Neoplastic Hematopoeitic Disorders 1 Through Mantle cell lymphoma - SRS Flashcards
What are the pathogenic factors involved in white cell neoplasia?
- Chromosomal Translocations and oncogenes
- Inherited genetic factors
- Environmental agents
- Iatrogenic
- Chromosomal translocations and acquired mutations
Inherited genetic factors that predispose to WBC neoplasia include contitions that promote genomic instability. What are three examples of this?
Bloom syndrome
Fanconi anemia
ataxia telagiectasia
What are 6 environmental agents that are associated with WBC neoplasia?
- Viruses
- Helicobacter pylori
- Gluten sensitive enteropathy
- insecticides and chemical agents
- HIV
- Smoking
What are the three viruses we discussed that lead to WBC neoplasia?
HTLV-1
EBV
KSHV/HHV-8
What type of WBC neoplasms is HLTV-1 associated with?
Adult T-cell leukemia/lymphoma
What specific WBC neoplasms is EBV associated with?
- Burkitt Lymphoma
- Hodgkin Lymphoma
- Extranodal NK/T cell lymphoma
- Diffuse Large B cell lymphoma - Transplant type with EBV infection
What type of WBC neoplasia is KSHV/HHV associated with?
Body cavity large cell lymphoma (B cell) = Effusion lymphoma
What organism is associated with gastric marginal zone lymphoma?
Also known as MALT lymphoma - associated with H. Pylori
What are two iatrogenic causes of WBC neoplasia?
Radiation therapy
Chemotherapy
What are three genes that play a role in the development, growth, and survival of the normal tumor counterpart?
BCL2
BCL10
MALT1
Lymphomas can be broadly distinguished by the mechanism that is used to ensure a survival advantage. What are the features?
Lymphomas that are highly proliferative
Lymphomas that evade apoptosis
those that do both
What would you describe Burkitt lymphoma as based on the mechanism of survival?
Highly proliferative
What would you describe mantle cell lymphoma based on the mechanism of survival advantage?
Has both high proliferation AND evasion of apoptosis
What would you classify a chronic lymphocytic leukemia as based on its mechanism of survival advantage?
Evasion of apoptosis
Which is more common, non-hodgkin lymphoma or Hodgkin’s lymphoma?
Non-hodgkins 85%
Hodgkins 15%
What are the two major types of non-hodgkin lymphomas?
B-cell (80-85%)
T-cell/NK-cell
How can we distinguish lymphoid neoplasms?
Only by the appearance and molecular characteristics of the tumor cells.
What are the classical subtypes of Hodgkin lymphoma? What is the non-classical one?
- Nodular sclerosis
- Mixed cellularity
- Lymphocyte-rich
- Lymphocyte depletion
- Lymphocyte predominance
B cells are CD20, CD10 positive. What, if seen on immunophenotyping antigen detection indicates a B cell lymphoma?
KAppa light chaing restricted
What are the immunophenotyping antigens for immature B-cells?
- TdT,
- CD19,
- CD10,
- sIg-
- (usually CD20-)
What are the immunophenotypic markers for mature-B cells?
- CD19
- CD20
- CD22
- sIg+
What are the immunophenotypic antigens for immature T cells?
- TdT,
- CD1a,
- CD2,
- CD5,
- CD7,
- CD4/CD8
- (usually surface CD3-)
What markers might you see on immunophenotyping of mature T cells?
- CD2,
- sCD3,
- CD4,
- CD5,
- CD7,
- CD8
- (TdT-, CD1a-)
B-cell acute lymphoblastic leukemia/lymphoma have their origin from bone marrow precursor B cells. What are the genes most commonly involved in childhood ALL?
How about adult ALL?
- Childhood
- t(12;21) RUNX1 and ETV6
- Adult
- t(9;22) / Bcr-Abl1
B-cell ALL occurs predominantly in what population?
What do the symptoms relate to?
What is the course?
Children
Symptoms relate to marrow replacement, pancytopenia
Course tends to be aggressive
T cell Acute lymphoblastic leukemia/lymphoma has its origin in the T cell population, often of thymic origin. What is the most common mutation?
NOTCH1 (50 - 70%)
T cell ALL occurs predominantly in what population?
What are the involved symptoms (big two)?
typical course?
Adolescent males
Thymic masses and variable bone marrow involvement
aggressive
What is the most common cancer associated with down syndrome?
Acute lymphoblastic leukemia
Describe three characteristic demographic aspects of ALL.
2X as common in whites as blacks
slightly more common in hispanics
slightly more common in males than females
How do B-cell precursor neoplasms present in young kids?
Extensive bone marrow involvement with peripheral blood“leukemic phase”
Occasionally present as “lymphoma” with a mass in the lymph nodes
How do T-cell precursor neoplasms tend to present?
In adolescent males as lymphoma with thymic involvement and possible leukemia
What is the major diagnostic cell for B or T cell neoplasms?
What are the peripheral blast counts typically?
What might a patient be?
- Lymphoblast - same morphologically for T-cell and B-cell neoplasms
- Peripheral blast count usually > 20,000 and commonly > 50,000
- May be aleukemic
What are these PAS+/Myeloperoxidase - cells with condensed nuclear chromatin, small nucleoli and scant agranular cytoplasm typical of?
Acute lymphoblastic leukemia/lymphoma
What is a specialized DNA polymerase present only in precursor B or T cells?
+ TdT (terminal deoxynucleotidyltransferase)
What are the precursor B-cell and T-cell immunophenotypes that Gomez listed in bold?
- •+ TdT (terminal deoxynucleotidyltransferase)
- B cells: CD19, PAX5
- T cells: CD1, CD2, CD5, CD7
What are the special stains for precursor B and T cell neoplasms?
PAS+ /Myeloperoxidase -
As far as cytogenetics/molecular genetics, what do roughly 90% of patients have in B cell leukemic cells?
What are the various characteristics?
Structural changes in chromosomes of B cell leukemic cells with…
- hyperdiploidy most common
- some hypodiploidy
- some expressing philadelphia chromosome
What is the philadelphia chromosome?
t9:22
What do 70% of T-ALL’s have a mutation in? What does the mutation do?
NOTCH1, with gain of function
You’re handed the attached flow cytometry results, what do you make of them?
In B - the lymphoblasts express the TdT and B cell marker CD22
In C - The same cells are positive for CD10 and CD19, commonly expressed on pre-B lymphoblasts
Thus this is a B-ALL
B-ALL and T-ALL have an abrupt/stormy onset. What are the classic leukemia symptoms associated with depressed marrow function?
- Fatigue (anemia)
- Infection & fever (neutropenia)
- Bleeding (thrombocytopenia)
Apart from the abrupt/stormy onset, and the classic depressed marrow function symptoms, what are another 6 symptoms of B and T cell neoplasms?
- Generalized Lymphadenopathy
- Bone pain and tenderness
- Splenomegaly
- Hepatomegaly
- CNS Symptoms
- Testicular involvement
What are the CNS symptoms associated with B and T cell neoplasms?
- meningeal involvement (headache, vomiting)
- nerve palsies
What are the remission and cure rates in childhood B-cell ALL?
95% achieve remission
75% cured
In adult B-cell ALL what is the cure rate?
only 35 - 40%
What are four bad prognostic indicators for B cell ALL?
(1) Age < 2 years (increased incidence of MLL gene mutations)
(2) Presentation in adolescence or adulthood
(3) Peripheral blast count > 100,000 cells/ul
(4) Presence of unfavorable cytogenetic aberrations
What specifically are the unfavorable cytogenetic aberrations that indicate a bad prognosis in B-cell ALL?
2
•Philadelphia chromosome t(9;22)
•Rearrangements of MLL (mixed lineage leukemia) gene
Here we see marrow between pink bone trabeculae that is roughly 100% cellular. What has the presence of these malignant leukemic cells lead to?
What symptoms does this occurance explain?
Replaced normal hematopoiesis
Explains…
- Infections d/t lack of granulocytes
- anemia d/t lack of RBCs
List as many peripheral B-cell neoplasms as you are able!!!
There are nine on the other side of this card.
- •Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma
- •Follicular Lymphoma
- •Diffuse Large B-cell Lymphoma
- •Burkitt Lymphoma
- •Mantle Cell Lymphoma
- •Marginal Zone Lymphoma
- •Hairy Cell Leukemia
- •Plasma Cell Neoplasms/Related Disorders (Myeloma)
- •Lymphoplasmacytic Lymphoma
Germinal center B cells are the origin of Burkitt lymphoma, what are the translocations typical to this condition?
What is a subset association?
c-MYC and Ig loci translocations typically t(8:14)
Subset associated with EBV
What is the typical population for Burkitt’s lymphoma?
What is the typical physical manifestation?
Clinical course?
Adolescents or young adults
Extranodal masses, or uncommonly “leukemia”
aggressive
Germinal center or post germinal center B cells give rise to diffuse large B cell lymphomas that affect all ages but most commonly adults. This typically appears as a rapidly growing mass, 30% extranodal, and with an aggressive course.
What are the most common genotypical rearrangements? 3
- BCL6 (30%)
- BCL2 (10%)
- c-MYC (5%)
Extranodal marginal one lymphomas arise from memory B cells at extranodal sites in adults with chronic inflammatory diseases and may remain localized, with an indolent course.
What are the key gene highlights associated with this?
What are the fusion genes created?
-
t(11;18), t(1;14), and t(14;18) creating the following fusion genes
- MALT1-IAP2,
- BCL10-IgH,
- and MALT1-IgH
Follicular lymphomas arise from germinal center B cells in older adults with generalized lymphadenopathy and marrow involvement, and typically have an indolent presentation. What gene is involved?
What fusion gene is created?
t(14;18) creating BCL2-IgH fusion gene
Mantle cell lymphomas arise from naive B cells and present in older males with disseminated disease and a moderately aggressive course.
What Gene is involved?
What is the fusion gene?
t(11;14) creating CyclinD1-IgH fusion gene
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma have the same morphology and immunophenotype of malignant cells but two different clinical presentations.
How does the initial presentation vary for each?
- CLL initially presents with greater than 5,000 abnormal B cells/uL blood
- SLL if presents initially as malignant lymphadenopathy
SLL presents with diffusely effaced lymph node architecture, small (6-12 micron) lymphocytes with irregular chromatin, variable numbers of prolymphocytes and rare large immunoblasts.
What is pathognomonic for SLL?
•Proliferation centers -prominent mitotically active foci with prolymphocytes
CLL will have peripheral blood and bone marrow lymphocytosis with small lymphocytes that have irregular nulear chromatin and present with hemolytic anemia and/or thrombocytopenia in some patients. What is a colloquial name for a cell seen in this?
Smudge cells
This image shows diffuse effacement of nodal architecture, at high power most cells are small round lymphocytes, and a large prolymphocyte with a centrally placed nucleuolus are present. What condition is this biopsy representative of?
SLL or CLL
(no mention of proliferation center so, I guess its either)
What is the arrow indicating in this high power view?
What conditions is this seen in?
A “prolymphocyte” - larger cell with a centrally placed nucleolus
along with the majority of cells being small round lymphocytic tumor cells, this is indicative of SLL/CLL lymph nodes
What is this neoplasm?
How can you tell?
What condition is coexistant in this patient and how do you know?
- SLL
- Note the small lymphocytes with condensed chromatin and presence of smudge cells.
- Coexistent autoimmune hemolytic anemia w/ spherocytes and nucleated erythroid cell
What is the classic immunophenotype finding for CLL/SLL?
What other markers will be +?
The presence of what marker indicates a worse prognosis?
- Classic finding is presence of T-cell marker CD5 on cells and also expresses CD23
- CD19 and CD20
- CD38 = worse
In CLL/SLL chromosomal translocations are rare, but can happen and will have either a poor or good prognosis, depending on the situation.
Which are associated with poor and good outcomes respectively?
- •Poor prognosis- trisomy 12q and deletions of 11q, 12q,17p
- •Good prognosis- deletion 13q (LUCKY 13)
What does this flow cytometry report say about the patient’s disease?
Coexpression of CD5 on CD19+ B cells is indicative of CLL/SLL
SLL and CLL tend to occur in males (2:1) over 50 y/o, and frequently asymptomatically. Hypogammaglobulinemia may be present and lead to increased infections, and there may be a small monoclonal Ig peak on electrophoresis.
What do 10-15% of patients have antibodies to?
10-15% patients have autoantibodies produced by non-neoplastic cells to red cells and/or platelets
What are two transformations associated with CLL/SLL?
- Prolymphocytic Transformation (Leukemia)
- Richter Transformation (Syndrome)
What is Richter Transformation (Syndrome)?
Transformation of CLL/SLL into Diffuse Large B-cell Lymphoma (3%) or EVB+ Hodgkin Lymphoma (0.5%) with more aggressive course
What is Prolymphocytic Transformation (Leukemia)?
a rare transformation with worsening of cytopenias
Follicular lymphoma comprises about 40% of adult non-hodgkin lymphomas and takes hold after 55 y/o, inflicting males and females equally.
This occurs predominantly in the L. nodes, and 85% of the time has marrow involvement. 10% have peripheral blood lymphocytosis (<20,000 cells/uL)
What are the two associated cell types?
Describe each (briefly)
- Centrocytes - small cleaved
- Centroblasts - Larger cell with open nuclear chromatin & ↑cytoplasm
What is the grading of follicular lymphoma based on?
Grade given based on number of centroblasts (e.g.: grade 3: >15 centroblasts/HPF)
What are the arrows pointing to?
What else do you see (or should you see)?
What condition does this patient have?
- Arrows = centroblasts
- Also seen are small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines = centrocytes
- Follicular lymphoma
These L. follicles are immunohistocem treated for BCL2 expression. Based on this, which is the Follicular lymphoma and which is the reactive follice?
Left = reactive follicle
Right = Follicular Lymphoma
What are the key markers for follicular lymphoma on immunophenotype? 6
- CD19,
- CD20,
- CD10 (CALLA)
- sIg
- BCL2 (apoptosis antagonist),
- BCL6
What is the cytogenic hallmark of follicular lymphoma?
14:18 translocation (90%)- BCL2 gene on 18 with IgH on 14
Follicular lymphoma occurs with painless generalized adenopathy and bone marrow involvement in 75% of cases.
How common is extranodal site involvement?
What is the median survival?
Involvement extranodal sites uncommon
Median survival 7 – 9 years (incurable)
Transformation occurs in 30-50% of follicular lymphoma patients, what two things are the likely transformation products?
How long following transformation is the typical survival?
- Usually to Diffuse Large B-Cell Lymphoma
- Sometimes c-MYC translocation leads to Burkitt-like lymphoma
- Following transformation, survival < 1 year
Diffuse large B cell lymphoma comprises about 25 - 50% of adult NHL, and 2/3 of “aggressive lymphomas”, with a slight male predominance and median onset age of 60. It is responsible for ~25% of childhood lymphomas.
Characterise the morphology by size and growth pattern.
Large size neoplastic lymphocyte
(2-5 times diameter of normal-sized lymphocyte)
Diffuse pattern of growth with effacement of node architecture
Diffuse large B cell lymphoma have immunophenotype including + CD19 and CD20, sIg, and variable expression germinal center markers (CD10, BCL6).
What is the most commonly dysregulated gene?
What does it do?
BCL6, a DNA binding Zinc finger
- transcription regulator
- inhibits expression of factors that regulate differentiation
- inhibits p53 activity
Diffuse Large B cell lymphoma typically presents with rapidly enlarging, often symptomatic mass at a single nodal or extranodal site. The oropharynx (waldeyer ring, tonsils and adenoids) are common sites.
What are the three important clinical subtypes?
- Mediastinal large B-cell lymphoma
- Immunodeficiency-associated large B-cell lymphoma
- Body cavity large cell lymphoma
Mediastinal large B-cell lymphoma occurs commonly in young women, with involvement of what two things?
Viscera
CNS
In what patients does Immunodeficiency-associated large B-cell lymphoma occur?
- occurs in end-stage HIV infection or bone marrow transplantation plus Epstein-Barr Virus
What associations are known for body cavity lage cell lymphoma (primary effusion lymphoma)?
KSHV/HHV-8 in HIV patients
What is the prognosis for a diffuse large B-cell lymphoma?
60-80% remission (50% of these cured)
What is this isolated large mass typical of?
Diffuse large B cell lymphoma of the spleen
Burkitt lymphoma comprises 30% of childhood lymphomas in the US, and 2-3% of adult lymphomas. What are the three types of Burkitt lymphomas?
- African (endemic)
- Sporadic US (nonendemic)
- Immunodeficiency-associated
African (endemic) Burkitt lymphoma in children and young adults involves the jaw and viscera. What is common to these cases?
EBV positive
Sporadic Burkitt lymphoma are mostly EBV negative, and presents with involvement in what body regions?
- Abdominal masses - most often ileocecal
- Bilateral Breast and ovaries
Immunodeficiency associated Burkitt lymphoma is, unsurprisingly, associated with HIV infection and may be the initial manifestation of AIDS. What is the course of this type of Burkitt lymphoma?
Highly aggressive
Burkitt lymphoma presents with involved tissues effaced by diffuse infiltrate neoplastic lymphocytes of intermediate size and possessing a moderate amount of amphophilic or basophilic cytoplasm.
These also have a high mitotic rate, why?
What pattern is associated with this neoplasm?
- High mitotic rate (Warburg effect with aerobic glycolysis and high biosynthesis)
- Apoptotic tumor cell death (“Starry Sky” pattern)
How often are the marrow and blood involved in Burkitt lymphoma?
Rarely
What does this histology sample depict?
Numerous pale tingible body macrophages are evident, producing a “starry sky” appearance. Evidence of Burkitt Lymphoma
What do all Burkit lymphomae have translocations of?
c-MYC gene and chromosome 8
What is the most common Burkitt translocation?
Less common?
What do these lead to?
- t(8;14) (IgH locus) common
- t(8;2) (kappa) or t(8;22) (lambda) less common
- INCREASED c-MYC EXPRESSION
In addition to mutations increasing c-MYC expression, what other mutations might a Burkitt Lymphoma present with?
p53 inactivation
What are all endemic Burkitt lymphoma tumors infected with?
EBV
What is the prognosis for Burkitt’s lymphoma?
Aggressive neoplasm, but sensitive to chemotherapy. “Most children and young adults can be cured”
A young patient presents with an intra-abdominal mass. Their karyotype is attached. What does this child have?
Karyotype 46, XY, t(8;14) - typical translocation for Burkitt Lymphoma
