells?
1 They translocated an oncogene to an IgH promotor
2 They found some other way to survive the germinal center
3 They deleted two copies of the p53 gene
4 They stopped expressing surface Ig’s
1 & 3
2 & 4
2 & 4
Stopping expression of Ig’s is what made it difficult to ID this as a lymphoma and helped them evade targeted destruction.
What morphologic feature distinguishes the Reed-Sternberg cells of Classical Hodgkin Lymphoma from the R-S-like cells of the Nodular Lymphocyte Predominant type?
“popcorn” cells in place of classic RS cells.
No red nucleoli
Still expressing nuclear transcription factors typical of B cells, not found on RS cells.
Suppose your pt has severe lower back pain and elevated protein in their serum. What are you concerned about and what test might you order next?
Concerned about multiple myeloma. Serum protein electrophoresis.
Which oncogene is translocated in Burkitt’s lymphoma>
Myc to an Ig promotor
