Hematologic Malignancies V: B-cell lymphomas/leukemias Flashcards
What happens to B cells if they react with the host, or fail to react with the pathogen?
they are induced to die – and their corpses litter the field in the form of macrophages containing remnants of their nuclei. The remnants tend to pick up hematoxyin – they are “tingible bodies.”
T or F. In general, malignancies which appear to derive from well differentiated cells are less aggressive.
T. These are termed chronic leukemias while those dealing with bone marrow precursor cells are termed acute leukemias.
But there are many exceptions.
Another general rule: malignancies which appear to derive from well differentiated cells (chronic) can transform into more aggressive forms (acute).
If an evil genius wanted to cause a B-cell malignancy, he (or she) would probably start by finding a way to translocate an oncogene to an Ig promoter. This is a key pathogenetic point and you need to know it.
It is highly likely that B and T cells precursors are predisposed to this type of cancer-causing translocation because somatic DNA recombination is an essential part of their development.
T or F. Most lymphoproliferative diseases manifest themselves in more than one organ system.
T. If the bloodstream is the predominant target, we use the term “leukemia.” If not, we use the term “lymphoma”.
In many cases the two overlap.
What happens in follicular lymphoma?
an oncogene (Bcl-2) translocates to an Ig promoter, leading to overexpression, and subsequent lymphoproliferative disease occurs primarily in lymph nodes
What is another example of a lymphoproliferative disease that involves a translation of an oncogene to an Ig promoter?
Burkitt’s lymphoma
What is an example of a lymphoproliferative disease that does NOT involves a translation of an oncogene to an Ig promoter?
Chronic lymphocytic Leukemia (small lymphocytic lymphoma)
aka CLL
CLL derives mainly from what cell?
from the most mature forms of B-cells. Most of those are inactive “memory B-cells”. Some are found in the “marginal zone”, a poorly defined region just outside the mantle zone.
Clinical presentation of CLL?
lymphocytosis in older males. High familial incidence
What are the main sites affected in CLL?
peripheral blood more than bone marrow, lymph nodes
in peripheral blood you will see small lymphocytes with little cytoplasm called “smudge” cells
How is CLL diagnosed?
- peripheral smear
- confirmed by immunophenotyping (flow cytometry).
Again, the patient’s lymphocytes are small with scant cytoplasm and mature (dense) chromatin.
What is unique about the appearance of lymph nodes in CLL?
- characteristic “pseudofollicular” appearance in lymph nodes.
- The pseudofollicles appear to be collections of slightly larger cells which are undergoing DNA synthesis and mitosis.
What abnormalities are normal in cytogenetic analysis of CLL?
80% show abnormalities by FISH
most common to least:
- del13q14.3
- trisomy 12
- del11q22-23, del17p13(p53 region)
Immunophenotype of CLL?
Light chain restricted (kappa or lambda),
CD20 weak,
CD5+, CD23+
ZAP-70, CD38 (presence of bad= bad prognosis)
Does a 17p deletion indicate a good or bad prognosis in CLL? What about 13q?
17p (deletes p53)= BAD
13q- better
What are some other prognostic markers in CLL?
- presence of >30% smudge cells (good)
- an increasing fraction of immature forms (“prolymphocytes”; bad)
- immunophenotypic markers
- certain genetic features.
Again: P53 (located on 17p) is a bad player in a number of malignancies and is a part of your genome with which you should become intimately familiar.
CLL is common, and at diagnosis you must distinguish it from a more aggressive lymphoproliferative disease with some similar properties: _______
Mantle cell lymphoma
normal counterpart: mantle cell
What is a key difference between CLL and MCL?
no proliferation centers in the lymph nodes in MCL
Clinical presentation of MCL?
Lymphadenopathy and/or Lymphocytosis in older males.
Can look clinically like CLL at presentation.
What are the main sites affected in MCL?
lymph nodes more than bone marrow, spleen, peripheral blood, and GI tract
Morphology of MCL?
peripheral blood: small lymphocytes with little cytoplasm (aka smudge cells)
Lymph nodes: usually homogeneous effacement , ‘starry sky’
Immunophenotype of MCL?
Important here
light chain restricted (kappa or lambda)
CD5+
CD20 strong, CD23-*
What genetic defect in common in MCL?
t(11;14)(q13;q32) (IgH;Cyclin D1) is ALWAYS seen BY FISH
translocation of an oncogene to the IgH promoter
Overexpression of cyclin D1 (CCND1) pushes the cell through the cell cycle (G1 phase to S-phase)
Is CML more or less aggressive than CLL?
more
key clinical predictors: Ki-67 immunization (mitotic rate)
What is normal counterpart in Burkitt lymphoma (sporadic)?
memory B cells
same in endemic Burkitt lymphoma
Clinical presentation of Burkitt lymphoma (sporadic)?
abdominal mass in children or young adults. Higher incidence in HIV+ individuals
Primary involved sites in Burkitt lymphoma (sporadic)?
ileo-cecal area/ ovaries/kidneys
Morphology of Burkitt lymphoma (sporadic)?
intermediate sized lymphocytes with very blue (basophilic) cytoplasm, unusual cytoplasmic vacuoles, and more variation in nuclear size and shape than we see in the low grade lymphomas like CLL/SLL. (same in endemic BL)
The cells are growing fast, and they die fast too - with the dead cells being taken up by macrophages scattered around in the tumor (the large cells with clear cytoplasm, which at low power make the tumor look like a ‘starry sky’). You can see dark fragments of dead nuclei in some of the macrophages. usually homogeneous effacement in tissue
Clinical presentation of endemic Burkitt lymphoma?
Jaw/facial bone mass in a child (age 4-7) in a p. falciparum malaria-endemic area (Ghana, Papua New Guinea)
In central africa and in Papua New Guinea, the tumor is more common, presents in a different anatomic location, and is the most common cancer in kids. We call it, in this context, “endemic Burkitts”, and the tumor cells usually contain EBV (yes, that EBV, the one that causes infectious mononucleosis).
EBV can clearly contribute an effective oncogene (It’s a DNA virus with a big genome full of products that can maximize DNA replication), but that alone doesn’t explain this type of lymphoma.
We know that malaria (and specifically, p. falciparum malaria) contributes, but the mechanism connecting EBV, malaria, and this lymphoma is still not clear.
Immunophenotype of endemic OR sporadic BL?
typical B cell markers (CD10, CD19, CD20)
Pathogenesis of BL (sporadic and endemic)?
translocation of MYC (on 8q24) to an Ig promoter:
either to IgH (14q32) OR to kappa light chain (2p12) OR to lambda light chain (22q11)
so translocations could be: (8,14), (8,2), OR (8,22)
Plasma cell neoplasms are common in what patient population?
the elderly.
What are the major affected sites in plasma cell neoplasms?
bone marrow WAY more than peripheral blood
Lab findings of plasma cell neoplasms?
in mild forms might see the presence of Reuleaux (little stacks of red cells) in peripheral smear
and increased total protein levels
Clinical presentation of plasma cell neoplasms? Mild vs. severe
common in older patients
mild forms: asymptomatic lab findings (monoclonal gammopathy of uncertain signifcance, MGUS)
severe forms: Multiple lytic bone lesions (plasma cell myeloma); pain, fractures, renal failure
What is you followup after seeing increased serum protein levels?
The lab can then help you make the diagnosis by electrophoresing the (non-reduced, non-denatured) serum proteins.
Most labs will “reflexively” identify any abnormal single protein species via IFE.
What happens in an IFE?
In IFE, six identical lanes of serum proteins are run and transferred to a solid support matrix. They are then visualized with a reagent that stains most proteins (ELP) or reagents that stain particular types of immunoglobulin proteins.
In normals, all of the immunoglobulin lanes show up as smears, collections of polyclonal immunoglobulins. When a clone secreting a single immunoglobulin is present, a single band (in this case, made up of monoclonal IgG kappa antibodies) is seen.
How do plasma cells appear?
- lot of cytoplasm, and a nucleus located off to one side of the cell (“eccentric”).
- clumpy chromatin in their nuclei
- large, obvious golgi apparati in the cytoplasm – usually evident as a perinuclear clear space that early hematopathologists called a “hof” (a house’s yard, in German).
Large collections of plasma cells in bone marrow tend to do what?
erode bone– and to leave radiologically evident bone lesions (hence the term multiple myeloma).
Immunophenotype of plasma cell neoplasms?
CD38+++, CD138+++,
CD19/CD20-
light chain restricted
Genetics of plasma cell neoplasms?
- Translocation of IgH to various oncogenes (FISH) in about 2/3 of cases.
- Trisomies (hyperdiploidy) of ODD NUMBERED CHROMOSOMES are common
Clinical courses of the different types of plasma cell neoplasms?
MGUS: 1%/yr progress to MM
Multiple myeloma: Median survival is 3-4 yrs
What are some key negative prognostic markers in plasma cell neoplasms?
Serum beta 2 microglobulin
t(4;14) FGFR3
t(14;16) C-MAF
t(14;20) MAFB
del 17p (p53 region)
What is critical to the pathogenesis of follicular lymphoma?
Failure of germinal center B-cells to apoptose (because they overexpress an anti-apoptotic protein, Bcl-2)
And that happens via our recurring theme, translocation of an oncogene to an IgH promoter region.
What do the lymph nodes look like in follicular lymphoma?
big, non-tender lymph nodes containing a proliferation of follicles.
What do the follicles look like in follicular lymphoma?
- no polarity (large to small cells)
- no tangible body macrophages
- ** very low number of mitotic figures** (they are usually high in cancers)
What is the clinical presentation of follicular lymphoma?
-lymphadenopathy in older individuals (otherwise asymptomatic usually)
What sites are most affected in follicular lymphoma?
bone marrow involved in 40-70% of cases
can involve peripheral blood
Immunophenotype of follicular lymphoma?
CD19/CD20/CD10+ (60%)
BCL-2+ (90%)
BCL-6+ (85%)
Genetics of follicular lymphoma?
t(14;18)(14q32;18q21)+ in >85%)
It is translocated to an IgH promoter region in most – but not all – FL cases.
Multiple other translocations/deletions can occur
Clinical course of follicular lymphoma?
Depends on stage, grade, and cytogenetics
30% progress eventually to diffuse large B-cell lymphoma
How is FL graded?
Pathologists grade FL on the basis of how many large cells (centroblasts) are present. That does predict prognosis.
grade 1= mostly centrocytes (small, dark)
grade 3= mostly centroblasts (larger)
Diffuse large B-cell lymphoma is a large category defined primarily by what?
morphology only (kind of a garbage can category for loosely defined B cell lymphomas)
25-30% of B-cell lymphomas
Clinical presentation of diffuse large B-cell lymphoma?
- rapidly growing adenopathy
- presents in elderly patients
40% present of patients with diffuse large B-cell lymphoma present with what?
extranodal disease (GI tract, bone marrow, other)
Immunophenotype of diffuse large B-cell lymphoma?
CD19/CD20/CD10 (30-60%)
Genetics of diffuse large B-cell lymphoma?
t(v, 3q27)(v, BCL-6) in ~30%;
t(14;18) in 20-30%
Multiple other translocations/deletions can occur
How does Hodgkin lymphoma present? population?
- Males, age 30-50
Localized or diffuse adenopathy
Often with involvement of cervical, mediastinal,
or abdominal lymph nodes, and/or spleen
What are Reed/Sternberg cells seen in HL?
Large lymphoid cells with mono- or bi-nucleate appearance, huge eosinophilic nucleoli; overall horseshoe shape is likely
Diverse background cells: small lymphocytes, plasma cells, eosinophils, neutrophils, histiocytes
Are Reed/Sternberg cells specific to HL?
No, Very similar cells can be seen in some reactive conditions, such as mononucleosis.
What are the subtypes of HL?
1) Classical hodgkin lymphoma
2) Nodular lymphocyte predominant Hodgkin Lymphoma
How are the Reed/Sternberg cells different in NLPHD?
they are small with less prominent nucleoli
They sometimes show large, densely staining nuclei with little cytoplasm, which pathologists refer to as ‘mummified’ forms.
What are R/S cells?
Reed Sternberg cells are B-cells which went into germinal centers expecting to die. But they acquired anti-apoptotic mutations, such as constitutive NFkB expression, mutation from EBV infection, or others that prevents it.
DO NOT express surface immunoglobulins due to “crippling” Ig promoter/transcription factor mutations
There is reason to think they acquired some genetic instability early in the process.
Immunophenotype of classical HL?
Flow cytometry not currently useful (RS cells too fragile, few)
CD30+ (>90%),
CD15+ (>80%),
Pax5+ (>90%) (B-cell transcription factor)
CD20-/weak
Clinical course of classical HL?
Curable with chemo/RT
97% 10-yr survival
How are R/S cells different in NLPHD compared to CHL?
they do express surface immunoglobulins (i.e.No “crippling” Ig promoter/transcription factor mutations)
everything else is the same about them
Is the clinical presentation of NLPHD different than CHL?
Nope, they are similar
What is different about the morphology of nodular hodgkins vs. classical?
- Nodular, with mostly lymphocytes in the background
- BUT with “popcorn” cells (lympho-histocytic “L&H” cells) in place of classic RS cells
Morphology alone is NOT sufficient to make the diagnosis
Immunophenotype of NLPHD?
(L&H cells):
Flow cytometry not currently useful (RS cells too fragile, few)
CD30- (~80%),
CD15- (~100%),
Pax5+ (>95%%) (B-cell transcription factor)
CD20+ (>95%)
T-cells ‘ringing’ the R/S cells
Clinical course of NLPHD?
80% 10-year survival
Treatment at Stage 1 may not be needed
3-5% progression to diffuse large B-cell lymphoma
