ICL 11.2: Lymphoma II Flashcards
what is the most common leukemia in adults?
CLL/SLL
Chronic lymphocytic leukemia/Small lymphocytic lymphoma
monoclonal small B-cells
what is the immunophenotype of CLL/SLL?
CD5+
CD19+
CD20+
CD23+
CD10-
what mutation causes CLL/SLL?
deletion of 13q, 11q, 17p or +12
what population is CLL/SLL most common in?
˜60 years old
what are the characteristics of CLL/SLL?
generalized lymphadenopathy & hepatosplenomegaly
slow, indolent course
hypogammaglobulinemia (infections)
there can be transformation to large cell lymphoma (Richter transformation) or PLL prolymphocytic leukemia
what does the blood smear of CLL/SLL look like?
high WBC count with lymphocytosis >4000
smudge cells
spherocytes
what is mantle cell lymphoma?
arising from mantle zone of lymphoid follicle
generalized lymphadenopathy
GI tract lymphomatous polyposis
small, mature-appear lymphocyte; condensed chromatin, small amount of cytoplasm and round to irregular nuclear contour
typically small lymphocyte lymphomas are indolent, mantle cell lymphoma is unusual and is clinically aggressive
what population is mantle cell lymphoma most common in?
M > F
˜60 years old
what mutation causes mantle cell lymphoma?
t(11;14)
this upregulates BCL1 gene which codes for cyclin D1, a protein involved in checkpoint between G1 and S phase, and subsequent uncontrolled proliferation
what is the immunophenotype for mantle cell lymphoma?
CD19+
CD20+
CD5+
CD23-
positive for cyclin D
what is the prognosis for mantle cell lymphoma?
poor prognosis
what does MALT stand for?
MALT = marginal zone lymphoma
also known as MALT or BALT
what is MALT?
Rare, indolent, nodal or extranodal lymphoma, especially stomach, lung, spleen
remain localized for long time and may
REGRESS if inciting agent is removed
what is the immunophenotype of MALT?
small B-cells negative for CD5, 23, 10
what mutations are associated with MALT?
some have t(11;18) or t(1;14) or t(14;18)
what diseases are associated with MALT?
MALT is associated with autoimmune or chronic inflammation
ex. Hashimoto thyroiditis, Sjogren disease
ex. stomach- Helicobacter pylori (gastric MALT) can be treated with antibiotics
MALT remains localized for a long time but can regress with the inciting agent is removed!
what infectious agent can cause MALT in the stomach? how do you treat it?
H. pylori
can treat with antibiotics like amoxicillin, clarithromycin, and PPI
what infectious agent can cause MALT in the ocular adenexa?
C. psittaci
what infectious agent can cause MALT in the small intestine?
C. jejuni
what infectious agent can cause MALT in the spleen?
HCV
what infectious agent can cause MALT in the skin?
borrelia burgdorferi
which lymphomas are small B-cell malignancies?
- CLL/SLL
- mantle cell
- MALT
- follicular lymphoma
what is the immunophenotype for CLL/SLL, mantle cell, MALT and follicular lymphoma? They’re the small B-cell lymphomas
CLL/SLL = CD5+, CD23+, CD10-
mantle cell = CD5+, CD23-, CD10-, cyclin+
marginal zone = CD5-, CD23-, CD10-
follicular lymphoma = CD10+
is Burkitt lymphoma HL or NHL?
NHL
it’s a very aggressive, high grade B-cell NHL
what pattern is Burkitt lymphoma and why?
Burkitt lymphoma has a short doubling time (shortest in all human cancers) = excessive tumor debris
it’s cleaned up by macrophages (tingible bodies).
they are light in background of dark blue – starry sky pattern
slide 17
what mutation is associated with Burkitt lymphoma?
t(8;14) 80% of cases
or t(2;8) 15%
or t(8;22) 5%
C-myc oncogene on 8, kappa light chain on 2, lambda light chain on 22, heavy chain on 14. c-myc is anti-apoptotic transcription factor that induces proliferation
what is the immunophenotype of Burkitt lymphoma?
CD19+ CD20+ CD22+ CD10+ BCL6+ IgM+ TdT-
how do you differentiate Burkitt lymphoma from ALL?
ALL and BL look similar morphologically
TdT (terminal deoxynucleotidyl transferase is found in lymphoblasts
ALL is positive and BL is negative for TdT
what does the BM of Burkitt lymphoma patient look like?
blast-like cells with multiple cytoplasmic vacuoles
vacuoles make the cells look like there’s white holes in them
slide 18
what are the 3 types of Burkitt lymphoma?
- endemic African type
- sporadic American type
- HIV-associated
what is endemic African type Burkitt lymphoma?
large mass under jaw
all infected with EBV
age 4-7
50% of pediatric cancers in equatorial Africa
what is sporadic American type Burkitt lymphoma?
abdominal location esp. ileocecum
low EBV association
<35 years old
M»F
1-2% of all lymphomas
what is HIV-associated Burkitt lymphoma?
low EBV
young, immunodeficient adults
2nd most common HIV+ NHL
which disease is associated with Burkitt lymphoma?
EBV
unclear EBV role in pathogenesis but EBV may induce B cell proliferation and expansion during which chromosomal translocations are likely to arise
given the equatorial location of endemic BL, the same location for malaria, there is some thought that malaria may prime B cells and make them more susceptible to EBV infections
how do you treat Burkitt lymphoma?
high dose chemotherapy and should be started within 48 hours of diagnosis
often includes intrathecal treatment (methotrexate or cytarabine) as well as rituximab (anti-CD20)
what does ALCL stand for?
Anaplastic large cell lymphoma
which mutation is associated with ALCL?
t(2;5)
gene abnormality produces constitutively active tyrosine kinase
ALK gene rearrangement is diagnostic!
what population is ALK most common in?
children/young adults
what is ALK?
anaplastic, bizarre large cells
CD30+
what is breast implant associated ALCL?
majority associated with textured implant
usually ALK negative, but has good prognosis
treatment is total capulectomy, removal of the implant
consider removing the contralateral implant
what type of cell is common in ALCL?
- horseshoe nucleus with lots of cytoplasm
- embryo nucleus - looks like a kidney bean
slide 23
what is mycosis fungoides/Sezary syndrome?
cutaneous T-helper CD4 lymphoma with slow, indolent course
skin resident effector memory T cells are the cells of origin of MF
cerebriform nucleus in sezary cells (slide 29)
skin changes-inflammatory (patch), plaque, tumor
collections of these cells in the epidermis = Pautrier microabscess (slide 27/28)
leukemic phase = Sezary syndrome, associated with generalized exfoliative erythroderma and usually only seen in older individuals
what is Sezary syndrome?
associated with generalized exfoliative erythroderma and usually only seen in older individuals
characterized by the presence of atypical T cells in skin, lymph nodes and peripheral blood
thought to arise from thymus memory T cells while skin resident effector memory T cells are the cells of origin of MF
what is extra nodal NK/T cell lymphoma?
nasal type, is a rare, fast-growing, highly aggressive type of NHL
it can start in T cells, but it develops most often in natural killer (NK) cells
this type of NHL is called extranodal because it develops in organs or tissues other than the lymph nodes
blood vessel wall destruction leads to extensive ischemic necrosis = angioinvasive and angiodestructive
what disease is extra nodal NK/T-cell lymphoma associated with?
high EBV association
what’s the immunophenotype of extra nodal NK/T-cell lymphoma?
+ EBV and usually CD56+, CD2+, CD3-
how do you treat extra nodal NK/T-cell lymphoma?
combined chemo and radiation
are T-cell lymphomas common?
no in the US
they also have a worse prognosis than B-cell lymphomas
what are T-cell lymphomas?
not classified into small cell or large cell
skin involvement is common
normal T-cells are +CD2,3,5,7, and either CD4 or 8
but lymphomas commonly have antigen dropout and/or coexpression of CD4 and CD8 or loss of both CD4 and CD8
all have diffuse pattern
what type of cells are involved in T-cel lymphomas?
all are peripheral (mature) T-cells except precursor T-ALL/lymphoblastic lymphoma
Tdt positive ONLY in lymphoblastic lymphoma
what is the only TdT+ T-cell lymphoma?
precuror-T lymphoblastic leukemia/lymphoma = T-cell ALL
what is adult T-cell leukemia/lymphoma caused by?
caused by HTLV-1 (human T-cell leukemia/lymphoma virus 1)
endemic in Japan, Caribbean basin
what is the immunophenotype for adult T-cell leukemia/lymphoma ?
CD4+
what are the characteristics of adult T-cell leukemia/lymphoma ?
caused by HTLV-1
leukemic variant is usually rapidly progressive and fatal
- skin lesions
- lymphadenopathy
- lymphocytosis with cloverleaf or floret nucleus
- hypercalcemia
what does the blood smear of adult T-cell leukemia/lymphoma show?
lymphocytes with cloverleaf or floret nucleus
slide 37
nucleus literally looks like a 3 leaf clover
what is large granular lymphocytic leukemia?
there’s T-cell (CD3+) or NK-cell (CD56+) variants
STAT3 mutation common = transcription factor
what are some characterstics of large granular lymphocytic leukemia?
usually indolent course
lymphocytosis and splenomegaly
neutropenia and anemia
sometimes pure red cell aplasia in BM
some cases of Felty syndrome have underlying LGL
what is pure red cell aplasia?
common in large granular lymphocytic leukemia (LGL)
Purered cell aplasia(PRCA) is a syndrome defined by a normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors from the bone marrow
what is Felty syndrome?
some cases of Felty syndrome have underlying LGL
Felty syndrome(FS), also known as ‘‘super rheumatoid’’ disease, is a severe form of rheumatoid arthritis (RA), characterized by a triad of RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections
what mutation is associated with mantle cell lymphoma?
t(11;14)
BCL1 on chromosome 11, translocation to 14 increases expression
BCL1 codes overexpression of Cyclin D1
what mutation is associated with follicular lymphoma?
t(14;18)
BCL2 – inhibits pro-apoptotic protiens, located on chromosome 18 and moves to heavy chain on 14
BCL2 over expression allows for lymphoma proliferation
what mutation is associated with Burkitt lymphoma?
t(8;14)
c-myc (chromosome 8) over expression by translocation to heavy chain on 14
makes up 80% of BL translocation, other less common translocations include t(2;8) 15%; or t(8;22) 5%
what mutation is associated with anaplastic large cell lymphoma?
t(2;5)
ALK gene rearrangements
what are myelodysplastic syndromes?
hematopoiesis dysfunction that results in the bone marrow filled with dysplastic cells that can’t leave the marrow, resulting in systemic cytopenias
patients present with symptoms of bone marrow failure like weakness, fatigue, bleeding
what disease are myelodysplastic syndrome patients at risk for?
high risk for transformation into AML
blast count must be from 0 – 19%
> 20% is AML
blast count can be prognostic
how do you treat myelodysplastic syndromes?
treatment includes observation, chemotherapy, high dose combination chemotherapy and/or stem cell transplant
what is multiple myeloma?
malignant proliferation of plasma cells in bone marrow
malignant plasma cells inhibit formation of normal polyclonal immunoglobulin = increase risk for infection
monoclonal IgG or IgA creates an M spike in SPEP - monoclonal immunoglobulin is closely correlated to amount of tumor mass present
how do diagnose multiple myeloma?
Serum Protein Electrophoresis (SPEP)
Urine Protein Electrophoresis (UPEP)
Bone Marrow Biopsy (at least 10% plasma cells)
Blood Smear
Free Ligh Chain Assay (FLC)
Bone survey
Urine Immunofixation Electrophoresis (UIFE)
Serum immunofixation Electrophoresis (SIFE)
what is UPEP looking for in MM?
Bence-Jones proteins
they’re light chain only proteins that are small enough to be filtered into the urine
what three things are characteristic of MM?
- Russel bodies – large, eosinophilic, cytoplasmic inclusions thought to represent distended endoplasmic reticulum (slide 45)
- Dutcher bodies – Excess cytoplasmic immunoglobulin invaginating into the nucleus give the appearance of intranuclear inclusions (slide 47)
- Rouleaux Formation – increased immunoglobulin in serum interferes with normal repellant force that pushes red cells apart, allowing them to stack upon each other (slide 46)
what is smoldering myeloma?
plasma cell disorder
> 10% plasma cells
M-spike, but no other end organ damage or biopsy proven amyloidosis to confirm MM
MGUS –> smoldering myeloma –> MM
what is MGUS?
plasma cell disorder
< 10% plasma cells; small M-spike
no lytic bone lesions, anemia, kidney dysfunction,
at risk of developing MM,
since MGUS can lead to multiple myeloma at the rate of about 1.5% a year, yearly monitoring is recommended
MGUS –> smoldering myeloma –> MM
what is LCDD vs. HCDD?
Light chain deposition disease (LCDD) – MM but not amyloidosis in kidney
Heavy chain deposition disease (HCDD – MM, produce both light and heavy immunoglobulin chains; unable to form amyloid fibrils so they don’t have hallmark histologic features of amyloidosis –identified via immunofluorescence
what is LCDD?
light chain deposition disease
it’s the deposition of monoclonal light chains in multiple organs. It is a rare disease characterized by deposition of non-amyloid immunoglobulin light chains, which do not stain with Congo red
LCDD is categorized as a monoclonal immunoglobulin deposition disease
a single clone of plasma cells is responsible for overproduction of kappa chains and, very rarely, lambda chains
a monoclonal population of plasma cells can be detected in the bone marrow, and an altered serum-free light chain ratio is present
in 25% of patients, an abnormal serum free light chain ratio is noted, even without an abnormal finding with serum and or urine electrophoresis with immunofixation
incidence of LCDD is unknown. The median age at diagnosis is 58 years, and it is more common in M than F
what is HCDD?
Heavy-chain deposition disease is the least common non-organized monoclonal immunoglobulin deposition disease
Unlike the more common LCDD an association of multiple myeloma or plasma cell dyscrasias with HCDD is less common, with only 7 of 23 (30%) reported cases being associated with development of demonstrable monoclonal plasmacytosis.
nodular glomerulosclerosis is the classic glomerular pattern of injury of all monoclonal immunoglobulin disorders, and the disease (though suspected on light microscopy) can be conclusively diagnosed only by an extended panel of immunofluorescence that includes antibodies against heavy-chain isotypes
what is systemic light chain amyloidosis?
characterized by decreased number of monoclonal plasma cells in the BM compared to MM
amyloid has an affinity for visceral organs and causes end organ damages
Congo Red stain is used to identify amoyloid deposits
what does Rituximab do?
target CD20
used for treatment of CLL, NHL
what does Brentuximab Vedotin do?
target CD30
used for HL, primary cutaneous large cell lymphoma, CD30+ MF
what does Bortezomib do?
proteasome inhibitor
used for tx of MM, amyloidosis
what does Bendamustine do?
nitrogen mustard chemotherapy
used for tx of CLL, MM, NHL
