Hematopoietic Neoplasia Flashcards
Breeds with high incidence of lymphoma
boxers, bullmastifs, bassets, st bernards, scottish terriers, airedales, pit bulls, briards, irish setters, rottweilers, and bulldogs
low risk - dachshunds and pomeranians
cant believe not goldens
what genetic alteration has been shown to have a prognostic advantage for dogs with lymphoma
trisomy of chromosome 13 - increased duration of first remission
what mutation has been proven in golden retrievers with lymphoma
somatic mutations leading to deficiencies in DNA repair mechanisms
Environmental factors implicated in lymphoma
exposure to tobacco, proximity to environmental waste, strong magnetic field proximity, lawn care products (2,4-D), maybe helicobacter
not flea and tick products
all are really unproven
immunologic factors associated with lymphoma development
ITP
one case of cyclosporin treatment
one atopic dermatitis and epitheliotropic lsa report - unknown if its the disease process or the treatments
prevalence of different lymphoma forms in dogs
multicentric - 80%
alimentary - 5-7%
mediastinal - 5 %
what dog breed has been shown to develop GI lymphoma from lymphocytic plasmacytic IBD
Basenjis
breeds association for GI lymphoma in dogs
shar-pei and boxer
prevalence of hypercalcemia in mediastinal lsa
10-40%
most commonly t cell
single case of gamma delta t cell lsa with large granular lymphs
cutaneous lymphoma phenotype
usually CD8+ t cells - in humans CD4
circulating cells = sezary syndrome (seen in dogs and cats)
non-epitheliotropic lymphoma definition histologically
spare the epidermis and papillary dermis and affect the middle and deep dermis and sq
phenotype of hepatosplenic lymphoma
gamma delta T cells - extremely aggressive
same in humans
intravascular (angiotropic) lymphoma-
what is it?
what anatomic locations is it associated with?
phenotype/
lymphocytes within the lumen of bloodvessels but no distinct mass or leukemia
includes CNS, peripheral nervous system and the eye
b cell is most common phenotype in humans but in dogs seems to be t cell or null cell, one b cell case report
what clinical sign is more common with mediastinal lymphoma than others
pre caval syndrome - pitting edema of the head neck and forelimbs due to compression or invasion of the cranial vena cava
phenotype and cns distribution of lymphoma
b cell = meningeal, perivascular, and periventricular
t cell = peripheral nerves
pathophysiology of hypercalcemia in lymphoma
may be pthrp
may also be IL1 TNFa TGFb and vit d analogs being released
what percent of multicentric lymphoma dogs will have radiographic changes to their chest
60-75%
1/3 have pulmonary infiltrates
2/3 have thoracic lymphadenopathy
can see pulm effusion
cxr pattern of pulmonary lymphoma infiltrates
usually interstitial to alveolar
rare bronchial
most common lab abnormality of a dog with lymphoma
anemia
frequency of thrombocytopenia
frequency of neutrophilia
frequency of lymphocytosis
thrombocytopenia 30 - 50% of cases
neutrophilia 25-40%
lymphocytosis 20%
frequency of monoclonal gamopathy in lsa
6%
large cell lymphoma cytologic characteristics
2 x rbc and larger than neut
visible nucleoli and basophilic cytoplasm with or without perinuclear clearing zone
fin chromatic with indistinct nucleoli
T cell markers
CD3 - pan T
CD4 - t helper
cd8 - cytoxic t
b cell markers
CD79a, CD20, CD21
indolent tzone can express CD21
sensitivity of parr for lsa in dogs
70-90%
5% fasle positive
Immunophenotype for
DLBCL
CD1+, CD20+ CD21+ CD45+ CD79a+, Pax5+ MCHII+ CD18 low
Immunophenotype for
peripheral t cell lymphoma
CD3+, CD79a–, CD21–, CD45+, CD5+, CD4+/–, CD8+/–, CD18high, TCRαβ
Immunophenotype for
marginal zone lymphoma
and histologic features
- nodal or splenic or extranodal mucosa
- nodular or follicular on histo
- intermediate sized cells
- rare mitotic activity - except nodal
- CD1+, CD20+, CD21+, CD45+,
CD79a+, MHCII+, CD18inter- mediate - similar to dlbcl but smaller sized cells
Immunophenotype for
Tzone lymphoma and histologic features
- CD45–, CD3+, CD5+, CD21+, CD4+/–, CD8+/–
- small to intermediate size with rare mitotic figures
Immunophenotype for
precursor t cell lymphoma
+ features
CD45+, CD34+/–, CD5+/–, CD3+/–, CD4+/–, CD8–
diffuse or leukemia
intermediate sized
high MC
Immunophenotype for
precursor b cell lymphoma
+ features
CD45+, CD18+, CD34+/–, CD79a+, CD21+/–, CD20+/–
diffuse or leukemia
intermediate sized
high MC
Immunophenotype for
mantle cell lymphoma
+ histologic features
- splenic white pulp
- nodular/follicular
- small to intermediate sized and variable MC
- CD20+, CD21+, CD45+, CD79a+, MHCII+
Immunophenotype for
follicular lymphoma
+ histologic features
- solitary or multiple lymph nodes
- mixed cell size mostly small 1-3 nucleoli
- CD20+, CD21+, CD45+, CD79a+, MHCII+
common causes of a false + parr
ehrlichiosis leishmaniasis
What percent of dogs with lymphoma are at least stage III at the time of diagnosis?
> 80%
What are myeloproliferative neoplasm (MPNs)? List different myeloproliferative neoplasms
- Characterized by excessive production of differentiated bone marrow cells
- Polycythemia vera, CML, essential thrombocythemia, primary myelofibrosis
What percent of dogs with multicentric lymphoma have thoracic involvement based on chest x-rays?
60-75%
1/3rd with pulmonary involvement, 2/3rd with lymphadenopathy
Most common AML subtypes in decreasing frequency
- Monocytic leukemia (M5a, M5b) - 42%
- myelomonocytic leukemia (M4) - 33%
- myeloblastic leukemia without differentiation (M1) - 13%
- megakaryoblastic leukemia (M7) - 5%
What AML subtype has not been identified in dogs?
acute promyelocytic leukemia (M3)
What mutation is associated with humans with polycythemia vera? This has been identified in 1 out of 5 dogs with PV.
JAK2
True or false: Both immature and mature neutrophils are present in CML
True
What chromosomal translocation is present in humans with CML? What is the analogous translocation in dogs?
In humans: Philadelphia chromosome (BCR-ABL translocation between chromosomes 9 and 22)
In dogs: “Raleigh Chromosome” (BCR-ABL translocation between chromosomes 9 and 26)
What characterizes an essential thrombocythemia?
Platelets consistently >600,000/uL with other causes of thrombocytosis ruled out (inflammation, IMHA, iron deficiency anemia, rebound from ITP, splenectomy, cancer)
What is myelodysplastic syndrome (MDS)?
Dysfunction of the bone marrow which usually presents with cytopenias in two or three cell lines. Sometimes referred to as preleukemia because it may progress to acute leukemia.
In polycythemia vera what is the typical PCV?
65-85%
What staining is used for neutrophil differentiation in AML?
Positive staining of blasts for peroxidase, Sudan Black B, and chloracetate
What staining is used for monocyte differentiation in AML?
Nonspecific esterases (α-naphthyl acetate esterase or α-naphthyl butyrate esterase)
What staining is used for megakaryocytes in AML?
Acetylcholinesterase; Also von Willebrand’s factor and platelet glycoproteins for megakaryocyte precursors
Is ALP a useful marker for AML?
Recent study indicated it was useful in a diagnosis of AML if neoplastic cells express only CD34
What cancers are CD34+ on flow?
ALL and AML
EPO is ~LOW or HIGH~ in polycythemia vera?
LOW
MST for AML with chemotherapy? With palliative care?
0.5 – 2 months with chemotherapy; 1-2 weeks with palliative care
Treatment for polycythemia vera?
- Phlebotomy – PCV should be reduced to 50-60% or by 1/6 of its starting value; making sure to replace lost volume and electrolytes with fluids
- Hydroxyurea
- JAK2 inhibitors and Radiophosphorus used in people
Treatment for CML?
- Imatinib used in humans
- Palladia and hydroxyurea used in dogs
Most common M component in multiple myeloma?
IgA and IgG – one report 78% were IgA
What is Waldenström’s macroglobulinemia?
When M component in multiple myeloma is IgM
What percentage of dogs with multiple myeloma have evidence of bony lysis or diffuse osteoporosis?
25-66%
What are the causes of bleeding diathesis in multiple myeloma?
M component may interfere with coagulation by:
1. Inhibiting platelet aggregating and the release of platelet factor 3
2. Causing adsorption of minor clotting proteins
3. Generating abnormal fibrin polymerization
4. Producing a functional decrease in calcium
What percentage of dogs and cats have clinical evidence of hemorrhage in multiple myeloma?
10-30% in dogs, up to 25% in cats
Hyperviscosity syndrome in multiple myeloma is most commonly present with which kinds of Ig?
IgM > IgA > IG
dimerized IgA
Hyperviscosity syndrome occurs in what percentage of dogs with multiple myeloma?
20-40%
What are the sequelae of hyperviscosity syndrome?
Bleeding diathesis, neurologic signs (e.g., dementia, depression, seizure activity, coma),
ophthalmic abnormalities (e.g, dilated and tortuous retinal vessels, retinal hemorrhage, retinal detachment), and increased cardiac workload with the potential for subsequent development of cardiomyopathy.
What percentage of dogs and cats with Multiple myeloma have renal disease?
50% of dogs, 30-40% of cats
Pathogenesis of renal failure in multiple myeloma?
Multifactorial: Bence Jones proteinuria, tumor infiltration into renal tissue, hypercalcemia, amyloidosis, diminished perfusion from HVS, dehydration, ascending urinary tract infections
Most common cause of death in animals with MM?
Susceptibility to infection and immunodeficiency
Percent of dogs and cats with multiple myeloma/MRD with Bence Jones Proteinuria?
25-40% of dogs, 40% of cats
Most common clinical signs of multiple myeloma/MRD in dogs and cats?
Lethargy, inappetence, weight loss, lameness, bleeding diathesis, ocular abnormalities, PU/PD, CNS changes, heart murmur (cats), concurrent cutaneous plasma cell tumor (cat)
Diagnosis of multiple myeloma?
Bone marrow plasmacytosis, osteolytic bone lesions, serum or urine myeloma proteins, visceral organ infiltration
Melphalan + prednisone protocols for multiple myeloma in dogs?
Daily: 0.1mg/kg PO q24 x 10days, then 0.05mg/kg PO q24h
Pulse dosing: 7mg/m2 PO for 5 days every 3 weeks
Prednisone: 0.5mg/kg PO q24h x 10days, then 0.5mg q48h for 60 days, then d/c
Most clinically significant toxicity with melphalan?
Delayed thrombocytopenia, which is slow to recover and can be irreversible
Treatment of choice for cats with multiple myeloma and why?
- Cyclophosphamide 250mg/m2 PO q2-3wks or 25mg/cat twice weekly and prednisolone
- Cats more sensitive to myelosuppressive effects of melphalan
Alternative agents for multiple myeloma treatment in dogs and cats?
Chlorambucil, Lomustine, Cyclophosphamide, tanovea
Treatment and prognosis for dogs with IgM macroglobulinemia?
Chlorambucil
MST 11 months
Response rates and MST of dogs treated with melphalan for multiple myeloma?
43% CR, 49% PR in one study; ORR of 86% in another study
540 days in one study; 930 in another
MST of cats with multiple myeloma?
8-13 months
Most common locations of extramedullary plasmacytoma in the dog?
Cutaneous (86%), mucous membranes of oral cavity and lips (9%), GI tract (4%)
Breeds with increased risk of extramedullary plasmacytoma?
American Cocker Spaniel, English Cocker Spaniel, Westies
What is MUM1+ aside from plasma cell tumors?
Cutaneous histiocytoma
What cat breed is over-represented in cases with lymphoma?
Siamese/Oriental
What form of lymphoma do Siamese/Oriental cats show a predisposition for?
Mediastinal, younger
What is the median age of onset of lymphoma in cats today? In the FeLV era?
Now - 11 - 12 yo
FeLV era - 3 - 5 yo
What forms of lymphoma more commonly show FeLV proviral insertion?
T - cell thymic and peripheral lymph node forms
What immunophenotype of lymphoma is more commonly associated with FIV? FeLV?
FIV - B-cell
FeLV - T-cell
What prevalence of mucosa invading bacteria were observed in feline large cell lymphoma in a case control study? Small cell? Lymphocytic-plasmacytic enteritis?
Large - 82% (80%)
Small - 18% (20%)
Enteritis - 3% (5%)
Where in the GIT is feline alimentary lymphoma most common?
Small intestine (4x more likely than the large)
LGAL - jejunum, ilium
Where in the GIT is feline large granular lymphoma most common?
Stomach, jejunum (NK), proximal large intestine
What is the treatment of choice and prognosis for feline low grade alimentary lymphoma?
Chlorambucil/pred, >80% response, MST 1.5 - 3 years
What is the treatment of choice and prognosis for feline intermediate/high grade alimentary lymphoma?
CHOP/COP, 50-60% response (30% CR), MST 3-10 months
What is the treatment of choice and prognosis for feline large granular lymphoma?
CHOP/COP or CCNU, 30% response, MST 45 - 90 d (1.5 - 3 mo)
How common is anemia in cats with alimentary lymphoma? Hypoproteinemia?
Anemia - 76% cases
Hypoproteinemia - 23%
What prognosis is reported for rescue protocols for feline LGAL?
MST 9 - 29 mos
What outcome was observed with radiation therapy in progressive feline lymphoma cases?
MST 7 mos
What is “Hodgkins-like” lymphoma in cats?
Solitary or regional lymph nodes in the head and neck, T-cell rich B-cell lymphoma, Reed-Sternberg-like cells (binucleated lymphocyte with eyeball appearance), more indolent
What is treatment of choice and outcome in Hodgkins-like lymphoma?
Surgical extirpation or RT, MST 1 year
What is the treatment of choice and outcome in cats with mediastinal lymphoma? FeLV(+) cats?
CHOP/COP, ORR 95%, MST 373 days (~1 year)
FeLV: MST 2-3 months
What is the sensitivity and specificity of PARR in cats?
Sensitivity - 80%
Specificity - not evaluated
What is the MST of nasal lymphoma in cats if not treated?
53 d (~2 months)
What is the treatment of choice for nasal lymphoma and what are the outcomes?
RT, CR 75-95%, MST 1.5 - 3 yrs
- if no CR, MST 4.5 months
What are the outcomes in nasal lymphoma cats treated with chemotherapy?
CR 75%, MST 2 years (cats that achieve CR)
Which kidney is feline renal lymphoma typically found in?
Bilateral >80%
What is the outcome in cats with renal lymphoma treated with COP/CHOP?
MST 4 - 7 months
Where do most cases of spinal lymphoma in cats occur?
Thoracolumbar or lumbosacral
What is the response and survival time in cats treated for CNS lymphoma with chemotherapy?
<50% RR, MST 1 - 4 months
Where is cutaneous lymphoma typically found in cats?
head and face
Where is subcutaneous lymphoma typically found in cats?
Lateral thoracic, lateral abdominal wall, intrascapular, tarsal
What is the PFS and OST after surgical removal of subcutaneous lymphoma in cats?
PFS - 101 days (3.4 months)
OST - 148 days (5 months)
What is the MST in feline subcutaneous lymphoma treated with chemotherapy?
6 months
In cats with laryngeal or tracheal lymphoma, what are the outcomes with systemic chemotherapy or RT?
90% CR to CHOP/COP
MSTs 5.5 - 9 months if achieve CR
What is the treatment of choice and outcome in cats with ocular lymphoma?
Enucleation
MST 6 mo - 4 years
What confirms a diagnosis of feline acute leukemia?
Bone marrow aspirate with >30% abnormal blast cells
What helps support a diagnosis of CLL in cats?
> 15% mature lymphocytes in BMA
What is the infectious disease status in cats with ALL? Immunophenotype?
60-80% FeLV (+)
T-cell
Conventional CHOP induces remission in approximately what percent of dogs (range)?
80-95%
What are treatment outcomes in cats with CLL?
Chlorambucil/pred - 90% RR, median remission duration 6 months
50% CR, median remission duration 14 months
Is there a sex predilection for dogs with AML?
More frequent in males, 2:1
Which disorders are included in myeloproliferative neoplasms?
polycythemia vera, CML, essential thrombocythemia, +/- primary myelofibrosis
What is the definition of aleukemic leukemia? Subleukemic leukemia?
Aleukemic - neoplastic blasts present in bone marrow but not in circulation
Subleukemic - normal or decreased WBC count with some neoplastic cells in circulation
Single agent Doxorubicin expected CR rate for canine lymphoma (range)? MST?
50-75% ; 6-8 months
List causes of lymphoma cell chemotherapy resistance
- Increased MDR1 expression in treated cells
- Inadequate dosing intensity or frequency
- Initial treatment w/ pred alone
- Failure to achieve high volumes of chemo in privileged sites
Reinduction rate of CHOP (i.e. CHOP #2)
80-90%
Target of Rituximab
CD20 antigen
What phenotype is canine colorectal lymphoma usually?
B- cell
Name two things on a flow cytometry report that may suggest a worse prognosis in B-cell lymphoma
Low MHC-II expression and low B5 antigen expression
Usual phenotype of CLL?
2/3rds T-cell (majority CD3+/CD8+), 1/3rd B-cell (CD21+). Note the third most common phenotype is atypical and is a combination of phenotypes
Usual phenotype of ALL?
B-cell (<10% T-cell)
