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Lymphoma Flashcards

1
Q

Canine lymphoma accounts for what % all canine tumors?

% of all canine hematopoietic tumors?

A

7-24% of all canine tumors and 83% of all canine hematopoietic tumors

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2
Q

Median age for dogs affected by LSA?

A

Affects primarily middle-aged to older dogs (6-9 years) – dogs with T-cell LSA may be younger

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3
Q

Gender predilection?

Sex predilection?

A

None

Intact females are at lower risk similar to people

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4
Q

What are the 11 high breed associated risk?

A

Boxer, bullmastiff, Basset hound, St. Bernard, Scottish terrier, Airedale, pitbull, Briard, Irish setter, Rottweiler, bulldog

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5
Q

Name 2 canine breeds with lower risk?

A

dachshund, Pomeranian

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6
Q

Etiology for canine LSA?

A

Unknown but probably multifactorial

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7
Q

Chromosomal translocations are catalyzed by what 2 proteins which can lead to chromosomal abnormalities in LSA?

A

RAG-1 and RAG-2 proteins during V(D)J gene rearrangement to form B-cell and T-cell receptors

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8
Q

What chromosomal abnormalities are seen in canine LSA?

A

Gain of chromosomes 13, 31- Trisomy of chromosome 13 associated with better prognosis

Loss of chromosome 14

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9
Q

What 2 canine breeds get T-cell LSA?

A

Boxers, Asian/Arctic breeds

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10
Q

What 3 canine breeds get B-cell LSA?

A

Cocker spaniel, Dobermans, Bassett hounds

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11
Q

What canine breed gets T-zone LSA?

A

Golden retriever

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12
Q

How does epigenetics play a role in canine LSA?

A

Global hypomethylation of DNA seen in most lymphoma cases tested, likely plays a role in cancer progression (genomic instability).

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13
Q

Specific mutations or signaling pathway dysregulations

A

N-ras, p53, Rb, Bcl-2 family proteins, telomerase, p16, NF-kB

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14
Q

Recurrent somatic mutations found in B-cell lymphomas

A

TRAF3-MAP3K14, FBXW7, POT1

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15
Q

Infectious factors associated with canine LSA?

A

No confirmed proof of retroviral etiology as in the cat

Possible association with EBV or EBV-like herpesvirus

Possible association of H. pylori with gastric MALT lymphoma (laboratory evidence)

Fecal microbiota of dogs with LSA is significantly different from that of healthy dogs, but no proven association with lymphomagenesis

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16
Q

Environmental factors associated with canine LSA?

A

2,4-D – Highly controversial with some studies citing increased risk with exposure and others questioning these findings. However, 2,4-D exposure is also a purported risk factor in humans.

OR for LSA was 1.3 in dogs exposed to lawns treated 4 or more times per year

2,4-D detectable in urine at > 50 mg/L in dogs exposed to lawn treatment within 7 days of application

Possible increase risk with exposure to paints and solvents and residency in industrial areas.

Possible association with exposure to strong magnetic fields (high-tension wires).

Proximity to environmental waste may be a risk indicator rather than a risk factor

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17
Q

Immunologic factors associated with canine LSA?

A

Major risk factor in humans with HIV/AIDS, transplant patients, elderly

Immune system dysfunction documented in dogs with LSA

Development of LSA subsequent to previous ITP

1 case of LSA developing after cyclosporine treatment (Somewhat dubious… dog was only on cyclosporine for 4 weeks prior to diagnosis of LSA).

Immunosuppressive drug therapy is a known risk factor for lymphoma in humans and cats

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18
Q

Multicentric LSA accounts for what % of all canine LSA?

A

80%

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19
Q

Alimentary LSA accounts for what %

Most GI LSA are what immunophenotype?

What breeds are pre-disposed?

A

5-7%

T-cells

Bosers and Shar-peis

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20
Q

What % are mediastinal LSA?

Immunophenotype?

A

~5%

Usually T-cell

Hypercalcemia in 10-40% of all dogs with LSA and is most common in mediastinal form

Characterized by enlargement of craniomediastinal LN’s, thymus, or both

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21
Q

Most common cutaneous LSA?

What cell type is affected? Humans?

What is sezary syndrome?

A

Epitheliotropic cutaneous T-cell lymphoma (mycosis fungoides) is most common type of cutaneous LSA

CD8+ (cytotoxic T) in dogs (as opposed to CD4+ (helper T) in humans)

Sézary syndrome – rare form of MF characterized by generalized cutaneous involvement (diffuse erythroderma in humans) and circulating neoplastic T-cells

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22
Q

Non-epitheliotropic LSA is what cell type?

Occurs where in the skin?

Common DDx?

A

Non-epitheliotropic LSA (can be either B-cell or T-cell) usually spares epidermis/papillary dermis and occurs in mid-deep dermis to subcutis. Tends to form multifocal to coalescing tumors/crusts rather than patches/plaques.

Must DDx other cutaneous/subcutaneous round cell tumors

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23
Q

How does hepatosplenic LSA present in dogs?

What immunophenotype?

A

Characterized by lack of peripheral lymphadenomegaly in the face of hepatic, splenic and bone marrow infiltration

Usually T-cell (gd T-cells)

gd refers to the form of the T-cell receptor (TCR) displayed by these T-cells. TCRs come in 2 basic types: ab and gd.

Highly aggressive, responds poorly to therapy

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24
Q

Intravascular lymphoma (aka angiotropic LSA or angioendotheliomatosis)

Commonly affected organs?

Immunophenotype?

A

Proliferation of neoplastic lymphocytes within the lumen and wall of blood vessels in the absence of a primary extravascular mass or leukemia

Eye, CNS commonly affected

Usually T-cell or null cell in dogs (B-cell in humans)

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25
Pulmonary lymphomatoid granulomatosis
Rare pulmonary infiltrative/nodular disorder characterized by a heterogenous accumulation of B- and T-lymphocytes with an angiocentric distribution. Possibly a pre-lymphomatous state? 3 grades in humans, with grade 1 being most akin to “pre-lymphoma, ” grade 2 akin to T-cell rich large B-cell lymphoma, and grade 3 akin to DLBCL Heterogeneous response to therapy (everything from durable CR to rapid death)
26
WHat are the 5 most common subtypes of LSA in decreasing order?
DLBCL\>PTCL-NOS\>TZL\>T-LBL\>MZL
27
What are 4 features of indolent (low grade) tumors?
Small mature lymphocytes Low mitotic rate Typically progress slowly Long survival but survivable
28
What are 4 features of high grade (aggressive) LSA?
Large immature lymphocytes, high mitotic rate, likely to response to chemotherapy but rapidly progressive, potentially curable in humans (rarely in dogs)
29
How are canine LSA graded?
Grade in the WHO/REAL system is assigned based upon mitotic index alone (low = 0-5/hpf, intermediate = 6-10/hpf, high = \>10/hpf)
30
What % are the following? B-cell T-cell Mixed B/T cell Null cell
60-80% of canine LSA are B-cell 10-38% are T-cell 22% Mixed B/T tumors (likely represent aberrant surface Ag expression, especially as assessed by flow cytometry) \<5% are null cell
31
High grade much more likely to have __ on chemotherapy than low-grade T-cell LSA have ___ rate of CR, ___ remission, ___ survival time (except TZL)
CR lower, shorter, shorter
32
Diffuse pulmonary infiltrates on rads in ___ % - up to ___ have lung involvement based on BAL
27-34% 2/3
33
Common clinical signs with GI LSA
GI lymphoma usually have vomiting, diarrhea, weight loss, malabsorption May see hepatosplenomegaly, mesenteric LN enlargement
34
What is pre-caval syndrome?
venous or lymphatic obstruction occurs causing pitting edema of head, neck, forelimbs
35
Ocular LSA
Iridal thickening, hypopyon, uveitis, hyphema, posterior synechiae, glaucoma 37% of dogs with multicentric LSA had ocular involvement in 1 study LSA accounted for 17% of uveitis cases in another study Primary solitary ocular lymphoma (PSOL) is an entity distinct from secondary ocular lymphoma in multicentric disease. MST for PSOL was 769 days vs. 103 days for multicentric with ocular involvement
36
Most common paraneoplastic syndrome in canine LSA?
anemia
37
What are the common signs exhibited in dogs with hypercalcemia?
Hypercalcemia depresses the activity of any excitable tissue (increases threshold potential). Many clinical signs are referable to this phenomenon: Skeletal muscle – weakness Smooth muscle – anorexia, vomiting Nerve – weakness, ataxia, CNS depression, anorexia, adipsia
38
Effect of hypercalcemia on kidenys?
Decreased responsiveness of collecting ducts to ADH – nephrogenic DI, primary polyuria Renal arterial vasoconstriction – ischemic injury, renal failure Direct cytotoxic effects to renal tubular epithelium With chronicity – Ca x P \>60 leads to nephrocalcinosis
39
Main cause of hypercalcemia is PTHrp, what are other causes?
IL-1, TNF-a, TGF-b, vitamin D analogs
40
41
Other PNS associated with canine LSA?
Monoclonal gammopathy/hyperglobulinemia Neuropathies Cancer cachexia
42
DDx for lymphadenomegaly
bacterial, viral, protozoal, fungal disease
43
What % of dogs will have ocular involvement?
33-50%
44
What is the most common hematological abnormality in canine LSA?
Anemia Usually anemia of chronic inflammatory disease but often multifactorial (hemorrhage, hemolysis, myelophthisis)
45
Thrombocytopenia is seen in what % of dogs?
Thrombocytopenia in 30-50%
46
Neutrophilia is see in what % of dogs?
Neutrophilia in 25-40%
47
Lymphocytosis is seen in what % of dogs with canine LSA?
~20% (dogmatically considered an indicator of bone marrow infiltration, but circulating lymphocytes can come from anywhere). Must DDx ALL/CLL (can usually be done with bone marrow evaluation, immunophenotyping (inc. CD34), and evaluation of clinical features)
48
Hypoproteinemia common in what type of LSA?
alimentary LSA
49
Monoclonal gammopathy in \_\_% of dogs with LSA
6%
50
Hypercalcemia is seen in what % of LSA? Mediastinal LSA? T-cell LSA?
15% of all LSA 30-40% of mediastinal LSA 35% of T-cell LSA
51
Azotemia if _____ or \_\_\_\_\_ Increased liver enzymes or bilirubin with \_\_\_\_\_ Proteinuria, isosthenuria may be seen on UA (note: early hypercalcemia causes hyposthenuria due to nephrogenic DI. Isosthenuria occurs with progressive renal injury)
hypercalcemic, renal infiltration hepatic infiltration
52
Histologic and cytologic evaluation of extranodal sites Cytologic samples acceptable for CSF, pleural effusion, intrathoracic masses Alimentary LSAWedge biopsy of intestine that does not penetrate lumen Adequate tissue must be obtained to DDx from LPE. Endoscopic samples may not be adequate for Dx. PARR may be less accurate for GI biopsies (likely due to mix of lymphoid and non-lymphoid tissue in organ sampled) Image-guided biopsy of secondarily involved LN’s may be acceptable Punch biopsies acceptable for cutaneous LSA Avoid secondarily infected lesions Biopsy disease interface with normal tissue for subtle lesions
53
Marker for T cell? Marker for B cell?
CD3 (T-cell) or CD79a (B-cell) expression
54
Other markers for B cell?
CD20, CD21 – B cell
55
Marker for Helper T-cell?
CD4
56
Marker for Cytotoxic T-cell?
CD8
57
\_\_\_\_\_ is a hallmark of malignancy?
Clonality, Theoretically, all cancers derive from a single malignant cell.
58
What is the Sn and Sp for PCR in dogs?
Sn – 91%, Sp – 96% (Burnett RC, et al. Vet Pathol 2003;40:32-41)
59
False positive for PCR can be seen with what disease? List 5 other differential diagnoses?
May get FP with rickettsial disease (monoclonal gammopathies also reported with rickettsial disease) as well as other diseases Ehrlichiosis, borreliosis, leishmaniasis, histiocytoma, myeloid leukemias
60
In one study, 57% of patients had cytologic evidence of BM involvement although only 28% had circulating neoplastic cells
61
List 3 DDx for increased numbers of large lymphocytes in BM?
GI parasitism IMHA Other immune mediated diseases
62
What % of dogs will have intrathoracic radiographic abnormalities? pulmonary infiltrate? lymphadenomegaly? craniomediastinal LN enlargement?
Approximately 60-75% of dogs with multicentric lymphoma will have intrathoracic radiographic abnormalities 1/3 will have pulmonary infiltrates 2/3 have lymphadenomegaly 20% have craniomediastinal LN enlargement Pleural effusion also may be present
63
What % of dogs show lymphadenomegaly on abdominal radiographs?
50% of cases will show lymphadenomegaly (mesenteric, sublumbar), hepatomegaly, and/or splenomegaly
64
MST for untreated LSA?
Untreated LSA – MST 4-6 weeks
65
CHOP-based protocol indice CR in what % of dogs?
80-95% of dogs
66
MST with CHOP for dogs with LSA? What % live 2 years or longer?
10-12 months depending on several factors ## Footnote About 20-25% live 2 years or longer (free drinks from me at VCS for anyone who can find me an article from the primary literature documenting a 2-year survival rate of this magnitude. Studies incorporating radiation or hematopoietic stem cell transplantation don’t count.)
67
CR associated with CHOP? MST?
CHOP – 80-90% CR, MST of ~12 months
68
CR associated with COP? MST?
COP – 60-70% CR, MST of 6-7 months
69
CR associated with single agent doxorubicin? MST?
50-75% CR, MST 6-8 months
70
Remission with prednisone?
Single-agent prednisone – short-lived remissions of 1-2 months
71
Response rate to single agent doxorubicin noted to be much poorer for T-cell than B-cell lymphoma in one study (86% CR for B-cell, 17% CR for T-cell)
72
What is the major role of MDR?
MDR usually develops and PgP/ABCB1 is thought to be a major player in MDR, but there are numerous other molecular players involved
73
What %of dogs experience CR second round of CHOP? How long is remission?
About 90% of dogs will experience CR on second go-around of CHOP, but remission usually shorter (≤50% duration of first remission)
74
What is the response to rescue protocols? Duration response?
Response to rescue protocols reportedly 40-90% (90% not particularly realistic if CHOP was the induction protocol) and durations of response generally 1.5-2.5 months (see Table 33.5 for rescue protocols)
75
Monoclonal antibody approaches Humans – addition of rituximab (anti-CD20 therapeutic monoclonal antibody) to CHOP significantly improves survival for many types of B-NHL Increased cure rate for DLBCL from ~30-40% to ~50-70% Rituximab has no activity in dogs due to inability to bind CD20 in vivo (epitope targeted by rituximab is on the intracellular surface of the canine cell membrane) on canine lymphoma cells and the inherent antigenicity of humanized monoclonal antibodies in dogs (therapeutic MoAbs for dogs need to be “caninized”) Therapeutic moAbs developed for dogs: Blontuvetmab (Blontress) – targeted CD20 (B-cell) Tametuvetmab (Tactress) – targeted CD52 (T-cell) After extensive clinical evaluation, the target specificity of these antibodies was found to be inadequate to have meaningful antitumor activity. Neither is available currently.
76
Alimentary Lymphoma Chemotherapy generally unrewarding CHOP has resulted in some durable remissions Consider surgery for rare localized alimentary lymphomas, or those presenting with obstruction/perforation A “small cell” variant, similar to EATL type II (LGAL) seen in cats, has been described, and is associated with a favorable outcome Colorectal B-cell LSA also seems to have a favorable clinical course
77
Primary CNS Lymphoma RARE – CNS involvement usually part of multicentric disease Localized may be treated with RT Generally poor response rate and short remission duration
78
Of cutaneous LSA which has better outcome?
Mucocutaneous cases appear to have a better outcome than cutaneous cases
79
Localied cutaneous LSA can be treated with?
RT
80
Diffuse cutanoeus LSA is best treated with? CCNU +/- pred is standard therapy, resulting in \_\_\_% ORR, but short PFS (\_\_\_ months), although some durable remissions reported
Diffuse best treated with chemotherapyCCNU +/- pred is standard therapy, resulting in ~80% ORR, but short PFS (~3 months), although some durable remissions reported
81
2 most improtant pronostic factors for canine LSA? Extranodal LSA are commonly what immunophenotype? What 2 factors with B cell LSA is assocaited with poor outcome?
-Immunophenotype – T-cell is worse and Substage b is worse Extranodal lymphomas are commonly T-cell, and these tend to have poor prognosis overall, but less clear whether it is T-cell immunophenotype or primary anatomic location that is the most important prognostic indicator. For B-cell tumors, low expression of B5 antigen and low expression of MHC II also predict poor outcome
82
Prognosis for LSA ## Footnote Stage I and II tend to be better than III-V, but the former are rare Proliferative indices (Ki67, AgNORs, BrdU uptake) may provide some prognostic information, but study results are contradictory Anatomic site – extranodal tends to be bad History of chronic inflammatory disease predicted earlier relapse in 1 study Gender Neutered females better prognosis Males may have higher incidence of T-cell and therefore worse Px Serum biomarkers (see table 33.8) LDH, TK-1, Glutathione-S-transferase, VEGF levels, CRP - require further validation
83
The Indolent Lymphomas Aggressive lymphomas are chemoresponsive but incurable and usually lethal Indolent lymphomas are poorly chemoresponsive but often associated with long-term survival One caveat is nodal MZL – PFS of 5 months and PS of 8.5 months Substantially less than splenic MZL NOTE: 1 study showed gene expression signatures of late stage nodal MZL to be essentially the same as those for DLBCL – maybe this isn’t always an indolent cancer…
84
2 breeds overrepresented fot lymphocytic leukemia? Most studies implicate what breed? ALL is seen in ___ dogs? CLL is seen in ____ dogs?
German shepherd and Golden retriever overrepresented in some studies More recent studies implicate small breed dogs as at risk for B-CLL ALL – often young dogs CLL – usually older dogs
85
ALL cell size? What marker is noted in ALL?
ALL – intermediate to large cells Distinguishable from myeloblasts by a more condensed chromatin pattern and less prominent nucleoli, although sometimes differentiation can be problematic without cytochemical staining or immunodiagnostics CD34 – early myeloid and lymphoid blasts (may DDx stage V lymphoma) Some T-ALL do not express it CD3/CD79a – T and B-cells (may not be present on very early blasts) ALL is usually B-cell (CD21+, CD3-, CD4-, CD8-) \<10% are T-ALL
86
What cell size is CLL?
CLL – small cells Morphologically indistinguishable from normal mature lymphocytes, Usually T-cell (CD8+) – LGLs B-cell less common NOTE – B-CLL and B-SLL are considered the same disease CLL with atypical immunophenotypes (e.g. CD3-, CD8+) is a rare variant of CLL in dogs Note that human CLL is essentially always a B-cell disease. T-CLL is exceptionally rare in humans.
87
Clinical signs associated with CLL? \_\_\_\_ present in advanced disease
Affected dogs usually ASYPTOMATIC/May see mild lethargy, decreased appetite Splenomegaly may be present, and can be marked in advanced disease Mild cytopenias common – may be more pronounced as lymphocyte count exceeds 30,000/ml Lymphocyte counts vary but may be enormous (I’ve seen ~1,000,000/ml) Extremes in lymphocyte count like this are due to increased lymphocyte lifespan rather than massive production. Remember, this is a slowly progressive disease.
88
4 paraneoplastic syndromes associated with CLL?
Paraneoplastic syndromes -Monoclonal gammopathy Macrogammaglobulinemia – production of IgA or IgM by neoplastic B-cells Waldenstrom’s macroglobulinemia – IgM monoclonal gammopathy associated with B-CLL - Hyperviscosity syndrome may develop - IMHA - Pure red cell aplasia (PRCA) Hypercalcemia (rare) – may be more common in B-CLL
89
For ALL, affected dogs are \_\_\_? Common clinical signs?
Affected dogs usually SICK PU/PD, weight loss, anorexia, lethargy Splenomegaly, hepatomegaly, lymphadenomegaly, petechial/ecchymotic hemorrhage Cytopenias common and often pancytopenic – extensive BM infiltration is the norm CNS signs, signs of bone pain also common
90
Normal lymphocyte subset distribution in peripheral blood 80% T cell (CD4+ \> CD8+) 15% B cell NK cells and CD4-/CD8- T-cells account for the rest Knowing these normal ratios is helpful when interpreting flow cytometry results in dogs with mature lymphocytosis PARR can also help distinguish neoplastic from non-neoplastic lymphocytosis, but occasional false positives (Ehrlichiosis)
91
When do you start treatment for CLL?
Cytopenias Lymphocyte count \>60,000 (arbitrary) Significant lymphadenopathy or splenomegaly Clinical signs of illness present
92
CR for CLL? What is Richters syndrome?
CR’s rare but MST’s usually 1-3 years due to indolent behavior Richter’s syndrome – rapidly progressive acute phase of disease in which CLL progresses to an immunoblastic lymphoma - associated with poor Px
93
Median remission/survival for CLL? MST for T-CLL? MST B-CLL? MST atypical CLL?
Excellent for CLL 70% have normalization of CBC, some have long-term survival with no treatment Median remissions/survivals 1-3 years are reported Immunophenotype may be prognostic MST T-CLL – 930 days (2.5 y) MST B-CLL – 480 days (1.3 y) MST atypical CLL – 22 days Degree of lymphocytosis may also be prognostic in dogs with CD8+ T-CLL Lymphocytes \>30,000/ml – MST 131 days Lymphocytes \<30,000/ml – MST 1098 days
94
MST for ALL with VCR/pred? MST with CHOP? MST B-ALL?
Very poor for ALL MST 120 days with VCR/pred (29% ORR), almost all dogs dead by 8 months MST 16 days in 46 dogs treated with CHOP MST 129 days in a series of dogs with B-ALL

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