Week 6 Flashcards
ways that we classify/characterize lymphoid neoplasms
- cell of origin: classification rely heavily either on the cell of origin or the normal cell that most closely resemble the tumor
- mono-lobulated or multilobulated (appearance of the cell): Divided based on their morphology, kinda their nuclear features
- Cell markers: Helps to characterize the cell and correlate it w/ the normal counterpart and can help us figure out the origin of the cell
- Stage of development: Has to do w/ cell of origin, there’s a diff phenotype/clinical presentation for lymphoid neoplasms that arise from immature vs mature cell
- Solid vs soluble: Diff between leukemia and lymphoma; Leukemia: present or arise from BM or blood or involve the peripheral blood; Lymphoma: primarily involve solid organs, LN, things like that
- Spread: Does it involve primary LN or extra-LN involvement (Very imp for some of the lymphomas - characterizing what regions of the body are involved); Can kinda relate somewhat to staging; Predictable spread (Hodgkin Lymphoma) vs less predictable
- background cells: influences how the tumor behaves ex. B cell lymphoma- the background macrophages, follicular DCs, and t cell, their involvement can either make the tumor more or less aggressive
- Adult vs children: Helpful indicator; Certain lymphoid neoplasms tend to occur predominately in kids, the majority occur in adults
- T cell vs B cell neoplasm: Tend to present differently
Flow cytometry
○ the key word is liquid specimens
○ What kind of info does it give us: gives us the markers on the surface of the cells, tells us what antigens are on the surface of the cells; Similar to when we talked about blood typing
○ Put Ab on the surface of other cells (ex lymphocytes) and w/ a laser it can detect if those Ab are present or not
immunophenotyping
- Helps us to tell the characteristics of the cells
- Solid tissues we used IHC (very common in cancer diagnosis)
- Flow cytometry is what we use in liquid (leukemias, lymphomas)
Lymphoma and flow cytometry
bc they are made up of these lymphocytes w/ a very lose connective tissue network, you can take the lymphomas and chop them up/shake them up in a tube w/ liquid and the cells will dissociates so you able to use that liquid w/ those dissociated cell in it just like you would blood. That is why we can also use the lymphomas in addition to the leukemias
LN biopsy
looking at the LN tissue is still a primary way to diagnose and classify lymphomas
Bone marrow aspirate and core biopsy
- Used for diagnosis or staging hematopoietic neoplasms
- Aspirate: gives you cellular features, tells you what the cells look like
- Core: tells you the architecture, the relationship of the cells to each other and their normal environment
Molecular testing
○ used to detect specific mutations, point mutations or for identifying clonality
○ What is clonality? A direct copy, multiple copies of an identical cell and that is typically how we define most of these lymphoid neoplasms (and just neoplasms in general is, can you identify a clone of the same cell bc that is typically what happens in these neoplasms)
Peripheral blood smear
○ Looking at an assessment to see if you can produce cells first of all (if you can’t they wont show up in the blood) & If they are being destroyed early they cant be preserved for their lifespan and that’ll decrease in the blood
Natural history in the context of neoplasm
the expected biologic behavior of the tumor, what would tend to happen to this tumor if you just left this untreated
Follicular lymphoma: Cell of origin
- germinal center B cells. What cells typically comprise the germinal center? Centroblasts & centrocytes
-Centroblasts: more immature. Differentiate into centrocytes; Role: converting from primary follicle into a secondary follicle (germinal center). Why do we need the centroblast? Were trying to develop plasma cells at the other end
§ Centrocyte: more differentiated
dark zone in Follicular lymphoma
- Somatic hypermutation, but before that proliferation
- Proliferation. In order to make all these differentiated and antigen specific B cells in the germinal center you have to proliferate so after there is exposure to antigen you’re retting up proliferation. So the evidence of that proliferation is the centroblasts, these are immature B cells that are rapidly dividing, they differentiate into centrocytes
grading of follicular lymphoma
- based on the ratio of centrocytes:centroblasts
- If it is predominantly or almost entirely centrocytes, its gonna be low grade
- Makes sense bc you would expect it to be less aggressive, less proliferative if they are more differentiated/mature cells than if they were blasts which their job is to proliferate
Pathogenesis/etiology of follicular lymphoma
driven by translocation between chromosome 14 & 18 t(14;18) IGH (on chromosome 14); BCL2 (on chromosome 18)
IGH
- Why is IGH important in the process of pathogenesis or neogenesis B cell lymphoma, what is it doing?
- What is another process that happens before that
-Immunoglobulin heavy chain
- Induces overexpression; Normal process as you go from centroblast to centrocyte: isotype switching
In order to have isotype switching, you have to have active genes
-Somatic hypermutation is also going on here, its almost uncontrolled proliferation in a way, uncontrolled mutation that is how you get the diversity of Ab specificity. So you’re just making a ton of diff Ab and seeing which one is more specific and that is kinda how you evolve the high affinity Ab
- IGH gene is a very active gene, a potent promoter so when you have a translocation that juxtaposes the IGH gene next to another gene, which in this case is BCL2, you have upregulation of that gene and that genes expression
-BCL2 is anti-apoptotic, it is a pro-survival gene
Clinical features/presentation of follicular lymphoma
painless & generalized (more than 1 LN/chain; obvious places would be cervical chain, axillary, inguinal, abdominal) lymphadenopathy, predominantly in the LN, pt pop: older adults, waxing & waning course
Natural hx of follicular lymphoma
indolent course, waxing & waning
Can we cure follicular lymphoma
Typically not, goal of treatment is not to treat it, the goal is to treat when they are symptomatic such as pain due to LN (when they enlarge and affect the adjacent organs, obstruction of structures (lymphatic, vascular), impingement of nerves)
do follicular lymphomas tend to involve bone marrow at presentation?
- Yes, bc of that you can have issue w/ hematopoiesis (can end up w/ anemia, thrombocytopenia) so give palliative low dose chemo (not trying to get rid of tumor, but alleviate the symptoms)
Treatment of follicular lymphoma
- Treatment doesn’t have efficacy in preventing transformation
- Pt most of the time will live w/ this for a long time, many pts bc its diagnosed late in life will die of something else
Imp diagnostic features of follicular lymphoma
disruption of architecture, the normal architecture should be replaced w/ more B cell. In lymphoma we have nodular or follicular growth. The lymphoma start in the primary/secondary follicle so they look like abnormal follicles they start out w/ follicular pattern
BCL2 IHC stain, what do you expect to find in FL and why
- Overexpression of BCL2 in the follicular lymphoma; in the reactive/follicular hyperplasia LN there is no expression of BCL2
- BCL2 inhibits apoptosis, why would you want apoptosis in a reactive LN? It’s a normal part of the process, the b cells that do not make Ab w/ high affinity should undergo apoptosis, you want to preserve apoptosis (is should be organized/programmed)
- In the middle of the follicle it is highly upregulated (so you have increased staining for BCL2 in the lymphoma vs negative in the reactive)
Burkitt lymphoma: cell of origin
germinal center B cells
Burkitt lymphoma Pathogenesis/etiology
- Translocation between chromosome 8 (cMYC) & 14 (IGH) t(8;14)
- IGH being juxtaposed w/ cMYC
cMYC
- Responsible for cell proliferation. In all of these lymphomas there is a gene upregulated that either promotes either survival or upregulated proliferation
- of all genes in the body, it’s the most responsible for this proliferation effect (Warburg effect) shunting glucose towards building AAs and growth as opposed to just using it for glycolysis
- any tumor that involves a MYC mutation or amplification is gonna be really really highly proliferative bc it is a gene that activates other transcription factors, its like an exponential effect
2 diff types/subsets of Burkitt lymphoma
§ Endemic: occurs in certain geographic locations, associated more with facial lesions (ex. mandibular lesion)
§ Sporadic: what we see moslty in the US. Illiocecal region, somewhere along the GI tract, or w/in the peritoneal cavity, its hard to know if initially it was from an abdominal LN or extraabdominal sites
§ Immunosuppressed individuals: Often also infected with EBV. EBV is one of the drivers of the endemic type of BL
EBV’s role in the development of Burkitt lymphoma
We don’t know exactly what the driver is, there seems to be a same clone of the virus in all the tumor cells, but regardless if it started w/ EBV or it’s a sporadic case they all have the MYC translocation. Its kinda just a driver of the immune response in general then over time the critical development is the MYC translocation or mutation
